Recent Scientific Abstracts of Melanoma

Undifferentiated malignant neoplasms of the sinonasal tract. Wenig BM. Arch Pathol Lab Med. 2009 May;133(5):699-712.

CONTEXT: The most commonly encountered malignant neoplasms of the sinonasal tract
are the keratinizing and nonkeratinizing types of squamous cell carcinoma.
However, this complex anatomic region may represent the site of aggressive,
non-squamous cell epithelial and nonepithelial malignant neoplasms of varying
histogenesis, which are grouped under the term undifferentiated malignant
neoplasms. Frequently, these undifferentiated malignancies share clinical and
light microscopic features, which makes differentiation of one from the other
virtually impossible without the use of adjunct analyses (eg,
immunohistochemistry, electron microscopy, or molecular biologic studies). These
tumors often are clinically aggressive and usually fatal, despite all attempts at
controlling disease. Nevertheless, differentiating these tumors has clinical
import because advances in therapeutic intervention may increase survival with
good quality of life, and in some instances may achieve a cure. OBJECTIVE: To
compare and contrast the clinical, light microscopic, and immunohistochemical
features of sinonasal undifferentiated malignant neoplasms. DATA SOURCES:
Case-derived material and literature review. CONCLUSIONS: A variety of
undifferentiated malignant neoplasms occur in the sinonasal tract with
overlapping clinical and pathologic findings. In limited biopsy material,
differentiation of these tumor types can be challenging. The pathologist plays a
primary role in establishing the correct diagnosis, which often necessitates the
use of adjunct studies that allow for differentiating among these neoplasms.

Should extraocular sebaceous carcinoma be investigated using sentinel node biopsy? Sawyer AR, McGoldrick RB, Mackey S, Powell B, Pohl M. Dermatol Surg. 2009 Apr;35(4):704-8.

Melanoma of the small intestine. Lens M, Bataille V, Krivokapic Z. Lancet Oncol. 2009 May;10(5):516-21.

Intestinal melanomas can be primary tumours or metastases of cutaneous, ocular,
or anal melanomas. Primary intestinal melanoma is extremely rare, whereas
metastatic melanoma of the small bowel is common because of the tendency for
cutaneous melanoma to metastasise to the gastrointestinal tract. Because
distinguishing between primary and metastatic intestinal melanoma can be
difficult, the main features of each are discussed, and the diagnostic images
used to detect intestinal melanoma are assessed. Routine barium examinations and
CT have limited sensitivity, but PET imaging can improve detection of melanoma
metastases to the small bowel. Although various treatment strategies have been
tried in patients with intestinal melanoma, surgical removal of intestinal
metastases is the treatment of choice in patients with resectable tumours. No
systemic therapy improves survival in patients with melanoma metastatic to the
intestines; thus, the prognosis for these patients is poor. Patients with primary
melanoma of the small intestine have a worse prognosis than do patients with
metastases of cutaneous melanoma.

Molecular pathogenesis of cutaneous melanocytic neoplasms. Ibrahim N, Haluska FG. Annu Rev Pathol. 2009;4:551-79.

Melanoma is the deadliest form of skin cancer without an effective treatment. An
understanding of the genetic basis of melanoma has recently shed light on some of
the mechanisms of melanomagenesis. This review explores the major genes involved
in familial and sporadic cutaneous melanoma with an emphasis on CDKN2A, CDK4,
MC1R, and MAPK pathway targets (e.g., RAS and BRAF), apoptosis regulators (e.g.,
BCL-2, AKT, and APAF-1), and the tumor-suppressor genes TP53 and PTEN. New
directions for therapeutics based on our current knowledge of the genes
implicated in melanoma are also discussed.

Strategies for early melanoma detection: Approaches to the patient with nevi. Goodson AG, Grossman D. J Am Acad Dermatol. 2009 May;60(5):719-35; quiz 736-8.

Given its propensity to metastasize and the lack of effective therapies for most
patients with advanced disease, early detection of melanoma is a clinical
imperative. Although there are no noninvasive techniques for the definitive
diagnosis of melanoma, and the “gold standard” remains biopsy with histologic
examination, a variety of modalities may facilitate early melanoma diagnosis and
the detection of new and changing nevi. This article reviews the general clinical
principles of early melanoma detection and various modalities that are currently
available or on the horizon, providing the clinician with an up to date
understanding of management strategies for their patients with numerous or
atypical nevi. LEARNING OBJECTIVE: After completing this learning activity,
participants should understand the clinical importance of early melanoma
detection, appreciate the challenges of early melanoma diagnosis and which
patients are at highest risk, know the general principles of early melanoma
detection, be familiar with current and emerging modalities that may facilitate
early melanoma diagnosis and the detection of new and changing nevi, know the
advantages and limitations of each modality, and be able to practice a combined
approach to the patient with numerous or clinically atypical nevi.

Temozolomide with radiation therapy in high grade brain gliomas: pharmaceuticals
considerations and efficacy; a review article.
Koukourakis GV, Kouloulias V, Zacharias G, Papadimitriou C, Pantelakos P,
Maravelis G, Fotineas A, Beli I, Chaldeopoulos D, Kouvaris J. Molecules. 2009 Apr 16;14(4):1561-77.

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have
a combined incidence of 5-8/100,000 population, represent the most common primary
central nervous system tumors. The treatment outcomes even with aggressive
approach including surgery, radiation therapy and chemotherapy are dismal with
median reported survival is less than 1 year. Temozolomide is a new drug which
has shown promise in treating malignant gliomas and other difficult-to-treat
tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating
agent which represents the leading compound in a new class of chemotherapeutic
agents that enter the cerebrospinal fluid and do not require hepatic metabolism
for activation. The efficacy of temozolomide was tested in vitro studies and has
demonstrated schedule-dependent antitumor activity against highly resistant
malignancies, including high-grade glioma (HGG). In addition, in clinical
studies, temozolomide consistently demonstrates reproducible linear
pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative
minimal myelosuppression that is rapidly reversible, and activity against a
variety of solid tumors in both children and adults. Moreover, preclinical
studies have evaluated the combination of temozolomide with other alkylating
agents and inhibitors of the DNA repair protein O(6)-alkylguanine
alkyltransferase to overcome resistance to chemotherapy in malignant glioma and
malignant metastatic melanoma. At the present time temozolomide is approved in
the United States for the treatment of adult patients with refractory anaplastic
astrocytoma and, in the European Union, for treatment of glioblastoma multiforme
showing progression or recurrence after standard therapy. Temozolomide’s
characteristics which make it a candidate for a wide range of clinical testing to
evaluate the potential of combination treatments in different tumor types are its
predictable bioavailability and minimal toxicity. An overview of the mechanism of
action of temozolomide and a summary of results from more important randomized
controlled clinical trials in high grade gliomas are presented here.

The ubiquitin ligase Siah2 and the hypoxia response. Nakayama K, Qi J, Ronai Z. Mol Cancer Res. 2009 Apr;7(4):443-51.

Growing evidence indicates that ubiquitin ligases play a critical role in the
hypoxia response. Among them, Siah2, a RING finger ligase, is an important
regulator of pathways activated under hypoxia. Siah2 regulates prolyl
hydroxylases PHD3 and 1 under oxygen concentration of 2% to 5%, thereby allowing
accumulation of hypoxia-inducible factor (HIF)-1alpha, a master regulator of the
hypoxia response within the range of physiological normoxic to mild hypoxic
conditions. Growing evidence also indicates an important function for Siah2 in
tumor development and progression based on pancreatic cancer, mammary tumor, and
melanoma mouse models. This review summarizes our current understanding of Siah2
regulation and function with emphasis on hypoxia and tumorigenesis.

Skin cancer: new markers for better prevention. Greinert R. Pathobiology. 2009;76(2):64-81. Epub 2009 Apr 9.

Skin cancer is the most frequent cancer in the white population worldwide.
Incidence of basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and
malignant melanoma (MM) is still increasing. This trend can be counteracted by
means of primary and secondary prevention because the main risk factor for skin
cancer – UV-radiation – is known, and, early detected, skin cancer can be cured
successfully. For early detection of skin cancer suitable risk (group) markers
have to be used to identify persons at risk. In order to increase the sensitivity
and specificity of early detection efforts (screening programs) new molecular
markers or biomarkers should be used in the future in the field of molecular
epidemiology. In this review the skin cancer problem is summarized and the
possible use of new biomarkers for skin cancer development, progression,
metastasis and prognosis is discussed. The review focuses on results of gene
expression profiling using array techniques and the new possibilities for the use
of epigenetic biomarkers.

Towards understanding the mode of action of the multifaceted cell adhesion
receptor CD146.
Ouhtit A, Gaur RL, Abd Elmageed ZY, Fernando A, Thouta R, Trappey AK, Abdraboh
ME, El-Sayyad HI, Rao P, Raj MG. Biochim Biophys Acta. 2009 Apr;1795(2):130-6. Epub 2009 Jan 29.

CD146, also known as melanoma cell adhesion molecule or MCAM, is a key cell
adhesion protein in vascular endothelial cell activity and angiogenesis. CD146
promotes tumor progression of many cancers including melanoma and prostate.
Strikingly, its expression is frequently lost in breast carcinoma cells, and it
may act as a suppressor of breast cancer progression. While upstream mechanisms
regulating CD146 are well documented, our understanding of the downstream
molecular events underlying its mode of action remains to be elucidated. This
review aims to focus on the progress in understanding the signaling mechanisms
and the functional relevance of CD146, a multifaceted molecule, in cancer with
particular emphasis on its role in inhibiting breast cancer progression.

Photodynamic therapy: off-label and alternative use in dermatological practice. Buggiani G, Troiano M, Rossi R, Lotti T. Photodiagnosis Photodyn Ther. 2008 Jun;5(2):134-8. Epub 2008 May 6.

Photodynamic therapy (PDT) is a treatment technique that permits the clearance of
different skin lesions with high success rates in many dermatological diseases.
Worldwide recognized uses for PDT in dermatology include non-melanoma skin
cancer, actinic keratoses, acne vulgaris, photorejuvenation, and hidradenitis
suppurativa. In the European Union, and in the USA, its indication is for the
treatment of nonhyperkeratotic actinic keratoses (AKs) of the face and scalp, for
basal cell carcinoma and for Bowen’s disease. However, due to its intriguing
mechanism of action, many dermatologists have begun to look at the use of PDT in
photorejuvenation, acne vulgaris and hidradenitis suppurativa. Moreover,
clinicians have to learn how to maximize this kind of therapy to treat other
dermatologic entities, and many anecdotic reports can already be found in the
literature. This paper aims to briefly but critically review these reports to
give the dermatologist a useful guide to what could be the future experiences in
PDT and how to target their efforts in clinics and research.

Treatment of radiation retinopathy following plaque brachytherapy for choroidal
melanoma. Wen JC, McCannel TA. Curr Opin Ophthalmol.
2009 May;20(3):200-4.

PURPOSE OF REVIEW: Radiation retinopathy and maculopathy are predictable
complications resulting from exposure to any source of radiation, including
external beam and plaque brachytherapy. Most choroidal melanomas are currently
treated with plaque brachytherapy. However, the ensuing complications frequently
compromise posttreatment vision. The purpose of this review is to discuss recent
studies on the management of radiation retinopathy and maculopathy. RECENT
FINDINGS: Intravitreal bevacizumab, intravitreal triamcinolone and laser
photocoagulation appear to transiently decrease macular edema, although
improvements in visual acuity are limited. In successful studies, recurrent
treatments were needed to sustain the effects. Case studies of photodynamic
therapy, oral pentoxyphylline and hyperbaric oxygen treatment describe positive
results, but further studies are required. One study suggests that laser
photocoagulation may be useful in prophylactically treating radiation
retinopathy. SUMMARY: Currently, there are no proven treatments for radiation
retinopathy or maculopathy. The current treatment methods require frequent
administration with variable improvement in visual acuity.

Clinical multiphoton tomography. König K. J Biophotonics. 2008 Mar;1(1):13-23.

Clinical multiphoton tomography and two-photon microendoscopy provide clinicians
and researchers with high-resolution in vivo optical biopsies based on two-photon
autofluorescence, second harmonic generation, and fluorescence lifetime imaging.
This review reflects state of the art technology and reports on applications in
the fields of early stage melanoma detection, skin aging, nanoparticle imaging,
tissue engineering, and in situ screening of pharmaceutical and cosmetical
products. So far, more than 500 patients and volunteers in Europe, Asia, and
Australia have been investigated with these novel molecular imaging tools.

Adjuvant radiation therapy for high-risk nodal metastases from cutaneous
melanoma.
Guadagnolo BA, Zagars GK. Lancet Oncol. 2009 Apr;10(4):409-16.

The role of radiotherapy for nodal metastases from malignant melanoma is
controversial. In patients with features that indicate high risk of recurrence of
nodal disease, adjuvant irradiation lowers recurrence rates. High-risk features
include extranodal spread of melanoma, more than two positive lymph nodes, large
nodal size, or recurrent disease in previously dissected nodal basin. Data from
randomised trials that confirm a benefit of adjuvant radiotherapy in patients
with nodal disease at high risk of recurrence are unavailable. However, the use
of adjuvant radiotherapy for high-risk nodal disease is increasingly widespread.
Recurrence rates and risk of complications differ with anatomic location of the
nodal basin involved, and treatment decisions should be made accordingly. Whether
to use hypofractionated radiotherapy or conventional fractionation regimens for
adjuvant irradiation to nodal basins is also a matter of debate.
Hypofractionation is the accepted approach when radiotherapy is recommended.
Technical issues have to be considered when hypofractionated regimens are given
because survival might be long and the potential for normal tissue toxicity is
high. Overall survival remains poor for patients with macroscopic nodal
metastases from malignant melanoma. Until advances in systemic treatment are
available, regional nodal control is an important endpoint for patients with this
disease.

Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human
melanoma.
Oble DA, Loewe R, Yu P, Mihm MC Jr. Cancer Immun. 2009 Apr 2;9:3.

Tumors contain variable numbers of lymphocytes, referred to as tumor infiltrating
lymphocytes (TILs). In melanoma, the intensity of this lymphocytic infiltrate is
believed to correlate with outcome, though there is some debate about the
applicability of this finding for all melanomas. Much research has gone into
classifying TILs with respect to antigen receptor structure and the antigen to
which melanoma-specific T cells react. However, these studies for the most part
did not immunophenotype TILs, and recent data has revealed that the composition
of tumoral lymphocytes is not homogenous, but rather represents varying
contributions from many lymphocytic subsets. Furthermore, the function of TILs is
often compromised as a result of the accumulation of immunoregulatory cells and
various tumor escape mechanisms. These recent insights stress the need to collect
more data on the composition and function of TIL infiltrates before definitive
conclusions about the prognostic significance of TILs can be drawn. Advances in
immunology have also facilitated the development of immunotherapeutic strategies,
examples of which will be discussed with a special emphasis on blocking
antibodies against CTLA-4, which are prototypical immunotherapeutic agents. This
flurry of novel “biological” therapies will undoubtedly complicate our already
incomplete understanding of TIL immunobiology as each of these agents has the
potential to uniquely distort the series of immunological events which normally
occur in untreated melanoma. Therefore, considerable research is needed to better
elucidate the function and prognostic significance of TILs in both untreated
melanoma and tumors treated with “biological” therapy.

Malignant melanoma in African-Americans. Kabigting FD, Nelson FP, Kauffman CL, Popoveniuc G, Dasanu CA, Alexandrescu DT. Dermatol Online J. 2009 Feb 15;15(2):3.

Although relatively uncommon, malignant melanoma in African-Americans and other
minority ethnic populations represents an aggressive disease highly associated
with invasive lesions and a more advanced stage of disease at diagnosis, and
consequently with a decreased survival compared with Caucasians. Data on biology
of melanoma in African-Americans is very limited, which complicates the analysis
of epidemiological information, as well as identification of accurate prognostic
variables. This review article explores critical features of melanoma in
African-Americans that distinguish it from disease seen in Caucasians, including
the clinical presentation, histological patterns, prognostic indicators, and
etiology. Emerging data from biologic and genetic studies will also be discussed,
raising the possibility that melanoma in pigmented skin may represent molecular
distinct cancers that are inherently more aggressive. Improved understanding of
the unique manifestations of melanoma in African-Americans, and its underlying
tumor biology, will help improve clinical detection, optimize preventative
measures through public health education, and potentially lead to the development
of novel targeted therapeutic approaches.

Linking somatic genetic alterations in cancer to therapeutics. Stuart D, Sellers WR. Curr Opin Cell Biol. 2009 Apr;21(2):304-10. Epub 2009 Mar 26.

Somatic genetic alterations provide the foundation for the evolution of human
tumors as well as significant opportunity for therapeutic intervention. This
review will cover the growing list of examples where somatic genetic alterations
have successfully been coupled with a targeted agent resulting in positive
clinical outcome. For example, recent data from randomized clinical trials
support the earlier observations that EGFR mutant lung tumors are most likely to
respond to EGFR kinase inhibitors, while wild-type tumors rarely respond.
Emerging data indicate that this principle may also apply to such intractable
diseases such as melanoma which has long been refractory to conventional
chemotherapeutics.

Tissue biomarkers for prognosis in cutaneous melanoma: a systematic review and
meta-analysis.
Gould Rothberg BE, Bracken MB, Rimm DL. J Natl Cancer Inst. 2009 Apr 1;101(7):452-74. Epub 2009 Mar 24.

In the clinical management of early-stage cutaneous melanoma, it is critical to
determine which patients are cured by surgery alone and which should be treated
with adjuvant therapy. To assist in this decision, many groups have made an
effort to use molecular information. However, although there are hundreds of
studies that have sought to assess the potential prognostic value of molecular
markers in predicting the course of cutaneous melanoma, at this time, no
molecular method to improve risk stratification is part of recommended clinical
practice. To help understand this disconnect, we conducted a systematic review
and meta-analysis of the published literature that reported
immunohistochemistry-based protein biomarkers of melanoma outcome. Three parallel
search strategies were applied to the PubMed database through January 15, 2008,
to identify cohort studies that reported associations between immunohistochemical
expression and survival outcomes in melanoma that conformed to the REMARK
criteria. Of the 102 cohort studies, we identified only 37 manuscripts,
collectively describing 87 assays on 62 distinct proteins, which met all
inclusion criteria. Promising markers that emerged included melanoma cell
adhesion molecule (MCAM)/MUC18 (all-cause mortality [ACM] hazard ratio [HR] =
16.34; 95% confidence interval [CI] = 3.80 to 70.28), matrix metalloproteinase-2
(melanoma-specific mortality [MSM] HR = 2.6; 95% CI = 1.32 to 5.07), Ki-67
(combined ACM HR = 2.66; 95% CI = 1.41 to 5.01), proliferating cell nuclear
antigen (ACM HR = 2.27; 95% CI = 1.56 to 3.31), and p16/INK4A (ACM HR = 0.29; 95%
CI = 0.10 to 0.83, MSM HR = 0.4; 95% CI = 0.24 to 0.67). We further noted
incomplete adherence to the REMARK guidelines: 14 of 27 cohort studies that
failed to adequately report their methods and nine studies that failed to either
perform multivariable analyses or report their risk estimates were published
since 2005.

Bilateral breast metastasis of ovarian carcinoma. Dursun P, Yanik FB, Kuscu E, Gultekin M, Ayhan A. Eur J Gynaecol Oncol. 2009;30(1):9-12.

Primary breast carcinoma is the most common malignancy in women, however,
metastatic breast carcinoma is rarely seen in clinical practice. It has been
reported that lymphoma-leukemia, melanoma and sarcomas, the most common primary
malignancies, can metastasize to the breast. On the other hand, ovarian carcinoma
and other gynecologic cancers rarely develop into breast metastasis. However, the
incidence of breast metastasis arising from ovarian carcinoma might be increasing
as a result of prolongation in survival and improvement in treatment modalities.
Bilateral breast metastasis originating from an ovarian carcinoma is an extremely
rare clinico-pathological situation. In our literature review we found just nine
cases of bilateral breast metastasis from primary ovarian carcinoma. In this
study, the mean age was 46 years (range 16-68). Mean interval from initial
diagnosis of ovarian carcinoma to bilateral breast metastases was 22 months
(range 11-24) and mean survival was 12 (range 5-27) months after the diagnosis of
breast metastasis. Serous papillary adenocarcinoma was the predominant
histological subtype. Interestingly, five of the nine (56%) cases reported were
from Turkey. This interesting observation can be explained by a genetic
predisposition, but it requires further research. In conclusion, although it is a
rare entity, breast metastasis should not be ruled out in patients with a history
of ovarian carcinoma, if patients present with any symptoms of breast diseases.

Gonadoblastoma locus and the TSPY gene on the human Y chromosome. Lau YF, Li Y, Kido T. Birth Defects Res C Embryo Today. 2009 Mar;87(1):114-22.

The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y
chromosome. It is postulated to serve a normal function in the testis, but could
exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or
dysfunctional testicular phenotypes. Recent studies establish the testis-specific
protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal
functions in male stem germ cell proliferation and differentiation, but is
ectopically expressed in early and late stages of gonadoblastomas, testicular
carcinoma in situ (the premalignant precursor for all testicular germ cell
tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression
stimulates protein synthetic activities, accelerates cell proliferation, and
promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances
an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition
in the cell cycle. TSPY also counteracts the normal functions of its X-homologue,
TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to
insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression
and actions of the Y-located TSPY gene in incompatible germ cells, such as those
in dysgenetic or ovarian environments and dysfunctional testis, disrupt the
normal cell cycle regulation and predispose the host cells to tumorigenesis. The
contrasting properties of TSPY and TSPX suggest that somatic cancers, such as
intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with
detectable TSPY expression could exhibit sexual dimorphisms in the initiation
and/or progression of the respective oncogenesis.

Metastatic tumors to the oral and maxillofacial region: a retrospective study of
19 cases in West China and review of the Chinese and English literature.
Shen ML, Kang J, Wen YL, Ying WM, Yi J, Hua CG, Tang XF, Wen YM. J Oral Maxillofac Surg. 2009 Apr;67(4):718-37.

PURPOSE: The aim of this article was to obtain an overview of metastatic tumors
to the oral and maxillofacial (OMF) region, especially the differences in the
constituent ratios of primary cancers between the United States and China.
PATIENTS AND METHODS: Clinical findings of 19 cases encountered in West China
Hospital of Stomatology were summarized and the English and Chinese literature
were reviewed and analyzed. The main clinical features of OMF metastases were
summarized, with an emphasis on primary cancers’ constituents. RESULTS: The lung,
breast, kidney, liver, and prostate were the top 5 common primary sites of
cancer. However, there was a significant difference in the primary cancers’
constituents between United States and China (P < .001). The breast, kidney,
prostate cancers, and melanoma of skin were more frequent primary cancers in
United States than in China, whereas that of the lung, thyroid, liver, esophagus,
and the stomach were more common in China than in United States. The proportions
of the OMF metastatic lesions originating in the lung, kidney, liver, thyroid,
and esophagus in all OMF metastatic tumors were higher than the corresponding
primary cancers’ prevalent proportions. CONCLUSIONS: The frequency of developing
OMF metastasis is not always consistent with primary cancers’ prevalence, which
suggests that different cancers have different potentiality to develop OMF
metastasis. Cancers of the kidney, liver, lung, thyroid, and esophagus were more
likely to spread to the OMF region. In general screening of primary cancer, it
would be helpful to take into account the metastatic potentiality of different
cancers and primary cancers’ prevalence in different countries in the case of
occult primary.

Photochemoprevention of cutaneous neoplasia through natural products. Filip A, Clichici S, Daicoviciu D, Adriana M, Postescu ID, Perde-Schrepler M,
Olteanu D. Exp Oncol. 2009 Mar;31(1):9-15.

Non-melanoma skin cancers such as squamous cell carcinoma and basal cell
carcinoma are the most common types of human tumors, representing 30% of the new
cases of malignancies diagnosed each year. Ultraviolet radiation (UV) from the
sun is a major cause of non-melanoma skin cancer in humans. The prevention and
mainly the photochemoprevention with natural products represent a simple but very
effective strategy in the management of cutaneous neoplasia. Here we review the
progress in the research of new and existing agents developed to protect the skin
exposed to UV. We also discuss the current state of knowledge on their
photosuppression mechanism in humans as well as in animal models, and efficiency
in cancer prevention.

Angiomatoid Spitz nevus: a clinicopathological study of six cases and a review of
the literature.
Tetzlaff MT, Xu X, Elder DE, Elenitsas R. J Cutan Pathol. 2009 Apr;36(4):471-6.

Angiomatoid Spitz nevus is a recently described subtype of desmoplastic Spitz
nevus. Six cases have been described in the literature thus far. Here, we
describe six additional cases of angiomatoid Spitz nevus and provide a review of
the literature on this entity. The features of classic angiomatoid Spitz nevus
are described in the context of important differential diagnostic considerations,
particularly regressed malignant melanoma.

Analysis of the potential for HIV-1 Vpr as an anti-cancer agent. Muthumani K, Lambert VM, Sardesai NY, Kim JJ, Heller R, Weiner DB, Ugen KE. Curr HIV Res. 2009 Mar;7(2):144-52.

Viral protein R (Vpr) is a 14kD, 96 amino acid accessory protein of the HIV
virion that has been demonstrated to have important functions in the viral
replication cycle including, among others, the induction of cell cycle arrest and
apoptosis in rapidly proliferating cells, which results in immune dysfunction in
infected individuals. Several investigators have studied the potential use of the
apoptosis inducing and cell cycle arrest effect of Vpr as an anti-tumor
therapeutic. In vitro studies have indicated that Vpr is cytotoxic against a
large number of different tumor cell types including a number that are p53
independent. Likewise, some in vivo tumor studies using different delivery
platforms/methods have indicated an anti-cancer effect mediated by Vpr. Our group
has used the aggressive and poorly immunogenic murine melanoma tumor line B16.F10
as a model to deliver, through in vivo electroporation, Vpr expressing plasmids
to established tumors and have demonstrated that this treatment regimen can
induce growth attenuation and tumor regression in a proportion of the treated
mice and appears to be associated with the induction of intratumoral apoptosis.
Overall, to date, the data from a number of research groups, including our own,
have indicated that Vpr has biological activity against a number of tumors in
both in vivo and in vitro models and, as such, may be a potential candidate for
testing in human clinical trials. In this report, we summarize the evidence
supporting this hypothesis.

TNF-based isolated hepatic perfusion. Bellavance EC, Alexander HR Jr. Front Biosci. 2009 Jan 1;14:1771-84.

Unresectable primary and metastatic cancers confined to the liver often determine
the prognosis for patients with primary hepatic cancers, colorectal cancer,
ocular melanoma, and neuroendocrine tumors. Although many locoregional therapies
have emerged as options for patients with unresectable liver malignancies, these
treatments frequently have limited clinical benefit. Isolated hepatic perfusion
(IHP) has emerged as a regional therapy effective in inducing tumor regression in
isolated liver metastases from multiple histologies. Tumor necrosis factor alpha
(TNF) is a biologic agent well suited to isolated therapy because of its
single-dose efficacy, synergistic effect with hyperthermia, and effects on tumor
neovasculature. When combined with chemotherapeutic agents in IHP, TNF may
improve response rates in patients with hepatic metastases of some histologies.
However, there are additional toxicities associated with the administration of
TNF and further studies are needed to determine whether TNF confers a clinical
advantage in IHP.

Genetics, cellular biology and tumor microenvironment of melanoma. Ch’ng S, Tan ST. Front Biosci. 2009 Jan 1;14:918-28.

Melanoma is an aggressive disease for which there is no effective curative
treatment beyond surgical excision of the primary lesion and regional disease.
Epidemiological, clinical, in vitro and in vivo studies have provided insight
into the biology of the disease. This review focuses on current understanding of
key molecular pathways, cellular interaction and tumor microenvironment, and the
respective aberrations identified in melanoma. Common mutations and/or
deregulated expressions of B-raf, N-ras, PTEN, protein kinase B (aka Akt),
CDKN2A, CDK4 and MDM2 were presented. In addition to genetic abnormalities,
important aspects of cellular biology including, (i) the loss of cell-cell
adhesion resulting in an altered state in the relative expression of cadherins,
catenins and integrins, (ii) the interaction between melanoma cells and
surrounding keratinocytes, fibroblasts, and immune cells, and (iii) tumor
angiogenesis and vascular mimicry, are discussed. Many ongoing clinical trials of
targeted biological therapies are based on current knowledge, the outcomes are
eagerly awaited.

Familial pancreatic cancer. Shi C, Hruban RH, Klein AP. Arch Pathol Lab Med. 2009 Mar;133(3):365-74.

CONTEXT: Approximately 5% to 10% of individuals with pancreatic cancer report a
history of pancreatic cancer in a close family member. In addition, several known
genetic syndromes, such as familial breast cancer (BRCA2), the Peutz-Jeghers
syndrome, and the familial atypical multiple mole melanoma syndrome, have been
shown to be associated with an increased risk of pancreatic cancer. The known
genes associated with these conditions can explain only a portion of the
clustering of pancreatic cancer in families, and research to identify additional
susceptibility genes is ongoing. OBJECTIVE: To provide an understanding of
familial pancreatic cancer and the pathology of familial exocrine pancreatic
cancers. DATA SOURCES: Published literature on familial aggregation of pancreatic
cancer and familial exocrine pancreatic tumors. CONCLUSIONS: Even in the absence
of predictive genetic testing, the collection of a careful, detailed family
history is an important step in the management of all patients with pancreatic
cancer. While most pancreatic cancers that arise in patients with a family
history are ductal adenocarcinomas, certain subtypes of pancreatic cancer have
been associated with familial syndromes. Therefore, the histologic appearance of
the pancreatic cancer itself, and/or the presence and appearance of precancerous
changes in the pancreas, may increase the clinical index of suspicion for a
genetic syndrome.

Taking the stress out of melanoma. Martin MJ, Carling D, Marais R. Cancer Cell. 2009 Mar 3;15(3):163-4.

A recent study published in Molecular Cell describes a mechanism whereby
oncogenic BRAF inhibits AMPK in melanoma cells. This may explain why cancer cells
expressing oncogenic BRAF grow under conditions of metabolic stress and may
provide new therapeutic opportunities to treat this life-threatening disease.

Concerns relating to the conduct and statistical analysis of the Multicenter
Selective Lymphadenectomy Trial (MSLT-1) in patients with melanoma.
Thomas JM. J Plast Reconstr Aesthet Surg. 2009 Apr;62(4):442-6. Epub 2009 Feb 26.

The first Multicenter Selective Lymphadenectomy Trial (MSLT-I) was designed to
test for a survival difference following wide excision of primary melanoma
between patients randomised to sentinel lymph node biopsy (SLNB) and early
lymphadenectomy when metastatic disease was identified (the biopsy arm) versus
observation alone and delayed lymphadenectomy when regional lymph nodes became
palpable (the observation arm). Contrary to that stated in the protocol, almost
half the patients entered to the observation arm of MSLT-I were investigated by
lymphoscintigraphy and regular targeted high-resolution ultrasound which detected
nodal metastasis in some patients before it became palpable, thus influencing the
primary end-point of the trial. The method of calculating disease-free survival
(DFS) in MSLT-1 has been successfully challenged and to avoid bias caused by
trial design, recent guidance from the National Cancer Institute states that this
end-point should in future be calculated either by excluding nodal recurrence as
an event or by expressing the end-point as distant disease-free survival.
Patients with melanoma die of distant metastatic spread and currently there is no
evidence that the SLNB procedure influences distant disease-free survival. The
provisional results of the fourth interim analysis of MSLT-I support the
hypothesis that prognostic false-positivity is the explanation for the large
survival advantage claimed for patients having early lymphadenectomy versus
delayed lymphadenectomy. This survival difference is best explained by a
prognostic difference in the two sub-groups of patients compared. In turn that
suggests that removing minimally involved sentinel nodes in a proportion of
patients offers no therapeutic benefit.

Nonmelanoma skin cancer of the head and neck I: histopathology and clinical
behavior.
McGuire JF, Ge NN, Dyson S. Am J Otolaryngol. 2009 Mar-Apr;30(2):121-33. Epub 2008 Jul 22.

Non-Melanoma skin cancer (NMSC) is the most commonly encountered malignancy in
almost every area of practice, but the cases that present to an Otolaryngology
practice will be advanced in nature. The major subtypes of NMSC include basal
cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma protuberans, merkel
cell carcinoma, and adnexal malignancies. In this review, we present the
epidemiology, histology, clinical presentation and management of these major
subtypes. Further, we present background on multimodality treatment for NMSC
lesions that have become metastatic from their primary site and an introduction
to the behavior and treatment of NMSC lesions in patients who have received organ
transplants. Understanding the clinical behavior of advanced NMSC is essential
knowledge for a general Otolaryngologist.

Behavior: a relevant tool for brain-immune system interaction studies. Costa-Pinto FA, Cohn DW, Sa-Rocha VM, Sa-Rocha LC, Palermo-Neto J. Ann N Y Acad Sci. 2009 Feb;1153:107-19.

Neuroimmunomodulation describes the field focused on understanding the mechanisms
by which the central nervous system interacts with the immune system, potentially
leading to changes in animal behavior. Nonetheless, not many articles dealing
with neuroimmunomodulation employ behavior as an analytical endpoint. Even fewer
papers deal with social status as a possible modifier of neuroimmune phenomena.
In the described sets of experiments, we tackle both, using a paradigm of social
dominance and subordination. We first review data on the effects of different
ranks within a stable hierarchical relationship. Submissive mice in this
condition display more anxiety-like behaviors, have decreased innate immunity,
and show a decreased resistance to implantation and development of melanoma
metastases in their lungs. This suggests that even in a stable, social,
hierarchical rank, submissive animals may be subjected to higher levels of
stress, with putative biological relevance to host susceptibility to disease.
Second, we review data on how dominant and submissive mice respond differentially
to lipopolysaccharide (LPS), employing a motivational perspective to sickness
behavior. Dominant animals display decreased number and frequency in several
aspects of behavior, particularly agonistic social interaction, that is, directed
toward the submissive cage mate. This was not observed in submissive mice that
maintained the required behavior expected by its dominant mate. Expression of
sickness behavior relies on motivational reorganization of priorities, which are
different along different social ranks, leading to diverse outcomes. We suggest
that in vitro assessment of neuroimmune phenomena can only be understood based on
the behavioral context in which they occur.

The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab
(MDX-010), a novel treatment strategy in cancer management. Movva S, Verschraegen C. Expert Opin Biol Ther. 2009 Feb;9(2):231-41.

BACKGROUND: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory regulator
of the T cell immune response against tumor cells. Ipilimumab (MDX-010) is a
monoclonal antibody directed against CTLA-4. OBJECTIVE: To describe the basic
mechanism of ipilimumab and discuss data available to date with regards to its
safety and efficacy profile. METHODS: Data from clinical trials including
abstracts were reviewed using the PubMed Database as well as the American Society
of Clinical Oncology Abstract Database. CONCLUSIONS: CTLA-4 inhibition with a
monoclonal antibody is usually well tolerated and has efficacy as a therapeutic
agent in a variety of cancers. The most clinically important toxicities have been
related to autoimmune events, and guidelines for treatment of these effects are
now available. Preliminary results indicate that therapy with ipilimumab leads to
durable responses. Pharmacokinetics and pharmacodynamics are different from those
of traditional chemotherapy agents. Phase III studies are currently underway for
melanoma.

Lenalidomide: a novel anticancer drug with multiple modalities. Galustian C, Dalgleish A. Expert Opin Pharmacother. 2009 Jan;10(1):125-33.

Over the past 5 years, lenalidomide (Revlimid, Celgene Co., Summit, NJ, USA), a
member of a class of drugs termed immunomodulatory drugs, has emerged as a
significant weapon in the arsenal of cancer-therapeutics. It is a lead
therapeutic in multiple myeloma and del-5q myelodysplastic syndromes and has also
been trialed for acute leukaemia and chronic lymphocytic leukaemia, relapsed or
refractory Hodgkin’s lymphoma, T-cell non-Hodgkin’s lymphoma, prostate cancer,
non-small cell lung cancer, malignant melanoma, renal cancer, advanced ovarian
and peritoneal carcinoma. The most significant development for lenalidomide has
been its FDA approval (US and Europe) for previously treated multiple myeloma in
combination with dexamethasone. The following review describes key clinical and
mechanistic breakthroughs that have made lenalidomide a leading cancer
therapeutic.

[Spitz tumor and pigmented epithelioid melanocytoma: New nosological frameworks
for commonly ill-defined tumors] [Article in French] Fraitag S, Vignon-Pennamen MD. Ann Dermatol Venereol. 2009 Feb;136(2):133-44. Epub 2009 Jan 22.

[Accurate diagnosis of adnexal tumours can be a matter of life or death] [Article in French] Cribier B. Ann Dermatol Venereol. 2009 Feb;136(2):125-32. Epub 2009 Jan 20.

Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug
targets. Knauf JA, Fagin JA. Curr Opin Cell Biol. 2009 Apr;21(2):296-303. Epub 2009 Feb 21.

Constitutive activation of MAPK in cancer occurs through activating mutations or
overexpression of upstream effectors in the pathway, primarily of genes encoding
receptor tyrosine kinases, RAS and BRAF. Arguably, the evidence for MAPK
activation is most compelling in thyroid cancers and in melanomas. In this review
we discuss the mechanisms of tumor development by oncogenic BRAF in these two
cancer cell lineages, since this kinase signals preferentially through this
pathway. We describe recent information on the mediators of BRAF-induced tumor
initiation and escape from senescence. In addition, we review the biochemical
events implicated in cellular growth triggered by oncogenic BRAF and the
determinants of oncogene addiction. The biology of thyroid cancers induced by
oncogenic BRAF is quite distinct, both in humans and in mice. There is great
interest in using these insights to design rational new therapies, for which it
will become crucial to understand the determinants of sensitivity and resistance
to compounds designed to block the pathway. In thyroid cancer, this interest is
further heightened by new information on the role of activated BRAF and MAPK
pathway activation in disrupting iodine transport and thyroid hormonogenesis.

Sentinel node biopsy in soft tissue sarcoma. Andreou D, Tunn PU. Recent Results Cancer Res. 2009;179:25-36.

While regional lymphatic spread develops in only 3%-4% of all patients with soft
tissue sarcoma, there are several histological subtypes associated with a
significantly higher propensity for regional lymph node metastasis. These include
clear cell sarcoma, synovial sarcoma, rhabdomyosarcoma, and epithelioid sarcoma.
To date there is no validated, noninvasive method to assess regional lymph node
status. A potentially useful diagnostic tool is lymphatic mapping with sentinel
lymph node biopsy, a concept that has revolutionized the treatment of patients
with intermediate thickness melanoma and early stage breast cancer. The purpose
of this study is to provide an overview of the procedure of sentinel lymph node
biopsy and the data available on its application in patients with soft tissue
sarcomas.

Canadian National Dose Registry of radiation workers: overview of research from
1951 through 2007. Zielinski JM, Shilnikova NS, Krewski D. Int J Occup Med Environ Health. 2008;21(4):269-75.

The National Dose Registry (NDR) of Canada is a unique resource for a direct
estimation of the potential health risks associated with low doses of ionizing
radiation. This is the largest national occupational radiation exposure database,
comprising records for about 600,000 nuclear, industrial, medical and dental
workers. An analysis of the NDR data based on a cohort of about 200,000 workers
first exposed before 1984 and followed through 1987 and 1988 for mortality and
cancer incidence, respectively, revealed that the mortality from most causes of
death considered was lower than that in the general population, which is typical
of occupational cohorts. Although the same was also observed for cancer
incidence, there was a significant increase in the incidence of thyroid cancer
and melanoma which, however, was not clearly related to radiation exposure. A
significant dose-response was found for mortality from all causes, all cancers,
lung cancer, cardiovascular diseases, accidents, for incidence of all cancers,
cancers of the rectum and lung, leukaemia, all cancers except lung, and all
cancers except leukaemia. In addition, in male workers, a significant
dose-response was found for the incidence of colon, pancreatic, and testicular
cancers. The estimates of cancer risks (mortality and incidence) were higher than
those in most other occupational cohorts and in the studies on atomic bomb
survivors. The biologically based dose-response models used to describe lung
cancer incidence in the NDR showed that for a protracted exposure to low
radiation doses there was a significant radiation effect on the promotion and
malignant conversion, but not on the initiation stage of carcinogenesis. This
stands in contrast to the findings for high-dose acute exposures in A-bomb
survivors, where the initiation and possibly promotion were found to be affected
by radiation exposure. Evidence of an inverse dose-rate effect (i.e. an increase
in the risk with a protraction of a given cumulative dose) was found in the NDR
cohort.

Hypoxia, melanocytes and melanoma – survival and tumor development in the
permissive microenvironment of the skin. Bedogni B, Powell MB. Pigment Cell Melanoma Res. 2009 Apr;22(2):166-74. Epub 2009 Feb 13.

The tissue microenvironment plays a critical role in cell survival and growth and
can contribute to cell transformation and tumor development. Cellular
interactions with the stroma and with other cells provide key signals that
control cellular arrest or division, survival or death, and entrance or exit from
a quiescent state. Together, these decisions are essential for maintenance of
tissue homeostasis. Tissue oxygenation is an important component of the
microenvironment that can acutely alter the behavior of a cell through the direct
regulation of genes involved in cell survival, apoptosis, glucose metabolism, and
angiogenesis. Loss of tissue homeostasis due to, for example, oncogene activation
leads to the disruption of these signals and eventually can lead to cell
transformation and tumor development. Here we review the role of tissue
oxygenation, and in particular physiologic skin hypoxia, on cell survival and
senescence and how it contributes to melanocyte transformation and melanoma
development.

The good and the bad of chemokines/chemokine receptors in melanoma. Richmond A, Yang J, Su Y. Pigment Cell Melanoma Res. 2009 Apr;22(2):175-86. Epub 2009 Feb 14.

Chemokine ligand/receptor interactions affect melanoma cell growth, stimulate or
inhibit angiogenesis, recruit leukocytes, promote metastasis, and alter the gene
expression profile of the melanoma associated fibroblasts. Chemokine/chemokine
receptor interactions can protect against tumor development/growth or can
stimulate melanoma tumor progression, tumor growth and metastasis. Metastatic
melanoma cells express chemokine receptors that play a major role in the
specifying the organ site for metastasis, based upon receptor detection of the
chemokine gradient elaborated by a specific organ/tissue. A therapeutic approach
that utilizes the protective benefit of chemokines involves delivery of
angiostatic chemokines or chemokines that stimulate the infiltration of cytotoxic
T cells and natural killer T cells into the tumor microenvironment. An
alternative approach that tackles the tumorigenic property of chemokines uses
chemokine antibodies or chemokine receptor antagonists to target the growth and
metastatic properties of these interactions. Based upon our current understanding
of the role of chemokine-mediated inflammation in cancer, it is important that we
learn to appropriately regulate the chemokine contribution to the tumorigenic
‘cytokine/chemokine storm’, and to metastasis.

The chemokine receptors CXCR4 and CXCR3 in cancer. Fulton AM. Curr Oncol Rep. 2009 Mar;11(2):125-31.

Chemokines comprise a superfamily of at least 46 cytokines that were initially
described based on their ability to bind to 18 to 22 G protein-coupled receptors
to induce the directed migration of leukocytes to sites of inflammation or
injury. In addition to mediating cellular migration, chemokine/chemokine receptor
pairs have been shown to affect many cellular functions, including survival,
adhesion, invasion, and proliferation, and to regulate circulating chemokine
levels. Most malignancies also express one or more chemokine receptors. Early
studies established a role for CXCR4 and CXCR7 in mediating breast cancer
metastasis, but other chemokine receptors, including CXCR3, now are implicated in
several malignancies as biomarkers of tumor behavior as well as potential
therapeutic targets. This review summarizes our current understanding regarding
the contribution of CXCR4 and CXCR3 to tumor behavior and how receptor expression
is regulated, transduces intracellular signals, and contributes at the molecular
level to tumor behavior. It also describes recent therapeutic approaches that
target these receptors or their ligands.

Melanoma(s) associated with a quadrant or segmental distribution of atypical
melanocytic nevi: case report and review of the literature. Zalaudek I, Nicolino R, Ferrara G, Capoluongo P, Roma P, Sgambato A, Argenziano G. Dermatol Surg. 2009 Feb;35(2):268-72.

Treatment of melanoma metastases confined to the liver and future perspectives. Vahrmeijer AL, van de Velde CJ, Hartgrink HH, Tollenaar RA. Dig Surg. 2008;25(6):467-72. Epub 2009 Feb 12.

The prognosis for patients with liver metastases derived from melanoma is very
poor. Although being the gold standard for colorectal metastases, hepatic
resection for melanoma lesions is rarely possible. For patients with liver
metastases from cutaneous melanoma, the liver is not the only site of
disseminated disease in the majority of the cases. Most experience has been
obtained in patients with liver metastases from uveal melanoma because in 40% of
these patients, the liver is the only site of disease. However, in these
patients, resection is frequently not possible due to the number and localization
of the metastases. Results from systemic chemotherapy are poor and therefore, in
order to increase response rate, regional treatment modalities like hepatic
artery infusion, isolated hepatic perfusion and hepatic arterial
chemoembolization can be considered. In this review, we will describe the various
treatment modalities as well as new developments. (c) 2009 S. Karger AG, Basel.

Pancreatic cancer screening: state of the art. Gemmel C, Eickhoff A, Helmstädter L, Riemann JF. Expert Rev Gastroenterol Hepatol. 2009 Feb;3(1):89-96.

Pancreatic cancer is a devastating disease with a median survival of
approximately 6 months after diagnosis. Many factors are associated with a worse
outcome; examples include late diagnosis, low resection rate, aggressive tumor
behavior and a lack of an effective chemotherapy regimen. Owing to the low
prevalence of pancreatic cancer relative to the diagnostic accuracy of present
detection methods and the absence of promising treatment modalities, even in
early stages, it is currently neither advisable nor cost effective to screen the
general population. Efforts are focused on early screening of selected
high-risk-cohorts, who account for approximately 10% of patients with pancreatic
cancer. These include patients with chronic pancreatitis, individuals with a
family history of pancreatic cancer, patients with hereditary pancreatitis,
Peutz-Jeghers syndrome, cystic fibrosis or familial atypical multiple mole
melanoma. At present, a multimodal-screening approach of endoscopic ultrasound,
computed tomography and endoscopic retrograde cholangiopancreatography appears to
be the most effective method to screen for pancreatic cancer in high-risk
patients. Continued efforts are needed to elucidate effective testing to identify
patients with nonhereditary risk factors who will benefit from screening
protocols. A combined approach of serum markers, genetic markers and specific
imaging studies may prove to be the future of pancreatic screening.

[Hematologic neoplasias and solid tumors in pregnancy. Part 2: Specific
treatment] [Article in German] Popp H, Spiekermann K, Wollenberg A, Spitzweg C, Loehrs B. Dtsch Med Wochenschr. 2009 Feb;134(8):361-4. Epub 2009 Feb 10.

Ipilimumab: controversies in its development, utility and autoimmune adverse
events. Weber J. Cancer Immunol Immunother. 2009 May;58(5):823-30. Epub 2009 Feb 6.

A promising new class of anti-cancer drugs includes antibodies that mediate
immune regulatory effects. It has become very clear over the last decade that
different types of immune cells and different pathways serve to suppress
anti-cancer immunity, particularly in the microenvironment of the tumor. The
first examples of immune modulating antibodies are those directed against
cytotoxic T lymphocyte antigen-4 (CTLA-4), a molecule present on activated T
cells. Human antibodies that abrogate the function of CTLA-4 have been tested in
the clinic and found to have clinical activity against melanoma. In this review,
we discuss some of the controversies surrounding the potential clinical utility
of one of those antibodies, ipilimumab, formerly MDX-010, from Medarex and
Bristol Myers Squibb. The optimal dose and schedule of ipilimumab was derived in
multiple clinical trials whose latest results are described below. Favorable
survival in patients with stage IV melanoma were observed that appear to be
associated with unique side effects of the drug called “immune-related adverse
events”. The management of these side effects is described, and the unusual
kinetics of anti-tumor response with ipilimumab as well as a newly proposed
schema for assessing anti-tumor responses in patients receiving biologic
compounds like ipilimumab, which may supercede RECIST or WHO criteria, are
addressed.

[Hematologic neoplasias and solid tumors in pregnancy. Part 1: diagnosis and
principal treatment options] [Article in German] Popp H, Spiekermann K, Wollenberg A, Spitzweg C, Loehrs B. Dtsch Med Wochenschr. 2009 Feb;134(7):311-5. Epub 2009 Feb 5.

[Pregnancy and the eye] [Article in Polish] Kubicka-Trzaska A, Karska-Basta I, Kobylarz J, Romanowska-Dixon B. Klin Oczna. 2008;110(10-12):401-4.

During pregnancy periodical hormonal, metabolic, hematological, vascular and
immunological changes can be observed, that can influence the function of the
eye. Some of them can be observed in an eye due to pregnancy itself and would
resolved spontaneously postpartum. Pregnancy can also induce or aggravate the
preexisting conditions such as diabetic retinopathy or uveal melanoma. The
autoimmune intraocular inflammation is modified by pregnancy manifesting by
regression of the ocular symptoms. Pregnancy can have also beneficial effects on
glaucoma because intraocular pressure has been reported to decrease during
pregnancy. The presence of any ocular symptoms in a pregnant woman requires
urgent ophthalmic examination and further management.

Immunosuppression and melanocyte proliferation. Zattra E, Fortina AB, Bordignon M, Piaserico S, Alaibac M. Melanoma Res. 2009 Apr;19(2):63-8.

Melanocytes are pigmented cells derived from the neural crest; their
proliferation is restrained by immune system. The eruption of nevi after an
immunosuppressive condition is a peculiar phenomenon indicating that the immune
system may play a major role in limiting proliferation of melanocytes. In this
review, we analyze the role of immunosuppressive regimens on melanocyte
proliferation. In particular, we discuss the eruptive nevi phenomenon, which is
determined by the inability of the immune system to inhibit melanocyte
proliferation. These clinical observations indicate that the immune system has a
pivotal role in restraining melanocyte proliferation. However, although the role
of the immune system in the development of nonmelanoma skin cancer has been shown
clearly in several studies involving organ transplant patients, the role of
immunosuppression in melanoma genesis has not yet been established. Further
investigations are required to establish the real immunogenicity of melanoma,
particularly in the light of the dichotomy between the eruptive nevi phenomenon
in immunosuppressed patients and the low incidence of melanoma in transplanted
patients.

Hyperthermia as an adjunctive treatment for soft-tissue sarcoma. Pennacchioli E, Fiore M, Gronchi A. Expert Rev Anticancer Ther. 2009 Feb;9(2):199-210.

The treatment for high-risk soft-tissue sarcomas (STSs) in adults remains a
challenge for the multidisciplinary approach. Despite aggressive local treatment,
high-risk STSs have a tendency for hematogenous spread, which is related, for
each histologically distinct sarcoma, to risk factors, such as pathologic grade,
size and location. The multimodality approach focuses on the combination of
radiochemotherapy in a neoadjuvant or adjuvant setting, surgery being considered
the mainstay of local treatment. Therefore, current clinical research aims
include preoperative treatment to control systemic microscopic disease and to
downsize the primary tumor mass. Within the past 20 years, the application of
hyperthermia has been integrated in multimodal treatment strategies in several
forms of advanced malignant tumors, as well as in STSs. Hyperthermia is of
clinical interest in the temperature range of 40-43 degrees C. Higher
temperatures of 44-46 degrees C are not clinically realistic. The rationale for
the combination of cytotoxic drugs with regional hyperthermia in the treatment of
STS is based upon experimental and clinical evidence that heat increases the
killing of tumor cells by direct thermal toxicity and enhances the efficacy of
some drugs, such as alkylating agents and platinum analogs. Moreover, recent
results show that hyperthermia may be able to modulate the immune system by
inducing the expression of heat-shock proteins. The approach of multimodality
treatment in STS has used regional hyperthermia with systemic chemotherapy within
a preoperative and postoperative strategy. The synergistic effect of hyperthermia
with chemotherapy is also used in locoregional treatments, such as isolated limb
perfusion and intraperitoneal chemotherapy.

Screening for skin cancer: an update of the evidence for the U.S. Preventive
Services Task Force. Wolff T, Tai E, Miller T. Ann Intern Med. 2009 Feb 3;150(3):194-8.

BACKGROUND: Skin cancer is the most commonly diagnosed cancer in the United
States. The majority of skin cancer is nonmelanoma cancer, either basal cell
cancer or squamous cell cancer. The incidence of both melanoma and nonmelanoma
skin cancer has been increasing over the past 3 decades. In 2001, the U.S.
Preventive Services Task Force (USPSTF) found insufficient evidence to recommend
for or against routine screening for skin cancer by using whole-body skin
examination for early detection of skin cancer. PURPOSE: To update the evidence
of benefits and harms of screening for skin cancer in the general population.
DATA SOURCES: MEDLINE and Cochrane Library searches from 1 June 1999 to 9 August
2005 for English-language articles; recent systematic reviews; reference lists of
retrieved articles; and expert suggestions. STUDY SELECTION: English-language
studies were selected to answer the following key question: Does screening in
asymptomatic persons with whole-body examination by a primary care clinician or
by self-examination reduce morbidity and mortality from skin cancer? Randomized,
controlled trials and case-control studies of screening for skin cancer were
selected. One author selected English-language studies to answer the following
contextual questions: Can screening with whole-body examination by primary care
clinicians or by self-examination accurately detect skin cancer? Does screening
with whole-body examination or by self-examination detect melanomas at an earlier
stage (thinner lesions)? DATA EXTRACTION: All studies for the key question were
reviewed, abstracted, and rated for quality by using predefined USPSTF criteria.
DATA SYNTHESIS: No new evidence from controlled studies was found that addressed
the benefit of screening for skin cancer with a whole-body examination by a
physician. One article of fair quality, which reanalyzed data from a 1996 study
identified for the 2001 report for the USPSTF, provides limited but insufficient
evidence on the benefit of skin self-examination in the reduction of morbidity
and mortality from melanoma. LIMITATIONS: Direct evidence linking skin cancer
screening to improved health outcomes is lacking. Information is limited on the
accuracy of screening by physicians or patients using real patients and lesions.
CONCLUSION: The limited evidence prevents accurate estimation of the benefits of
screening for skin cancer in the general primary care population.

TCR transgenes and transgene cassettes for TCR gene therapy: status in 2008. Uckert W, Schumacher TN. Cancer Immunol Immunother. 2009 May;58(5):809-22. Epub 2009 Feb 3.

The genetic introduction of T cell receptor genes into T cells has been developed
over the past decade as a strategy to induce defined antigen-specific T cell
immunity. With the potential value of TCR gene therapy well-established in murine
models and the feasibility of infusion of TCR-modified autologous T cells shown
in a first phase I trial, the next key step will be to transform TCR gene
transfer from an experimental technique into a robust clinical strategy. In this
review, we discuss the different properties of the TCR transgene and transgene
cassette that can strongly affect both the efficacy and the safety of TCR gene
transfer.

Multidisciplinary treatment of primary melanoma. Yao K, Balch G, Winchester DJ. Surg Clin North Am. 2009 Feb;89(1):267-81, xi.

This article covers the multidisciplinary treatment of primary melanoma. Excision
margins and the need for sentinel lymphadenectomy are mainly dictated by the
Breslow thickness although exceptions to this dictum do exist. Interferon is the
only FDA approved adjuvant therapy for high risk melanoma although its overall
survival benefit is minimal. Trials examining different doses or duration of
interferon therapy have not demonstrated any promising survival data so far.
There have been several randomized vaccine trials for melanoma but none have
shown an overall survival benefit. Research into T-cell regulation continues and
will hopefully bring promise for the future of melanoma treatment.

Emergency surgery in the era of molecular treatment of solid tumours. Rutkowski P, Ruka W. Lancet Oncol. 2009 Feb;10(2):157-63.

In the advancing era of molecular therapy of solid tumours, emergency treatment
of complications, such as bowel perforation, haemorrhage, and tumour rupture, is
likely to evolve into one of the main challenges of surgical oncology. These
complications might be caused by disease progression from resistance to therapy,
side-effects of therapy on normal vasculature, and therapeutic induction of
excessively responding tumours. This Review outlines the probability and
management of emergency operations during molecularly targeted therapy of solid
tumours. Special attention is given to advanced gastrointestinal stromal tumours
and colorectal cancer, and therapy with imatinib, sunitinib, and bevacizumab.

In vivo confocal laser scanning microscopy in the diagnosis of melanocytic skin
tumours. Gerger A, Hofmann-Wellenhof R, Samonigg H, Smolle J. Br J Dermatol. 2009 Mar;160(3):475-81. Epub 2009 Jan 10.

Melanoma of the skin represents one of the greatest challenges in early or
preventive detection. Whereas surgical excision in early stages of melanoma
development is almost always curative, delayed recognition puts the patient at
risk for destructive growth and death from disease once the tumour has progressed
to competence for metastasis. The worldwide introduction of dermoscopy has led to
improved diagnostic accuracy for melanocytic skin tumours. Whereas dermoscopy has
probably reached the method’s inherent potential diagnostic accuracy because of
the lack of cellular level evaluation, further improvements could be expected by
in vivo confocal laser scanning microscopy. In vivo confocal microscopy
represents a novel imaging tool that allows the noninvasive examination of skin
cancer morphology in real time at a ‘quasihistopathological’ resolution viewing
microanatomical structures and individual cells. Numerous morphological confocal
features of melanocytic skin tumours have been described and histopathological
correlates of confocal structures have been previously elucidated. Recently,
several studies have evaluated the diagnostic accuracy of in vivo confocal
microscopy for melanocytic skin tumours, investigating approximately 50,000
tumour images. Remarkably, sensitivity superior to the diagnostic accuracy
achieved with dermoscopy could be reached by this imaging modality. These studies
represent a significant contribution to the body of research necessary for the
evaluation and implementation of in vivo confocal microscopy in clinical practice
to avoid many currently unnecessary biopsies. In vivo confocal microscopy
probably augurs a sea change in the way we evaluate melanocytic skin tumours in
the future and will ultimately move the art of histological diagnosis closer to
the bedside.

[Does hormonal contraception increase the risk for tumors?] [Article in German] Braendle W, Kuhl H, Mueck A, Birkhäuser M, Thaler C, Kiesel L, Neulen J. Ther Umsch. 2009 Feb;66(2):129-35.

A non-contraceptive benefit of oral hormonal contraceptives (OC) is a diminished
risk for certain benign as well as malignant tumours, such as benign breast
tumours, uterine fibroids and ovarian cysts. Endometriosis itself is not
positively influenced by OC, but dysmenorrhea is decreased. Modern low-dose OC do
not increase the risk of liver cell adenomata or carcinomata. OC do not influence
melanoma. Modern data do not suggest an increased risk for breast carcinoma in OC
users. Long-term use of OC leads to a decreased risk of endometrial and
colorectal carcinomata. Cervical carcinoma is not influenced directly by OC, but
probably indirectly through a change in sexual behaviour. There is no increase of
vulvar or vaginal carcinoma, even after long-term use of OC.

Pathologic evaluation of unknown primary cancer. Oien KA. Semin Oncol. 2009 Feb;36(1):8-37.

The pathologic approach to metastases of unknown primary cancer (UPC) is stepwise
and uses the clinical context, morphology, and, where necessary,
immunohistochemistry (IHC). This review covers the initial approach to a UPC
biopsy; the diagnosis of malignancy and broad tumor typing into carcinoma,
melanoma, lymphoma, or sarcoma; and further subtyping of carcinoma into germ cell
(broadly included), squamous, neuroendocrine, and solid organ including liver and
renal, and adenocarcinomas. Finally, for adenocarcinoma, the prediction of
primary tumor site, including lung, pancreas, stomach, colon, ovary, prostate,
and breast, is discussed. For each tumor type, the morphologic features are
presented alongside established useful IHC markers, with a description of their
staining patterns and common diagnostic dilemmas. Optimal tissue handling and IHC
interpretation, quality assurance, and limitations also are discussed. The target
readership is oncologists, but other clinicians and trainee pathologists also may
find the content of use.

Cisplatin: a review of toxicities and therapeutic applications. Barabas K, Milner R, Lurie D, Adin C.

Cisplatin is a platinum chemotherapeutic used in a variety of malignancies. The
antineoplastic activity occurs from DNA cross-links and adducts, in addition to
the generation of superoxide radicals. Nephrotoxicity is the most well-known and
potentially most clinically significant toxicity. Unfortunately, the mechanism
for cisplatin nephrotoxicity has not been completely elucidated; however, many
theories have been developed. Other toxicities include gastrointestinal,
myelosuppression, ototoxicity and neurotoxicity. Saline diuresis is currently the
most accepted way to prevent cisplatin nephrotoxicity. Research has focused on
pharmaceuticals and enzyme/molecular alterations as alternatives to long-term
diuresis. No agents have currently been identified that can protect from all
toxicities. Cisplatin has shown activity against osteosarcoma, transitional cell
carcinoma, squamous cell carcinoma (SCC), melanoma, mesothelioma, carcinomatosis
and germinal cell tumours in the dog. In the cat, cisplatin cannot be utilized
because of fulminant pulmonary oedema that occurs at standard doses.
Intralesional cisplatin has been utilized in horses for the treatment of SCC and
sarcoids.

The most common challenges in melanoma diagnosis and how to avoid them. Marghoob AA, Changchien L, DeFazio J, Dessio WC, Malvehy J, Zalaudek I, Halpern
AC, Scope A. Australas J Dermatol. 2009 Feb;50(1):1-13; quiz 14-5.

Due to its particularly lethal nature and tendency to affect relatively young
individuals, the timely diagnosis of melanoma remains of paramount importance for
clinicians and their patients. Unfortunately, melanomas can mimic benign lesions
that are overwhelmingly more common in the population than are melanomas, and
misdiagnosis or delay in diagnosis of melanoma can occur. Misdiagnosis of
melanoma serves as one of the most common causes for malpractice litigation
brought against medical practitioners. In this review we describe seven clinical
scenarios that represent challenges in melanoma diagnosis and discuss potential
strategies for avoiding the errors that commonly give rise to those scenarios.

Prospects of photoacoustic tomography. Wang LV. Med Phys. 2008 Dec;35(12):5758-67.

Commercially available high-resolution three-dimensional optical imaging
modalities-including confocal microscopy, two-photon microscopy, and optical
coherence tomography-have fundamentally impacted biomedicine. Unfortunately, such
tools cannot penetrate biological tissue deeper than the optical transport mean
free path (approximately 1 mm in the skin). Photoacoustic tomography, which
combines strong optical contrast and high ultrasonic resolution in a single
modality, has broken through this fundamental depth limitation and achieved
superdepth high-resolution optical imaging. In parallel, radio frequency-or
microwave-induced thermoacoustic tomography is being actively developed to
combine radio frequency or microwave contrast with ultrasonic resolution. In this
Vision 20/20 article, the prospects of photoacoustic tomography are envisaged in
the following aspects: (1) photoacoustic microscopy of optical absorption
emerging as a mainstream technology, (2) melanoma detection using photoacoustic
microscopy, (3) photoacoustic endoscopy, (4) simultaneous functional and
molecular photoacoustic tomography, (5) photoacoustic tomography of gene
expression, (6) Doppler photoacoustic tomography for flow measurement, (7)
photoacoustic tomography of metabolic rate of oxygen, (8) photoacoustic mapping
of sentinel lymph nodes, (9) multiscale photoacoustic imaging in vivo with common
signal origins, (10) simultaneous photoacoustic and thermoacoustic tomography of
the breast, (11) photoacoustic and thermoacoustic tomography of the brain, and
(12) low-background thermoacoustic molecular imaging.

A comprehensive overview of radioguided surgery using gamma detection probe
technology. Povoski SP, Neff RL, Mojzisik CM, O’Malley DM, Hinkle GH, Hall NC, Murrey DA Jr,
Knopp MV, Martin EW Jr. World J Surg Oncol. 2009 Jan 27;7:11.

The concept of radioguided surgery, which was first developed some 60 years ago,
involves the use of a radiation detection probe system for the intraoperative
detection of radionuclides. The use of gamma detection probe technology in
radioguided surgery has tremendously expanded and has evolved into what is now
considered an established discipline within the practice of surgery,
revolutionizing the surgical management of many malignancies, including breast
cancer, melanoma, and colorectal cancer, as well as the surgical management of
parathyroid disease. The impact of radioguided surgery on the surgical management
of cancer patients includes providing vital and real-time information to the
surgeon regarding the location and extent of disease, as well as regarding the
assessment of surgical resection margins. Additionally, it has allowed the
surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic
procedures, while still maintaining maximum benefit to the cancer patient. In the
current review, we have attempted to comprehensively evaluate the history,
technical aspects, and clinical applications of radioguided surgery using gamma
detection probe technology.

Malignant melanoma metastatic to the thyroid gland: a case report and review of
the literature. Kung B, Aftab S, Wood M, Rosen D. Ear Nose Throat J. 2009 Jan;88(1):E7.

The thyroid gland is a relatively uncommon site for a secondary malignancy; even
less common is a case of malignant melanoma metastatic to the thyroid. We
describe the case of a 68-year-old man who presented with a neck mass in the
posterior triangle. Fine-needle aspiration biopsy (FNAB) identified the mass as a
malignant melanoma. The patient had had no known primary skin melanoma. He
underwent a left modified radical neck dissection, and the mass was discovered to
be a positive lymph node. Postoperatively, he declined to undergo radio- and
chemotherapy. Eighteen months later, he returned with a diffusely enlarged
thyroid. FNAB again attributed the enlargement to malignant melanoma. Soon
thereafter, the patient began experiencing seizures, and on magnetic resonance
imaging, he was found to have metastatic disease to the brain. He developed
ventilator-dependent respiratory failure and required a subtotal thyroidectomy
for the placement of a tracheostomy tube. Patients who present with a thyroid
nodule and who have a history of malignancy present a diagnostic dilemma: Is the
nodule benign, a new primary, or a distant metastasis? The findings of this case
and a review of the literature strengthen the argument that any patient with a
thyroid mass and a history of malignancy should be considered to have a
metastasis until proven otherwise.

Hsp receptors: the cases of identity and mistaken identity. Binder RJ. Curr Opin Mol Ther. 2009 Feb;11(1):62-71.

Immune responses elicited by Hsps have been harnessed for the therapy of cancer.
Hsps may also play a physiological role in the transfer of antigens in the form
of peptides between cells during the event known as cross priming. To elicit
these immune responses, Hsps engage antigen-presenting cells through their cell
surface receptors. Various molecules have been suggested as Hsp receptors since
their existence was first proposed 13 years ago. This review critically examines
the literature on Hsp receptors and highlights the experimental evidence that has
been provided or is lacking for each molecule. Two phase III clinical trials
conducted with Hsp-based vaccines in patients with melanoma or renal cell
carcinoma are also discussed.

Autoantibody targets and their cancer relationship in the pathogenicity of
paraneoplastic retinopathy. Adamus G. Autoimmun Rev. 2009 Mar;8(5):410-4. Epub 2009 Jan 23.

Paraneoplastic retinopathies (PR), including cancer-associated retinopathy (CAR)
or the closely related melanoma-associated retinopathy (MAR) occur in a small
subset of patients with retinal degeneration and systemic cancer. This autoimmune
syndrome is characterized by sudden, progressive loss of vision in association
with circulating anti-retinal autoantibodies. The PR syndromes are heterogeneous,
may produce a number of ocular symptoms, and may be associated with several
different neoplasms, including lung, breast, prostate, gynecological, and colon
cancer, melanoma, and hematologic malignancies. We examined the onset of
retinopathy in correlation to the diagnosis of cancer and the presence of
specific anti-retinal autoantibodies in PR patients. In some patients without
diagnosed malignant tumors, the onset of ocular symptoms and the presence of
autoantibodies preceded the diagnosis of cancer by months to years, including
anti-recoverin, anti-transducin-alpha, and anti-carbonic anhydrase II antibodies.
Although anti-retinal autoantibodies may not be a good predictor of a specific
neoplasm, they can be used as biomarkers for different subtypes of retinopathy.
Identification of autoantibodies involved in autoimmune-mediated PR will help
elucidate the mechanisms underlying the PR syndromes and develop targeted
therapies for these sight-threatening disorders.

[Bladder metastasis of malignant melanoma: a case report and review of
literature] [Article in French] Toledano H, Visée C, Arroua F, Rossi D, Bastide C. Prog Urol. 2009 Feb;19(2):139-41. Epub 2008 Nov 28.

Metastatic malignant melanoma to the urinary bladder remains rare in clinical
practice with less than 10 cases reported in the last 30 years in the literature.
According to our knowledge, our case report is the first in french language.

Prosthodontic treatment considerations for patients with oral sinonasal mucosal
malignant melanoma: a clinical report. Marunick M, Oh WS. J Prosthet Dent. 2009 Feb;101(2):85-91.

Patients with a diagnosis of mucosal malignant melanoma involving the maxilla or
paranasal sinuses requiring surgery are referred to the maxillofacial
prosthodontist for treatment. The standard protocol of surgical, interim, and
definitive obturator treatment is usually anticipated. Depending upon the stage
and presence or absence of metastasis, it is generally accepted that the
prognosis for cure of this disease is poor. This clinical report reviews the
current literature regarding treatment and the overall guarded prognosis for this
disease, and reports the prosthodontic treatment intervention for 8 patients.
Prosthodontic treatment strategies are recommended that are consistent with the
reality of the diagnosis to achieve optimal function and quality of life for
these patients.

Primary oral malignant melanoma–a case report and review of the literature. Gondivkar SM, Indurkar A, Degwekar S, Bhowate R. Quintessence Int. 2009 Jan;40(1):41-6.

Malignant melanoma is a neoplasm of melanocytic origin that arises from a benign
melanocytic lesion or de novo from melanocytes within otherwise normal mucosa or
skin. Melanoma arising from the mucosal surfaces of the head and neck is a very
rare disease and is considered among the most deadly of all human neoplasms.
Although it comprises 1.3% of all cancers, malignant melanoma of the oral cavity
accounts for only 0.2% to 8.0% of all reported melanomas. Because most mucosal
melanotic lesions are painless in their early stages, the diagnosis is
unfortunately often delayed until symptoms resulting from ulceration or growth
are noted. Oral malignant melanoma has an extremely poor prognosis. For
prevention of oral mucosal melanomas, any solitary pigmentation that has no
obvious explanation should be always biopsied. The case of a 40-year-old man with
primary malignant melanoma of the maxillary gingiva is reported

Integrating BRAF/MEK inhibitors into combination therapy for melanoma. Smalley KS, Flaherty KT. Br J Cancer. 2009 Feb 10;100(3):431-5. Epub 2009 Jan 20.

The discovery of BRAF mutations in melanoma has not yet translated into clinical
success, suggesting that BRAF/MEK inhibitors will need to be combined with other
agents. In the current review, we discuss other pathways likely to be important
for melanoma progression and suggest possible drug combinations for future
clinical testing.

Treatment choices for oral cancer in cats. What is possible? What is reasonable? Moore A. J Feline Med Surg. 2009 Jan;11(1):23-31.

Genetic predisposition and environmental risk factors to pancreatic cancer: A
review of the literature. Landi S. Mutat Res. 2009 Mar-Jun;681(2-3):299-307. Epub 2008 Dec 27.

Some cases of pancreatic cancer (PC) are described to cluster within families.
With the exception of PALLD gene mutations, which explain only a very modest
fraction of familial cases, the genetic basis of familial PC is still obscure.
Here the literature was reviewed in order to list the known genes, environmental
factors, and health conditions associated with PC or involved in the
carcinogenesis of the pancreas. Most of the genes listed are responsible for
various well-defined cancer syndromes, such as CDKN2A (familial atypical
mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53
(Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2
(breast-ovarian familial cancer), where PC is part of the cancer spectrum of the
disease. In addition, in this review I ranked known/possible risk factors
extending the analysis to the hereditary pancreatitis (HP), diabetes, or to
specific environmental exposures such as smoking. It appears that these factors
contribute strongly to only a small proportion of PC cases. Recent work has
revealed new genes somatically mutated in PC, including alterations within the
pathways of Wnt/Notch and DNA mismatch repair. These new insights will help to
reveal new candidate genes for the susceptibility to this disease and to better
ascertain the actual contribution of the familial forms.

Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and
novel treatment strategies for cancer medicine. Hewish M, Chau I, Cunningham D. Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):54-72.

The insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling
system has provoked considerable interest over recent years as a novel
therapeutic target in cancer. A brief outline of the IGF-1R signalling system and
the rationale for its use in cancer medicine is given. This is followed by a
discussion of the different possible targets within the IGF-1R system, and drugs
developed to interact at each target. A systems-based approach is then used to
review the in vitro and in vivo data in the published literature of the following
compounds targeting IGF-1R components using specific examples: growth hormone
releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists
(e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12,
SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase
inhibitors (e.g. BMS-536942, BMS-554417, NVP-AEW541, NVP-ADW742, AG1024, potent
quinolinyl-derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP,
Nordihydroguaiaretic acid Insm-18/NDGA). The following tumour types are
specifically discussed: lung, breast, colorectal, pancreatic, NETs, sarcoma,
prostate, leukaemia, multiple myeloma. Other tumour types are mentioned briefly:
squamous cell carcinoma of the head and neck, melanoma, glioblastoma, ovary,
gastric and mesothelioma. Results of early stage clinical trials, involving
recently patented drugs. are included where appropriate. We then outline the
current understanding of toxicity related to IGF-1R targeted therapy, and finally
outline areas for further research.

Recent approaches to improve the antitumor efficacy of temozolomide. Tentori L, Graziani G. Curr Med Chem. 2009;16(2):245-57.

Temozolomide (TMZ) is an oral anticancer agent approved for the treatment of
newly diagnosed glioblastoma in combination with radiotherapy. Moreover, TMZ has
shown comparable efficacy with respect to dacarbazine, the reference drug for
metastatic melanoma. Due to its favorable toxicity and pharmacokinetic profile,
TMZ is under clinical investigation for brain metastasis from solid tumors and
refractory leukemias. TMZ interacts with DNA generating a wide spectrum of methyl
adducts mainly represented by N-methylpurines. However, its antitumor activity
has been mainly attributed to O(6)-methylguanine, since tumor cell sensitivity
inversely correlates with the levels of O(6)-alkylguanine DNA alkyltransferase
and requires an intact mismatch repair system. Therefore, an increasing number of
studies have been performed in order to identify patients who will benefit from
TMZ treatment on the basis of their molecular/genetic profile. Unfortunately,
resistance to the methylating agent occurs relatively often and strongly affects
the rate and durability of the clinical response in cancer patients. Thus,
different approaches have been developed to abrogate resistance or to increase
the efficacy of TMZ and for many of them investigation is still underway. Herein,
we provide an overview on the recent findings of preclinical and clinical studies
on TMZ in combination with inhibitors of DNA repair, chemotherapeutic drugs with
different mechanisms of action or radiotherapy, anti-angiogenic agents and other
biological modulators.

Macrophage inhibitory cytokine-1: a new player in melanoma development. Yamashita T, Yoneta A, Hida T. J Invest Dermatol. 2009 Feb;129(2):262-4.

Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the TGF-beta
superfamily. Although it has been reported to exhibit both tumorigenic and
antitumorigenic activities, Boyle et al. report in this issue that MIC-1
expression was correlated with the tumorigenicity of melanoma cells. The
elucidation of signaling pathways around MIC-1 might contribute to prospective
targeting therapy for melanoma.

Nevus Spitz–everlasting diagnostic difficulties–the review. Situm M, Bolanca Z, Buljan M, Tomas D, Ivancić M. Coll Antropol. 2008 Oct;32 Suppl 2:171-6.

In 1910, Darier and Civatte described in details an unusual melanocytic tumor
characterized by rapid growth on the nose of a young child. They could not state
whether the tumor was benign or malignant. In 1947, Sophie Spitz described the
same lesion as juvenile melanoma in which prognosis was frequently excellent.
Later, the study was revised and it was concluded that juvenile melanoma was a
benign tumor and can affect adults. Although, the prognosis was mostly excellent,
Spitz reported in one of 13 cases fatal metastases from nevus Spitz. In 1999,
Barnhill et al described one fatal case of the patient for whom it was thought to
have typical Spitz nevus. Nowadays, there is still a lack of consensus about
histopathology and also a terminology of the tumors that are neither typical
nevus Spitz, neither malignant melanoma. All histopathological, clinical and
ancillary criteria must be weighed in the final interpretation of
epitheloid/spindle cell lesion. At the present, the final diagnosis remains
pathohistological, with important emphasis given to clinical impression.
Persistently changing lesion indicates malignancy potential of the lesion.
Barnhill recommends that all Spitz tumors are completely excised. Atypical tumors
should be excised with wider margins up to 1 cm. Patient should be carefully
monitored by regular examinations for recurrence and metastasis.

Vitamin D–the true and the false about vitamin D. Poduje S, Sjerobabski-Masnec I, Ozanić-Bulić S. Coll Antropol. 2008 Oct;32 Suppl 2:159-62.

Vitamin D has a positive impact on our overall health. Also there are a few
conditions with strong evidence for a protective effect of vitamin D, such as
bone diseases, internal cancers, multiple sclerosis, hypertension and DM type 1.
Skin is the major source of vitamin D through the action of UVB light on
keratinocytes, although the biologically active form of vitamin D is not
exclusively produced in the kidney but also in prostate, colon, skin and
osteoblast where it acts as an autocrine or paracrine hormone. In the past decade
raising incidence of skin cancers, especially melanoma and its connection with
sun exposure lead to a sun protection policies and practices as part of the
public health campaigns. The question is how much solar UV exposure is adequate
to maintain the balance between the risk and the benefit. We as dermatologists
have to raise public awareness of the potential health effects from excessive
exposure to UV radiation but also we have to be aware that adequate blood level
of vitamin D is necessary for optimal health. So future recommendation on sun
protection have to balance between the risk and benefits of sun exposure, as well
as to promote vitamin D supplementation as a safe alternatives in high risk
population.

Molecular and genetic mechanisms in melanoma. Gruber F, Kastelan M, Brajac I, Saftić M, Peharda V, Cabrijan L, Stanić Zgombić
Z, Simonić E. Coll Antropol. 2008 Oct;32 Suppl 2:147-52.

Recent studies have indicated an increasing incidence of melanoma worldwide.
Although UV signature mutations are found rarely in melanoma cells, there is some
evidence that intense intermittent exposure to sunlight can induce melanocyte
tumorigenesis, and this is also observed after UV irradiation in some animals.
The purpose of this paper is to review some of the most important mechanisms
involved in the pathogenesis of this tumor. Genetic studies showed the familiar
melanoma is linked to the mutation or deletion of the suppressor gene CDKN2A, and
perhaps to CDK4. Studies showed that BRAF mutation is frequent in primary and
metastatic melanoma cells but also in naevocytic nevi. This mutation activates
the RAF/MEK pathway. Exposure to UV radiation induces immunosuppression. Recent
investigations showed that chemokines, angiogenesis, metalloproteinases can play
a role in the mechanism of metastasis. In spite of these advances the initiating
events are still not completely understood. In conclusion, the pathogenesis of
melanoma is very complex because numerous genetic and epigenetic factors are
implicated in its development and progression, but some of the showed mechanisms
can be targets for new therapies.

Ipilimumab for advanced melanoma: a nursing perspective. Ledezma B. Oncol Nurs Forum. 2009 Jan;36(1):97-104.

PURPOSE/OBJECTIVES: To discuss the response patterns and side effects related to
ipilimumab, a new immunotherapeutic agent under investigation in the treatment of
advanced melanoma and other malignancies. DATA SOURCES: Published articles,
abstracts, research data, and clinical experience. DATA SYNTHESIS: Ipilimumab is
a fully human monoclonal antibody that inhibits the activity of cytotoxic
T-lymphocyte antigen-4 (CTLA-4), a naturally immunosuppressive molecule. The most
common side effects are immune mediated (e.g., inflammatory diarrhea, pruritus)
and appear to occur as a direct result of CTLA-4 inhibition and enhanced immune
system activation. Side effects generally are grade I or II and resolve with
standard treatments. Most grade III or IV events are managed successfully after
swift diagnosis and treatment with corticosteroids; steroid-refractory events
resolve after treatment with infliximab or mycophenolate. CONCLUSIONS: The
response patterns and side effects associated with ipilimumab therapy greatly
differ from those common to other advanced melanoma therapies (e.g.,
chemotherapy, cytokines, vaccines). IMPLICATIONS FOR NURSING: Nurses have an
important role in educating patients about the differences between anti-CTLA-4
therapy and chemotherapy. In addition, teaching patients to recognize
ipilimumab’s side effects and report them early can result in fast treatment to
prevent symptom progression from grade I or II to III or IV. Communication
between nurses and patients throughout the treatment process will help patients
benefit maximally from the new therapeutic strategy.

Melanoma biology and the promise of zebrafish. Ceol CJ, Houvras Y, White RM, Zon LI. Zebrafish. 2008 Dec;5(4):247-55.

Advantageous organismal and technical attributes of the zebrafish are being
increasingly applied to study cancer biology. Along with other tumor models,
zebrafish that develop melanomas have been generated. In both genetics and
phenotype, zebrafish melanomas are strikingly similar to their human
counterparts. For this reason, studies in the zebrafish are poised to make
significant contributions to melanoma biology. In this review, we summarize
important features of human melanoma and discuss how the zebrafish can be used to
address many questions that remain unanswered about this devastating disease.

[Skin and eyes] [Article in German] Kohl E, Hillenkamp J, Landthaler M, Szeimies RM. Hautarzt. 2009 Jan;60(1):63-74; quiz 75.

Numerous diseases affect both skin and eyes due to similar ontogenetic origin.
The eye is the second most common site of melanoma after the skin. The eyelids
are predisposed for development of toxic and allergic dermatitis as the skin in
this region is four times thinner than the other facial skin. The differential
diagnosis must include atopic and seborrhoeic eyelid dermatitis. Atopic and
vernal keratoconjunctivitis are associated with atopic eczema. Various
immunobullous disorders involve the conjunctiva with varying severity. Side
effects of dermatologic treatments with glucocorticoids, antimalarials,
psoralens, retinoids, or tetracyclines may involve the eye.

Pigment epithelium-derived factor prevents melanoma growth via angiogenesis
inhibition. Abe R, Fujita Y, Yamagishi S, Shimizu H. Curr Pharm Des. 2008;14(36):3802-9.

Pigment epithelium-derived factor (PEDF) has recently been shown to be the most
potent inhibitor of angiogenesis in the mammalian eye, and is involved in the
pathogenesis of angiogenic eye disease such as proliferative diabetic
retinopathy. However, a functional role for PEDF in tumor growth and angiogenesis
remains to be determined. Melanoma is one of the most highly invasive and
metastatic tumors. Malignant Melanoma is an increasingly common malignancy and
also one the most invasive and metastatic tumors, and its mortality rates have
been rapidly increasing above those of any other cancer in recent years. Surgical
resection and systemic chemotherapy are the main therapeutic strategies for the
treatment of malignant melanoma. However, these approaches are insufficiently
effective and may be associated with significant adverse effects. Angiogenesis, a
process by which new vascular networks are formed from pre-existing capillaries,
is required for tumors to grow, invade and metastasize. Tumor vessels are
genetically stable, and less likely to accumulate mutations that allow them to
develop drug resistance in a rapid manner. Therefore, targeting vasculatures that
support tumor growth, rather than cancer cells, is currently considered the most
promising approach to malignant melanoma therapy. Now, novel anti-angiogenic
agents with tolerable side effects are actually desired for the treatment of
patients with malignant melanoma. In this paper, we review the current
understanding of anti-angiogenic therapy for malignant melanoma, especially
focusing on PEDF, which was recently identified as the most potent endogenous
inhibitor of angiogenesis in the mammalian eye.

Glycosylation changes on serum glycoproteins in ovarian cancer may contribute to
disease pathogenesis. Saldova R, Wormald MR, Dwek RA, Rudd PM. Dis Markers. 2008;25(4-5):219-32.

Ovarian cancer is the most lethal of all gynaecological cancers among women.
Serum CA125 is the only biomarker that is used routinely and there is a need for
further complementary biomarkers both in terms of sensitivity and specificity.
N-glycosylation changes in ovarian cancer serum glycoproteins include a decrease
in galactosylation of IgG and an increase in sialyl Lewis X (SLe(x)) on
haptoglobin beta-chain, alpha1-acid glycoprotein and alpha1-antichymotrypsin.
These changes are also present in chronic inflammation but not in malignant
melanoma, where there are low levels of inflammatory processes. Acute phase
proteins carrying increased amounts of SLe(x) have an increased half-life.
Sialylation of acute phase proteins also decreases apoptosis favouring survival
of cancer cells. Cancer cells produce inflammatory cytokines which influence
glycosylation processing in liver parenchymal cells. Altered glycosylation of the
acute phase protein transferrin plays an important role in iron homeostasis.
Glycosylated transferrin and its glycans have anti-apoptotic properties and many
transferrin receptors in carcinoma could play a role in development of anaemia.
Decreased galactosylation and sialylation of IgG increases the cytotoxicity of
natural killer cells and complement activation via mannose-binding lectin (MBL).
Altered glycosylation of acute phase proteins and IgG suggests that cancer
regulates certain pathways favouring cancer cells survival.

Specification and loss of melanocyte stem cells. Robinson KC, Fisher DE. Semin Cell Dev Biol. 2009 Feb;20(1):111-6. Epub 2008 Dec 13.

The melanocyte stem cells of the hair follicle provide an attractive system for
the study of stem cells. The stem cells exist in an anatomically defined niche
clearly separated from their differentiated progeny, differentiated progeny can
be selected against by treatment with an inhibitor of Stem Cell Factor signaling,
perturbations which affect survival and differentiation have clearly visible
pigmentation phenotypes, and genetic mutations can impair or completely abolish
this lineage without lethality. In mice several coat color mutants have been
shown to have impaired specification or survival of melanocyte stem cells.
Furthermore understanding of the normal regulation and behaviors of melanocytes
and melanocyte stem cells will allow development of better strategies for cancer
treatment. This article will review the discovery and behaviors of melanoctye
stem cells as well as some aspects of melanocyte biology.

Lesion border detection in dermoscopy images. Celebi ME, Iyatomi H, Schaefer G, Stoecker WV. Comput Med Imaging Graph. 2009 Mar;33(2):148-53. Epub 2009 Jan 3.

BACKGROUND: Dermoscopy is one of the major imaging modalities used in the
diagnosis of melanoma and other pigmented skin lesions. Due to the difficulty and
subjectivity of human interpretation, computerized analysis of dermoscopy images
has become an important research area. One of the most important steps in
dermoscopy image analysis is the automated detection of lesion borders. METHODS:
In this article, we present a systematic overview of the recent border detection
methods in the literature paying particular attention to computational issues and
evaluation aspects. CONCLUSION: Common problems with the existing approaches
include the acquisition, size, and diagnostic distribution of the test image set,
the evaluation of the results, and the inadequate description of the employed
methods. Border determination by dermatologists appears to depend upon
higher-level knowledge, therefore it is likely that the incorporation of domain
knowledge in automated methods will enable them to perform better, especially in
sets of images with a variety of diagnoses.

Heat shock protein 90 as a drug target: some like it hot. Banerji U. Clin Cancer Res. 2009 Jan 1;15(1):9-14.

Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is
involved in the posttranslational folding and stability of proteins. Inhibition
at the NH(2)-terminal ATP-binding site leads to the degradation of client
proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the
degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the
combinatorial blockade of multiple signal transduction pathways, such as the
RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase
kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase
pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early
clinical evaluation. The clinical focus of these drugs should be solid tumors,
such as breast, prostate, and lung cancers, along with malignant melanoma, in
addition to hematologic malignancies, such as chronic myeloid leukemia and
multiple myeloma. HSP90 inhibitors can be used as single agents or in combination
with other targeted treatments or conventional forms of treatment such as
chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these
agents should include innovative designs to capture cytostasis evidenced by
clinical nonprogression and enrichment of patient populations by molecular
characterization. The results of clinical trials evaluating the efficacy of drugs
targeting this exciting target are awaited.

Exogenous proteases confer a significant chemopreventive effect in experimental
tumor models. Wald M. Integr Cancer Ther. 2008 Dec;7(4):295-310.

In this monograph, the chemopreventive effects of enterally administered
proteases (trypsin, chymotrypsin, and papain) have been documented in a series of
animal experimental tumor models. The experimental evidence demonstrates a
significant inhibition of growth of both the primary tumor and the metastatic
disseminations. Survival in animals treated with proteases is significantly
longer than in untreated animals. The results confirm the fundamental correlation
between early initiation of therapy and consequent growth of the tumorous
disease. Comparable results have been shown in solid tumors in animal models
(melanoma and Lewis lung carcinoma) and in human tumors (pancreatic and breast
cancers). In this article, details of the known mechanisms of systemic actions of
enterally administered proteases are documented and their relationship with
cancerogenesis is discussed.

[Small choroidal melanoma--a diagnostic problem] [Article in Polish] Romanowska-Dixon B, Kubicka-Trzaska A. Klin Oczna. 2008;110(7-9):308-13.

The aim of this paper is to present the most common diagnostic problem associated
with a small choroidal melanoma. In some cases other lesions such as a choroidal
naevus, an exudative type of age related macular degeneration (AMD) with the
presence of subretinal haemmorrhage, retinal pigment hypertrophy, choroidal
haemangioma and choroidal metastatic tumours may mimic small choroidal melanomas.
Based on the literature and on our own experience we present the basic clinical
features of these lesions, their characteristic fluorescein angiography,
indocyanine green angiography and ultrasonography pictures that can be helpful in
differential diagnosis.

The GPR54-Kisspeptin complex in reproductive biology: neuroendocrine significance
and implications for ovulation induction and contraception. Sills ES, Walsh AP. Neuro Endocrinol Lett. 2008 Dec;29(6):846-51.

KISS1 encodes the kisspeptin (KP) family of peptides which were originally
characterised as potent antimetastatic agents in breast cancer and malignant
melanoma cells. One member of this family of arginine-phenylalanine amide
peptides, KP-54, was subsequently identified as the natural ligand for the
G-protein coupled receptor-54 (GPR54). In addition to its importance as a
metastatic suppressor, KP has been found to play a major neuroregulatory role in
governing endogenous gonadotropin release by its modulation of the
hypothalamic-pituitary-gonadal (HPG) axis. In humans, KISS1 mRNA has been
localised to the hypothalamic anteroventral periventricular nucleus and arcuate
nucleus. Although GPR54 is expressed in human pituitary cells, it is not
presently known if gonadotrope cells themselves are targets for significant KP
activity. It was recently shown that full disruption of the KP/GPR54 complex
resulted in hypogonadotropic hypogonadism. Indeed, evidence now suggests that
KP/GPR54 signalling during gestation is necessary for sexual differentiation and
implicates activation of the KP/GPR54 complex as the single most important
upstream event regulating GnRH release. Several compelling studies have placed KP
as the leading candidate molecule responsible for initiating puberty, making this
receptor-ligand complex of fundamental importance to the neuroendocrinology of
reproduction. Here, we discuss key KP/GPR54 discovery events and present an
evolution of KP biology in the context of recent animal and human experimental
work. With evidence pointing to proper KP/GPR54 signalling as the principal
trigger for activation of GnRH neurons and subsequent ovulation, elucidation of
how this pathway is modulated is likely to bring novel pharmacologic strategies
for fertility treatment (and contraception) within reach. Because the
physiological significance KP is now acknowledged to extend well beyond cancer
biology (and may also contribute to the pathophysiology of pre-eclampsia), KP
represents an exciting research theme in human reproductive biology and
neuroendocrinology.

Subungual melanoma: a deceptive disorder. Patel GA, Ragi G, Krysicki J, Schwartz RA. Acta Dermatovenerol Croat. 2008;16(4):236-42.

Subungual melanoma is an uncommon form of acral melanoma that arises within the
nail bed. The incidence for acral melanomas is similar worldwide, but the
proportion is higher in dark-skinned individuals. The subungual form represents
about 2% of cutaneous non-sun induced melanomas in the western world, and up to
75% in Africans, 10% in Japanese, and 25% in the Chinese of Hong Kong. Up to 33%
of subungual melanomas are amelanotic. Black pigmentation of the adjacent nail
fold, termed Hutchinson’s sign, may be a diagnostic clue. Non-specific features
and symptoms along with a high incidence of amelanosis often lead to delayed
diagnosis, disease progression, and a poor prognosis with challenging treatment
options.

Melanoma biomarkers: current status and vision for the future. Larson AR, Konat E, Alani RM.

Melanoma is the leading cause of death from skin cancer in industrialized
countries. Clinical and histological variables such as primary tumor invasion,
ulceration, and lymph node status might fail to identify early-stage disease that
will eventually progress. Tumor biomarkers might help to identify patients with
early-stage melanoma who are likely to develop advanced disease and would benefit
from additional therapies. These biomarkers offer the possibility of improved
tumor staging through the molecular detection of microscopic lymph node
metastases that are not visible on routine histological examination. We focus on
biomarkers localized to the tumor tissue and those of prognostic value. We give
an overview of the melanoma biomarkers that are most helpful for prediction of
patients’ outcomes, and discuss the primary melanoma biomarkers that have been
shown to be of prognostic significance independent of primary tumor thickness and
other common clinical prognostic indicators. Although such tumor-associated
biomarkers are thought to have the greatest potential, a lack of reliable data
makes their true clinical utility difficult to determine. We conclude that
several biomarkers show promise in early studies; however, additional large-scale
studies are warranted. We suggest cautious optimism for the field of melanoma
biomarkers, which we expect to be translated into clinical practice over the next
few years.

Management of melanomas of the female genital tract. Sugiyama VE, Chan JK, Kapp DS. Curr Opin Oncol. 2008 Sep;20(5):565-9.

PURPOSE OF REVIEW: The significant increase in cutaneous melanomas over the past
30 years has led to studies resulting in advances in their diagnosis, staging,
surgical treatment, and adjuvant therapies. Similar approaches have been
investigated in patients with far rarer malignant melanomas of the female genital
tract. This review will summarize the current state of knowledge on the
incidence, causes, presenting symptoms, prognostic factors, therapeutic
approaches, and outcomes, site-by-site, for primary melanomas of the vulva,
vagina, urethra, ovary, and the uterine cervix. RECENT FINDINGS: Surgery remains
the initial treatment of choice for localized melanomas of the female genital
tract, with less radical, organ function preserving resections demonstrating
similar control rates compared with more radical surgical approaches in vulva and
possibly vaginal melanomas. Radiation therapy may play a role in the treatment of
patients with close resection margins, regional nodal metastasis, or unresectable
tumors. Sentinel lymph node studies, positron emission tomography and computed
tomography scans for staging and evaluation of response, and adjuvant chemo or
biochemotherapy warrant further investigation. SUMMARY: The results of treatment
for female genital tract melanomas remain poor. Although surgery remains the
initial treatment of choice for localized disease, adjuvant local-regional, and
systemic therapies are needed.

[Sentinel node biopsy and possibilities of use in current surgical oncology] [Article in Czech] Fait V. Klin Onkol. 2008;21(1):5-19.

Sentinel node biopsy originally developed for melanoma has gradually extended
into further fields of surgical oncology. It became a standard procedure in
melanoma and breast cancer, it appears to be a very helpful method in colorectal
cancer. The possibilities of use are tested throughout all of surgical oncology
in gastrointestinal, urological and gynecological tumors. It’s importance can be
displayed even in head and neck tumor, intrathoracical tumors and in thyroid
cancer.

Beyond the psychotherapy and survival debate: the challenge of social disparity,
depression and treatment adherence in psychosocial cancer care. Kissane D. Psychooncology. 2009 Jan;18(1):1-5.

The psychotherapy and cancer survival debate generated great interest in the
psychoneuroimmunological and bio-behavioral mechanisms that might mediate any
gain in survival. Recent methodologically-improved cognitive-existential,
supportive-expressive and psycho-educational group interventions for patients
with breast cancer and melanoma have not extended survival times. Shorter
survival has been associated with social disparity and untreated clinical
depression, potentially mediated by poorer adherence to anti-cancer treatments.
Group therapy both prevents and treats depression. Future research could address
these bio-behavioral mechanisms. (c) 2008 John Wiley & Sons, Ltd.

Ocular melanoma: relatively rare but requiring respect. Shields CL, Shields JA. Clin Dermatol. 2009 Jan-Feb;27(1):122-33.

Primary ocular melanoma can involve the uveal tract, conjunctiva, eyelid, or
orbit. Uveal melanoma is the most common ocular melanoma and carries a serious
prognosis, especially if the tumor is medium or large in size. Conjunctival
melanoma manifests on the surface of the eye and has been increasing in
incidence. Eyelid and primary orbital melanoma are the least common variants.
Early diagnosis from annual ocular examination by an experienced ophthalmologist
and treatment strategies are reviewed.

Nevi and melanoma in the pregnant woman. Driscoll MS, Grant-Kels JM. Clin Dermatol. 2009 Jan-Feb;27(1):116-21.

Multiple difficult questions arise when a pregnant woman presents to the
dermatologist with a changing melanocytic nevus or melanoma. Our review of the
literature provides some insight into these issues. We recommend that a changing
pigmented lesion in the pregnant woman should be biopsied promptly and can be
safely performed. Women who have dysplastic nevus syndrome require closer
monitoring during pregnancy. For the pregnant woman with a confirmed, localized
melanoma, prognosis does not appear to be affected by pregnancy. Likewise,
limited data indicate that pregnancy before or after a diagnosis of melanoma does
not affect prognosis. Wide local excision may be performed safely, but if
sentinel lymph node mapping and biopsy is indicated, the technique and safety of
this procedure in the pregnant woman remains controversial. There appears to be
no absolute contraindication to the prescription of oral contraceptive pills or
hormone replacement therapy in someone who has been previously diagnosed with
melanoma if no reasonable alternative exists.

The “dysplastic” nevus. Friedman RJ, Farber MJ, Warycha MA, Papathasis N, Miller MK, Heilman ER. Clin Dermatol. 2009 Jan-Feb;27(1):103-15.

Dysplastic nevi have become an increasing focus clinically, with evidence that
they are associated with a higher risk of developing melanoma. However, there
still is contention regarding the significance of dysplastic nevi. This
contribution provides an overview of the history, epidemiology, genetics,
clinical and histologic features, and procedures for clinical management of
dysplastic nevi. Since dysplastic nevi were described originally in 1978, a great
deal of research has examined the epidemiology of these lesions and the genetic
factors related to the development of dysplastic nevi. However, there is
disagreement regarding the clinical management of dysplastic nevi and the
histologic definition of dysplastic nevi. Current recommendations include
preventative measures, such as sun protection and careful surveillance and
biopsies of suspicious lesions as needed. The advent of new technologies, such as
computer-vision systems, have the potential to significantly change treatment of
dysplastic nevi in the future.

New techniques in dermatopathology that help to diagnose and prognosticate
melanoma. Carlson JA, Ross JS, Slominski AJ. Clin Dermatol. 2009 Jan-Feb;27(1):75-102.

Routine light microscopy supplemented with immunohistochemistry in cases of
metastatic or spindle cell melanoma are standards of care for the diagnosis and
staging of melanoma. Not all melanocytic tumors can be confidently classified as
melanoma or benign nevus by histology, however. In addition, tumor thickness and
ulceration, the current American Joint Classification on Cancer prognosticators
for primary cutaneous (stages I and II) melanoma used in clinical practice, do
not perfectly predict an individual’s clinical course. Recent advances in
molecular techniques and bioinformatics mandate testing and use of novel methods
for the detection, diagnosis, and classification of melanocytic tumors that can
accurately predict tumor behavior and help in selecting the most optimal and
individualized therapy.

Melanoma prognostic factors found in the dermatopathology report. Payette MJ, Katz M 3rd, Grant-Kels JM. Clin Dermatol. 2009 Jan-Feb;27(1):53-74.

Significant prognostic information is available in a routine melanoma
dermatopathology report. Features that are enumerated in the pathology report and
that portend a potentially poorer prognosis are older age, site (acral, head,
neck), male sex, increasing Breslow tumor thickness, increasing Clark’s level,
ulceration, increasing number of mitoses, vertical growth phase, regression,
absence of a host inflammatory response, increased tumor vascularity,
angiotropism, vascular invasion, neurotropism, marked atypia, and satellite
metastasis.

Melanoma and genetics. Nelson AA, Tsao H. Clin Dermatol. 2009 Jan-Feb;27(1):46-52.

As the incidence of malignant melanoma continues to increase and with the
completion of the sequencing of the human genome, there have been increasing
efforts to identify the “melanoma gene(s).” Although some patients and families
have significantly increased risks due to genetic predisposition, most melanoma
cases are sporadic and likely result from low to moderate risk genetic factors.
This review focuses on the genes that cover the greatest risk of developing
melanoma. It is important to remember that many–if not most–cases of melanoma
are the result of undiscovered variants. The strongest genetic risk for the
development of melanoma results from heritable alterations in cyclin-dependent
kinase inhibitor 2A (CDKN2A) gene, which encodes two separate but related
proteins, p16/INK4a and p14/ARF. These proteins help regulate cell division and
apoptosis, both of which are necessary to maintain cellular homeostasis. Other
important genes include CDK4/6 and retinoblastoma (RB1), which encode downstream
proteins in the same pathway as p16/INK4a and p14/ARF. Finally, we discuss the
relative importance of the melanocortin 1 receptor (MC1R) gene as a moderate risk
factor for melanoma. Although great advances have been made in understanding the
molecular basis and genetic predisposition of melanoma, many questions still
remain to be answered. Someday soon, it will be possible to predict a patient’s
risk of melanoma by DNA analysis; however, it is important to reconcile our
tremendous technologic capabilities with documented clinical utility.

Current and emerging technologies in melanoma diagnosis: the state of the art. Psaty EL, Halpern AC. Clin Dermatol. 2009 Jan-Feb;27(1):35-45.

Relative to other specialties, dermatologists have been slow to adopt advanced
technologic diagnostic aids. Most skin disease can be diagnosed by simple visual
inspection, and the skin is readily accessible for a diagnostic biopsy.
Diagnostic aids, such as total body photography and dermoscopy, improve the
clinician’s ability to diagnose melanoma beyond unaided visual inspection,
however, and are now considered mainstream methods for early detection. Emerging
technologies such as in vivo reflectance confocal microscopy are currently being
investigated to determine their utility for noninvasive diagnosis of melanoma.
This review summarizes the currently available cutaneous imaging devices and new
frontiers in noninvasive diagnosis of skin disease. We anticipate that multimodal
systems that combine different imaging technologies will further improve our
ability to detect, at the bedside, melanoma at an earlier stage.

Lymphoma look-alike. Skoog L, Tani E. Monogr Clin Cytol. 2009;18:64-75. Epub 2008 Dec 18.

Integrating tumor-initiating cells into the paradigm for melanoma targeted
therapy. Smalley KS, Herlyn M. Int J Cancer. 2009 Mar 15;124(6):1245-50.

There is growing evidence to suggest that not all cancer cells have similar
levels of malignant potential and that tumor progression may be driven by
specialized sub-sets of “tumor initiating” cells. It is likely that as tumor
initiating cells have lower proliferation rates and enhanced survival mechanisms
they may also drive drug resistance. Melanoma is known to be an exceptionally
therapy resistant tumor, with no treatment yet identified to alter the natural
progression of the disseminated disease. In the current review, we discuss
evidence for the existence of melanoma initiating cells and described possible
therapeutic strategies to eradicate this population via the targeting of specific
cell-surface markers or through the disruption of the interaction of the melanoma
initiating cells with their local microenvironment. It is hoped that the
targeting of melanoma initiating cells may be one approach to overcome the
incredible therapy resistance of this tumor.

TNK cells (NKG2D+ CD8+ or CD4+ T lymphocytes) in the control of human tumors. Maccalli C, Scaramuzza S, Parmiani G. Cancer Immunol Immunother. 2009 May;58(5):801-8. Epub 2008 Dec 17.

Innate and adaptive immune responses have many interactions that are regulated by
the balance of signals initiated by a variety of activatory and inhibitory
receptors. Among these, the NKG2D molecule was identified as expressed by T
lymphocytes, including most CD8+ cells and a minority of CD4+ cells, designated
TNK cells in this paper. Tumor cells may overexpress the stress-inducible NKG2D
ligands (NKG2DLs: MICA/B, ULBPs) and the NKG2D signaling has been shown to be
involved in lymphocyte-mediated anti-tumor activity. Aberrant expression of
NKG2DLs by cancer cells, such as the release of soluble form of NKG2DLs, can lead
to the impairment of these immune responses. Here, we discuss the significance of
NKG2D in TNK-mediated anti-tumor activity. Our studies demonstrate that NKG2D+ T
cells (TNK) are commonly recruited at the tumor site in melanoma patients where
they may exert anti-tumor activity by engaging both TCR and NKG2D. Moreover,
NKG2D and TCR triggering was also observed by peripheral blood derived T
lymphocyte- or T cell clone-mediated tumor recognition, both in melanoma and
colorectal cancer (CRC) patients. Notably, heterogeneous expression of NKG2DLs
was found in melanoma and CRC cells, with a decrease of these molecules along
with tumor progression. Therefore, through the mechanisms that govern NKG2D
engagement in anti-tumor activity and the expression of NKG2DLs by tumor cells
that still need to be dissected, we showed that NKG2D expressing TNK cells are a
relevant T cell subtype for immunosurveillance of tumors and we propose that new
immunotherapeutic interventions for cancer patients should be aimed also at
enhancing NKG2DLs expression by tumor cells.

Cutaneous melanoma: how does ultraviolet light contribute to melanocyte
transformation? Walker G. Future Oncol. 2008 Dec;4(6):841-56.

Ascribing a causal role to ultraviolet radiation in melanoma induction is
problematic, as the relationship between total lifetime sun exposure and melanoma
risk is not as strong as for some other skin cancers. Epidemiological studies
show that heightened melanoma risk is most associated with intermittent sunburns.
Despite this, lesions can develop on anatomical locations receiving intermittent
(e.g., the trunk) or chronic exposures (e.g., the head and neck). Individuals
developing melanoma on truncal sites tend to have more nevi, suggesting that in
addition to the differences in forms of sun exposure, there may also be innate
variation that makes one more susceptible to one or other mechanism of melanoma
development. Such differences may depend upon different responses at the time of
exposure (e.g., pigmentation characteristics, DNA repair capability and
melanocyte proliferative response), and/or the role of the skin microenvironment
in limiting proliferation of a ‘primed’ or mutated melanocyte during the latent
period leading up to the appearance of a melanocytic lesion.

Receptor activator of nuclear factor-kappa B ligand (RANKL) stimulates
bone-associated tumors through functional RANK expressed on bone-associated
cancer cells? Mori K, Ando K, Heymann D, Rédini F. Histol Histopathol. 2009 Feb;24(2):235-42.

Primary and secondary bone tumors clearly deteriorate quality of life and the
activity of daily living of patients. These undesirable diseases become a major
social and economic burden. As both primary and secondary bone tumors develop in
the unique bone tissue, it is therefore necessary to understand bone cell biology
in tumor bone environment. Recent findings of the Receptor Activator of Nuclear
Factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) molecular triad, the key
regulators of bone remodeling, opened new era of bone research. Although RANK is
an essential receptor for osteoclast formation, activation and survival,
functional RANK expression has been recently identified on several
bone-associated tumor cells. When RANK is expressed on secondary bone tumor
cells, it is implicated in tumor cell migration, whereas this is not the case for
primary bone tumors. In any case, RANK is not involved in RANK-positive cell
proliferation or death. In two models of bone metastases secondary to melanoma or
prostate carcinoma, in vivo neutralization of RANKL by OPG resulted in complete
protection from paralysis, due to metastases of vertebral body, and a marked
reduction in tumor burden in bones, but not in other organs. OPG also decreased
tumor formation and tumor burden in a mouse model of primary bone tumor,
osteosarcoma. In all these models, tumor cells express RANK. These data revealed
that local differentiation factors, such as RANKL, play an important role in cell
migration in a metastatic tissue-specific manner. These findings substantiate the
novel direct role of RANKL/RANK in bone-associated tumors, and its capability of
representing new therapeutic targets.

[Diagnosis tools for cutaneous melanoma] [Article in French] Guitera-Rovel P, Vestergaard ME. Ann Dermatol Venereol. 2008 Dec;135(12):828-34. Epub 2008 Nov 25.

BACKGROUND: A number of new tools have been developed in the last ten years to
improve the diagnosis of cutaneous melanoma. AIMS: To review the value of
diagnostic tools for cutaneous melanoma in a clinical setting. METHODS: Review of
multiple databases from 1987 to 2007 and classification of publications in terms
of level of evidence according to “The Australian Cancer Network”. RESULTS:
Dermoscopy has superior specificity and sensitivity to naked-eye examination
according to a meta-analysis of nine level-2 studies. Sequential digital
dermoscopic imaging allowed detection of melanoma in the absence of dermoscopic
evidence of melanoma in four level-2 studies. Total body photography, generally
performed for high-risk patients, seems to be equally valuable but has the
additional advantage of allowing self-examination by patients themselves.
Dermographic photographs with computer-assisted diagnosis of primary melanoma
appear to have equivalent diagnostic capacity to experts but very few studies
have been performed in a clinical setting. Optical methods still under
development yield in vivo information that is closely correlated with
histopathology data and may avoid unnecessary excision while providing improved
control of excision margins. They will doubtless be used as a second-line method
after clinical detection of suspect lesions and history-taking, which will
continue to be primordial regardless of the other tools available.

Combined and sequential treatment of oral and maxillofacial malignancies: an
evolving concept and clinical protocol. Zheng JW, Qiu WL, Zhang ZY. Chin Med J (Engl). 2008 Oct 5;121(19):1945-52.

OBJECTIVE: To introduce the concept and rational regimens and present the latest
development of combined treatment of oral and maxillofacial malignancies. Data
sources The related published literature was searched through the CNKI database
and MEDLINE using the terms of oral cancer, oral and maxillofacial malignancies,
combined and sequential therapy, multidisciplinary approach. Study selection The
available related literature was read and evaluated. Studies that met the
inclusion criteria were selected. RESULTS: The results show that oral and
maxillofacial malignancies diagnosed at an early stages (stages I and II) can be
well treated with surgery alone and/or radiotherapy with optimal outcome, but
advanced or recurrent diseases should be treated with rational combined and
sequential treatment modalities. The use of concomitant chemoradiotherapy,
taxane-containing, three-drug induction regimens and Cetuximab in combination
with chemotherapy or radiotherapy demonstrated favorable results in previously
untreated patients with head and neck squamous cell carcinoma. CONCLUSIONS: The
concept of combined and sequential treatment of advanced oral and maxillofacial
malignancies should be widely accepted, and the rational regimen for individual
and each type of entity should be determined based on the anatomical site and the
patient’s performance status.

Solitary dermal melanoma with prolonged survival. Cecchi R, Rapicano V. Clin Exp Dermatol. 2009 Jan;34(1):81-2.

Lentigo maligna. Smalberger GJ, Siegel DM, Khachemoune A. Dermatol Ther. 2008 Nov-Dec;21(6):439-46.

Lentigo maligna (LM), a melanoma in situ, is a fairly common melanocytic lesion
that usually develops on the chronically sun-exposed skin of the head and neck of
Caucasians. It occurs mostly in people older than 40 years, with an incidence
rate that increases with age and peaks in the seventh and eighth decades of life.
Its diagnosis and treatment remain challenging. In this article, we review the
history, epidemiology, clinical presentation, histology, and treatment of LM.

Management of primary melanoma of the female urogenital tract. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81.

Primary melanoma of the urogenital tract in women is rare, but biologically
aggressive. They usually affect elderly women and account for less than 10% of
all cancer of the urogenital tract in women and less than 10% of all melanoma
diagnosed in women. Tumours originate from melanocytes that are present in the
urogenital mucosal epithelium of about 3% of women. Tumour staging can be
challenging; however, the American Joint Committee on Cancer melanoma staging
system has been recommended for use in vulvar and vaginal melanoma. Surgery is
the treatment of choice; less-extensive surgery can be a sensible approach
because satisfactory locoregional control might be obtained from wide local
excision and radiotherapy, without the morbidity and disfigurement associated
with radical surgery. Complete regional lymphadenectomy does not seem necessary
if a sentinel lymph-node biopsy sample is negative; however, this decision should
be made with caution. Various chemotherapy and biotherapy (ie, immunotherapy and
biological-response modifiers) regimens have been used in advanced or metastatic
melanoma. However, the role of chemotherapy for women with urogenital-tract
melanoma has not been established, and biotherapy methods presented to date have
been anecdotal.

Reflectance confocal microscopy for in vivo skin imaging. Calzavara-Pinton P, Longo C, Venturini M, Sala R, Pellacani G. Photochem Photobiol. 2008 Nov-Dec;84(6):1421-30.

Reflectance confocal microscopy (RCM) is a novel noninvasive technique for “in
vivo” examination of the skin. In a confocal microscope, near- infrared light
from a diode laser is focused on a microscopic skin target. As this light passes
between cellular structures having different refraction indexes, it is naturally
reflected, and this reflected light is then captured and recomposed into a
two-dimensional gray scale image by computer software. Focusing the microscope
(adjusting the focal point on the z-axis) allows images to be obtained of
different levels within the skin. Commercially available microscope systems of
this type can create images with enough detail for use in histological analysis.
The first investigations using these microscopes served to identify the
appearance of the various cell populations living in the different layers of
normal skin. Today, the main interest has become focused on the use of these
microscopes as a diagnostic tool: a means of investigating benign and malignant
tumors of melanocytes and keratinocytes, and, more importantly, the findings of
this field of study can be used to develop a diagnostic algorithm which would be
not only highly sensitive but specific as well. The aim of the paper is to
provide an updated literature review and an in-depth critique of the
state-of-the-art of RCM for skin cancer imaging with a critical discussion of the
possibilities and limitations for clinical use.

Lymph node assessment in melanoma. Easson AM, Rotstein LE, McCready DR. J Surg Oncol. 2009 Mar 15;99(4):176-85.

The surgical management of lymph nodes continues to be important in melanoma
since effective systemic therapies are not available. Controversy exists around
the significance of the early detection and management of microscopically
positive lymph nodes detected by sentinel lymph node biopsy and this is the
subject of current surgical clinical trials. Complete lymphadenectomy is
recommended for lymph node metastases. The importance of proper surgical
technique is discussed.

[Immunology and BCG therapeutics] [Article in Spanish] Sánchez Olivas MA, Valencia Zavala MP, Montes Montes J, Sánchez Olivas JA, Flores Méndez I. Rev Alerg Mex. 2008 Jul-Aug;55(4):153-63.

The importance in the study of bacillus of Calmette-Guérin or BCG is related to
several functions derived from its influence on the immunological system, between
which it is found the prevention of the dissemination of the tubercular bacillus,
its utilization as immunomodulator in some oncologic illness (as vesical cancer)
in order to avoid post-surgical recidiva or in some forms of immunotherapy, as
the cytokine (interferon alpha and interleukin-2); in addition, BCG vaccine is
supplied like an immunomodulator in treatment of melanoma. It is important to
continue with the study of the BCG strains for its great utility in the treatment
of various diseases, example of the previous is the Tice strain, which is used in
the superficial cancer of bladder and in the production of new and more powerful
vaccines for the protection of tuberculosis.

High-grade transitional cell carcinoma and melanosis of urinary bladder: case
report and review of the literature. Sanborn SL, MacLennan G, Cooney MM, Zhou M, Ponsky LE. Urology. 2009 Apr;73(4):928.e13-5. Epub 2008 Dec 4.

Melanosis of the urinary bladder is a rare entity. It is generally regarded as a
benign condition, but it is sometimes associated with primary malignant melanoma
of the urinary bladder. It has never been reported to be connected with
transitional cell carcinoma. We present a case of a woman with melanosis of the
bladder who a year later developed high grade transitional cell bladder
carcinoma.

Management of familial melanoma and nonmelanoma skin cancer syndromes. Santillan AA, Cherpelis BS, Glass LF, Sondak VK. Surg Oncol Clin N Am. 2009 Jan;18(1):73-98, viii.

The clinical manifestations of hereditary skin cancer syndromes depend upon the
interplay between environmental and genetic factors. Familial melanoma occurs in
the setting of hereditary susceptibility, with a complex phenotype of early age
of onset, multiple atypical moles, multiple primary melanomas, multiple melanomas
in the family, and in some instances pancreatic cancer. Identification of
individuals who may have a hereditary susceptibility for the development of
melanoma is essential to provide an opportunity for primary prevention, and to
target high-risk groups for early diagnosis and treatment. Consequently, the
surgeon as one of the primary caregivers should be familiar with hereditary skin
cancer syndromes and their pathogenesis, diagnosis, management, and surveillance
recommendations. This article discusses a practical approach for some of the
issues likely encountered by the surgeon in the management of familial melanoma
and non-melanoma skin cancer.

The cancer cell–leukocyte fusion theory of metastasis. Pawelek JM, Chakraborty AK. Adv Cancer Res. 2008;101:397-444.

The cause of metastasis remains elusive despite vast information on cancer cells.
We posit that cancer cell fusion with macrophages or other migratory bone
marrow-derived cells (BMDCs) provides an explanation. BMDCs fused with tumor
cells were present in animal tumor xenografts where they were associated with
metastases. In myeloma patients, transcriptionally active myeloma nuclei were
incorporated into osteoclasts through fusion. In patients with renal cell
carcinoma arising poststem cell transplant, donor genes were incorporated in
recipient cancer cell nuclei, most likely through fusion, and showed tumor
distribution patterns characteristic of cancer stem cells. Melanoma-macrophage
hybrids generated in vitro contained chromosomes from both parental partners,
showed increased ploidy, and transcribed and translated genes from both parents.
They exhibited chemotactic migration in vitro toward fibronectin and exhibited
high frequencies of metastasis when implanted in mice. They produced
macromolecules that are characteristic of macrophages and known indicators of
metastasis (c-Met, SPARC, MCR1, GnT-V, and the integrin subunits alpha(3),
alpha(5), alpha(6), alpha(v), beta(1), beta(3)). They also produced high levels
of beta1,6-branched oligosaccharides-predictors of poor survival in patients with
melanoma or carcinomas of the breast, lung, and colon. We thus hypothesize that
such gene expression patterns in cancer are generated through fusion. Tumor
hybrids also showed active autophagy, a characteristic of both metastatic cancers
and macrophages. BMDC-tumor cell fusion explains epidermal-mesenchymal transition
in cancer since BMDCs express mesodermal traits and epithelial-mesenchymal
transition regulators (Twist, SPARC, and others). If BMDC-tumor cell fusion
underlies invasion and metastasis in human cancer, new approaches for therapeutic
intervention would be mandated.

Molecular markers detecting circulating melanoma cells by reverse transcription
polymerase chain reaction: methodological pitfalls and clinical relevance. Nezos A, Lembessis P, Sourla A, Pissimissis N, Gogas H, Koutsilieris M. Clin Chem Lab Med. 2009;47(1):1-11.

Herein, we expound the theory of circulating melanoma cells (CMCs) and their
detection with reverse transcription polymerase chain reaction as a molecular
staging approach. We discuss the molecular markers that have been used for CMC
detection focusing on the use of these markers for multiplex detection analysis.
Finally, we comment on the contradictory data of CMC detection studies in the
literature and we propose possible solutions which may contribute to the clinical
significance of CMC detection in patient management.

Molecular diagnosis in dermatopathology: what makes sense, and what doesn’t. Braun-Falco M, Schempp W, Weyers W. Exp Dermatol. 2009 Jan;18(1):12-23. Epub 2008 Oct 22.

Molecular techniques have provided us with a wealth of information about
biological events in healthy individual, and improved tremendously our
understanding about the pathogenesis of a huge variety of cutaneous diseases.
Those methods have originally been invented to support basic scientific
investigations on a molecular level and are translated increasingly into
sophisticated diagnostic tools changing the classic paradigm of diagnostic
pathology; among them are immunohistochemistry (IHC), polymerase chain reaction
(PCR), G-banding, loss of heterozygosity, fluorescence in situ hybridization
(FISH), chromogen in situ hybridization (CISH), comparative genomic hybridization
on chromosomes and microarray technology. Some of them such as IHC and PCR have
already been standardized to a level that allows its utility in daily routine
diagnostics for several dermatological diseases. For others like array-based
technologies, their optimal indications await to be fully determined. These
ancillary methods have the great potential to contribute important new
information to challenging cases, and will help to improve diagnostic accuracy
particularly in cases in which conventional histopathology is ambiguous. Thus,
they will broaden our armamentarium for diagnostic pathology. Herein, some key
techniques will be reviewed and their applicability towards the diagnosis of
dermatological diseases critically discussed.

Synchronous metastatic melanoma presenting as gingival and facial swelling: a
case report and review of the literature. Bonan PR, Laranjeira AL, Martelli-Júnior H, Guimarães AL, Vargas PA, Coletta RD. J Periodontol. 2008 Dec;79(12):2371-7.

BACKGROUND: Metastases to the oral cavity are unusual, and most cases affect the
jaws. The clinicopathologic features of a metastatic melanoma involving the
mandibular gingiva and facial skin are described. METHODS: A 42-year-old white
woman who had been treated for plantar melanoma 10 years ago showed concomitant
nodular lesions in the mandibular gingiva and facial skin. Incisional biopsy and
fine needle aspiration cytology were performed in the gingival and facial
swelling, respectively. RESULTS: Radiographs revealed irregular bone erosion and
widening of the periodontal ligament space associated with the gingival lesion,
whereas cranial computed tomography showed an irregular hyperdense mass
associated with the dermal tissue. The histopathologic findings were suggestive
of melanoma; immunohistochemical analysis revealed, in both lesions, neoplastic
cells strongly positive for S100 and HMB-45 antibodies and weak reactivity for
melan-A. The final diagnosis of these lesions was metastatic melanoma, and the
patient died before restarting treatment. CONCLUSIONS: To the best of our
knowledge, this is the first English-language report of metastatic melanoma
affecting the gingiva and facial skin concomitantly. The intraoral involvement of
disseminated melanoma indicates a very poor prognosis, as confirmed by the
current case.

Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in head
and neck cancers. Uppaluri R, Dunn GP, Lewis JS Jr. Cancer Immun. 2008 Dec 4;8:16.

The expanding and established literature that correlates tumor infiltrating
lymphocytes (TILs) with outcomes of patients with solid tumors has contributed
greatly to the appreciation of the interaction between the host immune system
with neoplastic growth. This analysis has been limited to specific tumors, such
as melanoma and ovarian cancer, and our understanding of TILs in relation to many
other malignancies has yet to be explored. We review one less well studied
malignancy, head and neck squamous cell carcinoma (HNSCC), and the initial
attempts to examine the impact of TILs on outcomes of these patients. To provide
a context for the discussion of TILs and HNSCC, we first review the epidemiology,
relevant head and neck anatomy, immune responses and discuss the historical data
regarding the unique immunobiology of these tumors. Finally, with this
perspective, we describe our current understanding of tumor infiltrating
lymphocyte data for head and neck cancers.

Adverse events from the treatment of Parkinson’s disease. Chou KL. Neurol Clin. 2008 Aug;26(3 Suppl):S65-83, vi.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized clinically
by resting tremor, rigidity, bradykinesia, and postural instability. Effective
medications exist to treat these motor symptoms but can be associated with
adverse effects. When severe, these adverse effects can interfere with a
patient’s quality of life. In this article, the most common adverse events from
PD treatment are discussed, including nausea, dyskinesias, somnolence, compulsive
behaviors, psychosis, and peripheral edema. Additionally, melanoma and weight
loss, two conditions that have been variably linked to PD treatment, are
reviewed.

Chemokines and the microenvironment in neuroectodermal tumor-host interaction. Somasundaram R, Herlyn D. Semin Cancer Biol. 2009 Apr;19(2):92-6. Epub 2008 Nov 13.

Chemokines and chemokine receptors play an important role in immune homeostasis
and surveillance. Altered or defective expression of chemokines and/or chemokine
receptors could lead to a disease state including autoimmune disorder or cancer.
Tumors from glioblastoma, melanoma, and neuroblastoma secrete high levels of
chemokines that can promote tumor growth and progression or induce stromal cells
present in the tumor microenvironment to produce cytokines or chemokines which,
in turn, can regulate angiogenesis, tumor growth, and metastasis. On the other
hand, chemokines secreted by tumor or stromal cells can also attract leukocytes
such as dendritic cells, macrophages, neutrophils, and lymphocytes which may
downmodulate tumor growth. New therapies that are aimed at limiting tumor growth
and progression by attracting immune effector cells to the tumor site with
chemokines may hold the key to the successful treatment of cancer, although this
approach may be hampered by possible tumor growth-stimulating effects of
chemokines.

Melanoma–part 2: management. Thirlwell C, Nathan P. BMJ. 2008 Dec 1;337:a2488. doi: 10.1136/bmj.a2488.

Speckled lentiginous naevus: which of the two disorders do you mean? Happle R. Clin Exp Dermatol. 2009 Mar;34(2):133-5. Epub 2008 Nov 24.

Speckled lentiginous naevus (synonym: naevus spilus) no longer represents one
clinical entity, but rather, two different disorders can be distinguished. Naevus
spilus maculosus is consistently found in phacomatosis spilorosea, whereas naevus
spilus papulosus represents a hallmark of phacomatosis pigmentokeratotica. The
macular type is characterized by dark speckles that are completely flat and
rather evenly distributed on a light brown background, resembling a polka-dot
pattern. In contrast, naevus spilus papulosus is defined by dark papules that are
of different sizes and rather unevenly distributed, reminiscent of a star map.
Histopathologically, the dark spots of naevus spilus maculosus show a ‘jentigo’
pattern and several nests of melanocytes involving the dermoepidermal junction at
the tips of the papillae, whereas most of the dark speckles of naevus spilus
papulosus are found to be dermal or compound melanocytic naevi. The propensity to
develop Spitz naevi appears to be the same in both types of speckled lentiginous
naevus, whereas development of malignant melanoma has been reported far more
commonly in naevus spilus maculosus.

Dendritic cells in the skin–potential use for melanoma treatment. El Marsafy S, Bagot M, Bensussan A, Mauviel A. Pigment Cell Melanoma Res. 2009 Feb;22(1):30-41. Epub 2008 Nov 27.

Melanoma is an aggressive malignancy with poor prognosis. Eradication of tumor
cells requires an effective interaction between melanoma cells and different
players of the immune system. As the most potent professional antigen-presenting
cells, dendritic cells (DCs) play a pivotal role in mounting a specific immune
response where their intratumoral and peritumoral density as well as their
functional status are correlated with clinical staging of the disease and with
patients’ survival. Under steady-state conditions, internalization of apoptotic
cells by immature DCs designates a state of tolerance to self-antigens.
Nevertheless, pathogens and necrotic cells interacting with pattern recognition
receptors trigger downstream signaling pathways that evoke maturation of DCs,
leading to the production of pro-inflammatory cytokines. These mature DCs are
essential for T-cell priming and subsequent development of a specific immune
response. Altered functions of DCs have an impact on the development of various
disorders including autoimmune diseases and cancers. Herein, we focus on the
checkpoints created throughout DCs antigen capturing and presentation to T cells,
with subsequent development of either tolerance or immune response, with an
emphasis on the role played by DCs in melanoma tumorigenesis and their
therapeutic potential.

Epigenetic marks in melanoma. Richards HW, Medrano EE. Pigment Cell Melanoma Res. 2009 Feb;22(1):14-29. Epub 2008 Nov 27.

Melanoma is a highly heterogeneous cancer that comes in different flavors
(lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma,
acral lentiginous/mucosal melanoma and other less common subtypes including
malignant cellular blue nevus, desmoplastic melanoma, nevoid melanoma, and
animal-type melanoma) and colors (black/bluish or unpigmented). Pathologists have
known for many years that melanoma displays notable changes in the nuclear
architecture including thick chromatic rims, presence of mitosis, nuclear
grooves, and more. It is now evident from other cancers that such changes reflect
not only genomic alterations but also non-genomic changes in both the structure
of DNA and the structure of chromatin to which the DNA is bound (nucleosomes).
Although aberrant gene expression resulting from DNA methylation has been known
for many years, genome alterations resulting from histone modifications became
evident in the current decade. In prostate and other cancers, some histone marks
have clinical diagnostic and/or prognostic value. Here, we review the current
data on epigenetic research in melanoma skin cancers, discuss ways to modify the
epigenetic landscape of melanoma for inhibiting its growth, and propose
strategies for identifying novel melanoma markers.

Melanoma and innate immunity–aActive inflammation or just erroneous attraction?
Melanoma as the source of leukocyte-attracting chemokines. Navarini-Meury AA, Conrad C. Semin Cancer Biol. 2009 Apr;19(2):84-91. Epub 2008 Nov 7.

Unwanted growth breeds response–in the garden as well as in the tumor
microenvironment. Innate immune cells mediate the earliest responses against
melanoma or its precursors. However, the actual benefit by those cellular efforts
is questionable. Why can early melanoma lesions actually develop in the face of
rapid innate responses, and why is neutrophil- and macrophage-attracting
chemokine secretion observed in melanoma? A surprisingly similar choice of
chemokine receptors and chemokines are present in both innate immune cells and
melanoma. Here we focus on analogies and differences between the two. Melanoma
cell clusters show active chemokine signalling, with mostly tumor
growth-enhancing and leukocyte-attracting effects. However, infiltrating
leukocytes have only weak tumoricidal effects. Therefore, the observed leukocyte
infiltration in melanoma might be at least in part an epiphenomenon of neoplastic
self-stimulation rather than a full-fledged innate anti-tumor immune response.

Merkel cell carcinoma. Becker JC, Schrama D, Houben R. Cell Mol Life Sci. 2009 Jan;66(1):1-8.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of
the skin. More than one-third of MCC patients will die from this cancer, making
it twice as lethal as malignant melanoma. Despite the fact that MCC is still a
very rare tumor, its incidence is rapidly increasing; the American Cancer Society
estimates for 2008 almost 1,500 new cases in the USA. These clinical observations
are especially disturbing as the pathogenesis of MCC is not yet fully understood;
however, a number of recent reports contribute to a better understanding of its
pathogenesis. Here we describe findings regarding the role of Wnt, MAPK and Akt
signaling as well as possible aberrations in the p14ARF/p53/RB tumor suppressor
network in MCC. Most important, and possibly with high impact on future
therapeutic approaches is the demonstration that a polyomavirus has frequently
integrated in the genome of the MCC cells prior to tumor development.

Current progress of immunostains in Mohs micrographic surgery: a review. Thosani MK, Marghoob A, Chen CS. Dermatol Surg. 2008 Dec;34(12):1621-36. Epub 2008 Oct 13.

Mohs micrographic surgery is often considered the treatment of choice for a
variety of skin malignancies. In recent years, the application of immunostaining
techniques has facilitated the successful removal of a number of common and less
common cutaneous malignancies, including basal cell carcinoma, squamous cell
carcinoma, malignant melanoma, dermatofibrosarcoma protuberans, microcystic
adnexal carcinoma, sebaceous carcinoma, atypical fibroxanthoma, extramammary
Paget’s disease, and even sarcomas. Immunostains highlight the tumor cells and
allow the Mohs surgeons to pinpoint and eliminate the residual tumor at the
surgical margin. It is especially helpful when a tumor presents with subtle or
nonspecific histologic features or when a tumor is masked in a pocket of dense
inflammation. However, the cost, the labor, and the time consumption are of
concern to many of our peers, as are the diversity of antigens, which may
overwhelm some. This article serves as a review of the literature on current uses
of immunostaining in Mohs micrographic surgery and as a summary of their
realistic applications in the dermatologic surgeon’s practice. We conclude that
immunohistochemical technique has played an important role in Mohs surgery
advancement. With greater use and more cost-effective staining methods, we
believe that the use of immunostains in a Mohs practice will become routine.

Targeted therapies in gynecologic cancers and melanoma. Ortega E, Marti RM, Yeramian A, Sorolla A, Dolcet X, Llobet D, Abal L, Santacana M, Pallares J, Llombart-Cussac A, Matias-Guiu X. Semin Diagn Pathol. 2008 Nov;25(4):262-73.

The article reviews the main molecular pathology alterations of endometrial and
ovarian carcinomas and melanoma. Several promising drugs targeting the genes most
frequently altered in these tumors are under consideration. The most promising
signaling pathways to be targeted for therapies in these tumors are the tyrosine
kinase receptor (EGFR, HER2, c-KIT), the RAS/B-RAF/MAPK, the PI3K-mTOR, and
apoptosis signaling pathways.

Chemokines in neuroectodermal tumour progression and metastasis. Raffaghello L, Cocco C, Corrias MV, Airoldi I, Pistoia V. Semin Cancer Biol. 2009 Apr;19(2):97-102. Epub 2008 Nov 1.

Chemokines and their receptors have emerged as pivotal regulators of tumour
growth, progression, and metastasis. Here we review the current knowledge on
chemokines and receptors likely involved in the development of metastasis of
neuroectodermal tumours, with emphasis on neuroblastoma. In this respect, we
discuss the controversial role of the CXCR4/CXCL12 axis in bone marrow
localization of neuroblastoma cells. In addition, we focus on the ability of
neuroblastoma-derived chemokines such as CCL2 and CX3CL1 to attract lymphoid
cells to the tumour site. Finally, chemokine receptor and function in other
neuroectodermal tumours of adulthood (i.e. melanoma and small cell lung cancer)
are discussed.

Role of PET in the initial staging of cutaneous malignant melanoma: systematic
review. Krug B, Crott R, Lonneux M, Baurain JF, Pirson AS, Vander Borght T. Radiology. 2008 Dec;249(3):836-44.

PURPOSE: To calculate summary estimates of the diagnostic performance of fluorine
18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) imaging in the
initial staging of cutaneous malignant melanoma (CMM), following the new American
Joint Committee on Cancer (AJCC) staging classification on per-patient and
per-lesion bases. MATERIALS AND METHODS: MEDLINE, EMBASE, Web of Science, and
Cochrane Database of Systematic Reviews databases, and reference lists of reviews
and included papers were searched, without any language restrictions, for
relevant articles published before March 2007. Two reviewers independently
assessed study eligibility and methodologic quality by using the quality
assessment of diagnostic accuracy studies checklist. A pooled random effect was
estimated and a fixed coefficient regression model was used to explore the
existing heterogeneity. RESULTS: Twenty-eight studies involving 2905 patients met
the inclusion criteria. The pooled estimates of FDG PET for the detection of
metastasis in the initial staging of CMM were sensitivity, 83% (95% confidence
interval [CI]: 81%, 84%); specificity, 85% (95% CI: 83%, 87%); positive
likelihood ratio (LR), 4.56 (95% CI: 3.12, 6.64); negative LR, 0.27 (95% CI:
0.18, 0.40); and diagnostic odds ratio, 19.8 (95% CI: 10.8, 36.4). Results from
eight studies suggested that FDG PET was associated with 33% disease management
changes (range, 15%-64%). CONCLUSION: There is good preliminary evidence that FDG
PET is useful for the initial staging of patients with CMM, especially as
adjunctive role in AJCC stages III and IV, to help detect deep soft-tissue, lymph
node, and visceral metastases. FDG PET-computed tomographic imaging seemed to be
more precise than PET alone, as suggested by four eligible studies. Further
evaluation by using a well-designed prospective study, with clinical
outcome-focused measures and cost effectiveness analysis, is needed to clarify
the appropriate role of FDG PET in CMM staging. SUPPLEMENTAL MATERIAL:
http://radiology.rsnajnls.org/cgi/content/full/249/3/836/DC1. RSNA, 2008

[Malignant melanoma: conceptual and therapeutic innovations based on
translational research] [Article in French] Piérard GE, Quatresooz P, Rorive A, Piérard-Franchimont C; Groupe Mosan D’Etude des Tumeurs Pigmentaires. Rev Med Liege. 2008 Oct;63(10):579-84.

The scientific information about melanoma is on the rise. It has a direct impact
on the diagnostic acuteness and on the therapeutic management. The most recent
aspects of the utmost importance are presented. The concept of the duality
between fast-growing (high malignancy) and slow-growing (reduced malignancy)
melanoma is stressed. A new international multicentric approach using adjuvant
therapy for stage III melanomas involves the clinical oncology department of the
CHU of Liège. It concerns a targeted immunotherapy directed to the Mage A3
protein.

Vitamin D and skin cancer: a meta-analysis. Gandini S, Raimondi S, Gnagnarella P, Doré JF, Maisonneuve P, Testori A. Eur J Cancer. 2009 Mar;45(4):634-41. Epub 2008 Nov 12.

A comprehensive bibliographic search of the literature was conducted to identify
studies on Cutaneous Malignant Melanoma (CMM) and non-melanoma skin cancer
(NMSC), Vitamin D receptor (VDR) polymorphisms, Vitamin D intake and 25(OH)D
serum levels. Fully adjusted risk estimates were found and extracted for the two
polymorphisms FokI and BsmI and Vitamin D intake. Ten studies were included in
the meta-analysis, with a total of 6805 skin cancer cases. We found an
association with CMM for both polymorphisms. The summary relative risks (SRR) for
the studies on CMM were: 1.21 (1.03-1.42) and 1.21 (0.95-1.54) for the Ff and ff
versus wild-type of FokI, respectively. The SRR for ff versus wild-type became
significant with the inclusion of NMSC. The SRR for the studies on CMM were: 0.78
(0.65-0.92) and 0.75 (0.59-0.95) for the Bb and BB versus wild-type of BsmI,
respectively. There is also a slight indication of a role of dietary Vitamin D in
CMM development. In conclusion, this meta-analysis suggests a possible
significant role of VDR FokI and BsmI polymorphism in CMM and NMSC risk. The
association with Vitamin D intake is less clear and further studies could be
useful to clarify the role of diet.

Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab
(MDX-010). Weber J. Oncologist. 2008;13 Suppl 4:16-25.

Targeted biologic therapies such as anti-cytotoxic T lymphocyte antigen (CTLA-4)
monoclonal antibodies, either as monotherapy or in combination with chemotherapy
or vaccines, have shown great promise in late-stage melanoma, which has a very
poor prognosis. Melanoma is relatively resistant to both chemotherapy and
radiotherapy. Blockade of CTLA-4, which inhibits T-cell proliferation, promotes
stimulation of adaptive immunity and T-cell activation, resulting in eradication
of tumor cells. Two human monoclonal antibodies are under investigation in
melanoma. Phase II and III clinical trials are currently evaluating the efficacy
and safety of ipilimumab (MDX-010, Medarex, Inc., Princeton, NJ, and
Bristol-Myers Squibb, Princeton, NJ) and tremelimumab (CP-675,206; Pfizer
Pharmaceuticals, New York) in melanoma. Data are available on ipilimumab, which
has been explored as monotherapy and in combination with vaccines, other
immunotherapies such as interleukin-2, and chemotherapies such as dacarbazine.
Overall response rates range from 13% with ipilimumab plus vaccine in patients
with stage IV disease to 17% and 22% with ipilimumab plus dacarbazine or
interleukin-2, respectively, in patients with metastatic disease. Responses have
been durable, and among those experiencing grade 3 or 4 autoimmune toxicities,
even higher response rates have been seen–up to 36%. While the optimal dose of
ipilimumab has yet to be established, studies also indicate that higher doses may
be more effective. Importantly, the lack of an initial clinical response may not
predict ultimate treatment failure, because the onset of a response may follow
progressive disease or stable disease. Pending results from registration studies
with ipilimumab and lessons learned from registration studies conducted with
tremelimumab will help to define the role of anti-CTLA-4 blockade in the
treatment of metastatic melanoma.

Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab
(CP-675,206). Ribas A. Oncologist. 2008;13 Suppl 4:10-5.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade therapies have been
evaluated in clinical trials and have shown promise as possible options for
treating patients with cancer. One agent under investigation is tremelimumab
(CP-675,206), a monoclonal antibody that has been demonstrated to be a safe and
efficacious treatment in patients with malignant melanoma. Results of a phase I
clinical trial suggested that a dose of 15 mg/kg of tremelimumab would be the
maximum-tolerated dose, with the most common grade 3-4 toxicities being diarrhea
and rash. Pharmacokinetic studies showed that the postinfusion plasma
concentration and area under the plasma disposition curve both increased in an
approximately proportional manner with dose. Studies also showed that
tremelimumab has a low clearance (0.132 ml/h x kg), a small volume of
distribution (81.2 ml/kg), and a long terminal-phase half-life (22.1 days). A
pivotal phase II clinical trial assessing single-agent tremelimumab as
second-line therapy in metastatic melanoma has completed accrual, with response
rate as the primary endpoint. A pivotal phase III trial has also completed
accrual; that study compared the overall survival of previously untreated
patients receiving single-agent tremelimumab versus dacarbazine or temozolomide.

The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell
activation. Wolchok JD, Saenger Y. Oncologist. 2008;13 Suppl 4:2-9.

The survival rate of patients diagnosed with late-stage melanoma is poor–only
5%-10%. Enlisting the immune system in the fight against cancers such as melanoma
could help improve the prognosis of these patients. Data have shown that
melanocyte proteins make good targets for immune system-based therapy in this
disease. However, self-tolerance, which develops to inhibit autoimmune attack,
makes this strategy difficult. Two proteins on the surface of T cells–CD28 and
cytotoxic T-lymphocyte antigen 4 (CTLA-4)–play important roles in the regulation
of immune activation and tolerance. CD28 provides positive modulatory signals in
the early stages of an immune response, while CTLA-4 signaling inhibits T-cell
activation, particularly during strong T-cell responses. CTLA-4 blockade using
anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of
inhibitory signals results in the generation of an antitumor T-cell response.
Both clinical and preclinical data indicate that CTLA-4 blockade results in
direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal
antibody therapy has shown promise in a number of cancers, particularly melanoma.
Interestingly, the occurrence of adverse events among patients treated with
CTLA-4 blockade helps shed light on the mechanism of action of anti-CTLA-4
monoclonal antibodies. Most adverse events involve immune-related toxicity to the
skin and gastrointestinal tract. Major gastrointestinal toxicity develops in up
to 21% of treated patients, and while an objective response occurs in
approximately 36% of melanoma patients who develop enterocolitis with treatment,
an objective response is found in only 11% of patients who do not experience this
adverse reaction.

Merkel cell carcinoma: molecular pathogenesis, clinical features and therapy. [Article in English, German] Becker JC, Kauczok CS, Ugurel S, Eib S, Bröcker EB, Houben R. J Dtsch Dermatol Ges. 2008 Sep;6(9):709-19

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of
the skin. The incidence of this rare tumor is increasing rapidly; the American
Cancer Society estimates for 2008 almost 1500 new cases in the U.S. Thus, the
incidence of MCC will exceed the incidence of cutaneous T-cell lymphoma.
Moreover, the mortality rate of MCC with 33% is considerably higher than that of
cutaneous melanoma. These clinical observations are especially disturbing as we
are only recently beginning to understand the pathogenesis of MCC. For the same
reason, the therapeutic approach is often unclear; reliable data are only
available for the therapy of locoregional disease.

Recent aspects of medical care of malignant melanoma. [Article in English, German] Terheyden P, Tilgen W, Hauschild A.

Recent developments in the epidemiology, diagnosis and therapy of malignant
melanoma are reviewed, with particular attention paid to established standards of
care. When melanoma metastases are inoperable, they respond poorly to the various
chemotherapy strategies, so that additional improvements are critically needed.
Cytotoxic T-lymphocyte antigen-4 antibodies, multikinase inhibitors,
anti-apoptotic strategies and several other approaches are in progress in Phase
III trials both as monotherapy as well as in combination with standard
chemotherapy.

Oncophage: step to the future for vaccine therapy in melanoma. di Pietro A, Tosti G, Ferrucci PF, Testori A. Expert Opin Biol Ther. 2008 Dec;8(12):1973-84.

Heat-shock proteins (HSPs) are a group of proteins whose expression is increased
when the cells are exposed to elevated temperatures or other stressful
conditions. This increase in expression is transcriptionally regulated. The
function of HSPs is similar in virtually all living organisms, from bacteria to
humans. Their expression also occu