Risk of prostate, breast and colorectal cancer after skin cancer diagnosis.

Ultraviolet radiation is the major cause of skin cancer, but promotes vitamin D synthesis, and vitamin D has been inversely related to the risk of several common cancers including prostate, breast and colorectum. We therefore computed the incidence of prostate, breast and colorectal cancer following skin cancer using the datasets of the Swiss cancer Registries of Vaud and Neuchâtel. Between 1974 and 2005, 6,985 histologically confirmed squamous cell skin cancers, 21,046 basal cell carcinomas and 3,346 cutaneous malignant melanomas were registered, and followed up to the end of 2005 for the occurrence of second primary cancer of the prostate, breast and colorectum. Overall, 680 prostate cancers were observed versus 568.3 expected (standardized incidence ratio (SIR) = 1.20; 95% confidence interval (CI): 1.11-1.29), 440 breast cancers were observed versus 371.5 expected (SIR = 1.18; 95% CI: 1.08-1.30) and 535 colorectal cancers were observed versus 464.6 expected (SIR = 1.15; 95% CI: 1.06-1.25). When basal cell, squamous cell and skin melanoma were considered separately, all the SIRs for prostate, breast and colorectal cancers were around or slightly above unity. Likewise, the results were consistent across strata of age at skin cancer diagnosis and location (head and neck versus others), and for male and female colorectal cancers. These findings, based on a population with a long tradition of systematic histologic examination of all surgically treated skin lesions, do not support the hypothesis that prostate, breast and colorectal cancer risk is decreased following skin cancer.

Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

BACKGROUND: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. METHODS: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data. RESULTS: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. CONCLUSIONS: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Une nouvelle Classification des néoptasies intraépithélates vulvaires [A new classification of vulvar intraepithelial neoplasia (VIN)]

Vulvar cancer is a rare disease and its screening is depending on the quality and the relevance of our clinical examination. Incidence of vulvar cancer and especially precancerous lesions, vulvar intraepithelial neoplasias (VIN), increased during these last years. The new terminology of vulvar intraepithelial neoplasia will help us to identify high risk groups which could develop a cancer: usual and differentiated VIN. An early diagnosis is essential to propose an adequate treatment. Management is a major point according to the rising incidence of these lesions in younger women. Until we can observe a benefit from the vaccination against human papillomavirus, we must increase the quality of screening by a careful examination of the vulva.

Cáncer de laringe en pacientes menores de 40 años comparado con mayores de 40 años: análisis de pares [Laryngeal cancer in patients younger vs older than 40 years old: a matched-paired analysis].

BACKGROUND: To compare clinical and demographic data between laryngeal cancer patients younger and older than 40 years old. METHODS: Is a matched-paired study, realized from 1989 to 2002. We selected 500 laryngeal cancer patients treated in the National Cancer Institute of Mexico. Fifteen cases of patients younger than 40 years that accomplished inclusion criteria were identified, pair-matched and compared by clinical stage with 33 patients older than 40 years. We analyzed demographic factors and disease-free and Overall Survival by Kaplan-Meier method. RESULTS: We included 9 male and 6 female patients with a mean age of 34 years in contrast to a mean age of 62 years in the comparison group. Four cases in clinical stage I, none clinical stage II, 6 in stage III and 5 in stage IV were included in the younger group and compared to 8 patients in stage I, 15 in stage III and 10 in stage IV in the older group. No differences in demographic variables or lifestyle habits were found. All patients in stage I, are alive in both groups. Disease-free survival not show any differences when comparing stages III and IV (p=NS). Mean disease-free survival was 66 months and mean overall survival was 83 months in the younger group. CONCLUSION: Laryngeal carcinoma is rare in patients younger than 40 years. No gender, clinical or prognostic differences could be identified among the two groups. The prognosis of these patients seems to be only determined by the initial clinical stage.

Opposing roles for calcineurin and ATF3 in squamous skin cancer.

Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.

PPARalpha governs glycerol metabolism.

Glycerol, a product of adipose tissue lipolysis, is an important substrate for hepatic glucose synthesis. However, little is known about the regulation of hepatic glycerol metabolism. Here we show that several genes involved in the hepatic metabolism of glycerol, i.e., cytosolic and mitochondrial glycerol 3-phosphate dehydrogenase (GPDH), glycerol kinase, and glycerol transporters aquaporin 3 and 9, are upregulated by fasting in wild-type mice but not in mice lacking PPARalpha. Furthermore, expression of these genes was induced by the PPARalpha agonist Wy14643 in wild-type but not PPARalpha-null mice. In adipocytes, which express high levels of PPARgamma, expression of cytosolic GPDH was enhanced by PPARgamma and beta/delta agonists, while expression was decreased in PPARgamma(+/-) and PPARbeta/delta(-/-) mice. Transactivation, gel shift, and chromatin immunoprecipitation experiments demonstrated that cytosolic GPDH is a direct PPAR target gene. In line with a stimulating role of PPARalpha in hepatic glycerol utilization, administration of synthetic PPARalpha agonists in mice and humans decreased plasma glycerol. Finally, hepatic glucose production was decreased in PPARalpha-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPARalpha on gluconeogenic gene expression was translated at the functional level. Overall, these data indicate that PPARalpha directly governs glycerol metabolism in liver, whereas PPARgamma regulates glycerol metabolism in adipose tissue.

Comparison of aminolevulinic acid and hexylester aminolevulinate induced protoporphyrin IX distribution in human bladder cancer.

PURPOSE: Successful photodynamic therapy of epithelial cancer requires a specific photosensitization of malignant tissue. We evaluate the intensity and localization of protoporphyrin IX (PpIX) in superficial transitional cell carcinoma and nonmalignant cells of the human bladder following topical administration of its precursor, either aminolevulinic acid (ALA) or hexylester aminolevulinate (HAL). MATERIALS AND METHODS: Solutions of ALA or HAL were instilled into the bladder of 18 patients presenting with recurrent transitional cell carcinoma. The distribution of PpIX through the bladder wall was studied on frozen biopsies using fluorescence microscopy and correlated with pathological findings. RESULTS: Topical bladder instillation with 180 mmol (3%) ALA administered for 6 hours or 8 mmol (0.2%) HAL administered for 4 hours gave similar results regarding intensity and tissue distribution of PpIX fluorescence, whereas 8 mmol HAL administered for 2 hours followed by 2 hours of resting time (2+2 hours concept) induced a PpIX fluorescence twice as high. The fluorescence remained limited to cancer cells. Only a trace of PpIX fluorescence was observed in suburothelial connective tissue, that is chorion, but none in the bladder smooth muscle regardless of experiment conditions. CONCLUSIONS: HAL is an excellent precursor for PpIX synthesis in bladder cancer. With the 2+2 hour topical administration condition it yielded the highest PpIX fluorescence intensity and fluorescence contrast between normal and malignant urothelial cells. This approach allows us to optimize PpIX tissue distribution for photodynamic therapy in superficial bladder cancer.

Clinical assessment of fluorescence cytoscopy during transurethral bladder resection in superficial bladder cancer.

The prognosis of superficial bladder cancer in terms of recurrence and disease progression is related to bladder tumor multiplicity and the presence of concomitant "plane" tumors such as high-grade dysplasia and carcinoma in situ. This study in 33 patients aimed to demonstrate the role of fluorescence cystoscopy in transurethral resection of superficial bladder cancer. The method is based on the detection of protoporphyrin-IX-induced fluorescence in urothelial cancer cells by topical administration of 5-aminolevulinic acid. The sensitivity and the specificity of this procedure on apparently normal mucosa in superficial bladder cancer are estimated to be 82.9% and 81.3%, respectively. Thus, fluorescence cytoscopy is a simple and reliable method for mapping the bladder mucosa, especially in the case of multifocal bladder disease, and it facilitates the screening of occult dysplasia.

A novel mucosal orthotopic murine model of human papillomavirus-associated genital cancers.

Cervical cancer results from infection with high-risk type human papillomaviruses (HPV). Therapeutic vaccines aiming at controlling existing genital HPV infections and associated lesions are usually tested in mice with HPV-expressing tumor cells subcutaneously implanted into their flank. However, effective vaccine-induced regression of these ectopic tumors strongly contrasts with the poor clinical results of these vaccines produced in patients with HPV-associated genital neoplasia. To assess HPV therapeutic vaccines in a more relevant setting, we have, here, established an orthotopic mouse model where tumors in the genital mucosa (GM) develop after an intravaginal instillation of HPV16 E6/E7-expressing tumor cells transduced with a luciferase-encoding lentiviral vector for in vivo imaging of tumor growth. Tumor take was 80-90% after nonoxynol-9 induced damage of the epithelium. Tumors remained localized in the genital tract, and histological analysis showed that most tumors grew within the squamous epithelium of the vaginal wall. Those tumors induced (i) E7-specific CD8 T cells restricted to the GM and draining lymph nodes, in agreement with their mucosal location and (ii) high Foxp3+ CD4+ infiltrates, similarly to those found in natural non-regressing HPV lesions. This novel genital HPV-tumor model by requiring GM homing of vaccine-induced immune responses able to overcome local immuno-suppression may be more representative of the situation occurring in patients upon therapeutic vaccination.

High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.

OBJECTIVE: Examination of the rate of grade III or grade IV radiation dermatitis during treatment of head and neck cancer (HNC) with radiotherapy (RT) and concurrent cetuximab in EORTC centres. MATERIALS AND METHOD: A questionnaire was sent to all members of the EORTC Radiation Oncology Group and Head and Neck Group (111 institutions) to evaluate the widespread use of cetuximab and radiotherapy in HNC and to estimate the frequency of grades III and IV skin reactions in the radiation portals associated with this protocol. Co-morbidities, RT schedules and co-medications were also recorded. RESULTS: We received responses from 28 institutions in 11 countries. A total of 125 HNC patients from 15 institutions were treated with cetuximab and concurrent RT. Information about the skin reactions was available from 71 patients. Of these 36 had no grade III/IV adverse effects in the RT field, 15 had a grade III and 20 had grade IV radiation dermatitis. No detectable relation of grades III and IV radiation dermatitis with co-morbidities such as liver insufficiency or renal dysfunction was found. CONCLUSION: According to the results of the questionnaire, grade III/IV radiation dermatitis is observed in 49% of HNC patients treated with cetuximab and concurrent RT. A systematic clinical monitoring of cutaneous side effects during RT plus cetuximab is advised to ensure the safety of this protocol.

Medulloblastomas in adults: prognostic factors and lessons from paediatrics.

Purpose of reviewMedulloblastomas are very rare in adults. Usual treatment consists of craniospinal radiation with or without chemotherapy. Current efforts focus on a better understanding of tumour biology, stratifying patients into risk groups and adapting treatment accordingly. This review discusses clinical and new molecular risk factors that will help to optimize treatment in adult medulloblastoma patients.Recent findingsThe clinical risk stratification should be complemented with new molecular prognostic markers. Gene-expression profiling has permitted identification of four to six molecular medulloblastoma subgroups. The WNT subgroup shows overexpression of genes of the WNT/wingless signalling pathway with frequent mutations of the CNNTB1 gene, loss of chromosome 6 and accumulation of nuclear beta-catenin, and is most often seen in children with medulloblastomas of classical histology. This variant has a good prognosis. Activation of the sonic hedgehog pathway with frequent mutations of the PTCH and SUFU genes, loss of 9q, and positivity for GLI1 and SFRP1 is more frequent in children less than 3 years old and in adults, commonly associated with desmoplastic histology. Other subgroups are not so well defined and have overlapping characteristics, but MYC/MYCN amplification, 17q gain and, large cell/anaplastic histology are factors of poor prognosis.SummaryNew molecular subgroups will help tailor treatment and further develop new targeted therapies. Prospective and ideally randomized trials should be performed in adults, including risk stratification by molecular markers, to identify optimal treatment for each risk group.

Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.

It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-Jκ, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through upregulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix-remodeling enzymes. In human skin samples, stromal fields adjacent to multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer.

Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature.

Eyelid tumors are the most common neoplasm in daily ophthalmology practice and encompass a wide variety of benign and malignant tumors. In this retrospective study, we report the clinical and histological features of 5504 eyelid skin tumors diagnosed at the Laboratory of Ophthalmopathology of the Hôpital Ophtalmique Jules Gonin, Lausanne, Switzerland, between January 1989 and December 2007. Benign tumors largely predominated over malignant ones, representing 84% of cases in this series, and the 5 most frequent subtypes were squamous cell papilloma (26%), seborrheic keratosis (21%), melanocytic nevus (20%), hidrocystoma (8%), and xanthoma/xanthelasma (6%). Basal cell carcinoma was the most frequent malignant tumor (86%), followed by squamous cell carcinoma (7%) and sebaceous carcinoma (3%). For several tumor subtypes, there was a poor correlation between clinical and histological diagnosis, stressing the numerous pitfalls in the diagnosis of eyelid tumors. We further discuss our results with reference to previously published series.