Epidemiology and Molecular Profile of Mucosal Melanoma: A Population-Based Study in Southern Europe.

BACKGROUND: Mucosal melanoma is a rare neoplasm on which few epidemiological population-based studies have been published. A good surgical approach is the standard treatment, but the prognosis is worse than that of skin melanoma. The analysis of mucosal melanoma's mutational profile can help to develop target therapies in advanced disease or adjuvant settings. METHODS: We analyzed the database of the Cancer Registry of Girona, a region located in the north-east of Spain, in the period of 1994-2018. We selected cases of primary invasive melanoma, excluding those located in the skin, eye, central nervous system and an unknown primary site. Epidemiological analysis included incidence and survival. Mutational profile analysis was performed with a custom gene panel. RESULTS: Forty-two patients were identified: 14 (33%) had vulvar-vaginal melanoma, 15 (35.7%) had rectal melanoma, 12 (28.6%) had melanoma located in the head and neck sphere and 1 male patient had a urethral melanoma. European age-standardized incidence rates for vulvar-vaginal, rectal and head and neck melanoma were 0.09, 0.1 and 0.09 cases/100,000 inhabitant-years, respectively. Five-year observed survival rates were 37.5%, 20% and 25% for these types of cancers. NRAS Q61 was the most frequent mutation found. CONCLUSION: Our study confirms the steady incidence and low survival of mucosal melanomas in a region of southern Europe. NRAS and NF1 play a role in the molecular landscape of mucosal melanoma. MEK and PI3K/mTOR inhibitors could be reasonable treatment options and are being studied in clinical trials.

Population-based analysis of the prevalence of BRAF mutation in patients diagnosed with cutaneous melanoma and its significance as a prognostic factor.

The prevalence of BRAF mutation has been reported in between 38% and 48% of melanoma patients, based on mainly Stage III or metastatic melanoma, however, information based on population-based studies is scarce. We performed a population-based retrospective cohort study to determine the prevalence of the BRAF mutation in patients diagnosed with in situ and infiltrating cutaneous malignant melanoma in the province of Girona between 2009 and 2011. Using the database of the Girona Cancer Registry, we performed BRAF mutation analysis based on paraffin-embedded tissue. This data was then correlated with other known clinical and histological prognostic factors for survival. We found 286 incident cases of cutaneous melanoma in the Girona Cancer Registry database. Excluding missing cases, BRAF-mutated patients constituted 38.9% of "in situ" melanoma cases and 53.8% of invasive melanoma cases. Five-year relative survival was not statistically different between BRAF-mutated patients (93.6%; 95% CI: 87.1-100.5) and non-mutated patients (84.3%, 95% CI: 75.3-94.8). Only stage was significant as a prognostic factor for survival based on multivariate analysis. From our population-based study, we conclude that BRAF mutation is not an independent prognostic factor for melanoma survival.

Acute tubulointerstitial nephritis induced by the tyrosine kinase inhibitor vandetanib.

Few cases of immunoallergic tubulointerstitial nephritis associated with tyrosine kinase inhibitors have been described. We describe the first report case associated with vandetanib, a tyrosine kinase inhibitor indicated for the treatment of aggressive and symptomatic medullary thyroid cancer (CMT) in patients with locally advanced or metastatic non-resectable disease.

Fatty acid synthase expression and its association with clinico-histopathological features in triple-negative breast cancer.

Triple-Negative Breast Cancer (TNBC) has poor prognosis and no approved targeted therapy. We previously showed that the enzyme fatty acid synthase (FASN) was largely expressed in a small TNBC patients' cohort and its inhibition synergized with cetuximab in TNBC preclinical mouse models. Here, we evaluated FASN and EGFR expression in a cohort of TNBC patients and we study their prognostic role and their association with clinico-histopathological features, intrinsic TNBC subtypes and survival. FASN, EGFR, CK5/6 and vimentin expression were retrospective evaluated by Immunohistochemistry in 100 primary TNBC tumors. FASN expression was classified into high and low FASN groups. EGFR, CK5/6 and vimentin expression were used in TNBC intrinsic subtypes classification. FASN was expressed in most of the TNBC patients but did not correlate with overall survival or disease-free survival in this cohort. High FASN group was significantly associated with positive node status. FASN expression was significantly higher in Basal-Like patients than in Mesenchymal-Like ones. EGFR expression was positive in 50% of the tumors, and those patients showed poorer DFS. Altogether, our findings provide a rationale for further investigation the prognostic role of FASN and EGFR expression in a larger cohort of TNBC patients.

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC. EXPERIMENTAL DESIGN: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models. RESULTS: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity. CONCLUSIONS: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC. Clin Cancer Res; 22(18); 4687-97. ©2016 AACR.

Population-based survival analyses of central nervous system tumors from 1994 to 2008. An up-dated study in the temozolomide-era.

The present population-based study describes the survival of malignant central nervous system (CNS) tumors diagnosed during 15 years. Also, we obtained individual data regarding the use of temozolomide to analyze the impact of this drug on the survival of patients diagnosed with glioblastoma. From 1994 to 2008, a total of 679 incident cases of primary CNS tumors were reported by the Girona Cancer Registry after excluding 39 cases diagnosed by death certificate only. Number of cases and the corresponding proportion for each CNS histological subtype in the study population were: 25 oligodendroglial and oligoastrocytics (3.7%), 22 ependymal tumors (3.2%), 24 embryonal (3.5%), 372 astrocytic (54.8%), 1 choroid plexus (0.1%) and 235 without histological confirmation (34.6%). Observed survival after 5 years since diagnosis for the histological subtype were: 58.8%; 47.5%; 37.0%; 14.5% and 6.5%, respectively (p<0.001). Survival of patients diagnosed with glioblastoma according to temozolomide treatment (yes/no) was 60.8% vs. 13.6% and 5.9% vs. 2.5% after 1 and 5 years since diagnosis, respectively. Short-term survival was higher for patients diagnosed with glioblastoma and treated with temozolomide than patients not treated with temozolomide.

Diagnóstico prenatal en la provincia de Girona en el período 1999-2009 / Prenatal diagnosis in the Girona area in the period 1999-2009

Objetivo. El objetivo de este trabajo es dar una visión global del uso y evolución del diagnóstico citogenético prenatal en la provincia de Girona en el período 1999-2009 y relacionar el diagnóstico citogenético con el cribado prenatal de aneuploidías. A partir de los datos recogidos se obtuvieron diversos indicadores presentados básicamente en forma de gráficos y tablas descriptivas. Resultados. Los resultados obtenidos indican lo siguiente: el uso del diagnóstico citogenético prenatal y posnatal aumentó a través del tiempo. El cribado prenatal de aneuploidías de procedencia pública en el período 1999-2009 mostró una tendencia creciente hasta el año 2005 y decreciente hasta el año 2009, cuando volvió a aumentar ligeramente. En pacientes del PASSIR Gironès-Pla de l’Estany la detección de la trisomía 21 fue del 88,9% en el cribado del primer trimestre y del 45% en el del segundo trimestre. La tasa media de detección de los cariotipos prenatales anómalos fue del 1,4% sin una tendencia temporal clara. Conclusiones. Las conclusiones principales son: - Se constata un aumento del uso del diagnóstico citogenético en el período 1999-2009. - La casuística de anomalías cromosómicas coincide con la bibliografía. - La sustitución del cribado del segundo trimestre por el del primer trimestre ha supuesto un incremento importante en la detección de aneuploidías. -La contribución de las pruebas de cribado prenatal es importante(AU)

Objective. The main goal of this research is to give a broad view of the use and evolution of prenatal cytogenetic diagnosis in Girona province between 1999 and 2009 and linking prenatal cytogenetic diagnosis with aneuploidy prenatal screening. The information collected allowed several indicators to be extracted, primarily presented as descriptive tables and charts. Results. The results show as follows: The use of prenatal and postnatal cytogenetic diagnosis increased in the mentioned period. The evolution of demand for aneuploidy prenatal screening in public health services during 1999-2009 showed an upward trend until 2005. From then on, it varied following a downward path until 2009, when it had a slight increase. Among PASSIR Gironès-Pla de l’Estany patients, detection of trisomy 21 through first-trimester screening was 88.9%, and through second-trimester screening was 45%. The average detection rate of abnormal prenatal karyotyping was 1.4%, with no clear trend in the above mentioned period. Conclusions. The main conclusions of this work are the following: - A rise in the use of cytogenetic diagnosis has been detected in Girona province between 1999 and 2009. - Case studies of chromosome abnormalities match the literature consulted. - Moving from second-trimester to first-trimester screening has meant a significant increase in aneuploidy detections. - Prenatal cytogenetic diagnosis is seen as an interdisciplinary field in which the extent of prenatal screening tests is crucial(AU)

Population-based incidence and survival of central nervous system (CNS) malignancies in Girona (Spain) 1994-2005.

The purpose of this study was to describe the incidence and survival of primary Central Nervous System (CNS) malignancies using data from the population-based cancer registry for Girona province (north-east Spain).We included all cases of primary CNS malignancies registered between 1994 and 2005. Pathological diagnoses were reviewed and grouped according to the 2007 WHO Classification. Meningeal, soft tissue tumours, spinal cord tumours and primary CNS lymphoma were not included. Cases notified only by death certificate were excluded from the survival analysis. Kaplan and Meier survival curves were calculated from date of diagnosis to death or end of study (31 December 2005), as was relative survival. A total of 493 new CNS cancer patients were registered during the study period: 49.3% astrocytic, 3.4% oligodendroglial and oligoastrocytic tumours, 2.6% ependimal tumours, 3.7% embryonal tumours, 0.2% choroid plexus and 41% without histological confirmation. The mean age (in years) for embryonal tumours was 18.17 years, these being the younger patients in the sample, and 66.34 years for those without histological confirmation, the older patients. Overall, the age standardised incidence rate was 5.88 cases/100,000 people/year (men = 6.81; women = 4.99) with an increasing trend by age until the 70-74 age group. Five-year observed survival rates were: 14.6% for astrocytic tumours, 35.7% for oligodendroglial and oligoastrocytic tumours, 41.0% for ependymal tumours, 32.4% for embryonal tumours and 7.5% for those without histological confirmation (log rank test: P < 0.001). Five-year observed survival rates for astrocytic tumours were analyzed separately by tumour grading, with 37% for diffuse astrocytoma, 7.1% for anaplastic astrocytoma and 4.7% for glioblastoma (log rank test: P < 0.001).Our results show that astrocytic tumours are most frequently diagnosed and glioblastoma patients have the worst survival figures for the area covered by our population cancer registry.The high observed incidence of histologically unverified tumours is most probably due to easy access to state of the art CNS imaging in our area.

Serine 2481-autophosphorylation of mammalian target of rapamycin (mTOR) couples with chromosome condensation and segregation during mitosis: confocal microscopy characterization and immunohistochemical validation of PP-mTOR(Ser2481) as a novel high-contrast mitosis marker in breast cancer core biopsies.

The prognostic abilities of breast cancer gene expression signatures are due mostly to the detection of proliferation activity. One of the strongest, yet simple and well-reproducible proliferation-associated prognostic factors is the mitotic activity index (MAI). However: a) counting mitotic figures is regarded by many histopathologists as cumbersome and time-consuming, and b) most available immunohistochemical markers are much weaker predictors than the MAI. We have investigated the spatio-temporal sub-cellular distribution of the Serine 2481-autophosphorylated form of mTOR (PP-mTOR(Ser2481)) during the G(1)/S-to-M-phase transition both in cultured cancer cells and in cancer tissue specimens. Using a high-resolution, automated confocal high-content imaging system, we observed that mitotic cells notably accumulated a distinct pattern of nuclear and cytoplasmic immunolabelings of PP-mTOR(Ser2481). Parallel experiments examining site-specific phosphorylation (i.e., Serine 10 and Serine 28) of the G(2)/M marker Histone H3 (PP-H3) revealed that PP-H3(Ser10/Ser28) staining efficiently detected mitotic cells from prophase until the beginning of anaphase, but not during late anaphase, telophase and cytokinesis. PP-mTOR(Ser2481) staining associated near and between separating chromosomes not only during early mitotic stages but also to the midzone and to midbody at ana/telophase through cytokinesis. We then evaluated the usefulness of PP-mTOR(Ser2481) immunostaining for improving the efficiency of mitotic counting using. Anti-PP-mTOR(Ser2481)-labeled mitotic figures (MFs) were easily seen and permitted a quick identification of mitotic hotspots in formalin-fixed cancer tissues, even at low magnification. Importantly, average mitotic counts were significantly higher when using PP-mTOR(Ser2481) staining than with the hematoxylin and eosin (H&E) protocol in breast cancer core biopsies. Mitotic count based on PP-mTOR(Ser2481) immunostaining increased tumor grade by one grade in 2 of 9 breast carcinomas. These findings warrant forthcoming studies to confirm both the accuracy and the prognostic value of PP-mTOR(Ser2481) as a novel high-contrast immunohistochemical mitosis marker in larger populations of human breast carcinomas.

[Merkel cell cancer of the skin: population-based incidence and survival, 1995-2005]. / Carcinoma de células de Merkel cutáneo: incidencia y supervivencia poblacional, 1995-2005.

BACKGROUND AND OBJECTIVE: We aimed to assess the population-based incidence and survival of primary Merkel cell carcinoma. MATERIAL AND METHOD: From January 1995 to December 2005, 19 patients diagnosed with primary Merkel cell carcinoma were recruited in the population-based Cancer Registry of Girona. RESULTS: The age-adjusted incidence was 1,3 per 10(6) person-year; higher in males (1,5) than in females (1,1). Cases occurred mostly in people older than 65 years (94,7%), especially involving the head (79%). CONCLUSIONS: To our knowledge, this study is the first to define the incidence and survival of Merkel cell carcinoma in Europe. The age-adjusted incidence of primary Merkel cell carcinoma in our area is similar than the age-adjusted incidence of the 2000 US standard population.

Carcinoma de células de Merkel cutáneo: incidencia y supervivencia poblacional, 1995–2005 / Merkel cell cancer of the skin: population-based incidence and survival, 1995–2005

Fundamento y objetivo: Conocer la incidencia y supervivencia poblacional del carcinoma de células de Merkel. Material y método: De enero de 1995 a diciembre de 2005 se registraron un total de 19 casos de carcinoma primario de células de Merkel en la población cubierta por el Registro de Cáncer Poblacional de Girona. Resultados: La incidencia ajustada por edad a la población estándar mundial fue de 1,3 casos por 106 personas-año, siendo superior en varones (1,5) que en mujeres (1,1), con predominio de los casos en mayores de 65 años (94,7%). La región anatómica de la cabeza fue la localización afectada con mayor frecuencia (79%). Conclusiones: Se trata del primer trabajo, en nuestro conocimiento, que estima la incidencia y la supervivencia poblacional del carcinoma de células de Merkel en Europa. La incidencia observada en nuestra área es similar a la incidencia observada en EE. UU (AU)

Background and objective: We aimed to assess the population-based incidence and survival of primary Merkel cell carcinoma. Material and method: From January 1995 to December 2005, 19 patients diagnosed with primary Merkel cell carcinoma were recruited in the population-based Cancer Registry of Girona. Results: The age-adjusted incidence was 1,3 per 106 person-year; higher in males (1,5) than in females (1,1). Cases occurred mostly in people older than 65 years (94,7%), especially involving the head (79%). Conclusions: To our knowledge, this study is the first to define the incidence and survival of Merkel cell carcinoma in Europe. The age-adjusted incidence of primary Merkel cell carcinoma in our area is similar than the age-adjusted incidence of the 2000 US standard population (AU)