Skin Cancer Risk of Narrow-Band UV-B (TL-01) Phototherapy: A Multi-Center Registry Study with 4,815 Patients.

Narrow-band TL-01 ultraviolet B phototherapy (TL-01) is an effective and widely used treatment for many skin diseases. The purpose of the investigation was to assess the risk of skin cancers in patients treated with TL-01 phototherapy who have not received any other phototherapy modalities. This cohort study included 4,815 TL-01 treated patients in Finland with psoriasis or atopic dermatitis. Clinical information was collected from the hospital records and linked with Finnish Cancer Registry data. The follow-up started from the first TL-01 treatment and the mean follow-up time was 8.4 years. Standardized incidence ratios were calculated for basal cell carcinoma, cutaneous melanoma, and squamous cell carcinoma. The standardized incidence ratio for basal cell carcinoma was 2.5 (95% confidence interval 1.8-3.5), for cutaneous melanoma 4.0 (95% confidence interval 2.1-6.8) and for squamous cell carcinoma 3.7 (95% confidence interval 1.7-7.0). For basal cell carcinoma and squamous cell carcinoma, the standardized incidence ratios remained similar during the whole follow-up time while the standardized incidence ratio for cutaneous melanoma was markedly higher during the first 5 years of follow-up. In conclusion, an increased incidence of skin cancers was observed among TL-01 treated patients. It should be confirmed in the future whether the skin cancer risk of TL-01 phototherapy will remain high in a longer follow-up.

Incidence and profile of skin cancers in patients following ultraviolet phototherapy without psoralens: A retrospective cohort study.

BACKGROUND: Psoralen + ultraviolet-A (PUVA) is associated with photocarcinogenesis. However, carcinogenic risk with other ultraviolet phototherapies remains unclear. OBJECTIVE: Evaluate whether phototherapy without psoralens increases skin cancer risk. METHODS: Retrospective cohort study of patients treated at a teaching-hospital phototherapy center (1977-2018). Skin cancer records were validated against pathology reports. Age-standardized incidence rates (ASIRs) of skin cancer were evaluated for gender, skin phototype, diagnosis, ultraviolet modality, anatomical site; and compared to provincial population incidence rates (2003). RESULTS: In total, 3506 patients treated with broadband-ultraviolet-B, narrowband-UVB and/or combined UVAB were assessed with a mean follow-up of 7.3 years. Majority of patients had psoriasis (60.9%) or eczema (26.4%). Median number of treatments was 43 (1-3598). Overall, 170 skin cancers (17 melanoma, 33 squamous cell carcinoma and 120 basal cell carcinoma) occurred in 79 patients. Patient-based and tumor-based ASIR of skin cancer was 149 (95% CI: 112-187)/100,000 and 264 (219-309)/100,000 person-years, respectively. There was no significant difference between tumor-based ASIRs for melanoma, squamous cell carcinoma, and basal cell carcinoma compared to the general population; or in phototherapy patients with-psoriasis or eczema; or immunosuppressants. No cumulative dose-response correlation between UVB and skin cancer was seen. LIMITATIONS: Treatment and follow-up duration. CONCLUSION: No increased risk of melanoma and keratinocyte cancer was found with phototherapy.

Melanoma and CLL co-occurrence and survival: role of KC history.

BACKGROUND: Survival following melanoma and chronic lymphocytic leukemia (CLL) have both been individually associated with previous history of non-melanoma skin cancers (specifically keratinocyte carcinomas [KC]). Furthermore, melanoma and CLL have been reported to occur within the same patients. The survival experience of patients with both cancers is understudied, and the role of history of KC is unknown. Additional research is needed to tease apart the independent associations between KC and CLL survival, KC and melanoma survival, and the co-occurrence of all three cancers. METHODS: A retrospective cohort study was conducted among patients who were diagnosed with melanoma and/or CLL at a comprehensive cancer center between 2008 and 2020. Multivariable Cox regression models were used to examine the association between history of KC and survival following melanoma and/or CLL with careful consideration of calendar year of diagnosis, treatment regimens and other risk factors. A nested case-control study comparing patients with both CLL and melanoma to those with only CLL or only melanoma was conducted to compare blood parameters across the three groups. RESULTS: A time-dependent association was observed between history of KC and favorable melanoma survival within 4 years following diagnosis and poorer survival post 7 years after melanoma diagnosis. History of KC was not significantly associated with survival following the diagnosis of CLL, after adjustment for clinical factors including historical/concurrent melanoma. Patients with co-occurring melanoma and CLL tended to be diagnosed with melanoma first and had elevated blood parameters including white blood cell and lymphocyte counts as compared with patients who were diagnosed with only melanoma. CONCLUSIONS: History of KC was an independent predictor of survival following melanoma but not of CLL. Additional studies are needed to determine if blood parameters obtained at the time of melanoma diagnosis could be used as a cost-effective way to identify those at high risk of asymptomatic CLL for the promotion of earlier CLL diagnosis.

Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma.

Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients' quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.

Regular use of vitamin D supplement is associated with fewer melanoma cases compared to non-use: a cross-sectional study in 498 adult subjects at risk of skin cancers.

There are conflicting results on the role of vitamin D system in cutaneous carcinogenesis. Therefore, it was investigated whether the use of oral vitamin D supplements associates with photoaging, actinic keratoses, pigment cell nevi, and skin cancers. In this cross-sectional study, 498 adults (aged 21-79 years, 253 males, 245 females, 96 with immunosuppression) subjects at risk of any type of skin cancer were examined, and possible confounding factors were evaluated. The subjects were divided into three groups based on their self-reported use of oral vitamin D supplements: non-use, occasional use, or regular use. The serum level of 25-hydroxyvitamin-D3 was analyzed in 260 subjects. In 402 immunocompetent subjects, vitamin D use did not associate with photoaging, actinic keratoses, nevi, basal, and squamous cell carcinoma. In contrast, there were lower percentages of subjects with a history of past or present melanoma (32/177, 18.1% versus 32/99, 32.3%, P = 0.021) or any type of skin cancer (110/177, 62.1% versus 74/99, 74.7%, P = 0.027) among regular users compared to non-users. In the logistic regression analysis, the odds ratio for melanoma was 0.447 ( P = 0.016, 95% confidence interval, 0.231-0.862) among regular users. Furthermore, the investigator-estimated risk class of skin cancers was significantly lower among regular users. Serum 25-hydroxyvitamin-D3 did not show marked associations with skin-related parameters. The results on 96 immunosuppressed subjects were somewhat similar, although the number of subjects was low. In conclusion, regular use of vitamin D associates with fewer melanoma cases, when compared to non-use, but the causality between them is obscure.

Eficacia y seguridad de vemurafenib más cobimetinib para el tratamiento de pacientes adultos con melanoma maligno avanzado o metastásico, con mutacion BRAF V600E, inoperable y con ECOG 0-1 / Efficacy and safety of vemurafenib plus cobimetinib for the treatment of adult patients with advanced or metastatic malignant melanoma, with BRAF V600E mutation, inoperable and with ECOG 0-1

INTRODUCCIÓN: El melanoma maligno (MM), es un tipo de cáncer de piel agresivo que afecta a los melanocitos. El MM representa solo el 4 % de los tumores malignos de la piel, pero es el responsable del 80 % de las muertes por estos tumores. Actualmente, la quimioterapia se usa con menos frecuencia que la inmunoterapia o la terapia dirigida. La inmunoterapia inhibe la proteína PD-1; y la terapia dirigida inhibe la proteína mutada BRAF y las proteínas quinasas MEK. A diferencia de la inmunoterapia (que puede usarse para todos los pacientes con MM metastásico), la terapia dirigida está indicada solo para aquellos pacientes con la mutación BRAF V600. La mutación BRAF está presente en el 50 % de los casos de MM y el 70 % de las mutaciones BRAF son de tipo V600E. En EsSalud, los pacientes adultos con MM avanzado o metastásico, con mutación BRAF V600E, inoperable y con ECOG 0-1 disponen de la inmunoterapia (nivolumab) y la quimioterapia como tratamientos de primera línea. No obstante, los especialistas en oncología señalan que la terapia dirigida podría ser más eficaz, en aquellos con la mutación BRAF V600E, que las opciones disponibles en EsSalud. De esta forma, sugieren el uso de vemurafenib más cobimetinib (V+C) como tratamiento de primera línea para estos pacientes. OBJETIVO: El objetivo del presente dictamen fue evaluar la eficacia y seguridad de V+C, comparado con nivolumab o quimioterapia, para el tratamiento de pacientes adultos con MM avanzado o metastásico, con mutación BRAF V600E, inoperable y con ECOG 0-1. METODOLOGÍA: Tras la búsqueda de la evidencia, se incluyeron cinco guías de práctica clínica (GPC) elaboradas por la National Comprehensive Cancer Network (NCCN), la American Society of Clinical Oncology (ASCO), el Cancer Council Australia (CCA), la European Society for Medical Oncology (ESMO) y la Scottish Intercollegiate Guidelines Network (SIGN); tres evaluaciones de tecnologías sanitarias (ETS) realizadas por el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH) y el Institute for Quality and Efficiency in Healthcare (IQWiG); y dos revisiones sistemáticas con metaanálisis en red (RSMAR) desarrolladas por Zoratti et al. 2019 y Pike et al. 2017. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica con respecto al uso de V+C como tratamiento de primera línea en pacientes adultos con MM avanzado o metastásico, con mutación BRAF V600E, inoperable y con ECOG 0-1. CONCLUSIONES: El presente dictamen preliminar tuvo por objetivo evaluar la mejor evidencia disponible sobre la eficacia y seguridad de V+C, comparado con nivolumab o quimioterapia, para el tratamiento de pacientes adultos con MM avanzado o metastásico, con mutación BRAF, inoperable y con ECOG 0-1. Los desenlaces de interés fueron SG, calidad de vida y eventos adversos. Tras la búsqueda de la literatura se identificaron cinco GPC elaboradas por NCCN, CCA, ASCO, ESMO y SIGN; tres ETS desarrolladas por NICE, CADTH e IQWiG. No se identificaron ECA o estudios observacionales comparativos que respondieran a la pregunta PICO. Por tal motivo, se optó por incluir dos estudios que evaluaron de manera indirecta (metaanálisis en red) V+C vs. nivolumab o quimioterapia (la RSMAR de Zoratti et al. 2019 y la RSMAR de Pike et al. 2017). Cuatro GPC (NCCN, ASCO, ESMO, CCA) de las cinco evaluadas recomiendan nivolumab o V+C; la guía restante (SIGN), solo nivolumab; y ninguna guia mencionó a la quimioterapia como tratamiento de primera línea. La ESMO recomienda a los inhibidores de PD-1(nivolumab) como el tratamiento estándar de primera línea para los pacientes con MM metastásico, además, la CCA y la ESMO señalaron que es preferible iniciar con anti PD-1 (nivolumab); sobre todo en pacientes con buen estado de salud y cuya enfermedad no progrese rápidamente. Las ETS fueron disimiles en sus recomendaciones. La CADTH condicionó su recomendación a la reducción en el precio del medicamento; IQWiG concluyó que existe beneficio adicional a favor de V+C; pero que la información sobre eventos adversos (EA) presenta limitaciones importantes. Por su parte NICE no recomendó el uso de V+C por no ser costo-efectivo. Es de destacar que las tres ETS no incluyen entre sus comparadores a nivolumab o quimioterapia, medicamentos que son alternativas disponibles y con las que se tienen experiencia de uso en EsSalud. Las RSMAR sugieren que V+C es similar a nivolumab en términos de SG y EA. Aunque sugieren diferencias a favor de V+C, en comparación con quimioterapia, las estimaciones indirectas no cumplieron con el criterio de transitividad y presentaron limitaciones que afectan su validez. Además, reportes más recientes muestran una alta incidencia de EA serios para V+C diferentes a los reportados por las RSMAR. Dado que la evidencia disponible no ha mostrado que la relación riesgo-beneficio sea favorable a V+C, en comparación con nivolumab o quimioterapia, la aprobación de uso de V+C en EsSalud no sería una decisión costo-oportuna; tomando en cuenta la disponibilidad del tratamiento con nivolumab, el cual fue aprobado al ser comparado con quimioterapia, eficaz y seguro, recomendado por guías internacionales, con el cual se tiene experiencia de uso y es menos costoso. Por lo expuesto, el IETSI no aprueba el uso de vemurafenib más cobimetinib para el tratamiento de pacientes adultos con melanoma maligno avanzado o metastásico, con mutación BRAF, inoperable y con ECOG 0-1.

Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.

Importance: In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. Objective: To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. Design, Setting, and Participants: In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Main Outcomes and Measures: Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Results: Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. Conclusions and Relevance: In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

Plaque brachytherapy for choroidal melanoma with vitreous haemorrhage: a therapeutic challenge.

A 47-year-old man presented with profound loss of vision in right eye and relative afferent pupillary defect. On fundus examination, posterior pole details were obscured due to dense vitreous haemorrhage. B-scan ultrasonography was performed that revealed a mushroom-shaped hyperechoic lesion with medium internal reflectivity on A-scan ultrasonography. After performing contrast-enhanced MRI of the orbit, a diagnosis of choroidal melanoma was established. Patient was managed using plaque brachytherapy based on multiplanar MRI. This was followed 10 months later by pars plana vitrectomy and cataract extraction. Vision postoperatively improved to 20/60. A systematic clinical assessment along with supportive ancillary investigations augments diagnostic accuracy and reduces delay in definitive management.

Mycosis fungoides development after combined immune checkpoint blockade therapy in a patient with malignant melanoma: a case report.

Immune checkpoint blockade therapy can induce immune-related toxicity, but cutaneous lymphoma development has not been reported. A 56-year-old woman presented with two well-demarcated erythematous macules on the right sole and vitiligo on her extremities. Her facial melanoma had been treated with combination therapy (ipilimumab and pembrolizumab), followed by pembrolizumab monotherapy, a year prior. Microscopy revealed small-to-medium-sized lymphocytes permeating along with the basal epidermal layer. These were immuno-positive for CD2, CD3, and CD5, and showed complete CD7 loss; CD30, TCR-beta F1, and PD-1 were also detected. They exclusively expressed CD8, not CD4, and had a Ki-67 labeling index of 30-40%. Epstein-Barr virus in-situ hybridization was negative. Clonal T-cell receptor beta and gamma chain gene rearrangements were detected. Hence, the lesions were diagnosed as mycosis fungoides. This is the first report of mycosis fungoides development after anti-melanoma immunotherapy. The patient is currently on steroid ointments and phototherapy.

Combination therapy with ropivacaine-loaded liposomes and nutrient deprivation for simultaneous cancer therapy and cancer pain relief.

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. Method: Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. Results: Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. Conclusion: Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

Feasibility of an online mindfulness-based program for patients with melanoma: study protocol for a randomised controlled trial.

BACKGROUND: People with a melanoma diagnosis are at risk of recurrence, developing a new primary or experiencing disease progression. Previous studies have suggested that fear of a cancer recurrence is clinically relevant in this group of patients and, if not addressed, can lead to distress. Mindfulness-based interventions have been shown to alleviate symptoms of anxiety and depression among various groups of cancer patients. Online mindfulness-based interventions have the potential to reach people unable to attend face-to-face interventions due to limitations such as cancer-related illness, transportation or time constraints. This study aims to (1) examine whether individuals with a melanoma diagnosis are willing to participate and adhere to a 6-week online mindfulness-based intervention and (2) explore potential benefits of the program on fear of cancer recurrence, worries, rumination, perceived stress and trait mindfulness to inform the design of a clinical trial. METHODS/DESIGN: This is a single-site randomised controlled trial of a feasibility study. Seventy-five participants with stage 2c or 3 melanoma will be recruited from a melanoma outpatient clinic and randomised (2:1) either to an online mindfulness-based program (intervention) or to usual care (control). The intervention is a 6-week program specifically developed for this study. It consists of videos describing the concept of mindfulness, short daily guided meditation practices (5-10 min), automated meditation reminders and instructions for applying mindfulness in daily life to enhance wellbeing. All participants will complete questionnaires at baseline and at 6-week post-randomisation. Participants in the control group will be given access to the online program at the end of the study. Primary outcomes are overall recruitment; retention; extent of questionnaire completion; and usability and acceptability of, and adherence to, the program. The secondary outcomes are fear of cancer recurrence, worries, rumination, perceived stress and trait mindfulness measured using validated instruments. DISCUSSION: This feasibility study will evaluate participants' satisfaction with the program and identify barriers to recruitment and adherence. The recruitment and data collection process will highlight methodological aspects to address in the planning of a larger scale study assessing the impact of an online mindfulness-based intervention on fear of cancer recurrence and wellbeing. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617000081314 . Registered on 16 January 2017.

Clinical impact of ulceration width, lymphovascular invasion, microscopic satellitosis, perineural invasion, and mitotic rate in patients undergoing sentinel lymph node biopsy for cutaneous melanoma: a retrospective observational study at a comprehensive cancer center.

The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting. To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single-institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008. We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow-up of 6.7 years. By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI. The pathologic measures with the strongest influence on recurrence-free survival (RFS) were tumor thickness and positive SLN status. Ulceration width and presence of MS were also significantly associated with RFS while PNI was not. Factors with the strongest influence on melanoma-specific survival (MSS) were positive SLN status and mitotic rate. In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

Akt1/NFκB signaling pathway activation by a small molecule DMA confers radioprotection to intestinal epithelium in xenograft model.

Normal tissue protection and recovery of radiation-induced damage are of paramount importance for development of radioprotector. Radioprotector which selectively protects normal tissues over cancerous tissues improves the therapeutic window of radiation therapy. In the present study, small bisbenzimidazole molecule, DMA (5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxy-phenyl)-5'-benzimidazolyl]-benzimidazole) was evaluated for in vivo radioprotective effects to selectively protect normal tissue over tumor with underlying molecular mechanism. Administration of single DMA dose prior to radiation has enhanced survival of Balb/c mice against sublethal and supralethal total body irradiation. DMA ameliorated radiation-induced damage of normal tissues such as hematopoietic (HP) and gastrointestinal tract (GI) system. Oxidative stress marker Malondialdehyde level was decreased by DMA whereas it maintained endogenous antioxidant status by increasing the level of reduced glutathione, glutathione reductase, glutathione-s-transferase, superoxide dismutase and total thiol content in hepatic tissue of irradiated mice. Mechanistic studies revealed that DMA treatment prior to radiation leads to Akt1/NFκB signaling which reduced radiation-induced genomic instability in normal cells. However, these pathways were not activated in tumor tissues when subjected to DMA treatment in similar conditions. Abrogation of Akt1 and NFκB genes resulted in no radioprotection by DMA and enhanced apoptosis against radiation. Plasma half-life of DMA was 3.5h and 2.65h at oral and intravenous dose respectively and 90% clearance was observed in 16h. In conclusion, these data suggests that DMA has potential to be developed as a safe radioprotective agent for radiation countermeasures and an adjuvant in cancer therapy.

Successful Restoration of Fecal Continence Using Sacral Nerve Stimulation Following Chemoradiation and Transanal Excision of an Anal Melanoma With Partial Internal Anal Sphincter Resection: A Case Report.

OBJECTIVE: This case report provides evidence for our hypothesis that use of a sacral nerve stimulator may be considered in patients with fecal incontinence (FI) following chemoradiation and transanal operations in the setting of cancer including partial internal sphincter resections. MATERIALS AND METHODS: A 57-year-old female with a history of anal melanoma was treated with neoadjuvant chemoradiation followed by wide local, transanal tumor excision with partial internal anal sphincter resection that resulted in ≥2 full fecal incontinent episodes/week with gas, liquid, and solid stool leakage ≥10/day requiring pad changes. After seven years of progressive FI, a sacral nerve stimulator was implanted following pre-placement anorectal manometry. Pre and post implant validated Cleveland Cleveland Clinic/Wexner Fecal Incontinence questionnaires and daily stool diaries (Medtronic) were completed. Data was stored in and collected from the patient's electronic health record. RESULTS: The patient had a single episode of FI during the two week trial phase, but reports complete resolution of FI, urgency, and leakage since implantation through her 1-year post-implant follow-up visit. Additional improvements were noted in FI questionnaires: Cleveland Clinic/Wexner Fecal Incontinence Score of 17 at baseline to 3 post-implant and Fecal Incontinence Quality of Life Score of 3.585 at baseline to 3.93 post-implant. CONCLUSIONS: The application of sacral nerve stimulation may not be as limited as previously thought and should be considered for cancer survivors following chemoradiation and sphincter-sparing rectal and transanal resections. Though this single case report is suggestive, further research is necessary and would include a research protocol designed specifically for patients who have undergone chemoradiation and/or sphincter-sparing operations. We are currently working on such protocol at our institution.

Nanosecond Pulsed Electric Fields Enhance the Anti-tumour Effects of the mTOR Inhibitor Everolimus against Melanoma.

The PI3K/mTOR/AKT pathway is activated in most melanomas, but mTOR inhibitors used singly have limited activity against advanced melanomas. The application of nanosecond pulsed electric fields (nsPEFs) is a promising cancer therapy approach. In this study, we evaluated the synergistic anti-tumour efficacy of the mTOR inhibitor everolimus in conjunction with nsPEFs against melanoma. The combined treatment of nsPEFs and everolimus gradually decreased cell growth concurrent with nsPEF intensity. nsPEFs alone or combined with everolimus could promote melanoma cell apoptosis, accompanied with a loss in cellular mitochondrial membrane potential and an increase in Ca2+ levels. In vivo experiments showed that a combination of the mTOR inhibitor everolimus and nsPEFs improved the inhibitory effect, and all skin lesions caused by nsPEFs healed in 1 week without any observed adverse effect. Combination treatment induced caspase-dependent apoptosis through the upregulation of the pro-apoptotic factor Bax and downregulation of the anti-apoptotic factor Bcl-2. Everolimus and nsPEFs synergistically inhibited angiogenesis by decreasing the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and CD34. Our findings indicate that nsPEFs in combination with an mTOR inhibitor can be used as a potential treatment approach for advanced melanoma.

Co-existence of psoriasis and melanoma in a large urban academic centre population: a cross-sectional retrospective study.

BACKGROUND: Psoriasis has been linked to increased malignancy risk, particularly lympho-haematopoietic and non-melanoma skin cancers; however, its association with cutaneous melanoma remains unclear. OBJECTIVE: The aim of this study was to determine if there is an association between melanoma and psoriasis in a large, urban academic population through an electronic medical record database. METHODS: We searched our institution's electronic medical record database (EDW-Electronic Data Warehouse) from 1/2001 to 11/2013. Subjects were identified by ICD-9 codes. Melanoma diagnosis was included only if documented at least 1 month after the psoriasis diagnosis was documented. Odds ratio (OR) was obtained for association between cutaneous melanoma and psoriasis. The OR was then adjusted for phototherapy and age. To minimize detection bias, we also obtained the OR for association between cutaneous melanoma and atopic dermatitis. RESULTS: We identified 10 947 patients with psoriasis, 64 of whom had a subsequent diagnosis of cutaneous melanoma. We detected a significant association between melanoma and psoriasis (OR = 1.77; 95%CI 1.38-2.26; P < 0.0001; total n = 1 525 252). After adjusting for phototherapy and age, a statistically significant association between melanoma and psoriasis remained detectable (OR = 1.9; 95%CI 1.55-2.55; P < 0.0001 and OR = 1.64; 95%CI 1.17-2.26; P = 0.003 respectively). The OR for melanoma with atopic dermatitis in the same patient database showed a statistically significant inverse association between the two diseases (OR = 0.35; 95%CI 0.16-0.73; P = 0.005). CONCLUSION: Our findings show a statistically significant association between psoriasis and melanoma. After adjusting the OR for phototherapy and age, a statistically significant association remained. Further investigations exploring these associations are warranted in order to establish the relative risk for melanoma in psoriasis patients.

Radionuclide leakage monitoring during hyperthermic isolated limb perfusion for treatment of local melanoma metastasis in an extremity.

INTRODUCTION: The aim is to describe the importance of leakage monitoring in hyperthermic isolated limb perfusion (ILP). It is generally recommended that leakage should not exceed 10% because of risk of systemic toxicity. MATERIAL AND METHODS: Data retrieved by retrospective analysis of 131 perfusions performed in 115 consecutive patients (77 women and 38 men; median age 66 years) with recurrent and/or clinically apparent, cutaneous or subcutaneous melanoma metastases in an extremity. Radionuclide monitoring was performed with continuous, precordial count rate determinations of an intravascular (99m) Tc-labelled tracer infused into the isolated limb circulation. RESULTS: One hundred and sixteen of 131 procedures were completed. In 13%, a leakage of ≥10% was detected; in 6% (n = 8), the cytotoxic drug was never infused because of constant leakage; in 7% (n = 9), leakage ≥10% was measured during the perfusion resulting in two perfusions being terminated before 30 min, 5 perfusions were considered completed though with early termination (after 30 min, before 60 min), and 2 fully completed. No patients had systemic toxicity requiring treatment, whereas considerable or serious local toxicity were observed in 14%. Three of the patients with leakage ≥10% were successfully treated in a repeated procedure. CONCLUSION: Leakage monitoring using a threshold of 10% during ILP saves the patients from systemic toxicity, however, at the expense of early termination or cancellation of ILP treatment in a few patients and repeated ILP procedures in some.

Sunlight, vitamin D and malignant melanoma: an update.

Solar radiation represents an essential requirement for life, not only by spending the thermal energy for photosynthesis in plants, which provides our atmosphere with oxygen, but also by facilitating the cutaneous synthesis of vitamin D in vertebrates and many other organisms. It is well known that humans and most vertebrates have to obtain an adequate source of vitamin D, in order to develop and maintain a healthy mineralized skeleton and in order to be protected against cancer and a broad variety of other diseases. On the other hand, solar UV radiation can be assumed to be the most relevant environmental carcinogen causing melanoma and nonmelanoma skin cancer with increasing incidences. During the last decades, epidemiological studies and experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the south american oppossum and human skin xenografts, have further elucidated the multi-step process of UV-induced melanomagenesis. It has to be emphasized that, in contrast to intermittent, short-term high-dose solar UV-exposure, more chronic less intense exposure (which is recommended by many experts in the field to obtain a sufficient vitamin D status) has not been found to be a risk factor for the development of melanoma and in fact has been found in several studies to be protective. Interestingly, several independent lines of investigation have demonstrated convincing evidence that vitamin D and/or analogs may be effective in the prevention and treatment of melanoma. This essay summarizes our present understanding about the pathogenic role of UV radiation and of vitamin D for malignant melanoma.

Minimizing skin cancer surgical scars using ablative fractional Er:YAG laser treatment.

BACKGROUND AND OBJECTIVE: Scars from skin cancer surgery on the face can be quite prominent and not easily obscured by makeup. This report evaluates the use of an ablative fractional Er:YAG laser device for minimizing or blending scar lines in two patients who underwent repair of skin cancer defects on the face. METHODS: Two patients underwent surgery to remove facial skin cancer tumors. The resulting scars after reconstruction of these skin cancer defects on the left cheek (Case 1) and right cheek (Case 2) each received 3 treatments with a fractional ablative laser device (ProFractional-XC, Sciton, Inc., Palo Alto, CA). Treatments were spaced about 1 month apart. Topical anesthetic cream applied 1 hour before treatment minimized patient discomfort during the procedure. Treatment depths ranged from 150 to 200 microns, 2 passes were performed, and coverage per pass was typically 22% and then 11% in the coagulation mode. Results were evaluated by digital photography before the initial treatment, approximately 4-5 weeks after each of the 3 treatments, and at approximately 7 months after the surgical procedures. RESULTS: The fractional Er:YAG laser device significantly improved postsurgical scar lines in each patient without significant adverse effects. Prior to the laser sessions, these scars demonstrated hypopigmentation, hyperpigmentation, neovascularization, or diminished pore structures compared to the surrounding skin. These pigmentary, vascular or textural issues were all significantly improved by the fractional ablative Er:YAG laser. CONCLUSION: The ablative fractional laser device of the present report safely minimizes and improves facial scars demonstrating not only textural alterations but also some pigmentary and vascular changes after reconstruction of skin cancer defects.