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Summary: Background: The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM). Objectives: To investigate whether the extent of ulceration (EoU) predicts relapse‐free survival (RFS) and overall survival (OS) in PCM. Materials and methods: We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU. Results: A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1‐mm increase) 1·26, 95% confidence interval (CI) 1·08–1·48, P = 0·0047] and OS [HR (1‐mm increase) 1·25, 95% CI 1·05–1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour‐infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01–4 mm and > 4 mm BT. Conclusions: This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports. What is already known about this topic? Ulceration is a well‐known prognostic factor in melanoma.There are conflicting results on the prognostic value of the extent of ulceration. What does this study add? The extent of ulceration is an independent prognostic factor in primary cutaneous melanoma with Breslow thickness (BT) ≤ 2 mm.The extent of ulceration should be incorporated into the pathology report as a required, core element.Patients with extensive ulceration with a BT ≤ 2 mm are at high risk of recurrence and should be included in prospective adjuvant trials. Linked Comment: Wilkinson and Gyorki. Br J Dermatol 2021; 184:192–193. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis (TB) is an important cause of morbidity and mortality among people living with HIV (PLHIV). Current WHO-recommended strategies for diagnosing TB among hospitalized PLHIV rely on symptom screening and disease severity to assess eligibility for urine lipoarabinomannan lateral flow (LF-LAM) and molecular testing. Despite these recommendations, autopsy studies show a large burden of undiagnosed TB among admitted PLHIV. The EXULTANT trial aims to assess the impact of an expanded screening strategy using three specimens (sputum, stool, and urine) for TB diagnosis among PLHIV admitted to hospitals in two high HIV and TB burden African countries., Methods: This is a multicenter, pragmatic, individually randomized controlled trial conducted across eleven hospitals in Tanzania and Mozambique. Participants in the intervention arm will be tested with Xpert MTB/RIF Ultra® from expectorated sputum, stool, and urine samples, with additional urine LF-LAM testing in the first 24 h after hospital admission, irrespective of the presence of the symptoms. The control arm will implement the WHO standard of care recommendations. Hospitalized adults (≥ 18 years) with a confirmed HIV-diagnosis, irrespective of antiretroviral (ART) therapy status or presence of TB symptoms will be assessed for eligibility at admission. Patients with a pre-existing TB diagnosis, those receiving anti-tuberculosis therapy or tuberculosis preventive treatment in the 6 months prior to enrolment, and those transferred from other hospitals will not be eligible. Also, participants admitted for traumatic reasons such as acute abdomen, maternal conditions, scheduled surgery, having a positive SARS-CoV2 test will be ineligible. The primary endpoint is the proportion of participants with microbiologically confirmed TB starting treatment within 3 days of enrolment., Discussion: The EXULTANT trial investigates rapid implementation after admission of a new diagnostic algorithm using Xpert MTB/RIF Ultra® in several non-invasive specimens, in addition to LF-LAM, in hospitalized PLHIV regardless of TB symptoms. This enhanced strategy is anticipated to detect frequently missed TB cases in this population and is being evaluated as an implementable and scalable intervention., Trial Registration: Trial reference number: NCT04568967 (ClinicalTrials.gov) registered on 2020-09-29., (© 2024. The Author(s).)

Background: Standardized health-data collection enables effective disaster responses and patient care. Emergency medical teams use the Japan Surveillance in Post-Extreme Emergencies and Disasters (J-SPEED) reporting template to collect patient data. EMTs submit data on treated patients to an EMT coordination cell. The World Health Organization's (WHO) EMT minimum dataset (MDS) offers an international standard for disaster data collection., Goal: The goal of this study was to analyze age and gender distribution of medical consultations in EMT during disasters., Methods: Data collected from 2016 to 2020 using the J-SPEED/MDS tools during six disasters in Japan and Mozambique were analyzed. Linear regression with data smoothing via the moving average method was employed to identify trends in medical consultations based on age and gender., Results: 31,056 consultations were recorded: 13,958 in Japan and 17,098 in Mozambique. Women accounted for 56.3% and 55.7% of examinees in Japan and Mozambique, respectively. Children accounted for 6.8% of consultations in Japan and 28.1% in Mozambique. Elders accounted for 1.32 and 1.52 times more consultations than adults in Japan and Mozambique, respectively., Conclusions: Study findings highlight the importance of considering age-specific healthcare requirements in disaster planning. Real-time data collection tools such as J-SPEED and MDS, which generate both daily reports and raw data for in-depth analysis, facilitate the validation of equitable access to healthcare services, emphasize the specific needs of vulnerable groups, and enable the consideration of cultural preferences to improve healthcare provision by EMTs.

Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission.Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor's microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection.Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Melanoma guidelines recommend surgical excision with 10 mm margins for T1 melanomas (invasive melanomas with Breslow thickness ≤1 mm), including those in radial growth phase, which are without metastatic potential; however, such margins may be problematic on head-and-neck., Objective: We compared outcomes of wide (10 mm margins) versus narrow (5 mm margins) excisions in patients with radial growth phase T1 melanoma on head-and-neck including face., Methods: We retrospectively examined 610 consecutive patients excised with wide versus narrow margins, from 2001 to 2018, at six European centres. In all cases, radial growth phase, and clear margins with 5 or 10 mm of clearance, were ascertained histologically. Multivariable models investigated associations of margins and other factors with overall survival and local recurrence., Results: Three hundred and sixteen (51.8%) patients received wide excision, 219 (69.3%) with primary wound closure, 97 (30.7%) with reconstruction; 294 (48.2%) patients received narrow excision, 264 (89.8%) with primary wound closure, 30 (10.2%) with reconstruction (p < 0.001). Median follow-ups were 88 months (wide) and 187 months (narrow) (inter-quartile ranges 43-133 and 79-206, respectively). Ten-year overall survival (95% confidence interval) was 96.7% (94.2%-99.3%) in wide and 98.2% (96.4%-100%) in narrow patients. Ten-year local recurrence incidence was 6.4% (4.1%-10.1%) in wide and 7.8% (5.3%-11.6%) in narrow groups. Lentigo maligna melanoma subtype appeared associated with increased risk of local recurrence in narrow versus wide patients (15.0% vs. 7.5%; p = 0.190)., Conclusions: Narrower excision margins for T1 radial growth phase melanoma are not associated with worse overall survival (hazard ratio 0.97, p = 0.996) or increased local recurrence (subdistribution hazard ratio: 0.87; p = 0.751) compared to wider margins, and may be safely applied to such lesions, although caution may be required in the presence of lentigo maligna melanoma., (© 2023 European Academy of Dermatology and Venereology.)

Importance: Melanoma guidelines recommend surgical excision with 10-mm margins for T1 melanoma. However, this procedure may be problematic at sites close to critical structures such as the scalp, face, external genitalia, acral, periumbilical, and perineal areas., Objective: To compare outcomes of wide (10-mm margins) vs narrow (5-mm margins) excision in patients with T1a melanoma near critical structures., Design, Setting, and Participants: This cohort study was a retrospective comparison of 1341 consecutive patients aged 18 years or older from the National Cancer Institute of Milan, Italy, diagnosed between 2001 and 2020 with T1a cutaneous melanoma close to critical structures who accepted wide excision vs narrow excision., Exposures: Local recurrence and melanoma-specific mortality (MSM) rates with 5-mm vs 10-mm excision margins., Main Outcomes and Measures: The primary aim of the study was to ascertain whether a narrower (5-mm) vs wider (10-mm) excision margin was associated with local recurrence and MSM. The secondary aim was to compare the need for reconstructive surgery in the groups defined by excision margin width. Between April 28 and August 7, 2022, associations were assessed by weighted Cox and Fine-Gray univariable and multivariable models., Results: A total of 1179 patients met the inclusion criteria (median [IQR] age, 50.0 [39.5-63.0] years; female, 610 [51.7%]; male, 569 [49.3%]). Six hundred twenty-six patients (53.1%) received a wide excision (434 [69.3%] with linear repair and 192 [30.7%] with flap or graft reconstruction) and 553 (46.9%) received a narrow excision (491 [88.8%] with linear repair and 62 [11.2%] with flap or graft reconstruction). The weighted 10-year MSM was 1.8% (95% CI, 0.8%-4.2%) in the wide group and 4.2% (95% CI, 2.2%-7.9%) in the narrow group; the weighted 10-year local recurrence rate was 5.7% (95% CI, 3.9%-8.3%) in the wide group and 6.7% (95% CI, 4.7%-9.5%) in the narrow group. Breslow thickness greater than 0.4 mm (subdistribution hazard ratio [sHR] for 0.6 vs 0.4 mm, 2.42; 95% CI, 1.59-3.68; P < .001) and mitotic rate greater than 1/mm2 (sHR for a single increment, 3.35; 95% CI, 2.59-4.32; P < .001) were associated with worse MSM. Multivariable analysis showed that acral lentiginous melanoma, lentigo maligna melanoma, and increasing Breslow thickness were associated with a higher incidence of local recurrence., Conclusions and Relevance: The study's findings suggest that local excision with 5-mm margins for T1a melanoma may not be associated with an increased risk of local recurrence. Breslow thickness greater than 0.4 mm, mitotic rate greater than 1/mm2, and acral lentiginous melanoma and lentigo maligna melanoma subtypes were associated with a higher risk of recurrence. These findings may be useful for future melanoma treatment guidelines.

Introduction: During a disaster, comprehensive, accurate, timely, and standardized health data collection is needed to improve patient care and support effective responses. In 2017, the World Health Organization (WHO) developed the Emergency Medical Team (EMT) Minimum Data Set (MDS) as an international standard for data collection in the context of disasters and public health emergencies. The EMT MDS was formally activated for the first time in 2019 during the response to Cyclone Idai in Mozambique., Study Objective: The aim of this study was to analyze data collected through the EMT MDS during Cyclone Idai of 2019 and to identify the benefits of and opportunities for its future use., Methods: The EMT MDS was used for data collection. All 13 international EMTs deployed from March 27 through July 12 reported data in accordance with the EMT MDS form. The collected data were analyzed descriptively., Results: A total of 18,468 consultations, including delivery of 94 live births, were recorded. For children under-five and those five-years and older, the top five reasons for consultation were minor injuries (4.5% and 10.8%, respectively), acute respiratory infections ([ARI] 12.6% and 4.8%, respectively), acute watery diarrhea (18.7% and 7.7%, respectively), malaria (9.2% and 6.1%, respectively), and skin diseases (5.1% and 3.1%, respectively). Non-disaster-related health events accounted for 84.7% of the total health problems recorded. Obstetric care was among the core services provided by EMTs during the response., Conclusion: Despite of challenges, the EMT MDS reporting system was found to support the responses and coordination of EMTs. The role of the Mozambican Ministry of Health (MOH), its cooperation with EMTs, and the dedicated technical support of international organizations enabled its successful implementation.

The genetic landscape of melanoma resistance to targeted therapy with small molecules inhibiting BRAF and MEK kinases is still largely undefined. In this study, we portrayed in detail the somatic alterations of resistant melanoma and explored the associated biological processes and their integration with transcriptional profiles. By targeted next-generation sequencing and whole-exome sequencing analyses, a list of 101 genes showing imbalance in metastatic tumors from patients with a complete/durable response or disease progression during therapy with vemurafenib or with dabrafenib and trametinib was defined. Classification of altered genes in functional categories indicated that the mutational pattern of both resistant tumors and melanoma cell lines was enriched in gene families involved in oncogenic signaling pathways and in DNA repair. Integration of genomic and transcriptomic features showed that the enrichment of mutations in gene sets associated with anabolic processes, chromatin alterations, and IFN-α response determined a significant positive modulation of the same gene signatures at the transcriptional level. In particular, MTORC1 signaling was enriched in tumors from poorly responsive patients and in resistant tumors excised from treated patients. Results indicate that genetic patterns are associated with melanoma resistance to targeted therapy and disclose the underlying key molecular pathways to define drug combinations for improved personalized therapies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Burn injuries are common in low- and middle-income countries (LMICs) and their associated disability is tragic. This study is the first to explore burn scars in rural communities in Mozambique. This work also validated an innovate burn assessment tool, the Morphological African Scar Contractures Classification (MASCC), used to determine surgical need., Methods: Using a stratified, population-weighted survey, the team interviewed randomly selected households from September 2012 to June 2013. Three rural districts (Chókwè, Nhamatanda, and Ribáuè) were selected to represent the southern, central and northern regions of the country. Injuries were recorded, documented with photographs, and approach to care was gathered. A panel of residents and surgeons reviewed the burn scar images using both the Vancouver Scar Scale and the MASCC, a validated visual scale that categorizes patients into four categories corresponding to levels of surgical intervention., Results: Of the 6104 survey participants, 6% (n = 370) reported one or more burn injuries. Burn injuries were more common in females (57%) and most often occurred on the extremities. Individuals less than 25 years old had a significantly higher odds of reporting a burn scar compared to people older than 45 years. Based on the MASCC, 12% (n = 42) would benefit from surgery to treat contractures., Conclusion: Untreated burn injuries are prevalent in rural Mozambique. Our study reveals a lack of access to surgical care in rural communities and demonstrates how the MASCC scale can be used to extend the reach of surgical assessment beyond the hospital through community health workers., (© 2022. The Author(s).)

Aims: We present a field evaluation of the diagnostic accuracy of Xpert MTB/RIF ("Xpert") and Xpert MTB/RIF Ultra ("Ultra") using two cohorts in a high tuberculosis/HIV burden setting in Southern Mozambique., Methods: Single respiratory specimens from symptomatic adults accessing healthcare services (passive case finding (PCF) cohort) and from household and community close contacts (active case finding (ACF) cohort) were tested by smear microscopy, culture, Xpert and Ultra. Liquid and solid culture served as a composite reference standard. We explored the impact of trace results on specificity via their recategorisation to negative (in all and just among those previously treated individuals)., Results: 1419 and 252 participants were enrolled in the PCF and ACF cohorts, respectively. For the PCF cohort, Ultra showed higher sensitivity than Xpert overall (0.95 (95% CI 0.90-0.98) versus 0.88 (96% CI 0.82-0.93); p<0.001) and among smear-negative patients (0.84 (96% CI 0.71-0.93) versus 0.63 (96% CI 0.48-0.76)). Ultra's specificity was lower than Xpert's (0.96 (96% CI 0.95-0.97) versus 0.98 (96% CI 0.97-0.99); p=0.008). For ACF, sensitivities were the same (0.67 (95% CI 0.22-0.96) for both tests), although Ultra detected a higher number of microbiologically confirmed samples than Xpert (4.7% (12 out of 252) versus 2.7% (seven out of 252)). Conditional recategorisation of trace results among previously treated participants maintained differences in specificity in the PCF cohort., Conclusion: These results add evidence on the improved sensitivity of Ultra and support its use in different case finding scenarios., Competing Interests: Conflict of interest: B. Saavedra has nothing to disclose. Conflict of interest: E. Mambuque has nothing to disclose. Conflict of interest: D. Nguenha has nothing to disclose. Conflict of interest: N. Gomes has nothing to disclose. Conflict of interest: S. Munguambe has nothing to disclose. Conflict of interest: J.I. Garcia has nothing to disclose. Conflict of interest: S. Izco has nothing to disclose. Conflict of interest: S. Acacio has nothing to disclose. Conflict of interest: A. Murias-Closas has nothing to disclose. Conflict of interest: M. Cossa has nothing to disclose. Conflict of interest: I. Losada has nothing to disclose. Conflict of interest: H. Pernas-Pardavila has nothing to disclose. Conflict of interest: L. Oliveras has nothing to disclose. Conflict of interest: G. Theron has nothing to disclose. Conflict of interest: A.L. García-Basteiro has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Outcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity after sustained response are unknown., Materials and Methods: This retrospective case series analysis conducted at a single Cancer Center in Italy included patients with BRAF mutated metastatic melanoma treated with a BRAF inhibitor as a single agent or in combination with a MEK inhibitor between June 1, 2011 and January 1, 2020 and interrupted treatment due to cumulative toxicity after achieving complete response (CR) or long-lasting partial response (PR; i.e. >12 months)., Results: We included 24 patients with a median treatment duration of 59.4 months (95% confidence interval [CI], 55.4-63.4; range, 12-88). CR and PR were achieved in 71% and 29% of patients, respectively. At a median follow-up after treatment discontinuation of 37.8 months (95% CI, 33.7-41.9), the 12-month progression-free survival after discontinuation (dPFS) rate was 70.8% (95% CI 54.8-91.6) and 24-month dPFS rate was 58.3% (95% CI, 41.6-81.8). Baseline patient and tumor characteristics as well as treatment duration and best response did not significantly impact on dPFS. Patients with CR and negative circulating tumor DNA (ctDNA) at time of discontinuation had a significantly improved dPFS compared with patients with either radiological residual disease or ctDNA positivity (p = .007). No patient in CR with undetectable ctDNA experienced progression., Conclusion: The risk of progression is high even in patients with sustained sensitivity to BRAF/MEK inhibitors. Integration of liquid biopsy in clinical trials investigating the optimal management of patients with sustained sensitivity to BRAF/MEK inhibitors is warranted., Implications for Practice: Outcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity are unknown. This study analyzed patients with sustained responses (median treatment duration 59.4 months). Twelve- and 24-month progression-free survival following discontinuation were 70.8% and 58.3%, respectively. Complete response and negative circulating tumor DNA at time of discontinuation are promising prognostic biomarkers in this setting., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.

Background: Prognostic parameters in sentinel node (SN)-positive melanoma are important indicators to identify patients at high risk of recurrence who should be candidates for adjuvant therapy. We aimed to evaluate the presence of melanoma cells beyond the SN capsule-extranodal extension (ENE)-as a prognostic factor in patients with positive SNs., Methods: Data from 1,047 patients with melanoma and positive SNs treated from 2001 to 2020 at the Istituto Nazionale dei Tumori in Milano, Italy, were retrospectively investigated. Kaplan-Meier survival and crude cumulative incidence of recurrence curves were estimated. A multivariable logistic model was used to investigate the association between ENE and selected predictive factors. Cox models estimated the effect of the selected predictors on survival endpoints., Results: Median follow-up was 69 months. The 5-year overall survival rate was 62.5% and 71.7% for patients with positive SNs with and without ENE, respectively. The 5-year disease-free survival rate was 54.0% and 64.0% for patients with positive SNs with and without ENE, respectively. The multivariable logistic model showed that age, size of the main metastatic focus in the SN, and numbers of metastatic non-SNs were associated with ENE (all P<.0001). The multivariable Cox regression models showed the estimated prognostic effects of ENE associated with age, ulceration, size of the main metastatic focus in the SN, and number of metastatic non-SNs (all P<.0001) on disease-free survival and overall survival., Conclusions: ENE was a significant prognostic factor in patients with positive-SN melanoma. This parameter may be useful in clinical practice as a selection criterion for adjuvant treatment in patients with stage IIIA disease with a tumor burden <1 mm in the SN. We recommend its inclusion as an independent prognostic determinant in future updates of melanoma guidelines.

Introduction: Surgery plays a critical role in sustainable healthcare systems. Validated metrics exist to guide implementation of surgical services, but low-income countries (LIC) struggle to report recommended metrics and this poses a critical barrier to addressing unmet need. We present a comprehensive national sample of surgical encounters from a LIC by assessing the National Health Services of Mozambique., Material and Methods: A prospective cohort of all surgical encounters from Mozambique's National Health Service was gathered for all provinces between July and December 2015. Primary outcomes were timely access, provider densities for surgery, anesthesiology, and obstetrics (SAO) per 100,000 population, annualized surgical procedure volume per 100,000, and postoperative mortality (POMR). Secondary outcomes include operating room density and efficiency., Results: Fifty-four hospitals had surgical capacity in 11 provinces with 47,189 surgeries. 44.9% of Mozambique's population lives in Districts without access to surgical services. National SAO density was 1.2/100,000, ranging from 0.4/100,000 in Manica Province to 9.8/100,000 in Maputo City. Annualized national surgical case volume was 367 procedures/100,000 population, ranging from 180/100,000 in Zambezia Province to 1,897/100,000 in Maputo City. National POMR was 0.74% and ranged from 0.23% in Maputo Province to 1.78% in Niassa Province., Discussion: Surgical delivery in Mozambique falls short of international targets. Subnational deficiencies and variations between provinces pose targets for quality improvement in advancing national surgical plans. This serves as a template for LICs to follow in gathering surgical metrics for the WHO and the World Bank and offers short- and long-term targets for surgery as a component of health systems strengthening.

Background: Sentinel Node Biopsy (SNB) is routinely performed for primary melanoma, but its role in the treatment of Local Recurrence (LR) and In-Transit metastasis (IT) is controversial. This study aims to assess the role of SNB in melanoma patients who developed first loco-regional recurrence., Methods: A series of consecutive melanoma patients who received SNB for a first IT or LR at the National Cancer Institute of Milan, Italy, from 2000 to 2015 were selected from a prospective database. Clinicopathological characteristics were analyzed., Results: Seventy-two patients met selection criteria. Forty-three patients (59.7%) received SNB for LR and 29 (40.3%) for IT. The average interval between treatment of primitive melanoma and first recurrence diagnosis was 19 months (interquartile range: 6.9-49.0). SN identification rate was 97.2%. SN positivity was detected in 26 (37.1%) patients. The SN-positive ratein melanoma patients who had LR or IT was significantly higher than reported for primary tumours. Of patients with nodal involvement 17 had LR and 9 IT lesions. Disease Free Survival (DFS) was slightly higher in SN negative patients, in the absence of statistically significant differences. Overall Survival (OS) analysis showed similar values in the two groups., Conclusion: Since DFS and OS do not show significant differences between SN negative and positive patients, our data do not give clear indications about performing SNB in case of first LR or IT. However, we suggest submitting patients with LR to this procedure to obtain a more accurate staging and eventually candidate these patients to adjuvant treatment., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM., Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort., Results: in the training cohort, 100 Stage II-III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4 + intratumoral T-cells (aHR [100 cell/mm 2 increase] 0.98, 95%CI 0.95-1.00, p = 0.041) and CD163 + inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32-0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28-0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18-0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8 + T-cells and CD68 + macrophages as compared to those with low density of both intratumoral CD8 + T-cells and CD68 + macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8 + and CD3 + T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10-0.56, p < 0.001) and those with high density of both intratumoral CD8 + and CD68 + were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09-0.86, p = 0.025)., Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II-III melanoma patients.

Introduction: Treatment of metastatic melanoma has rapidly changed during the last years, and patients often require a multidisciplinary approach to achieve effective results. We aimed to assess the survival benefit achieved through surgical approach to patients with small bowel (SB) metastases from cutaneous melanoma, to emphasize the potential role of surgery in association with novel therapies., Methods: Ninety consecutive patients with cutaneous melanoma diagnosed as having resectable SB metastases from 1995 to 2015 were retrospectively investigated., Results: Median age at surgery of melanoma metastases was 53.4 years. Among 30 patients who had a curative-intent resection, the 5- and 10-year survival rates were 61% and 54%, respectively, while among 60 patients treated with a palliative surgery the corresponding rates were both 4%. Among 29 patients, for whom the interval time between the occurrence of SB metastases and the previous surgical event on GI tract was ≥36 months, the 5-year overall survival rate was 42%; for 56 patients who had an interval time <36 months the corresponding survival rate was 14%. Within the whole series, an absence of any residual disease after surgery (R0) was a factor affecting better survival, regardless of the evidence of metastases in other organs., Conclusion: Our observational data showed that surgical treatment for patients with SB metastases from melanoma might increase survival, but further studies are needed to confirm this finding. In the age of novel available therapies, the increase in survival time given by surgery may offer important chances for patients to benefit from systemic therapies., Competing Interests: Declaration of competing interest All authors disclose that there are no financial and personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: Mozambique is currently experiencing an increase in chronic diseases including cancer. There is a large unmet need for cancer surgery in Mozambique. The aim of this study was to define the content and the design of a training program for practicing surgeons in surgical oncology that would be consensually regarded as adequate to care for oncological patients requiring surgical interventions., Design & Setting: A 3-round modified-Delphi approach was implemented to obtain consensus on surgical oncology training curriculum. The participants were purposefully selected experts in surgical oncology working in Mozambique. In round 1, participants answered a questionnaire with open-ended questions regarding the content of the curriculum and the timing and venue of training. In round 2, answers from the first round were presented to a purposeful selected sample of nationally recognized experts in oncology and surgical oncology, including members of the Mozambican College of Surgeons and leadership of the Ministry of Health. A final round was carried out to discuss the draft version of the training program aiming to achieve a predetermined consensus level of 80%., Participants: Fifteen of 23 experts (65.2%) responded to round one.The response rate for round 1 and 3 was 80% (12 of the 15 participants in round one)., Results: The responses collected in the first round were analyzed and revealed that basic principles of oncology and basic principles of surgical oncology should be included in the curriculum of surgical residency in Mozambique (80% of the experts agree; Cronbach α = 0.93); a 24-months fellowship in surgical oncology should take place after residency in the surgical field (86.6% of experts agree; Cronbach α = 0.97); and should occur at Maputo Central Hospital and at comprehensive cancer centers abroad (100% agree). In round 2 the proposal for the program of surgical oncology fellowship obtained a strong agreement amongst the experts (97.3%). The final proposal for the program was divided into the following structure: (1) theoretical components; (2) duration; (3) location; (4) methodology; (5) technical skills in oncology; and (6) competency and paid particular attention to the oncological diseases prevalent in Mozambique. The agreement amongst the experts was 97.3%., Conclusions: The experts reached a consensus regarding the general structure for a cancer surgery postgraduate training program in Mozambique, which should be a 24-months fellowship after residency in surgical disciplines. This fellowship should mostly take place in Mozambique, but it should also include dedicated internships in recognized cancer hospitals abroad. Such curricula embrace the Global Curriculum in Surgical Oncology including in particular the oncological nosology of Mozambique and should advance the quality of oncology surgical care provided in the country., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs., Patients and Methods: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method., Results: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup., Conclusions: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.

Background: Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance., Methods: The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy., Results: miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor., Conclusions: Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Video Abstract.

Purpose: Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB., Patients and Methods: The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram., Results: Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines., Conclusion: We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.

Introduction: Immunotherapy has shown efficacy in the treatment of different malignancies. Nivolumab, an immune checkpoint inhibitor directed against programmed death-1, has been approved for non-small cell lung cancer (NSCLC) in pretreated patients. Although it is generally well-tolerated, immunotherapy may be complicated by a wide range of immune-mediated adverse events. We describe the case of an uncommon skin toxicity arising as alopecia universalis induced by nivolumab in a patient with NSCLC., Case Description: A 58-year-old man received nivolumab for metastatic NSCLC after progression to 3 lines of chemotherapy. The treatment was prescribed in June 2016, and induced a rapid and significant disease response. Nivolumab was well-tolerated until May 2017, when partial alopecia at hair and eyelashes appeared. In the next months, alopecia became complete and extended to the whole body surface. The dermatologic picture was compatible with alopecia areata. A topical steroid therapy was attempted, without benefit. The patient refused systemic treatments and is still undergoing nivolumab without new toxicities and with persistent disease response., Conclusions: This case suggests that alopecia areata may be a rare immune-related adverse event of immune checkpoint agents. Its late onset in our patient is uncommon and unexpected, underlining that the risk of nivolumab-induced toxicity is not limited to the beginning of treatment. Despite its rarity, alopecia areata should be considered in the range of adverse events potentially induced by immune checkpoint inhibitors even in the long term. Potential association between toxicity and efficacy of immunotherapy in NSCLC warrants further investigation.

Introduction: Cancer is a growing concern in Mozambique. However, the country has limited facilities and few oncologists. Surgical oncologists are an unmet need. The aim of this study was to assess residents' knowledge in prevalent cancer domains and to identify and characterize prevalent cancers treated by surgery at Maputo Central Hospital, the largest hospital in Mozambique. The expectations were that the findings shall inform the development of a comprehensive curriculum in surgical oncology fellowship fit for the Hospital., Methods: To identify and characterize prevalent cancers, we performed a retrospective analysis of individual cancer patient registries of Maputo Central Hospital (MCH), Mozambique. Information was recorded into data collection sheets and analyzed with SPSS ® 21. To assess MCH residents oncologic knowledge, we invited Twenty-six junior residents (49% of all residents) of different specialties to take a 30 item multiple choice written test used elsewhere in previous studies. The test focused on the domains of Basis of oncology, Radiotherapy, Pathology, Chemotherapy, Pain management, Surgical oncology and Clinical Pathway. The test was administered anonymously and without prior notice. We analyzed the overall test and topic performance of residents., Results: The study covered a period of 3 years and 203 patients. The most prevalent malignant tumors treated by general and thoracic surgery in MCH cancer registry were esophageal (7%), female breast (6.5%) and colorectal cancer (2.8%). Globally these malignancies were diagnosed at an advanced stage of the disease and required a multimodal treatment. The mean percent correct score of residents was 37.3%. The dimension with the highest percent correct score were clinical management (46%) and surgical oncology (28%) showed the lowest correct score., Conclusion: In Maputo, Mozambique esophageal, breast and colorectal cancer were the most prevalent malignancies treated, with surgery, by thoracic or general surgery in MCH. The test scores suggest that, among residents, the knowledge in oncology needs to be improved, rendering support to the need of a surgical oncology training tailored to suit the local needs. Specific training should take into account local cancer prevalence, resources, their quality and the support of surgical oncology services with volume and experience., Competing Interests: The authors declare no competing interests.

Introduction: Intrapericardial congenital diaphragmatic hernia (IPCDH) is extremely rare: only 18 cases in children have been reported in the literature since 1981. We report the 19th case of infantile IPCDH in a 6-month-old girl and compare with previous reports., Presentation of Case: Our patient initially presented with four days of dyspnea and was diagnosed with CDH by preoperative radiography. She was taken to the operating room, where an IPCDH was discovered, and successfully reduced., Discussion: CDH may present with cardiopulmonary compromise, but IPCDH directly compress the heart, leading to acute or subacute heart failure., Conclusion: Pediatric surgeons should be aware of and prepared for the possibility of IPCDH when making surgical plans to correct CDH., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.