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Diabetic cardiomyopathy is associated with an increase in oxidative stress. However, antioxidant therapy has shown a limited capacity to mitigate disease pathology. The molecular mechanisms responsible for the modulation of reactive oxygen species (ROS) production and clearance must be better defined. The objective of this study was to determine how insulin affects superoxide radical (O2•–) levels. O2•– production was evaluated in adult cardiomyocytes isolated from control and Akita (type 1 diabetic) mice by spin-trapping electron paramagnetic resonance spectroscopy. We found that the basal rates of O2•– production were comparable in control and Akita cardiomyocytes. However, culturing cardiomyocytes without insulin resulted in a significant increase in O2•– production only in the Akita group. In contrast, O2•– production was unaffected by high glucose and/or fatty acid supplementation. The increase in O2•– was due in part to a decrease in superoxide dismutase (SOD) activity. The PI3K inhibitor, LY294002, decreased Akita SOD activity when insulin was present, indicating that the modulation of antioxidant activity is through insulin signaling. The effect of insulin on mitochondrial O2•– production was evaluated in Akita mice that underwent a 1-week treatment of insulin. Mitochondria isolated from insulin-treated Akita mice produced less O2•– than vehicle-treated diabetic mice. Quantitative proteomics was performed on whole heart homogenates to determine how insulin affects antioxidant protein expression. Of 29 antioxidant enzymes quantified, thioredoxin 1 was the only one that was significantly enhanced by insulin treatment. In vitro analysis of thioredoxin 1 revealed a previously undescribed capacity of the enzyme to directly scavenge O2•–. These findings demonstrate that insulin has a role in mitigating cardiac oxidative stress in diabetes via regulation of endogenous antioxidant activity.

The cAMP-dependent protein kinase (PKA) signaling pathway is the primary means by which the heart regulates moment-to-moment changes in contractility and metabolism. We have previously found that PKA signaling is dysfunctional in the diabetic heart, yet the underlying mechanisms are not fully understood. The objective of this study was to determine if decreased insulin signaling contributes to a dysfunctional PKA response. To do so, we isolated adult cardiomyocytes (ACMs) from wild type and Akita type 1 diabetic mice. ACMs were cultured in the presence or absence of insulin and PKA signaling was visualized by immunofluorescence microscopy using an antibody that recognizes proteins specifically phosphorylated by PKA. We found significant decreases in proteins phosphorylated by PKA in wild type ACMs cultured in the absence of insulin. PKA substrate phosphorylation was decreased in Akita ACMs, as compared to wild type, and unresponsive to the effects of insulin. The decrease in PKA signaling was observed regardless of whether the kinase was stimulated with a beta-agonist, a cell-permeable cAMP analog, or with phosphodiesterase inhibitors. PKA content was unaffected, suggesting that the decrease in PKA signaling may be occurring by the loss of specific PKA substrates. Phospho-specific antibodies were used to discern which potential substrates may be sensitive to the loss of insulin. Contractile proteins were phosphorylated similarly in wild type and Akita ACMs regardless of insulin. However, phosphorylation of the glycolytic regulator, PFK-2, was significantly decreased in an insulin-dependent manner in wild type ACMs and in an insulin-independent manner in Akita ACMs. These results demonstrate a defect in PKA activation in the diabetic heart, mediated in part by deficient insulin signaling, that results in an abnormal activation of a primary metabolic regulator.

BackgroundThe healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Diabetes mellitus disrupts this metabolic flexibility and promotes cardiomyopathy through mechanisms that are not completely understood. Phosphofructokinase 2 (PFK‐2) is a primary regulator of cardiac glycolysis and substrate selection, yet its regulation under normal and pathological conditions is unknown. This study was undertaken to determine how changes in insulin signaling affect PFK‐2 content, activity, and cardiac metabolism. Methods and ResultsStreptozotocin‐induced diabetes mellitus, high‐fat diet feeding, and fasted mice were used to identify how decreased insulin signaling affects PFK‐2 and cardiac metabolism. Primary adult cardiomyocytes were used to define the mechanisms that regulate PFK‐2 degradation. Both type 1 diabetes mellitus and a high‐fat diet induced a significant decrease in cardiac PFK‐2 protein content without affecting its transcript levels. Overnight fasting also induced a decrease in PFK‐2, suggesting it is rapidly degraded in the absence of insulin signaling. An unbiased metabolomic study demonstrated that decreased PFK‐2 in fasted animals is accompanied by an increase in glycolytic intermediates upstream of phosphofructokianse‐1, whereas those downstream are diminished. Mechanistic studies using cardiomyocytes showed that, in the absence of insulin signaling, PFK‐2 is rapidly degraded via both proteasomal‐ and chaperone‐mediated autophagy. ConclusionsThe loss of PFK‐2 content as a result of reduced insulin signaling impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a pathological impairment in diabetes mellitus.

Mutations of the von Hippel-Lindau ( VHL ) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4-6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance.

Eight sample digestion procedures were compared to determine 41 elements in rice samples by ICP-MS and CV-AFS. Analytical methods were evaluated using certified rice flour reference material (NIST 1568b) and recovery experiments. The microwave-assisted digestion of 0.5 g rice sample and reagent mixture of 2 mL HNO 3 , 0.5 mL H 2 O 2 , and 0.5 mL deionized water yielded the best recovery for all elements ranging from 90 to 120% at three different levels, bias% within 10%, and precision (coefficient of variation percent, CV% intra- and inter-day) below 15%. The best analytical method was applied to the elemental determination in nine types of rice available on the Italian market. Daily or weekly rice consumption meets the nutritional and safety requirements of EFSA and WHO. The present study allows extensive and detailed knowledge of the content of essential and non-essential/toxic elements in different types of rice produced or packaged in Italy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Compared with standard excision with a two-dimensional histological examination, Mohs micrographic surgery offers a lower recurrence rate and a greater extent of healthy tissue sparing for the treatment of high-risk basal cell carcinoma (BCC). The aims of this study were to first quantify the healthy tissue spared through the micrographic technique compared to traditional surgery for high-risk tumours. Then, to speculate, through the analysis of the distal micrographic resection margin, the adequate width of safety margins for standard excision., Method: A cohort of patients with high-risk BCC was treated with Mohs surgery. Safety margins, tumours residual final breach and hypothetical standard excision safety margins areas were recorded., Results: A total of 96 patients were included. A reduction of 27.96% (95% Confidence Interval (CI): 17.90-38.02) of healthy skin removed was observed using a micrographic method compared to the standard approach. Standard excision with a 6mm safety margin was associated with 86.46% (95% CI: 79.62-93.30) of complete excision. Greater margins were not associated with a statistically significant improvement of complete excision., Conclusion: Mohs surgery should be considered the gold standard operative treatment for high-risk BCC. However, if micrographic techniques are not feasible, the standard excision with a predetermined margin of 6 mm, should be considered as the best option.

CDKN2A pathogenic variants are well known to be associated with cutaneous melanoma and noncutaneous tumors (NCTs). Herein, we investigated the temporal correlation between the first cutaneous melanoma and NCT both in CDKN2A mutation carriers (MUT) and in wild-type melanoma patients, a poorly explored issue to date. Two hundred forty-five cutaneous melanoma patients were genotyped for the CDKN2A gene and divided into 51 MUT and 189 wild-type; the remaining five variant carriers were excluded from the analyses. MUT developed a significantly higher number of cutaneous melanoma than wild-type, while 13.7% in both genotyped groups received a diagnosis of at least one malignant NCT, without statistically significant differences. The onset of the first cutaneous melanoma preceded that of the first malignant or benign NCT in both MUT and wild-type patients by an average of 4.5 and 3.02 years, respectively. Considering only malignant tumors, the diagnosis of melanoma preceded that of the first NCT on an average of 8 and 4.34 years, in MUT and wild-type patients respectively. We emphasize the relevance to adopt a global vision for the primary and secondary surveillance of patients affected by cutaneous melanoma, not only limited to high-risk for multiple primary skin cancers but also to NCT that may develop several years after the diagnosis of the first cutaneous melanoma., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The association of systemic sclerosis (SSc) and cancer is well known from several decades suggesting common genetic and environmental risk factors involved in the development of both diseases. Immunosuppressive drugs widely used in SSc may increase the risk of cancer occurrence and different SSc clinical and serological features identify patients at major risk to develop malignancy. In this context, among serological features, presence of anti-RNA polymerase III and anti-topoisomerase I autoantibodies seems to increase cancer frequency in SSc patients (particularly lung and breast cancers). Lung fibrosis and a long standing SSc pulmonary involvement have been largely proposed as lung cancer risk factors, and the exposure to cyclophosphamide and an upper gastrointestinal involvement have been traditionally linked to bladder and oesophagus cancers, respectively. Furthermore, immune checkpoint inhibitors used for cancer therapy can induce immune-related adverse events, which are more frequent and severe in patients with pre-existing autoimmune diseases such as SSc. The strong association between SSc and cancer occurrence steers clinicians to carefully survey SSc patients performing periodical malignancy screening. In the present review, the most relevant bilateral relationships between SSc and cancer will be addressed., (© 2022. The Author(s).)

Background: During the first Italian lockdown period, the imponent amount of hospital COVID-19 patients forced the healthcare system to re-organize visits but no information are available on outpatient ethnical patterns. Here we evaluated healthcare management changes on dermatological outpatient non-surgical settings visits during the SARS-CoV-2 pandemic., Methods: In this retrospective study we collected data of scheduled, performed and not-performed visits, together with patients' characteristics (i.e., age, gender) with a particular attention for ethnicities among the outpatients accessing during the first Italian lockdown (March 5-April 30, 2020). Then, we compared these data with the corresponding ones in 2019 (before COVID-19 pandemic)., Results: During the Italian lockdown the dermatological department registered a great decrement (-83.5%, P<0.001) in visits compared to the corresponding time period in 2019. Performed and scheduled visits to non-oncological stable patients together with emergency accesses to dermatology decreased. Non-Italian patients decreased accesses, especially the South East Asians (-70.4%) and North Africans (-90.0%)., Conclusions: Hospitals policy and mass media deeply condition the public opinion, and this aspect may explain a different access to the hospital among non-Italian patients. Telemedicine should be promoted especially among non-Italian communities in Italy to overgo patients' skepticism and incentivize prevention and early treatment in dermatological conditions.

Background: Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC., Methods: In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression-free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated., Results: After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4-NR) in actively treated patients and 3 months (95% CI: 2-4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1-6 vs. 2-5; p = 0.6) and OS (12 and 4 months, 95% CI: 3-NR vs. 2-NR; p = 0.2)., Conclusion: After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Biliary tract cancers (BTCs) are frequently diagnosed in advanced stages and are highly lethal. Immunotherapy may play a role in the treatment of these patients. Promising results come from monotherapy or combination therapy studies in pretreated patients. In addition, several studies have demonstrated the safety and efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy in treatment-naive patients. Numerous biomarkers have been investigated to define their predictive role in response to ICIs. However, the full extent of the benefit of immunotherapies has not yet been fully established and, except for high microsatellite instability status, no other biomarkers were uniquely predictive of response to ICIs.

Hintergrund: Elektrochemotherapie (ECT) ist eine wirksame lokale Behandlung von Hauttumoren. Ziel dieser Studie war es, die Wirksamkeit der ECT bei ulzerierten gegenüber nichtulzerierten Tumoren zu vergleichen und den Effekt auf tumorassoziierte Symptome zu untersuchen., Methodik: 20 Krebszentren des International Network for Sharing Practices on Electrochemotherapy (InspECT) sammelten prospektiv Daten. Die ECT wurde nach dem ESOPE-Protokoll durchgeführt. Das Therapieansprechen wurde anhand der Entwicklung der Läsionsgröße bewertet. Zusätzlich wurden Schmerzen, Symptome, Leistungsstatus (ECOG-Index) und Gesundheitszustand (EQ-5D-Fragebogen) untersucht., Ergebnisse: 716 Patienten mit ulzerierten (n = 302) und nichtulzerierten (n = 414) Hauttumoren und Metastasen wurden eingeschlossen (Mindest-Nachsorge 45 Tage). Nicht-ulzerierte Läsionen sprachen besser auf die ECT an als ulzerierte Läsionen (vollständiges Ansprechen: 65 % gegenüber 51 %, p = 0,0061). Nur 38 % (115/302) der Patienten mit ulzerierten Läsionen vor der ECT wiesen bei der letzten Nachuntersuchung ulzerierte Läsionen auf. Patienten mit ulzerierten Läsionen berichteten über stärkere Schmerzen und schwerere Symptome im Vergleich zu Patienten mit nichtulzerierten Läsionen, die sich nach der ECT signifikant und kontinuierlich besserten. Bei Patienten mit nichtulzerierten Läsionen hingegen nahmen die Schmerzen während der Behandlung vorübergehend zu. Es wurden keine schwerwiegenden Nebenwirkungen beobachtet., Schlussfolgerungen: Die ECT ist eine sichere und wirksame lokale Behandlung von Hauttumoren. Während die ECT die Symptome insbesondere bei Patienten mit ulzerierten Läsionen verbessert, sollte auf Basis der Daten die Implementation eines perioperativen Schmerzmanagements besonders bei nichtulzerierten Läsionen während der ECT erwogen werden., (© 2022 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Background: Electrochemotherapy (ECT) is an effective local treatment for cutaneous tumors. The aim of this study was to compare the effectiveness of ECT in ulcerated vs. non-ulcerated tumors and investigate the effect on tumor-associated symptoms., Methods: Twenty cancer centers in the International Network for Sharing Practices on Electrochemotherapy (InspECT) prospectively collected data. ECT was performed following ESOPE protocol. Response was evaluated by lesion size development. Pain, symptoms, performance status (ECOG-Index) and health status (EQ-5D questionnaire) were evaluated., Results: 716 patients with ulcerated (n = 302) and non-ulcerated (n = 414) cutaneous tumors and metastases were included (minimum follow-up of 45 days). Non-ulcerated lesions responded to ECT better than ulcerated lesions (complete response 65 % vs. 51 %, p = 0.0061). Only 38 % (115/302) with ulcerated lesions before ECT presented with ulcerated lesions at final follow-up. Patients with ulcerated lesions reported higher pain and more severe symptoms compared to non-ulcerated lesions, which significantly and continuously improved following ECT. In non-ulcerated lesions however, pain spiked during the treatment. No serious adverse events were reported., Conclusions: ECT is a safe and effective local treatment for cutaneous tumors. While ECT improves symptoms especially in patients with ulcerated lesions, data suggest the implementation of a perioperative pain management in non-ulcerated lesions during ECT., (© 2022 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic is challenging healthcare systems worldwide. Dermatology had to re-prioritize visits, guarantee urgent care, and ensure continuity for chronic patients., Objectives: To evaluate the COVID-19 impact on dermatologic surgery outpatient management., Material and Methods: In this real-life retrospective observational study, we evaluated both major and minor outpatient surgeries (MaOS and MiOS) performance in 2020, before and during the first month of lockdown declaration, in a primary referral center in Northern Italy. During the lockdown, all lifesaving and cancer surgery, (approximately 80% of our usual activities), were continued. Data from 2020 were compared with the 2019 corresponding periods to assess the real-life impact of COVID-19 in dermatologic surgical activities., Results: From January 1st to April 3rd, 2020 we performed 769 interventions, compared to 908 over the corresponding 2019 period. After the lockdown, scheduled surgeries were reduced by 14.8%; overall performed ones displayed a reduction of 46.5% (51.6% MaOS, 44.2% MiOS). 52.9% and 12.5% procedures were canceled due to patients' renunciation and due to confirmed/suspected COVID-19, respectively., Conclusions: While reduced in number, dermatologic surgeries, similarly to other surgical specialties, remained operative to provide oncological and/or life-saving procedures.

The aims of this study were to assess the presence of dysgeusia in patients receiving anticancer therapy and to explore possible factors influencing its occurrence. A total of 242 adult patients with histological diagnoses of malignant neoplasia and undergoing all types of anticancer treatment were included in the analysis. Data were collected from May 2019 to November 2019 at the Unit of Medical Oncology of Careggi University Hospital, Florence, Italy. Dysgeusia was assessed using the Chemotherapy-induced Taste Alteration Scale (CiTAS), while treatment-related symptoms were assessed using the Common Terminology Criteria for Adverse Events (CTCAE). Patients were aged 68 ± 13 years, mostly males (65%). A large proportion of them was undergoing chemotherapy (42.2%), while the others were receiving immunotherapy (20.7%), hormone therapy (15.5%), targeted therapy (12.8%), or a combination of them. Overall, 21.5% of patients reported dysgeusia, 17.4% nausea, 10.7% dysosmia, 9.9% xerostomia, 4.5% mucositis, and only 3.7% vomiting. The targeted therapy showed the greatest adverse effects, followed by chemotherapy, immunotherapy, and hormone therapy. When patients with dysgeusia were analyzed, phantogeusia and parageusia was the most affected dimension of gustatory disorders. Significant differences ( p  < 0.05) in CiTAS scores were found according to treatment-related symptoms for nausea and mucositis.

Background: Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy., Methods: We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group., Results: The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS ( p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS ( p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 [95% CI 0.36-0.97], p = 0.037)., Conclusions: This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients.

Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC-IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% ( p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively ( p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively ( p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.

In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tartarone, Lapadula, Di Micco, Rossi, Ottanelli, Marini, Giorgione, Ferrari, Catalano, Voltolini, Mini and Roviello.)

Purse-string suture (PSS) and full-thickness skin graft (FTSG) are two different approaches to the closure of circular skin defects. In this study, we compare the feasibility and the aesthetic outcome of these two techniques in high operatory risk non-melanoma skin cancer (NMSC) patients. We performed a retrospective study on 65 patients, treated with PSS or FTSG, and evaluated after a minimum follow-up of 6 months. The post-surgery assessment was based on the Vancouver scar scale (VSS) and differences in terms of defect areas, operative and healing times were performed both with parametric and nonparametric tests. Operative times in PSS were significantly lower than those needed for FTSG, without perioperative adverse events; PSS required a waiting time before removing the suture greater than FTSG. After surgery, PSS resulted in a median defect area reduction of 73%. No significant differences were found in the median value for VSS in the two groups. Based on our clinical experience, the PSS advantages in terms of feasibility, rapidity of execution, and mean defect area reduction were confirmed. So, this technique seems to be appropriate for fragile patients affected by NMSC, that cannot hold long surgical sessions., (© 2021 Wiley Periodicals LLC.)

Introduction : Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide. Areas covered: This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones. Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients., Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group., Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction ( n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11-0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13-0.84) p = 0.020]., Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response.

Abstract: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that usually presents as a painful ulcer with erythematous and undermined borders and is often characterized by pathergy. Although this condition precludes a surgical approach, in cases resistant to treatment with immunosuppressive agents, skin grafts and amputation are considered last resorts. Both expose the patient to the risk of developing new lesions. A minimally invasive autologous graft, "minced micrografts," is a possible alternative to speed up the healing process, reducing the risk of pathergy.This procedure was implemented in a 28-year-old man with PG who was prescribed prednisone and dapsone and who had a large ulcer on the arm and armpit that had persisted for 4 months and was undergoing slow re-epithelialization. A sample of finely minced skin previously taken from the clavicular region suspended in a hydrogel was spread on the wound bed in a proportion of less than 1:6 with respect to the receiving site. Seven days later, initial signs of re-epithelialization appeared, and the wound healed in 3 months.In patients with PG, the minced micrograft method could facilitate ulcer healing by releasing cytokines, chemokines, and growth factors, thus promoting granulation tissue formation, neoangiogenesis. Because this method does not require special equipment or complex surgical techniques and is very low cost, it should be an integral part of the arsenal of procedures aimed at improving the quality of life of patients with PG., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Electrochemotherapy (ECT) is a treatment for both primary and secondary cutaneous tumours. The international Network for sharing practices on ECT group investigates treatment outcomes after ECT using a common database with defined parameters., Methods: Twenty-eight centres across Europe prospectively uploaded data over an 11-year period. Response rates were investigated in relation to primary diagnosis, tumour size, choice of electrode type, route of bleomycin administration, electrical parameters recorded and previous irradiation in the treated field., Results: Nine hundred eighty-seven patients, with 2482 tumour lesions were included in analysis. The overall response (OR) rate was 85% (complete response [CR]: 70%, partial response rate: 15%, stable disease: 11%, and progressive disease: 2%). For different histologies, OR and CR rates for metastases of malignant melanoma were 82% and 64%, basal cell carcinoma were 96% and 85%, breast cancer metastases were 77% and 62%, squamous cell carcinoma were 80% and 63% as well as Kaposi's sarcoma were 98% and 91%, respectively. Variance was demonstrated across histotypes (p < 0.0001) and in accordance with size of lesion treated (dichotomised at diameter of 3 cm (p < 0.0001). Hexagonal electrodes were generally used for larger tumours, but for tumours up to 3 cm, linear array electrodes provided better tumour control than hexagonal electrodes (80%:74%, p < 0.003). For tumours more than 2 cm, intravenous administration was superior to intratumoural (IT) administration (p < 0.05). Current recorded varied across tumour histologies and size but did not influence response rate. In previously irradiated areas, responses were selectively lower for IT administration., Conclusions: These cumulative data endorse efficiency of ECT across a broad range of histotypes. Analysis of 2482 lesions details subgroup analysis on treatment response informing future treatment choices., Competing Interests: Conflict of interest statement The following authors have conflict of interest: A.J.P.C. reports receiving travel fees for a meeting related to manuscript preparation by IGEA. F.d.T. is an employee of IGEA. J.O. reports receiving travel fees and accommodation fees from IGEA. L.G.C. reports receiving travel support for the International Network for Sharing Practice in Electrochemotherapy (InspECT) meeting from IGEA. D.M. reports receiving travel fees and accommodation fees for InspECT meeting from IGEA. A.D.M.R. reports receiving flight and accommodation fees for electrochemotherapy meeting and has aso received an honorarium. J.G. reports receiving travel fees and accommodation for a meeting related to manuscript preparation from IGEA. The other authors report no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Germline mutations on the CDKN2A gene, the most important known genetic factors associated with cutaneous melanomas (CMs), predispose carriers to multiple primary CMs (MPMs) with higher frequency and younger onset compared to non-carriers. Most of the largest published studies concerning clinical and histological characteristics of CMs with CDKN2A mutation carriers did not specify if the described CMs are first or subsequent to the first, and they used sporadic CMs from non-genotyped patients as controls. We conducted a single-centre observational study to compare clinical and histological CM features of 32 unrelated carriers (MUT) of 5 germline CDKN2A mutations (one of which was never previously described) compared to 100 genotyped wild-type (WT) patients. We stratified the data based on time of diagnosis, anatomical site and histological subtype of CMs, demonstrating several significant unreported differences between the two groups. MUT developed a higher number of dysplastic nevi and MPMs. We proved for the first time that anatomical distribution of CMs in MUT was independent of gender, unlike WTs. MUTs developed in situ and superficial spreading melanomas (SSMs) more frequently, with significantly higher number of SSMs on the head/neck. In MUTs, Breslow thickness was significantly lower for all invasive CMs. When CMs were stratified on the basis of the time of occurrence, statistical significance was maintained only for SSMs subsequent to the first. In WTs, Clark level was significantly higher, and ulceration was more prevalent than in MUTs. Significant differences in ulceration were observed only in SSMs. In nodular CMs, we did not find differences in terms of Breslow thickness or ulceration between WTs and MUTs. In situ CMs developed 10 years earlier in MUTs with respect to WTs, whereas no significant differences were observed in invasive CMs. In contrast to those reported previously by other authors, we did not find a difference in skin phototype.

Primary carcinoid tumors of the skin are exceptional, with only ten cases reported from 1975 to date. We describe a case of a 66-year-old woman with a primary cutaneous carcinoid developed on the scalp. The tumor was completely excised and clinical investigations as well as diagnostic studies failed to reveal internal primary site, neither at the time of the excision, neither during follow-up. Nevertheless, 7 years after the surgical excision, she developed a recurrence of the lesion on the same site. To the best of our knowledge, this is the first report of a primary relapsing carcinoid of the skin described up to now. Interestingly, the tumour expresses estroprogestinic receptors.

The advent of immune checkpoint inhibitors anti-PD-1/PD-L1 has delivered new and effective treatment options with proven clinical benefits for patients affected by metastatic melanoma. The 30-40% of treated patients experience an objective tumour regression, with a significantly prolonged survival and an improved quality of life. Here, we report a case of a 75-year-old Caucasian woman affected by a massive cutaneous metastasis from a BRAF wild-type melanoma who experienced multiple relapses after surgery and repeated electrochemotherapy treatments. A poor response was observed after systemic therapy with ipilimumab, whereas a marked reduction in the lesion size was obtained during the treatment with nivolumab, with an objectively complete response after 6 months. Therapy was well tolerated, without immune-related side effects. During treatment, LDH levels decreased up to the standard values. Our experience confirms the good efficacy and the safety of anti-PD-1 nivolumab for the treatment of relapsed or refractory massive skin lesions, also in elderly patients.

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aim: The aim of this study was to review our experience with regards to patients with cutaneous melanoma diagnosed from 1983 to 2009, followed-up in our Dermatological Department of Novara., Methods: A retrospective study of 762 patients diagnosed with cutaneous melanoma in the Dermatological Department of Novara between 1983 and 2009 was conducted. Information was extracted from our melanoma patient database. The database included demographical, clinical and pathological variables of the patient. Clinical and pathological factors predicting survival were analyzed using the Kaplan-Meier curves and the Log-Rank Test (univariate analysis)., Results: Staging (American Joint Committee on Cancer 2001) of patients (P=0.000), Breslow thickness (P=0.000), primary ulceration and regression of the lesion (P=0.000), type of first (P<0.039) and second recurrence (P<0.011) were strongly correlated with overall and disease free survival. Sentinel lymph node biopsy was not correlated with disease free survival (P=0.153), it influences only overall survival (P=0.007) CONCLUSION: Our results confirms that sentinel node biopsy, Breslow thickness, ulceration, regression, staging, first and second recurrence are important variable for overall survival and disease free survival, sentinel lymph node status influence only overall survival instead.

A case of herniation of small bowel through a defect of the transverse meso-colon with secondary herniation through the gastrocolic ligament and re-entry into the greater peritoneal cavity is reported. This form of lesser sac hernia is rare and only one hundred half cases have been reported in literature.

In order to evaluate the clinical utility of autologous splenic transplantation in the omental pouch, a pneumococcal challenge was performed in 3 groups of rats, after demonstration of vitality of the intraperitoneal inoculum: Group A: splenectomized rats; Group B: reimplanted rats; Group C: sham operation. No statistically significant difference was found between the first two groups regarding resistance against infection (p less than 0.982), while normal rats proved more resistant (p less than 0.031). Between group A and B significant differences (p less than 0.001) exists only for a more precocious mortality in the first group. The poor clinical utility of the technique is demonstrated.