Cutaneous melanoma in older patients.

BACKGROUND: In industrialized countries, the aging population is steadily rising. The incidence of cutaneous malignant melanoma (CMM) is highest in old people. This study focuses on the clinicopathological profile of CMM and indicators of diagnostic-therapeutic performance in older patients. METHODS: This retrospective population-based cohort study included 1,368 incident CMM, as recorded in 2017 by the Regional Veneto Cancer Registry (Northeast Italy). Older subjects were defined as ≥ 80, old as 65-79, and adults as < 65 years of age. The strength of association between pairs of variables was tested by Cramer's-V. Using age groups as the dependent variable, ordered logistic regression was fitted using the clinicopathological CMM profiles as covariates. In each of the three age-groups, the indicators of clinical performance were computed using the Clopper-Pearson exact method. RESULTS: Compared to patients aged younger than 80 years (1,187), CMM in older patients (181; 13.2%) featured different CMM topography, a higher prevalence of ulcers (43.3% versus 12.7%; p < 0.001), a higher Breslow index (p < 0.001), a lower prevalence of tumor-infiltrating lymphocytes (64.4% versus 76.5%, p < 0.01), and a more advanced pTNM stage at clinical presentation (p < 0.001). Elderly patients with a positive sentinel-lymph node less frequently underwent sentinel- lymph node biopsy and lymphadenectomy (60.0% versus 94.2%, and 44.4% versus 85.5%, respectively; p < 0.001). CONCLUSIONS: In older CMM patients, the clinicopathological presentation of CMM shows a distinctive profile. The present results provide critical information to optimize secondary prevention strategies and refine diagnostic-therapeutic procedures tailored to older patients.

Morbidity and Outcomes After Distal Pancreatectomy for Primary Retroperitoneal Sarcoma: An Analysis by the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Multi-visceral resection often is used in the treatment of retroperitoneal sarcoma (RPS). The morbidity after distal pancreatectomy for primary pancreatic cancer is well-documented, but the outcomes after distal pancreatectomy for primary RPS are not. This study aimed to evaluate morbidity and oncologic outcomes after distal pancreatectomy for primary RPS. METHODS: In this study, 26 sarcoma centers that are members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) retrospectively identified consecutive patients who underwent distal pancreatectomy for primary RPS from 2008 to 2017. The outcomes measured were 90-day severe complications (Clavien-Dindo ≥ 3), postoperative pancreatic fistula (POPF) rate, and oncologic outcomes. RESULTS: Between 2008 and 2017, 280 patients underwent distal pancreatectomy for primary RPS. The median tumor size was 25 cm, and the median number of organs resected, including the pancreas, was three. In 96% of the operations, R0/R1 resection was achieved. The 90-day severe complication rate was 40 %. The grades B and C POPF complication rates were respectively 19% and 5% and not associated with worse overall survival. Administration of preoperative radiation and factors to mitigate POPF did not have an impact on the risk for the development of a POPF. The RPS invaded the pancreas in 38% of the patients, and local recurrence was doubled for the patients who had a microscopic, positive pancreas margin (hazard ratio, 2.0; p = 0.042). CONCLUSION: Distal pancreatectomy for primary RPS has acceptable morbidity and oncologic outcomes and is a reasonable approach to facilitate complete tumor resection.

Management of melanoma patients during COVID-19 pandemic in an Italian skin unit.

Due to the COVID-19 crisis, many scheduled medical and surgical activities have been suspended. This interruption to the healthcare system can negatively affect the diagnosis and management of melanoma. Neglecting melanoma throughout the outbreak may be associated with increased rates of mortality, morbidity, and healthcare expenses. We performed a retrospective review of all dermatological and surgical activity performed in our Melanoma Skin Unit between 23 February 2020 and 21 May 2020 and compared these data with those from the same period in 2019. During the lockdown period, we observed a decrease in dermatologic follow-up (DFU) (-30.2%) and in surgical follow-up (SFU) (-37%), and no modification of melanoma diagnosis (-3%). Finally, surgical excisions (SE) (+ 31.7%) increased, but sentinel lymph node biopsy (SLNB) (-29%) and lymph node dissections(LND) (-64%) decreased compared to the same period in 2019. Our experience supports the continuation of surgical and diagnostic procedures in patients with melanoma during the COVID-19 pandemic. Surgical and follow-up procedures for the diagnosis and treatment of melanoma should not be postponed considering that the pandemic is lasting for an extended period.

Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. METHODS: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018. FINDINGS: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events. INTERPRETATION: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma. FUNDING: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.

The role of radiological and hybrid imaging for muscle metastases: a systematic review.

AIM OF THE STUDY: Skeletal muscle metastases (SMM) are a rare entity, mainly detected at autopsy. Nevertheless, radiological and nuclear medicine imaging can contribute to the diagnosis with a significant impact on the treatment and prognosis of neoplastic patients. This study aimed to systematically review the features of SMM at imaging considering the primary tumors and the sites of occurrence. MATERIALS AND METHODS: We conducted a systematic search of three electronic database (i.e., PubMed, Science Direct, and Web of Science) up to May 2019, without any language or time interval restriction. Two reviewers performed the search and selection process, data extraction, and synthesis. We resolved disagreements by consensus and/or involving a third reviewer. The included studies have been classified according to the Oxford Centre for Evidence Based Medicine (CEBM) grading system. RESULTS: Out of 8598 and 1077 articles respectively for radiological and hybrid imaging, 29 papers were included. According to CEBM, twelve were level 4. Computed tomography (CT) is mainly applied and, despite the existence of CT and magnetic resonance-based classifications, these are rarely used. Positron emission tomography/CT allowed the detection of small and subtle lesion also in the extremities. Muscles of the trunk were mostly affected and mainly respiratory tumors are associated with this type of metastatic spread. CONCLUSION: Radiological and hybrid imaging allow a precise characterization of SMM. However, a more systematic approach, including also the application of available classification systems, may increase the diagnostic accuracy for this rare type of metastases. KEY POINTS: • Skeletal muscle metastases have heterogeneous characteristics at imaging but mostly abscess-like features and high metabolic activity are described. • Skeletal muscle metastases mainly affect the muscles of the trunk. • Pulmonary, urological, and gastrointestinal cancers are the most frequent cause of skeletal muscle metastases.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Growth rate and myofibroblast differentiation of desmoid fibroblast-like cells are modulated by TGF-ß signaling.

Desmoid-like fibromatosis (DF) is a rare myofibroblastic benign tumor, often associated with local and repeated injuries, spontaneous regression and stabilization of disease progression suggesting the involvement of altered Wnt/ß-catenin signaling activation and/or aberrant response of the DF cells to external environmental stimuli. The aim of this study was to investigate the response of DF cells to microenvironmental factors such as inflammatory and growth factors or hormones. We observed that the inflammatory cytokine, transforming growth factor-ß (TGF-ß1) stimulated cell growth and myofibroblast differentiation of DF cells regardless of the presence of a ß-catenin mutation. The role of TGF-ß1 in cell growth and myogenic differentiation of in vitro cultures of primary DF cells and normal fibroblasts was investigated by gene and protein expression analyses. We demonstrated that TGF-ß1 exerted its role via the canonical Smad pathway with the phosphorylation of Smad3 being crucial for TGF-ß1 dependent DF cell growth and myofibroblastic differentiation. Furthermore we demonstrated that cell confluence is a critical determinant of TGF-ß1 inducing the DF myofibroblast differentiation, implying that the intercellular communications have an important role on the DF myofibroblast behavior. We observed the formation of an increased stress-fiber pattern in DF cells with increased projected cell area and stronger cell-cell contacts in presence of TGF-ß1. These results demonstrated that TGF-ß1 plays a crucial role in the DF cells growth and, together with cell-cell interactions, in DF myofibroblast conversion; we also highlighted that the cellular sensitivity to this cytokine was an intrinsic feature of the DF cells.

miRNA deregulation targets specific pathways in leiomyosarcoma development: an in silico analysis.

BACKGROUND: MicroRNA (miRNA) mediate post-transcriptional gene repression and are involved in a variety of human diseases, including cancer. Soft tissue sarcomas are rare malignancies with a variety of histological subtypes which may occur virtually anywhere in the human body. Leiomyosarcoma is one of the most common subtypes, shows a smooth muscle phenotype and its cancerogenesis is still unclear. The aim of our study was to investigate the potential role of miRNA differential expression in leiomyosarcoma development. METHODS: We first employed the Sarcoma microRNA Expression Database, a repository that describes the patterns of over 1000 miRNA expression in various human sarcoma types, to identify differentially expressed miRNA comparing leiomyosarcoma and smooth muscle samples. Subsequently, we identified putative target genes of those miRNAs with the TargetScan prediction tool. Finally, we evaluated whether the retrieved pool of putative targets was enriched in genes belonging to specific molecular pathways by means of the Enrichr analysis tool. Protein-protein network analysis was analyzed by means of the STRING web tool. RESULTS: Out of 1120 miRNAs tested, the expression of 301 miRNAs was statistically significantly different between leiomyosarcoma and smooth muscle samples. The hypothetical targets could be predicted for 172 miRNAs. 438 genes were predicted to be the targets with high confidence (cumulative weighted context score cut-off level less than - 1.0) and analyzed for belonging to specific molecular pathways. Pathway analysis suggested that RNA Polymerase III, tRNA functions and synaptic neurotransmission (with special regard to dopamine mediated signaling) could be involved in leiomyosarcoma development. CONCLUSIONS: Our results demonstrate that data mining of publicly available repositories can be useful to suggest molecular pathways underlying the pathogenesis of rare tumors such as leiomyosarcoma.

Long-term response to first-line trabectedin in an elderly female patient with a metastatic leiomyosarcoma unfit for anthracycline.

Systemic chemotherapy comprising anthracycline monotherapy is the standard regimen for metastatic soft tissue sarcomas, particularly leiomyosarcomas, which have limited sensitivity to ifosfamide. However, the optimal chemotherapy regimen for elderly patients, especially those considered unfit for anthracyclines, is undefined. Trabectedin is a potent marine-derived antineoplastic drug with documented activity in liposarcomas and leiomyosarcomas. It is registered in Europe for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. We report the long-term response to first-line trabectedin therapy in an elderly patient with metastatic leiomyosarcoma unfit for standard therapy. A 66-year-old woman underwent resection of a pelvic epithelioid leiomyosarcoma with positive margins in December 2002, followed by postoperative radiotherapy. In February 2012, she was diagnosed with multiple lung lesions and local relapse in the pelvis. As she was considered unsuitable for both anthracycline and ifosfamide because of cardiovascular comorbidities and because she was highly anxious at the prospect of developing alopecia, vomiting, and fatigue, we commenced treatment with trabectedin at 75% of the standard dose of 1.5 mg/m every 3 weeks. Treatment was well tolerated, and the patient continued treatment for 25 cycles, with disease stabilization according to the RECIST criteria and a partial response according to the Choi criteria. Disease progression was observed in November 2013 and the patient died 20 months after the diagnosis of metastases. Trabectedin may represent an alternative option for highly selected elderly patients with metastatic sarcoma and unfit for anthracyclines; careful monitoring of toxicities is strongly recommended.

Hyperthermic isolated limb perfusion in locally advanced limb soft tissue sarcoma: A 24-year single-centre experience.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) is a locoregional treatment aimed at avoiding amputation in patients with advanced extremity soft tissue sarcomas (STS). Over the last 25 years, HILP procedure has been implemented to maximise its therapeutic ratio. METHODS: A retrospective analysis including 117 patients who underwent HILP from 1989 to 2013 was performed. Three different drug schedules were applied: 1) doxorubicin (n = 47), 2) high dose (3-4 mg) tumour necrosis factor-alpha (TNF-α) plus doxorubicin (n = 30), 3) low dose (1 mg) TNF-α plus melphalan (L-PAM) (n = 40). Tumour response was evaluated by MRI or CT and surgical specimens. Toxicity and local progression-free survival (LPFS) were also evaluated. RESULTS: In total 92 (78.6%) patients had primary, 25 (21.4%) had recurrent and 17 (14.5%) had metastatic disease. The subjects in the three groups were homogeneous for clinical-pathological features. Pathological response was complete in 55 patients (47%), partial in 35 (29.9%), regardless of drug schedule (p = 0.501) and tumour presentation (p = 0.094). Wieberdink III-V toxicity was registered in 19.1%, 20% and 2.5% of patients, respectively (p < 0.051). Twenty-eight patients (23.9%) received adjuvant radiotherapy with no relevant toxicity. Five-year LPFS was 81.6% and 74.2% in patients with primary or recurrent disease, respectively (p = 0.652). After a median follow-up of 36.5 months, the limb sparing rate was 77.8%. CONCLUSIONS: HILP performed with different drugs was equally active, either in primary, recurrent or metastatic STS, providing effective limb sparing and durable local control. Low dose TNF-α plus L-PAM had the most favourable toxicity profile. Adjuvant radiotherapy was not associated with relevant toxicity.

Response to trabectedin in a patient with advanced synovial sarcoma with lung metastases.

Trabectedin is an alkylating agent registered in Europe for the treatment of advanced metastatic soft-tissue sarcomas, whose activity has been documented mainly in liposarcomas or leiomyosarcomas. Here, we report the response achieved in a patient with lung metastases from synovial sarcoma. A man with a large synovial sarcoma of the axilla underwent three cycles of neoadjuvant epirubicin+ifosfamide before complete excision, followed by three additional cycles of chemotherapy and radiotherapy. After 14 months, bilateral lung metastases appeared and were first treated with a prolonged 14-day continuous infusion of high-dose ifosfamide without response, and then with second-line trabectedin. A partial radiological response was achieved; dosage was reduced to 1.1 mg/m because of mild asthenia, grade 3 neutropenia, grade 3 nausea and vomiting, and reversible transaminase elevation. After 9 months of treatment, the lung nodules progressed, the patient received sorafenib, but further progressed and died 19 months after the first appearance of lung metastases. Trabectedin was the only drug that led to a radiological response in this patient with synovial sarcoma, despite being administered at 75% of the standard dose because of dose-limiting nausea and vomiting, in line with more recent data demonstrating activity in translocated sarcomas. We believe that trabectedin represents an attractive option for the treatment of metastatic synovial sarcoma and further clinical studies are warranted.

Isolated Limb Perfusion and Immunotherapy in the Treatment of In-Transit Melanoma Metastases: Is It a Real Synergy?

BACKGROUND: Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape. METHODS: This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor). RESULTS: A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group (p = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group (p = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group (p = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group (p = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS (p = 0.01) and DSS (p = 0.007) but not local DFS (p = 0.13) and distant DFS (p = 0.21). CONCLUSIONS: Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.

Technical considerations for isolated limb perfusion: A consensus paper.

BACKGROUND: Isolated limb perfusion (ILP) is a well-established surgical procedure for the administration of high dose chemotherapy to a limb for the treatment of advanced extremity malignancy. Although the technique of ILP was first described over 60 years ago, ILP is utilised in relatively few specialist centres, co-located with tertiary or quaternary cancer centres. The combination of high dose cytotoxic chemotherapy and the cytokine tumour necrosis factor alpha (TNFα), mandates leakage monitoring to prevent potentially serious systemic toxicity. Since the procedure is performed at relatively few specialist centres, an ILP working group was formed with the aim of producing technical consensus guidelines for the procedure to streamline practice and to provide guidance for new centres commencing the technique. METHODS: Between October 2021 and October 2023 a series of face to face online and hybrid meetings were held in which a modified Delphi process was used to develop a unified consensus document. After each meeting the document was modified and recirculated and then rediscussed at subsequent meeting until a greater than 90% consensus was achieved in all recommendations. RESULTS: The completed consensus document comprised 23 topics in which greater than 90% consensus was achieved, with 83% of recommendations having 100% consensus across all members of the working group. The consensus recommendations covered all areas of the surgical procedure including pre-operative assessment, drug dosing and administration, perfusion parameters, hyperthermia, leakage monitoring and theatre logistics, practical surgical strategies and also post-operative care, response evaluation and staff training. CONCLUSION: We present the first joint expert-based consensus statement with respect to the technical aspects of ILP that can serve as a reference point for both existing and new centres in providing ILP.

Nuclear GSK-3ß segregation in desmoid-type fibromatosis.

AIMS: Desmoid-type fibromatosis (DF) is a rare benign myofibroblastic neoplasm of the connective tissue that is unable to metastasize but is associated with a high local recurrence rate. Nuclear ß-catenin is the most commonly used histological marker of DF; however, clinical and biological predictive markers guiding the treatment and follow-up of DF are still lacking. Normally, ß-catenin is regulated by the cytoplasmic multiprotein complex of adenomatous polyposis coli (APC), axin, casein kinase 1α (CK1α), and glycogen synthase kinase 3ß (GSK-3ß); this phosphorylates and degrades ß-catenin, which would otherwise translocate to the nucleus. The aim of this study was to analyse the expression and localization of the ß-catenin-protein complex of the Wnt pathway in cells isolated from DF patients. METHODS AND RESULTS: We isolated cells from biopsies of DF patients, and demonstrated, by immunofluorescence and immunoblot analyses, that it is almost exclusively nuclear GSK-3ß that colocalizes and interacts with ß-catenin. The nuclear translocation of ß-catenin and GSK-3ß is not correlated with CTNNB1 mutations. In DF samples, the multiprotein complex is disrupted, as the cytoplasmic localization of APC and axin makes interaction with the nuclear ß-catenin and GSK-3ß impossible. CONCLUSIONS: Our data suggest that GSK-3ß is an additional DF marker with an important role in the aetiopathogenesis of this entity.

Imaging of soft-tissue tumors.

The objective of this review is to highlight the major imaging characteristics of the main soft-tissue sarcoma histotypes observed in the group "Sarcomi" of the Istituto Oncologico Veneto in the last 5 years. A literature review was performed using PubMed and textbooks. Radiological imaging can guide the diagnosis for the subset of lesions that have typical clinical and imaging features. Soft-tissue tumors are common in clinical practice and a systematic clinical and imaging approach may guide the diagnosis.

Highly biocompatible material for enhanced abdominal wall repair: a retrospective study with EGIS® porcine dermal matrix.

In the early 2000s, medical devices based on acellular matrices multiplied in number. Nowadays, the use of porcine ADMs is to be considered a well-established technology, commonly applied in different surgical specialties. In this retrospective analysis of 110 cases, the use of non-crosslinked porcine ADM EGIS® results a safe and effective tool in many procedures and specialties.

Do Tumor SURVIVIN and MDM2 Expression Levels Correlate with Treatment Response and Clinical Outcome in Isolated Limb Perfusion for In-Transit Cutaneous Melanoma Metastases?

Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases.

Soft Tissue Sarcoma Mimicking Melanoma: A Systematic Review.

BACKGROUND: Sarcoma may show similarities to malignant melanoma in terms of morphologic and immunohistochemical aspects, making it difficult to differentiate between these two neoplasms during the diagnostic process. This systematic review aims to summarize available evidence on cases of sarcoma that were initially diagnosed as melanoma. METHODS: A comprehensive search of the MEDLINE/Pubmed, EMBASE, and SCOPUS databases was conducted through March 2023. We included case series and case reports of sarcoma patients that were initially diagnosed as malignant melanoma. PRISMA guidelines were followed. RESULTS: Twenty-three case reports and four case series with a total of 34 patients were included. The clinical presentation was heterogeneous, and the most involved anatomical regions were lower limbs (24%), head/neck (24%), and upper limbs (21%). IHC positivity was reported for S100 (69%), HMB45 (63%), MelanA (31%), and MiTF (3%). The main reasons for a second assessment were unusual presentation (48%) and uncertain diagnosis (28%). EWSR1 translocation was investigated in 17/34 patients (50%) and found to be positive in 16/17 (94%). The final diagnosis was clear cell sarcoma (50%) or other soft tissue sarcomas (50%). CONCLUSIONS: Melanoma and some histotypes of sarcoma share many similarities. In cases of atypical lesions, a second diagnosis should be considered, and ESWR1 translocation should be investigated.