In vivo and ex vivo confocal microscopy for the evaluation of surgical margins of melanoma.

We report the first series of melanomas (MMs) where the surgical margins were evaluated both by ex vivo confocal microscopy (EVCM) and in vivo reflectance confocal microscopy (RCM). We evaluated the surgical margins of 42 cutaneous MMs of lentigo maligna/lentigo maligna melanoma type and 2 mucosal MMs with EVCM. Cutaneous MMs also underwent RCM mapping. Imaging results were compared with histopathology. The rate of correct identification of the tumor margins (invaded or not invaded) was 97.6% for RCM (evaluations of cutaneous MMs) and 95.5% for EVCM (evaluations of both cutaneous and mucosal MMs). Our study showed that the MM extension is visible under EVCM and that the combination of in vivo RCM and EVCM can be a new strategy for the evaluation of surgical margins of MMs.

Surgical oncology in the elderly.

Poor cancer-specific outcomes in the elderly group are primarily a surgical failure. Surgeons are insufficiently trained to draw a line between fit and frail patients; this results in over-treatment of the frail patient, as well as under-treatment of the fit one. Communication skills should be improved to better understand the patient's requests. The timing of the surgical procedure is crucially important; all efforts should be put in place to optimize the patient's conditions before the surgery takes place.

Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy used as treatment of colo-rectal carcinomatosis: a multicentric study.

The aim of this study is to assess the morbidity and mortality related to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colo-rectal carcinomatosis. A retrospective multi-institutional study from seven Italian Centers was performed. One hundred and seventy-two patients, submitted to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) to treat carcinomatosis of colorectal origin, were recorded. Postoperative morbidity was evaluated in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Post-operative mortality was evaluated as patients' death within 60 days from surgical procedures. Predictors of morbidity were evaluated with univariate and multivariate analyses. Post-operative morbidity occurred in 83 patients (48.3%): grades 1-2 in 29 cases (16.9%), and grades 3-4 in 54 (31.4%). Mortality occurred in four cases (2.3%). Number of anastomoses (OR 1.45; 95% CI 1.05-2.00; p = 0.024), number of blood transfusions (OR 1.31; 95% CI 1.11-1.54; p = 0.001) and chemotherapy regimen [Oxaliplatin (OX): OR 2.87; 95% CI 1.22-6.75; p = 0.015] remained, in multivariate analysis, in a statistically significant correlation with overall morbidity. The only variable that was proven to have statistically significant correlation with 3-4 morbidity was the number of blood transfusions (OR 1.25; 95% CI 1.07-1.46; p = 0.005). Morbidity and mortality do not preclude the use of CRS plus HIPEC in the treatment of peritoneal carcinomatosis of colorectal origin.

Different Features of Tumor-Associated NK Cells in Patients With Low-Grade or High-Grade Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells. We show that while in the peritoneal fluid (PF) of low-grade PC most CD56dim NK cells show a relatively immature phenotype (NKG2A+KIR-CD57-CD16dim), in the PF of high-grade PC NK cells are, in large majority, mature (CD56dimKIR+CD57+CD16bright). Furthermore, in low-grade PC, PF-NK cells are characterized by a sharp down-regulation of some activating receptors, primarily NKp30 and DNAM-1, while, in high-grade PC, PF-NK cells display a higher expression of the PD-1 inhibitory checkpoint. The compromised phenotype observed in low-grade PC patients corresponds to a functional impairment. On the other hand, in the high-grade PC patients PF-NK cells show much more important defects that only partially reflect the compromised phenotype detected. These data suggest that the PC microenvironment may contribute to tumor escape from immune surveillance by inducing different NK cell impaired features leading to altered anti-tumor activity. Notably, after CRS/HIPEC treatment, the altered NK cell phenotype of a patient with a low-grade disease and favorable prognosis was reverted to a normal one. Our present data offer a clue for the development of new immunotherapeutic strategies capable of restoring the NK-mediated anti-tumor responses in association with the CRS/HIPEC treatment to increase the effectiveness of the current therapy.

Mitochondrial protein enriched extracellular vesicles discovered in human melanoma tissues can be detected in patient plasma.

Extracellular vesicles (EVs), including exosomes and microvesicles, are secreted from all cells, and convey messages between cells in health and disease. However, the diversity of EV subpopulations is only beginning to be explored. Since EVs have been implicated in tumour microenvironmental communication, we started to determine the diversity of EVs specifically in this tissue. To do this, we isolated EVs directly from patient melanoma metastatic tissues. Using EV membrane isolation and mass spectrometry analysis, we discovered enrichment of mitochondrial membrane proteins in the melanoma tissue-derived EVs, compared to non-melanoma-derived EVs. Interestingly, two mitochondrial inner membrane proteins MT-CO2 (encoded by the mitochondrial genome) and COX6c (encoded by the nuclear genome) were highly prevalent in the plasma of melanoma patients, as well as in ovarian and breast cancer patients. Furthermore, this subpopulation of EVs contains active mitochondrial enzymes. In summary, tumour tissues are enriched in EVs with mitochondrial membrane proteins and these mitochondrial membrane proteins can be detected in plasma and are increased in melanoma, ovarian cancer as well as breast cancer.

BRAF status as a predictive factor for response in isolated limb perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution. METHODS: Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria. RESULTS: Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months. CONCLUSION: In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.

Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma.

BACKGROUND: Isolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP. METHOD: Between 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68 second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien-Dindo). RESULTS: The results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p = 0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93 months (p = 0.02). CONCLUSION: As a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.

Sentinel node for malignant melanoma: An observational study of a consecutive single centre experience.

INTRODUCTION: Sentinel node biopsy (SNB) for melanoma gives prognostic information, however the success is dependent on several factors. The aim of this study was to describe outcome data after the introduction of the technique at our centre, including analysis of false negative rate (FNR), predictive factors for positive sentinel node (SN) and non-sentinel node (NSN), as well as prognostic factors for melanoma-specific survival (MSS). MATERIALS AND METHODS: This is a retrospective observational study of a prospectively kept database at Sahlgrenska University Hospital. Between March 2000 and December 2013, 769 consecutive patients with cutaneous malignant melanoma undergoing SNB were included. The median follow-up time was 55 months (2-179 months). Tumour load in the SN was categorized according to the largest tumour deposit, low when ≤1 mm and high when >1 mm. RESULTS: The FNR was 20% and the SN positivity rate was 14% with a decrease in both FNR and SN positivity rate during the study period. In multivariate analysis the only predictive factor for a positive SN was Breslow thickness. The 5-year melanoma specific survival (MSS) was 81% and in multivariate analysis the prognostic factors were SN-status (low metastatic load HR = 2.6, p = 0.001; high metastatic load HR = 2.7, p = 0.004) followed by Breslow thickness and ulceration. CONCLUSIONS: In this study Breslow thickness was the only independent predictive factor for a positive SN, no predictive factors were identified for NSN. Independent prognostic factors for MSS were SN status, Breslow thickness and ulceration. Interestingly, there was no survival difference depending on SN tumour burden when using 1 mm as cut-off.

Bowel vaginoplasty: a systematic review.

Among surgical procedures for constructing a neovagina, positive outcomes are reported in literature for bowel vaginoplasty for male-to-female transgenders and patients with vaginal aplasia. This systematic review shows outcomes of bowel vaginoplasty procedures, and rates the quality of evidence of the included studies. A search of the literature was performed in PubMed, Medline, Cochrane Library and SveMed+, in accordance with the PRISMA statement, between January 2016 and February 2018. The PICOS (patients, intervention, comparator, outcomes and study design) approach was used as inclusion criteria. Among 251 analyzed studies only 34 met inclusion criteria. Quality of evidence and methodology were rated according to GRADE and MINORS, respectively. Data from the included studies were extracted based on study characteristics, participants? specifics, type of intervention/treatment and type of outcome measures into data extraction forms. All studies were non-randomized with a high risk of bias and very low quality of evidence according to GRADE. Vaginal reconstruction with isolated bowel segments provides a self-lubricating neovagina with low rates of failure and revision, and without routine dilatation need. Furthermore, the use of laparoscopic techniques offers a better postoperative cosmetic appearance of the abdomen and a shorter hospital stay. Vaginoplasty using bowel segment is a safe and effective procedure that obtains excellent long-term results as reported by the included studies. Despite that further researches are needed improving methodology with larger populations, retrospective qualitative studies and report of outcome measurements using standardized evaluation tools as the Female Sexual Function Index.

The effect of perfusate buffering on toxicity and response in isolated hepatic perfusion for uveal melanoma liver metastases.

BACKGROUND: Isolated hepatic perfusion (IHP) is a treatment option for patients with liver metastases. Previous studies have found that liver toxicity is one of the limiting factors, and in an attempt to reduce the toxicity a buffering agent was added to the perfusate. The aim was to retrospectively analyse if this buffering reduced toxicity and complication rates. METHODS: A retrospective review of 52 consecutive patients with uveal melanoma liver metastases treated with IHP between 2005 and 2013. Patients were followed by daily liver function tests (LFT). Toxicity was graded according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE; United States Department of Health & Human Services, Washington, D.C), complications according to Clavien-Dindo and response according to RECIST-criteria. RESULTS: Thirty-six patients were treated with a buffered perfusate and 16 patients without buffer. There was no difference in age, gender, largest tumour size or number of tumours between the groups. There was a significantly lower mean in peak ALT, AST, PK (INR) and bilirubin when comparing buffer with no-buffer. There were five major complications without a significant difference between the groups (8.3 vs. 12.5%, p = 0.33). There was a lower complete response (CR) rate (11 vs. 44%, p = 0.023) and a trend for shorter time to local progression (9.2 vs. 17.6 months, p = 0.096); however, not significant in multivariate analysis. There was no difference in survival (24.2 vs. 26.0 months, p = 0.43) between the two groups. CONCLUSIONS: Adding buffer to the perfusate during IHP significantly reduces postoperative LFTs; however, without a reduced complication rate. Interestingly, buffering also seems to reduce the response rate; however, this did not translate into a survival difference. To address if buffering adds any clinical benefit to the patients concerning toxicity, a larger prospective trial is necessary.

Isolated limb perfusion as a treatment option for rare types of tumours.

BACKGROUND: Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours. METHODS: Patients with Merkel cell carcinoma (MCC) (n = 4), squamous cell carcinoma (SCC) (n = 2), B-cell lymphoma (n = 1), desmoid tumours (n = 3), pigmented villonodular synovitis (PVNS) (n = 1) and giant cell tumour (n = 1) were treated with ILP and analysed retrospectively. RESULTS: The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%). CONCLUSIONS: These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed.

Health-Related Quality of Life for Patients Who have In-Transit Melanoma Metastases Treated with Isolated Limb Perfusion.

BACKGROUND: The incidence of malignant melanoma is increasing, and up to 5 % of patients will experience in-transit metastases. Normally, the initial treatment is surgical excision, but when not possible, locoregional treatment options such as isolated limb perfusion (ILP) are an alternative. This study aimed to assess health-related quality of life (HRQoL) prospectively for patients whose in-transit metastases is treated with ILP. More specifically, the study aimed to describe HRQoL for patients with in-transit extremity melanoma metastases, to describe changes in HRQoL after ILP, and to correlate HRQoL with local toxicity and clinical response after ILP. METHODS: The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) consists of 51 items comprising the Functional Assessment of Cancer Therapy-General (FACT-G), the melanoma subscale , and the melanoma surgery scale. Forty-five patients answered the FACT-M questionnaire before ILP (52 procedures) and at 3, 6 and 12 months after ILP. Response and toxicity were analyzed and correlated with the changes in the HRQoL of the patients. RESULTS: Patients with in-transit metastasis have an HRQoL mainly influenced by tumor burden, defined as more or <10 tumors (FACT-M: 142.5 vs. 128.4 points; p = 0.02). After ILP, there was a trend toward a decrease in FACT-G (+0.1 vs. -7.3 points; p = 0.05) and FACT-M (+1.6 vs. -8.9 points; p = 0.08) when Wieberdink classifications 1-2 and 3-4 were compared at 3 months. A significant difference in FACT-G (+1.0 vs. -13.0 points; p = 0.04) was observed 12 months after ILP as well as a trend for FACT-M (+1.7 vs. -14.6 points; p = 0.08) when the patients who had a complete response were compared with those who did not. CONCLUSION: This study found that patients with in-transit metastases have an HRQoL mainly influenced by tumor burden. After ILP, there is an initial decrease in HRQoL due to local toxicity. After 12 months, the patients with a complete response maintained an HRQoL at baseline level, strengthening the use of ILP as a palliative treatment.

Long-Term Follow-Up Evaluation of 68 Patients with Uveal Melanoma Liver Metastases Treated with Isolated Hepatic Perfusion.

BACKGROUND: This report describes the outcomes and long-term follow-up data from all isolated hepatic perfusions (IHPs) performed at a single institution in Sweden between the years 1989 and 2013 for patients with isolated uveal melanoma metastases. METHODS: A total of 68 patients (median age, 61 years) were treated consecutively at Sahlgrenska University Hospital. Of the 68 patients, 67 % had fewer than 10 tumors. The median diameter of the largest lesion was 2.5 cm. The patients underwent IHP with either melphalan alone or the addition of either tumor necrosis factor-alpha or cisplatin. The response was assessed after 8-12 weeks by computed tomography or magnetic resonance imaging. RESULTS: The overall response rate was 67 and 20 % of the patients had a complete response. The median times to local and systemic progression were respectively 10 and 14 months. The prognostic factors for time to local recurrence were response and number of tumors. The median survival time was 22 months. The prognostic factors for survival were response, largest tumor diameter, and number of tumors. Five patients (7 %) died within 30 days, and six patients (9 %) experienced major complications (Clavien-Dindo 3/4). CONCLUSIONS: Isolated hepatic perfusion is a treatment option with high response rates and tolerable mortality and morbidity. Whether IHP has a survival benefit compared with other treatment options currently is being investigated in a randomized trial.

Which is the Ideal Breast Size?: Some Social Clues for Plastic Surgeons.

To provide plastic surgeons with more detailed information as to factors affecting the perception of female attractiveness, the present study was aimed to investigate whether the interaction effect of breast and body size on ratings of female attractiveness is moderated by sociodemographic variables and whether ratings of shapeliness diverge from those of attractiveness.A community sample of 958 Italian participants rated the attractiveness and the shapeliness of 15 stimuli (5 breast sizes × 3 body sizes) in which frontal, 3/4, and profile views of the head and torso of a faceless woman were jointly shown.Bigger breast sizes obtained the highest attractiveness ratings, but the breast-by-body size interaction was also significant. Evidence was found of a moderator role of sex, marital status, and age. When the effects of breast and body size and their interaction had been ruled out, sex differences were at best very slight and limited to very specific combinations of breast and body sizes. Ratings of attractiveness and shapeliness were highly correlated and did not significantly differ.Results suggest that to address women's psychological needs, concerns, and expectations about their appearance, plastic surgeons should not simply focus on breast size but should carefully consider the 'big picture': the body in its entirety.

Extraction of a foreign body in the liver using single incision laparoscopic surgery: a new application for minimally invasive surgical procedures.

Ingestion of foreign bodies is a common medical problem frequently observed in children, psychiatric patients and prisoners. Various cases have been found in the medical literature, with different diagnostic and therapeutic approaches. We report a case of a 41-year-old male inmate, hospitalized for right upper quadrant pain of the abdomen due to the ingestion of two syringe needles two weeks previously. We describe the diagnostic procedure and the removal of one of the two needles that had migrated into the liver parenchyma, using a single-incision laparoscopic surgical technique. The operation was carried out safely through a 2.5 cm transverse incision below the umbilicus. The dissection and the removal of the foreign body were easily conducted under direct visualization using a minimally invasive surgical technique. Our case report demonstrates the efficacy and the security of the laparoscopic treatment in such a challenging area, employing a single port access only.

Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: preliminary analysis of a multicentre study.

AIM: To assess the incidence of morbidity and mortality of Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy. PATIENTS AND METHODS: A retrospective multicentric study was performed. Six hundred and eighty-three patients were recorded. Predictors of morbidity and mortality were evaluated with univariate and multivariate analysis. RESULTS: In univariate analysis, older age, Eastern Cooperative Oncology Group score, a greater value of Peritoneal Cancer Index (PCI) and sub-optimal cytoreduction were correlated with higher mortality, while older age, presence of ascites, ovarian origin of carcinomatosis, closed technique, a greater value of PCI, longer operative time and sub-optimal cytoreduction were predictors of higher morbidity. In multivariate analysis, older age and a greater value of PCI were correlated with higher mortality; older age, ovarian origin of tumor, presence of ascites, closed technique and longer operative time were predictors of higher morbidity. CONCLUSION: Careful patient selection has to be performed to improve clinical outcomes.