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BackgroundThe development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer.MethodsThe Italian Peritoneal Surface Malignancies Oncoteam—S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers.ResultsA total of 91 patients with a median age of 58 years (range 26–75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8–28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4–10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1–16.2; treated patients: 35.3 months, 95% CI 2.8–67.8; p = 0.022).ConclusionsIn referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.

Background and Objectives: Incisional hernia is a common complication following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This study aimed to identify patient and surgical factors associated with its occurrence. Materials and Methods: We conducted a retrospective analysis of 122 patients undergoing CRS and HIPEC. Logistic regression models were applied to identify predictors of incisional hernia development. Results: Incisional hernia occurred in 23.8% of patients. Hypertension was identified as an independent factor associated with increased risk. Peritoneal Cancer Index (PCI), operative time, and abdominal wall closure technique were not found to be significantly associated with hernia development. Conclusions: Preoperative identification of high-risk patients may support the adoption of targeted preventive strategies, including prophylactic mesh placement and enhanced postoperative surveillance.

BackgroundAlthough gallstone disease increases with aging, elderly patients are less likely to undergo cholecystectomy. This is because age itself is a negative predictor after cholecystectomy. The ACS-NSQIP risk calculator can therefore help surgeons decide whether to operate or not. However, little is known about the accuracy of this model outside the ACS National Surgical Quality Improvement Program. The aim of the present study is to evaluate the ability of the ACS-NSQIP model to predict the clinical outcomes of patients aged 80 years or older undergoing elective or emergency cholecystectomy.Study designThe study focused on 263 patients over 80 years of age operated on between 2010 and 2019: 174 were treated as emergencies because of acute cholecystitis (66.2%). Outcomes evaluated are those predicted by the ACS-NSQIP calculator within 30 days of surgery. The ACS-NSQIP model was tested for both discrimination and calibration. Differences among observed and expected outcomes were evaluated.ResultsWhen considering all patients, the discrimination of mortality was very high, as it was that of severe complications. Considering only the elective cholecystectomies, the discrimination capacity of ACS-NSQIP risk calculator has consistently worsened in each outcome while it remains high considering the emergency cholecystectomies. In the evaluation of the emergency cholecystectomy, the model showed a very high discriminatory ability and, more importantly, it showed an excellent calibration. Comparisons between main outcomes showed small or even negligible differences between observed and expected values.ConclusionThe results of the present study suggest that clinical decisions on cholecystectomy in a patient aged 80 years or older should be assisted through the ACS-NSQIP model.

BackgroundCytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.MethodsData were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).ResultsThe study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4–51.2 months], and the median DFS was 13.6 months (95% CI, 12.3–14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4–24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.ConclusionFor patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

Background Dendritic cells (DCs) are the most efficient antigen-presenting cells and play a central role in the immune system, orchestrating immune response against tumors. We previously demonstrated that DC-based vaccination effectively induces anti-tumor immunity, yet at the same time showing a robust safety profile, making this treatment a potential candidate for effective adjuvant immunotherapy. To explore this possibility, we designed a randomized phase II trial (EudraCT no. 2014-005123-27) to provide a complementary autologous DC vaccination to patients (pts) with resected stage III/IV melanoma. Methods Overall, a total of 18 eligible pts were included in this study, 10 of whom received 6 monthly DC vaccination cycles combined with IL-2 administration (arm A), and 8 pts were enrolled in the follow-up observational cohort (arm B). A deep immune biomarkers profiling by multiplex immunoassay, human leukocyte antigens (HLA) typing, multiparametric flow cytometry and in situ tumor microenvironment analysis was performed for the entire pts cohort. The immunological response was assessed in vivo by DTH test and ex vivo against selected melanoma-associated antigens applying the IFN-γ ELISPOT assay. Results Pts receiving DC vaccination showed a better relapse-free survival compared to the observational cohort (median 6.6 months, 95% CI, 2.3–not reached (nr) (arm A) vs 5.2 months, 95% CI, 2.5–nr (arm B), not significant), with a favorable trends for female pts (median 15.5 months, 95% CI, 2.6–nr (female) vs 3.3, 95% CI, 2.3–nr (male)), pts with less than 60 years (median 22.5 months, 95% CI, 2.6–nr (age < 60) vs 4.7 months, 95% CI, 2.3–nr (age ≥ 60), and pts with wild-type BRAF status (median 22.5 months, 95% CI, 8.6–nr (BRAF wt) vs 3.8 months, 95% CI, 2.3–nr (BRAF mutated). The toxicity profile was favourable, with no severe adverse events and only mild, manageable reactions. Moreover, additional immune response data suggested increased immune modulation in vaccinated patients, which may reflect a shift in immune dynamics. Conclusions Our findings support the safety and tolerability of DC vaccination as an adjuvant treatment for melanoma, demonstrating significant immune modulation at both the tumor site and peripherally in relapsed and non-relapsed patients. These results highlight the potential of autologous, personalised DC-based therapies and pave the way for the development of innovative immunotherapy combinations in future treatment strategies. Trial registration ClinicalTrials.gov NCT02718391; EudraCT no. 2014-005123-27.

Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3 regulatory CD4 T cells (Treg) and GZMB cytotoxic CD8 T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8 TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1 tumor cells, which significantly correlated with intratumoral CD8 T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8 T cell, as measured by the numbers of GZMB T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies.

Multimodal treatment in peritoneal metastases (PM) from colorectal neoplasms may improve overall survival (OS). In this study, we reported our experience in using cytoreductive surgery (CRS) combined with intraperitoneal chemohyperthermia (HIPEC) for the treatment of peritoneal metastases (PM) from colorectal neoplasms. The first aim was to evaluate the overall survival of these patients. Furthermore, using the results of the Prodige 7 Trial and incorporating them with the entropy balance statistical tool, we generated a pseudopopulation on which to test the use of CRS alone. We performed a retrospective analysis based on a prospective database of all 55 patients treated with CRS + HIPEC between March 2004 and January 2023. The median OS was 47 months, with 1-, 3- and 5-year survival rates of 90.8%, 58.7% and 42.7%, respectively. There was no significant difference in the data in the pseudogroup generated with entropy balance. This finding confirms the critical role of complete cytoreduction in achieving the best OS for patients with PM. PCI > 6 seems to be the most important prognostic factor influencing OS. At present, CRS + HIPEC seems to be the therapeutic strategy that guarantees the best results in terms of OS for patients with relatively low PCI and in whom a CCS ≤ 1 can be achieved.

Background In case of Krukenberg tumor (KT) of gastric origin it is controversial and debated whether radical surgery in case of synchronous KT or metastasectomy in case of metachronous ones is associated with additional benefits. Role of perioperative treatments is unclear. Methods Among 2515 female patients who were diagnosed with gastric cancer between January 1990 and December 2012 from 9 Italian centers, 63 presented simultaneously or developed KT as recurrence. Results Thirty patients presented with synchronous KT, while 33 developed metachronous ovarian metastases during follow-up. The differences between the two groups were analyzed and compared. The median age of 63 patients was 48.0 years (range 31–71). Resection was possible in 53 patients (20 synchronous and 33 metachronous). Twelve patients in the synchronous group and 15 patients of the metachronous group underwent hyperthermic intraperitoneal chemotherapy after resection of KT. All of them underwent adjuvant chemotherapy after KT resection. The median survival for all population was 23 months (95 % confidence interval, 7–39 months). The median survival time in the metachronous group was 36 months, which was significantly longer than that in the synchronous group, 17 months, p  < 0.0001. Conclusions KT remains a clinical challenge for gastric cancer therapy. The extent of disease and feasibility of removal of the metastatic lesion must be carefully evaluated prior to surgery to define the patients group who could benefit most from a resection associated with perioperative treatments.

Background Duodenal stump fistula (DSF) is a severe complication of gastrectomy. Although nonsurgical therapy is preferred, surgery is still mandatory in one third of DSF patients. The aim of this article is to analyze the surgical management of DSF and factors related to its outcome. Methods We performed a retrospective multicenter study using data from January 1990 to November 2011 in 16 Italian surgery centers. We collected 8,268 elective gastrectomies for malignancies, 7,987 by the laparotomic and 281 by the laparoscopic approach. Two hundred five patients developed a DSF, 75 of whom underwent surgery for DSF. We analyzed mortality and DSF healing time as well as the impact of clinical, oncological, and surgical characteristics. Results The laparoscopic approach increased the risk of DSF development (odds ratio 5.6, 95 % confidence interval 2.7–10.6, P  < 0.001). The indication for first DSF surgery was intra-abdominal sepsis; the failure rate was over 30 %, associated with the appearance of fistulas of neighboring organs, bleeding, and the need for reoperations. The mortality rate was 28 % and was related to the presence of vascular disease ( P  = 0.04), more than one reoperation ( P  = 0.05), sepsis ( P  < 0.001), and renal failure ( P  < 0.001). Fifty-four patients recovered after a median of 39 days (interquartile range 22–68 days); the need to perform more reoperations ( P  < 0.01) and the presence of an abdominal abscess ( P  < 0.01) led to an increase in healing time. Conclusions Surgery for DSF has a poor prognosis. Our data will help to identify patients at risk of death, but unfortunately could not establish the best surgical procedure applicable to all cases of DSF.