Breaking the Mucin Barrier: A New Affinity Chromatography-Mass Spectrometry Approach to Unveil Potential Cell Markers and Pathways Altered in Pseudomyxoma Peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare peritoneal mucinous carcinomatosis with largely unknown underlying molecular mechanisms. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the only therapeutic option; however, despite its use, recurrence with a fatal outcome is common. The lack of molecular characterisation of PMP and other mucinous tumours is mainly due to the physicochemical properties of mucin. RESULTS: This manuscript describes the first protocol capable of breaking the mucin barrier and isolating proteins from mucinous tumours. Briefly, mucinous tumour samples were homogenised and subjected to liquid chromatography using two specific columns to reduce mainly glycoproteins, albumins and immunoglobulin G. The protein fractions were then subjected to mass spectrometry analysis and the proteomic profile obtained was analysed using various bioinformatic tools. Thus, we present here the first proteome analysed in PMP and identified a distinct mucin isoform profile in soft compared to hard mucin tumour tissues as well as key biological processes/pathways altered in mucinous tumours. Importantly, this protocol also allowed us to identify MUC13 as a potential tumour cell marker in PMP. CONCLUSIONS: In sum, our results demonstrate that this protein isolation protocol from mucin will have a high impact, allowing the oncology research community to more rapidly advance in the knowledge of PMP and other mucinous neoplasms, as well as develop new and effective therapeutic strategies.

Laparoscopic versus open approach for interval cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in advanced epithelial ovarian cancer: a matched comparative study.

BACKGROUND: The use of the laparoscopic approach for the treatment of carcinomatosis from epithelial ovarian cancer (EOC) is controversial. The aim of this study was to compare the short-term outcomes of both laparoscopic and open approach for interval CRS+HIPEC in a matched cohort of patients with advanced EOC. METHODS: A retrospective analysis of a prospectively maintained database including 254 patients treated with interval CRS-HIPEC between January 2016 and December 2021 was performed. Patients with primary disease and limited carcinomatosis (PCI ≤ 10) were selected. A comparative analysis of patients treated by either open (O-CRS-HIPEC) or the laparoscopic (L-CRS-HIPEC) approach was conducted. Overall survival (OS), disease-free survival (DFS), and perioperative outcomes were analysed. RESULTS: Fifty-three patients were finally selected and enrolled into two comparable groups in this study. Of these, 14 patients were treated by interval L-CRS-HIPEC and 39 by interval O-CRS-HIPEC. The L-CRS-HIPEC group had a shorter hospital stay (5.6 ± 1.9 vs. 9.7 ± 9.8 days; p < 0.001) and a shorter time to return to systemic chemotherapy (4.3 ± 1.9 vs. 10.3 ± 16.8 weeks; p = 0.003). There were no significant differences in postoperative complications between both groups. The 2-year OS and DFS was 100% and 62% in the L-CRS-HIPEC group versus 92% and 60% in the O-CRS-HIPEC group, respectively (p = 0.96; p = 0.786). CONCLUSION: This study suggests that the use of interval L-CRS-HIPEC for primary advanced EOC is associated with shorter hospital stay and return to systemic treatment while obtaining similar oncological results compared to the open approach. Further prospective research is needed to recommend this new approach for these strictly selected patients.

Intraoperative metabolic changes associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) causes considerable hemodynamic, respiratory, and metabolic changes during the perioperative period. OBJECTIVES: To evaluate metabolic changes associated with this procedure. Understanding perioperative factors and their association with morbidity may improve the perioperative management of patients undergoing this treatment. METHODS: A retrospective review of a prospectively maintained database was performed. All consecutive unselected patients who underwent CRS plus HIPEC between January 2018 and December 2020 (n = 219) were included. RESULTS: The mean age was 58 ± 11.7 years and 167 (76.3%) were female. The most frequent histology diagnosis was serous ovarian carcinoma 49.3% (n = 108) and colon carcinoma 36.1% (n = 79). Mean peritoneal cancer index was 14.07 ± 10.47. There were significant variations in pH, lactic acid, sodium, potassium, glycemia, bicarbonate, excess bases, and temperature (p < 0.05) between the pre-HIPEC and post-HIPEC periods. The closed HIPEC technique resulted in higher levels of temperature than the open technique (p < 0.05). Age, potassium level post-HIPEC potassium level, and pre-HIPEC glycemia were identified as prognostic factors for morbidity in multivariate analysis. CONCLUSION: The administration of HIPEC after CRS causes significant changes in internal homeostasis. Although the closed technique causes a greater increase in temperature, it is not related to higher morbidity rates. The patient's age, post-HIPEC potassium level, and pre-HIPEC glycemia are predictive factors for morbidity.

Learning curve for minimal invasive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) procedures.

PURPOSE: The benefits of the minimally invasive approach for performing cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (L-CRS + HIPEC) have been described previously, associating an early recovery with similar oncologic outcomes in patients with limited peritoneal carcinomatosis. Currently, no studies are focusing on the learning curve for this emerging procedure. This study aimed to evaluate the L-CRS + HIPEC learning curve and its knock-on effect on the perioperative outcomes. METHODS: We identified all consecutive unselected patients who underwent L-CRS + HIPEC by a single surgeon between April 2016 and January 2022 (n = 51). Patients who underwent risk-reducing CRS + HIPEC (PCI = 0) or initial conversion due to an intraoperative PCI > 10 were excluded from the final analysis. To evaluate the learning curve, perioperative data were analysed using the cumulative sum (CUSUM) analysis. RESULTS: Twenty-six patients were included in the final analysis. Major morbidity occurred in one patient (3.8%). The difficulty of the L-CRS + HIPEC procedures was categorised as low in 23.1% (n = 6), intermediate in 19.2% (n = 5), and advanced in 57.7% (n = 15). The mean length of hospital stay was 5.4 ± 1.5 days. No patient had a conversion to open surgery. The learning curve was divided into two distinct phases: the learning phase (1-14) and the consolidation phase (15-26). A significant decrease in the operative time (375 ± 103.1 vs 239.2 ± 63.6 min) was observed with no differences in complexity, the number of peritonectomy procedures, or morbidity. CONCLUSION: L-CRS + HIPEC is a complex procedure that must be performed in a high-volume and experienced oncologic unit, requiring a learning curve to achieve the consolidation condition, which could be established after 14 procedures.

A Proposal for Modification of the PSOGI Classification According to the Ki-67 Proliferation Index in Pseudomyxoma Peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignancy, classified according to the Peritoneal Surface Oncology Group International (PSOGI) classification, whose response to treatment remains highly heterogeneous within the high-grade (HG) category. Molecular profiling of PMP cases might help to better categorize patients and predict treatment responses. METHODS: We studied the Ki-67 proliferation rate and P53 overexpression in tissue samples from our historical cohort of HG-PMP patients. We established as cut-off levels the third quartile of each marker to perform univariate and multivariate Cox regression survival analyses. According to these results, the HG-PMP category was divided into subcategories and a new survival analysis was performed. RESULTS: A total of 90/117 patients with PMP undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) were selected for secondary analysis. The survival analysis of the HG-PMP category for preoperative variables showed that a proliferation index defined by Ki-67 >15% is a bad prognostic factor, with a hazard ratio (HR) of 3.20 (95% confidence interval [CI] 1.24-8.25). Accordingly, the HG-PMP group was divided using the Ki-67 15% cut-off. The new PSOGI/Ki-67 variable was an independent prognostic factor for overall survival (OS), with an HR of 3.74 (95% CI 1.88-7.47), and disease-free survival (DFS), with an HR of 4.184 (95% CI 1.79-9.75). The estimated 5-year OS rate was 100%, 70% and 24% for the LG-PMP, HG-PMP ≤15% and HG-PMP >15% groups, respectively (p = 0.0001), while the 5-year DFS rate was 90%, 44% and 0%, respectively (p = 0.0001). CONCLUSION: Division of the HG-PMP category of the PSOGI classification, according to the Ki-67 proliferation index, provides two well-defined subcategories, with significant differences in terms of OS and DFS, and hence high prognostic value.

From the Ronnett to the PSOGI Classification System for Pseudomyxoma Peritonei: A Validation Study.

BACKGROUND: Several classifications have been used for pseudomyxoma peritonei (PMP), and among these, the Ronnett classification is the most commonly used. However, a new consensual Peritoneal Surface Oncology Group International (PSOGI) classification has recently been proposed. Nonetheless, to date, the ability of the PSOGI classification to predict survival based on its different disease histologic categories has not been validated. METHODS: This study enrolled 117 patients with PMP who had undergone cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) between 1997 and 2020. Cox proportional hazards regression models and time-dependent curve receiver operating characteristic (ROC) analyses were used to assess the predictive capacity of both classification systems for the overall survival (OS) and disease-free survival (DFS) of these patients. RESULTS: Significant differences in the 5-year OS rate were found for the different histologic grades according to each of the classifications. The completeness of cytoreduction score (CCS) was identified as a factor that predicted patient OS prognosis (p = 0.006). According to the time-dependent ROC curves at the "100" time point, adjusted by the CCS and DFS, the capacity to predict OS was optimal and achieved an area under the curve (AUC) of about 69% for OS and approximately 62% for DFS. CONCLUSIONS: Both the Ronnett and PSOGI classifications were able to predict survival optimally for this patient cohort. However, when the classifications were adjusted by the CCS, the predictive availability for OS was better with the PSOGI classification than with the Ronnett classification.

Efficacy of systemic Chemotherapy on high-risk stage II and III Mucnious colon cancer. CHEMUCCA study part I.

BACKGROUND: Locally advanced colon cancer is a high-risk condition for tumour recurrence with poor survival. The current treatment is surgery followed by adjuvant chemotherapy based on fluoropyrimidines and oxaliplatin. This approach has improved the oncological outcomes on this population, however the mucinous condition has not been studied in depth and although the evidence is weak, it is thought to have a worse response to systemic chemotherapy. The CHEMUCCA study aims to answer this question. OBJECTIVE: To evaluate the effectiveness of adjuvant systemic chemotherapy using the disease-free survival for stage II and III mucinous colon cancer who underwent surgical resection plus systemic adjuvant chemotherapy vs. surgery alone. PATIENTS AND METHODS: Retrospective analytical study including patients diagnosed with high-risk stage II and stage III colon cancer, treated between 2010 and 2021, with a minimum follow-up of 3 years. Demographic variables and tumour features were analysed. The primary endpoint was disease-free survival. Log rank test and Cox regression were used. RESULTS: Of 1134 patients with high-risk stage II and III colon cancer disease, 206 (18,17 %) had mucinous histology and 928 (81,83 %) had non-mucinous histology. 708 patients who received adjuvant chemotherapy, 129 (62,62 %) in mucinous group and 579 (62,39 %) in the non-mucinous group. Adjuvant systemic chemotherapy in stage II and III mucinous colon cancer improved the DFS (HR = 0.58 [95 % CI 0.37-0.91]; p = 0,017). However, in a stratified analysis, patients with high-risk stage II mucinous colon cancer showed no benefit with this approach (HR = 0.4541 [95 % CI 0.19-1.03]; p = 0.06). CONCLUSION: Adjuvant chemotherapy has demonstrated to be effective in locally advanced mucinous colorectal cancer improving the oncological outcomes. However, this benefit could be diminished in high-risk stage II mucinous colon cancer patients. The administration of adjuvant chemotherapy on this patient's sub-group must be balanced according to risk versus benefits.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Urothelial Origin: a Case Report and Literature Review.

Introduction: Urothelial carcinomas (UC) are the fourth most common tumours. Approximately, 50% of patients with invasive bladder cancer relapse after radical cistectomy (RC). In this report, we present the case of peritoneal carcinomatosis from bladder UC treated with cytoreductive surgery plus the administration of hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Case Presentation: A 34-year-old woman diagnosed with high-grade bladder cancer with peritoneal recurrence in 2017. She underwent cytoreductive surgery followed by HIPEC with mitomycin C. Histopathological results showed metastases from UC in the left ovary and right diaphragmatic peritoneum. In 2021, the patient underwent surgery after treatment with atezolizumab for abdominal wall recurrence. Today, the patient is alive and free of tumor recurrence 12 months after the last surgery. Discussion: Despite advances in surgical technique and patient selection, the risk of relapse remains high among patients with muscle-invasive bladder cancer. We face the case of a young female patient with local, peritoneal, and lymphatic recurrence of bladder cancer after RC who had a partial response to chemotherapy. The possibility of CRS + HIPEC is offered by the surgical oncology unit, referent in the management of peritoneal carcinomatosis. Surgery is capable of resecting residual tumor in patients with a partial response or who have been erroneously underdiagnosed. Conclusion: CRS + HIPEC might be a valid option to be considered in well-selected patients and to be performed in reference units. There is a need for more collaborative clinical trials and prospective studies addressing the role of surgery in patients with metastatic bladder cancer.

Normothermic Regional Perfusion in Controlled Donation After Circulatory Determination of Death Simultaneous Pancreas - Kidney Transplantation.

BACKGROUND: Simultaneous pancreas-kidney transplantation is the optimal treatment for patients with type 1 diabetes and renal failure. The use of pancreas grafts from donation after circulatory death (DCD), using normothermic regional perfusion (NRP), is still marginal worldwide, mainly due to possible additional risks of graft dysfunction and complications compared with grafts from donors after brain death. METHODS: Case series of patients who underwent simultaneous pancreas-kidney transplantation after DCD-NRP between January 2018 and September 2022. This study evaluated early postoperative grafts and survival outcomes. RESULTS: Four patients were included. One patient lost the pancreatic graft due to arterial thrombosis requiring transplantectomy. Another patient required a laparotomy due to hemoperitoneum. Overall, 1-year pancreas and kidney graft survival was 75% and 100%, respectively. One patient developed a lymphoma during the follow-up. CONCLUSION: The use of pancreas grafts from DCD after NRP preservation is safe and feasible. Comparative studies with donors after brain death grafts and larger series are required to confirm the feasibility of DCD-NRP pancreas transplantation.

Intraoperative oxygen tension and redox homeostasis in Pseudomyxoma peritonei: A short case series.

Introduction: Pseudomyxoma peritonei (PMP) is a rare malignant disease characterized by a massive multifocal accumulation of mucin within the peritoneal cavity. The current treatment option is based on complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. However, the recurrence is frequent with subsequent progression and death. To date, most of the studies published in PMP are related to histological and genomic analyses. Thus, the need for further studies unveiling the underlying PMP molecular mechanisms is urgent. In this regard, hypoxia and oxidative stress have been extensively related to tumoral pathologies, although their contribution to PMP has not been elucidated. Methods: In this manuscript, we have evaluated, for the first time, the intratumoral real-time oxygen microtension (pO2mt) in the tumor (soft and hard mucin) and surrounding healthy tissue from five PMP patients during surgery. In addition, we measured hypoxia (Hypoxia Inducible Factor-1a; HIF-1α) and oxidative stress (catalase; CAT) markers in soft and hard mucin from the same five PMP patient samples and in five control samples. Results: The results showed low intratumoral oxygen levels, which were associated with increased HIF-1α protein levels, suggesting the presence of a hypoxic environment in these tumors. We also found a significant reduction in CAT activity levels in soft and hard mucin compared with healthy tissue samples. Discussion: In conclusion, our study provides the first evidence of low intratumoral oxygen levels in PMP patients associated with hypoxia and oxidative stress markers. However, further investigation is required to understand the potential role of oxidative stress in PMP in order to find new therapeutic strategies.

Antitumor effect of a small-molecule inhibitor of KRASG12D in xenograft models of mucinous appendicular neoplasms.

Pseudomyxoma peritonei (PMP) is a rare disease characterized by a massive accumulation of mucus in the peritoneal cavity. The only effective treatment is aggressive surgery, aimed at removing all visible tumors. However, a high percentage of patients relapse, with subsequent progression and death. Recently, there has been an increase in therapies that target mutated oncogenic proteins. In this sense, KRAS has been reported to be highly mutated in PMP, with KRASG12D being the most common subtype. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in a high-grade PMP xenograft mouse model carrying a KRASG12D mutation. The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRASG12D-PMP tumors and provide a rationale for clinical trials.

Efficacy and Safety of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer: A Phase 3 Randomized Clinical Trial.

Importance: Peritoneal metastasis in patients with locally advanced colon cancer (T4 stage) is estimated to recur at a rate of approximately 25% at 3 years from surgical resection and is associated with poor prognosis. There is controversy regarding the clinical benefit of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. Objective: To assess the efficacy and safety of intraoperative HIPEC in patients with locally advanced colon cancer. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted in 17 Spanish centers from November 15, 2015, to March 9, 2021. Enrolled patients were aged 18 to 75 years with locally advanced primary colon cancer diagnosed preoperatively (cT4N02M0). Interventions: Patients were randomly assigned 1:1 to receive cytoreduction plus HIPEC with mitomycin C (30 mg/m2 over 60 minutes; investigational group) or cytoreduction alone (comparator group), both followed by systemic adjuvant chemotherapy. Randomization of the intention-to-treat population was done via a web-based system, with stratification by treatment center and sex. Main Outcomes and Measures: The primary outcome was 3-year locoregional control (LC) rate, defined as the proportion of patients without peritoneal disease recurrence analyzed by intention to treat. Secondary end points were disease-free survival, overall survival, morbidity, and rate of toxic effects. Results: A total of 184 patients were recruited and randomized (investigational group, n = 89; comparator group, n = 95). The mean (SD) age was 61.5 (9.2) years, and 111 (60.3%) were male. Median duration of follow-up was 36 months (IQR, 27-36 months). Demographic and clinical characteristics were similar between groups. The 3-year LC rate was higher in the investigational group (97.6%) than in the comparator group (87.6%) (log-rank P = .03; hazard ratio [HR], 0.21; 95% CI, 0.05-0.95). No differences were observed in disease-free survival (investigational, 81.2%; comparator, 78.0%; log-rank P = .22; HR, 0.71; 95% CI, 0.41-1.22) or overall survival (investigational, 91.7%; comparator, 92.9%; log-rank P = .68; HR, 0.79; 95% CI, 0.26-2.37). The definitive subgroup with pT4 disease showed a pronounced benefit in 3-year LC rate after investigational treatment (investigational: 98.3%; comparator: 82.1%; log-rank P = .003; HR, 0.09; 95% CI, 0.01-0.70). No differences in morbidity or toxic effects between groups were observed. Conclusions and Relevance: In this randomized clinical trial, the addition of HIPEC to complete surgical resection for locally advanced colon cancer improved the 3-year LC rate compared with surgery alone. This approach should be considered for patients with locally advanced colorectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02614534.

Short- and Long-Term Intestinal Complications After Combined Pancreas-Kidney Transplantation.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice in patients with type 1 diabetes and end-stage renal disease, because it improves survival and quality of life. Currently, enteric exocrine drainage is the most commonly used method. Intestinal complications continue to be a major cause of posttransplant morbidity despite improvements in surgical technique. This study analyzed early and late intestinal complications related to SPK transplantation. MATERIALS AND METHODS: We performed a retrospective analysis of 100 adult patients undergoing SPK transplantation between January 2009 and December 2019. We performed systemic venous drainage and exocrine enteric drainage with duodenojejunostomy. Statistical analysis was performed using SPSS v2. This study was performed in accordance with the Declaration of Istanbul and the 1964 Declaration of Helsinki. Informed consent was obtained from all participants involved in the study. RESULTS: Intestinal complications were reported in 18 patients. Ten patients (10%) had the following early intestinal complications including: ileus (n = 4), intestinal obstruction (n = 2), graft volvulus (n = 1), duodenal graft fistula (n = 1), and jejunal fistula after pancreas transplantation (n = 1). Two cases required relaparotomy: graft repositioning with Roux-en-Y conversion (n = 1) and Y-roux conversion (n = 1). Eight patients had repeated episodes of intestinal obstruction (8%), of whom 2 required surgery for resolution with 100% postoperative mortality. CONCLUSIONS: SPK transplantation with enteric drainage via duodenojejunostomy has a low rate of short- and long-term postoperative intestinal complications. Surgery in patients with recurrent intestinal obstruction has a high mortality risk and should be performed in reference transplant centers.