Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy to Treat Pseudomyxoma Peritonei of Ovarian Origin: A Retrospective French RENAPE Group Study.

BACKGROUND: Ovarian pseudomyxoma peritonei (OPMP) are rare, without well-defined therapeutic guidelines. We aimed to evaluate cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat OPMP. METHODS: Patients from the French National Network for Rare Peritoneal Tumors (RENAPE) database with proven OPMP treated by CRS/HIPEC and with histologically normal appendix and digestive endoscopy were retrospectively included. Clinical and follow-up data were collected. Histopathological and immunohistochemical features were reviewed. RESULTS: Fifteen patients with a median age of 56 years were included. The median Peritoneal Cancer Index was 16. Following CRS, the completeness of cytoreduction (CC) score was CC-0 for 9/15 (60%) patients, CC-1 for 5/15 (33.3%) patients, and CC-2 for 1/15 (6.7%) patients. The median tumor size was 22.5 cm. After pathological review and immunohistochemical studies, tumors were classified as Group 1 (mucinous ovarian epithelial neoplasms) in 3/15 (20%) patients; Group 2 (mucinous neoplasm in ovarian teratoma) in 4/15 (26.7%) patients; Group 3 (mucinous neoplasm probably arising in ovarian teratoma) in 5/15 (33.3%) patients; and Group 4 (non-specific group) in 3/15 (20%) patients. Peritoneal lesions were OPMP pM1a/acellular, pM1b/grade 1 (hypocellular) and pM1b/grade 3 (signet-ring cells) in 13/15 (86.7%), 1/15 (6.7%) and 1/15 (6.7%) patients, respectively. Disease-free survival analysis showed a difference (p = 0.0463) between OPMP with teratoma/likely-teratoma origin (groups 2 and 3; 100% at 1, 5, and 10 years), and other groups (groups 1 and 4; 100%, 66.6%, and 50% at 1, 5, and 10 years, respectively). CONCLUSION: These results suggested that a primary therapeutic strategy using complete CRS/HIPEC for patients with OPMP led to favorable long-term outcomes.

[Contribution of intraperitoneal chemotherapy in the treatment of colorectal peritoneal carcinoma. HIPEC, PIPAC, state of the art and future directions]. / La chimiothérapie intra-péritonéale dans le traitement de la carcinose péritonéale d'origine colorectale. CHIP, PIPAC, état des lieux et perspectives.

After more than a decade of good results using the combination of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinosis of colorectal origin, the PRODIGE7 study, which specifically evaluated the role of HIPEC, failed to show any superiority in terms of overall and disease-free survival for the CRS+HIPEC combination compared with CRS alone. This study constituted a radical change in the knowledge and therapeutic attitudes observed to date. After reviewing the literature and the consensus of national and international experts, a synthesis is provided, together with an outlook on the questions raised and the therapeutic trials and innovations of the near future. An analysis of recent advances due to the advent of a new technique, PIPAC, is also proposed, as well as a review of current therapeutic trials in this field.

Prevention of post-hepatectomy liver failure after major resection of colorectal liver metastases: is hepato-biliary scintigraphy the optimal tool?

Background: Liver failure is the most threatening complication after hepatectomy for colorectal liver metastases. Recent studies indicate that liver functional evaluation by hepatobiliary scintigraphy (HBS) could be more sensitive than volumetry to predict the risk of post-hepatectomy liver failure (PHLF). The aim of this study was to evaluate the performance of 99mTc-mebrofenin HBS, when used as the main preoperative assessment before major hepatectomy in patients with liver metastases from colorectal cancer. Methods: This retrospective study reviewed data from all patients with colorectal liver metastases treated at Montpellier Cancer Institute between 2013 and 2020. Only patients who underwent HBS before surgery were included. The primary aim was to evaluate how the use of this functional imaging modifies the surgical management of patients with colorectal liver metastases. Results: Among the 80 patients included, 26 (32.5%) underwent two-stage hepatectomy and 13 (16.3%) repeated hepatectomies. Severe postoperative complications occurred in 16 patients (20%) and all-grade liver failure occurred in 13 patients (16.3%). Seventeen patients (21.3%) underwent major liver surgery based on sufficient mebrofenin uptake, although the retrospectively evaluated future liver remnant (FLR) volume was insufficient (<30% of total liver). None of these patients had PHLF. Conclusions: This study showed the reliability of HBS for the preoperative functional assessment of patients with colorectal liver metastases. Indeed, it allowed performing major hepatectomy safely in 20% more patients who would not have been considered for surgery on the basis of volumetric assessment.

Liver Venous Deprivation Versus Portal Vein Embolization Before Major Hepatectomy for Colorectal Liver Metastases: A Retrospective Comparison of Short- and Medium-Term Outcomes.

BACKGROUND: Liver venous deprivation (LVD) is a recent radiological technique performed to induce hypertrophy of the future liver remnant. Medium-term results of major hepatectomy after LVD have never been compared with the actual standard of care, portal vein embolization (PVE). METHODS: We retrospectively compared data from 33 consecutive patients who had undergone LVD (n = 17) or PVE (n = 16) prior to a right hemi-hepatectomy or right extended hepatectomy indicated for colorectal liver metastases (CRLM) between May 2015 and December 2019. RESULTS: The 1-year and 3-year overall survival (OS) rates in the LVD group were 81.3% (95% confidence interval [CI]: 72-90) and 54.7% (95% CI: 46-63), respectively, against 85% (95% CI: 69-101) and 77.4% (95% CI: 54-100) in the PVE group; the differences were not statistically significant (p = 0.64). The median disease-free survival (DFS) rate was also comparable: 6 months (95% CI: 4-7) in the LVD group and 12 months (95% CI: 1.5-13) in the PVE group (p = 0.29). The overall intra-operative and post-operative complication rates were similar between the two groups. The mean daily kinetic growth rate (KGR) was found to be higher after LVD than after PVE (0.2% vs. 0.1%, p = 0.05; 10 cc/day vs. 4.8 cc/day, p = 0.03), as was the mean increase in future liver remnant volume (FLR-V) (49% vs. 27%, p = 0.01). CONCLUSIONS: The LVD technique is well tolerated in patients undergoing right hemi-hepatectomy or right extended hepatectomy for CRLM. When compared with the PVE technique, the LVD technique has similar peri-operative and medium-term outcomes, but higher KGR and FLR-V increase.

Perioperative chemotherapy in colorectal cancer with peritoneal metastases: A global propensity score matched study.

Background: There is a paucity of studies evaluating perioperative systemic chemotherapy in conjunction with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colorectal cancer peritoneal metastases (CRCPM). The aim was to evaluate neoadjuvant and/or adjuvant systemic therapy in CRCPM. Methods: Patients with CRCPM from 39 treatment centres globally from January 1, 1991, to December 31, 2018, who underwent CRS+HIPEC were identified and stratified according to neoadjuvant/adjuvant use. Crude data analysis, propensity score matching (PSM) and Cox-proportional hazard modelling was performed. Findings: Of 2093 patients, 1613 were included in neoadjuvant crude evaluation with 708 in the PSM cohort (354 patients/arm). In the adjuvant evaluation, 1176 patients were included in the crude cohort with 778 in the PSM cohort (389 patients/arm). The median overall survival (OS) in the PSM cohort receiving no neoadjuvant vs neoadjuvant therapy was 37.0 months (95% CI: 32.6-42.7) vs 34.7 months (95% CI: 31.2-38.8, HR 1.08 95% CI: 0.88-1.32, p = 0.46). The median OS in the PSM cohort receiving no adjuvant therapy vs adjuvant therapy was 37.0 months (95% CI: 32.9-41.8) vs 45.7 months (95% CI: 38.8-56.2, HR 0.79 95% CI: 0.64-0.97, p = 0.022). Recurrence-free survival did not differ in the neoadjuvant evaluation but differed in the adjuvant evaluation - HR 1.04 (95% CI: 0.87-1.25, p = 0.66) and 0.83 (95% CI: 0.70-0.98, p = 0.03), respectively. Multivariable Cox-proportional hazard modelling in the crude cohorts showed hazard ratio 1.08 (95% CI: 0.92-1.26, p = 0.37) for administering neoadjuvant therapy and 0.86 (95% CI: 0.72-1.03, p = 0.095) for administering adjuvant therapy. Interpretation: Neoadjuvant therapy did not confer a benefit to patients undergoing CRS+HIPEC for CRCPM, whereas adjuvant therapy was associated with a benefit in this retrospective setting. Funding: None.

The landscape of cancer-associated fibroblasts in colorectal cancer liver metastases.

Rationale: Patients with colorectal cancer die mainly due to liver metastases (CRC-LM). Although the tumor microenvironment (TME) plays an important role in tumor development and therapeutic response, our understanding of the individual TME components, especially cancer-associated fibroblasts (CAFs), remains limited. Methods: We analyzed CRC-LM CAFs and cancer cells by single-cell transcriptomics and used bioinformatics for data analysis and integration with related available single-cell and bulk transcriptomic datasets. We validated key findings by RT-qPCR, western blotting, and immunofluorescence. Results: By single-cell transcriptomic analysis of 4,397 CAFs from six CRC-LM samples, we identified two main CAF populations, contractile CAFs and extracellular matrix (ECM)-remodeling/pro-angiogenic CAFs, and four subpopulations with distinct phenotypes. We found that ECM-remodeling/pro-angiogenic CAFs derive from portal resident fibroblasts. They associate with areas of strong desmoplastic reaction and Wnt signaling in low-proliferating tumor cells engulfed in a stiff extracellular matrix. By integrating public single-cell primary liver tumor data, we propose a model to explain how different liver malignancies recruit CAFs of different origins to this organ. Lastly, we found that LTBP2 plays an important role in modulating collagen biosynthesis, ECM organization, and adhesion pathways. We developed fully human antibodies against LTBP2 that depleted LTBP2+ CAFs in vitro. Conclusion: This study complements recent reports on CRC-LM CAF heterogeneity at the single-cell resolution. The number of sequenced CAFs was more than one order of magnitude larger compared to existing data. LTBP2 targeting by antibodies might create opportunities to deplete ECM-remodeling CAFs in CRC-LMs. This might be combined with other therapies, e.g., anti-angiogenic compounds as already done in CRC. Moreover, we showed that in intrahepatic cholangiocarcinoma, in which ECM-remodeling CAF proportion is similar to that of CRC-LM, several genes expressed by ECM-remodeling CAFs, such as LTBP2, were associated with survival.

The desmoplastic growth pattern is associated with second-stage completion and longer survival in 2-stage hepatectomy for colorectal cancer liver metastases.

BACKGROUND: Two-stage hepatectomy for bilobar colorectal cancer liver metastases is potentially curative for selected patients. Histological growth patterns of colorectal liver metastases (desmoplastic, replacement, and pushing) have prognostic value. Our aim was to evaluate their association with pathologic response to preoperative treatment, second-stage hepatectomy completion, and survival in patients treated with a curative-intent 2-stage hepatectomy. METHODS: In 67 patients planned for 2-stage hepatectomy, colorectal liver metastases resected from the first-stage hepatectomy were retrospectively evaluated for growth patterns and pathologic response according to Tumor Regression Grading, modified Tumor Regression Grading, and Blazer grading. Tumor Regression Grading 1 to 3, modified Tumor Regression Grading 1 to 3, and Blazer 0 and 1 defined good responders. RESULTS: Desmoplastic growth patterns (GP) were more frequent among good responders (P < .001). Second-stage hepatectomy completion was associated with desmoplastic growth patterns and pathologic response on univariate analysis and multivariable analyses (P = .017 and P = .041, respectively). Median follow-up was 84 months (95% confidence interval: 53.4 [not reached]). Nondesmoplastic GP patients and nonresponders had a poorer overall survival (hazard ratio = 3.86, 95% confidence interval: 2.11-7.07, P < .001 and hazard ratio = 2.14, 95% confidence interval: 1.19-3.83, P = .009, respectively) on univariate analysis. Nondesmoplastic growth pattern was the only factor associated with a poorer overall survival on multivariable analysis (hazard ratio = 4.17, 95% confidence interval: 1.79-9.74, P < .001). Nondesmoplastic GP was also associated with a poorer recurrence-free survival (hazard ratio = 2.05, 95% confidence interval: 1.13-3.70, P = .017). CONCLUSION: Desmoplastic GP could represent a useful morphological marker for early identification of patients who might benefit from 2-stage hepatectomy completion.

Liver venous deprivation versus associating liver partition and portal vein ligation for staged hepatectomy for colo-rectal liver metastases: a comparison of early and late kinetic growth rates, and perioperative and oncological outcomes.

BACKGROUND: Different techniques have been developed to optimize the Future Liver Remnant (FLR). Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) and liver venous deprivation (LVD) have shown the higher hypertrophy rates, but their place in clinical practice is still debated. METHODS: Thirty-two consecutive ALPPS and LVD procedures for CRLM performed between December 2015 and December 2019 were included. This retrospective study evaluated kinetic growth rates (KGR) as primary outcome, and perioperative and oncological outcomes as secondary endpoints. RESULTS: A total of 17 patients underwent LVD before surgery, whereas 15 underwent ALPPS. On early evaluation (7 vs 9 days, respectively), KGR did not differ between ALPPS and LVD cohort (0.8% per day vs 0.3% per day, p = 0.70; 23 cc/day vs 26 cc/day, p = 0.31). Late evaluation (21 vs 9 days) showed a KGR significantly decreased in the LVD group (0.6% per day vs 0.2% per day, p = 0.21; 20 cc/day vs 10 cc/day p = 0.02). Mean FLR-V increase was comparable in the two groups (60% vs 49%, p 0.32). Successful resection rate was 100% and 94% in LVD and ALPPS group, respectively. The hospital stay (p < 0.0001) and severe complications rate (p = 0.05) were lower after LVD. One and 3-years overall survival (OS) were 72,7% and 27,4% in the ALPSS group, versus 81,3% and 54,7% in LVD group (p = 0.10). The Median DFS was comparable between both techniques (6.1 months and 5.9 respectively, p = 0.66). CONCLUSIONS: LVD and ALPPS shows similar KGR during the early period following preparation as well as similar survival outcomes. Hospital stay and severe complications are lower after LVD.

Feasibility and Safety of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy With or Without Intraoperative Intravenous 5-Fluorouracil and Leucovorin for Colorectal Peritoneal Metastases: A Multicenter Comparative Cohort Study.

BACKGROUND: This retrospective multicenter cohort study compared the feasibility and safety of oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-Ox) with or without intraoperative intravenous 5-fluorouracil (5-FU) and leucovorin (L). METHODS: Our study included consecutive patients with histologically proven unresectable and isolated colorectal peritoneal metastases (cPM) treated with PIPAC-Ox in seven tertiary referral centers between January 2015 and April 2020. Toxicity events and oncological outcomes (histological response, progression-free survival, and overall survival) were compared between patients who received intraoperative intravenous 5-FU/L (PIPAC-Ox + 5-FU/L group) and patients who did not (PIPAC-Ox group). RESULTS: In total, 101 patients (263 procedures) were included in the PIPAC-Ox group and 30 patients (80 procedures) were included in the PIPAC-Ox + 5-FU/L group. Common Terminology Criteria for Adverse Events v4.0 grade 2 or higher adverse events occurred in 48 of 101 (47.5%) patients in the PIPAC-Ox group and in 13 of 30 (43.3%) patients in the PIPAC-Ox + 5-FU/L group (p = 0.73). The complete histological response rates according to the peritoneal regression grading score were 27% for the PIPAC-Ox + 5-FU/L group and 18% for the PIPAC-Ox group (p = 0.74). No statistically significant differences were observed in overall or progression-free survival between the two groups. CONCLUSIONS: The safety and feasibility of PIPAC-Ox + 5-FU/L appears to be similar to the safety and feasibility of PIPAC-Ox alone in patients with unresectable cPM. Oncological outcomes must be evaluated in larger studies.

Imaging Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry of oxaliplatin derivatives in human tissue sections.

Mass Spectrometry Imaging is an effective technology that allows to determine the in-situ distribution of endogen and/or exogen small molecules. It is a rapidly emerging approach for visualizing drugs and their metabolites within biological tissues. Matrix-Assisted Laser Desorption Ionization (MALDI) Mass Spectrometry Imaging (MSI) coupled to high resolving power analyzer (e.g. TOF) was already investigated for metallodrug localization and metabolization studies, but was proved to suffer from a lack of sensitivity and resolution, leading to poor coverage and assignment. To counter these technological limitations, the use of ultra-high resolving power analyzer such as Fourier Transform Ion Cyclotron Resonance (FTICR) could be revealed as a technique of choice. The high field FTICR MS provides ultra-high resolving power and mass accuracy that allows exhaustive molecule coverage and non-ambiguous molecular formula assignments. Platinum derivatives, such as oxaliplatin, are widely used as therapeutic agents for cancer treatment. The assessment of their intake, distribution and metabolism within the organs is important to know the risks associated with their use. In this study, MALDI FTICR MSI analyses were performed to better understand the penetration and metabolization of platinum derivatives in ovaries of women treated by Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for peritoneal metastasis of colorectal or appendicular origin. Twelve ovary sections, from six ovary samples in six women donors, before and after treatment, were analyzed with 120 µm spatial resolution. For the first time, the high resolving power (220,000 at m/z 457) and sub-ppm accuracy (<1 ppm) of the FTICR combined with an Isotopic Fine Structure study enabled to distinguish two Pt-isobaric species derived from oxaliplatin in biological tissues. One of these, which is unknown, was specifically localized at the contour of the ovary.

Appendiceal tumors and pseudomyxoma peritonei: French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (RENAPE, RENAPATH, SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFR).

INTRODUCTION: This document is a summary of the French Intergroup guidelines regarding the management of appendicular epithelial tumors (AT) and pseudomyxoma peritonei (PMP) published in March 2020, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: All French medical societies specialized in the management of AT and PMP collaboratively established these recommendations based on literature until December 2019 and the results of a Delphi vote carried out by the Peritoneal Surface Oncology Group International experts, and graded into 4 categories (A, B, C, Expert Agreement) according to their level of evidence. RESULTS: AT and PMP are rare but represent a wide range of clinico-pathological entities with several pathological classification systems and different biological behaviors. Their treatment modalities may vary accordingly and range from simple surveillance or laparoscopic appendectomy to complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) and / or systemic chemotherapy. The prognosis of these neoplasms may also largely vary according to their pathological grade and spreading at diagnosis or during the follow-up. Given the rarity of certain situations, the therapeutic strategy adapted to each patient, must be discussed in a specialized multidisciplinary meeting after a specialized pathological and radiological pre-therapeutic assessment and a clinical examination by a surgeon specializing in the management of rare peritoneal malignancies. CONCLUSION: These recommendations are proposed to achieve the most beneficial strategy in a daily practice as the wide range and the rareness of these entities renders their management challenging. These guidelines are permanently being reviewed.

Laparoscopic cytoreductive surgery and HIPEC in LAMN with small volume of peritoneal disease: a valuable option of treatment for good patient-related experience measures (PREMs).

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the best effective treatment for pseudomyxoma peritonei (PMP). In the last years, the advances in histopathology have stratified PMP lesions in different degrees of aggressivity suggesting the possibility of a tailored treatment. In a subset of patients with small volume peritoneal disease, laparoscopic CRS and HIPEC is feasible. The aim of this study is to analyze the results of laparoscopic CRS + HIPEC in a monocentric series of patients under patient-related experience measures (PREMs). METHODS: All consecutive patients who underwent laparoscopic CRS-HIPEC with curative intent at Cancer Institute of Montpellier were retrieved from a prospectively maintained database and analyzed. Selection criteria for laparoscopic approach were low-grade PMP with pathological confirmation prior to CRS-HIPEC, age < 75 years, no extra-peritoneal disease, peritoneal cancer index (PCI) < 10, and a limited history of abdominal surgery. A PREMS interview was conducted before analysis with all the included patients. Outcomes of interest included postoperative morbidity, medium-term survival, and PREMs. RESULTS: Fourteen patients were operated on for low-grade PMP with a laparoscopic approach at our institution. Conversions to laparotomy were necessary in three patients, and postoperative complications were observed in three patients (Clavien 3b in one patient). In-hospital postoperative median stay was 9.5 days. No death or recurrence was observed during the study period. CONCLUSIONS: Laparoscopic CRS-HIPEC for LAMN in presence of small peritoneal disease is feasible in terms of postoperative morbidity and mortality. According to our PREMs questionnaire, patients' expectations were satisfied.

Half of Postoperative Deaths After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Could be Preventable: A French Root Cause Analysis on 5562 Patients.

OBJECTIVE: To perform a retrospective root-cause analysis of postoperative death after CRS and HIPEC procedures. BACKGROUND: The combination of CRS and HIPEC is an effective therapeutic strategy to treat peritoneal surface malignancies, however it is associated with significant postoperative mortality. METHODS: All patients treated with a combination of CRS and HIPEC between January 2009 and December 2018 in 22 French centers and died in the hospital, were retrospectively analyzed. Perioperative data of the 101 patients were collected by a local senior surgeon with a sole junior surgeon. Three independent experts investigated the typical root cause of death and provided conclusions on whether postoperative death was preventable (PREV group) or not (NON-PREV group). A typical root cause of preventable postoperative death was classified on a cause-and-effect diagram. RESULTS: Of the 5562 CRS+HIPEC procedures performed, 101 in-hospital deaths (1.8%) were identified, of which a total of 18 patients of 70 years old and above and 20 patients with ASA score of 3. Etiology of peritoneal disease was mainly colorectal. A total of 54 patients (53%) were classified in the PREV group and 47 patients (47%) in the NON-PREV group. The results of the study show that in the PREV group, WHO performance status 1-2 was more frequent and the Median Peritoneal Cancer Index was higher compared with those of the NON-PREV group. The cause of death in the PREV group was classified as: (i) preoperatively for debatable indication (59%), (ii) intraoperatively (30%) and (iii) postoperatively in 17 patients (31%). A multifactorial cause of death was found in 11 patients (20%). CONCLUSION: More than half of the postoperative deaths after combined CRS and HIPEC may be preventable, mainly by following guidelines regarding preoperative selection of the patients and adequate intraoperative decisions.

Evaluation of the environmental contamination and exposure risk in medical/non-medical staff after oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a technique to directly deliver chemotherapeutic drugs in the abdomen for the treatment of peritoneal metastases. Pressurization improves the treatment efficacy but increases the risk of exposure for the medical/non-medical staff who can be exposed by dermal or ocular contact, or inhalation of aerosols containing the cytotoxic drugs. The aim of this study was to evaluate the risk of exposure for the medical/non-medical staff (nurses, surgeons, anaesthesiologists and cleaning personnel; n = 13) during PIPAC with oxaliplatin performed according to the protocol recommended in France. Blood samples were collected 1 h before and immediately after PIPAC, and urine samples 1 h before, and then 3 h and the morning after PIPAC. In the control, non-exposed group (n = 7), only one urine and blood sample were collected. Surface contamination in the operating room was assessed in water- and Surfanios-impregnated wipe samples. The total elemental platinum in each sample was quantified by inductively coupled plasma mass spectrometry, using a method adapted to quantify trace amounts (ng.L-1) in very low volumes (100 µl). No surface contamination was detected. Although 25% of urine samples in the exposed group contained platinum, no statistical difference was observed in urine and plasma samples collected before and after PIPAC and with the control group samples. These findings suggest that the French PIPAC protocol does not increase the risk of exposure to platinum in all staff categories involved. This protocol could be considered in future occupational policies and consensus statements. Trial registration: NCT04014426.

99mTc-mebrofenin hepatobiliary scintigraphy and volume metrics before liver preparation: correlations and discrepancies in non-cirrhotic patients.

BACKGROUND: Accurate identification of insufficient future liver remnant (FLR) is required to select patients for liver preparation and limit the risk of post-hepatectomy liver failure (PHLF). The objective of this study was to investigate the correlations and discrepancies between the most-commonly used FLR volume metrics and 99mTc-mebrofenin hepatobiliary scintigraphy (HBS). METHODS: In 101 non-cirrhotic patients who underwent HBS before major hepatectomy, we retrospectively analyzed the correlations and discrepancies between FLR function and FLR volume metrics: actual percentage (FLRV%), standardized to body surface area (FLRV%BSA) and weight (FLRV%weight), and FLR to body weight ratio (FLRV-BWR). RESULTS: Among 67 patients with FLR function ≥2.69%/min/m2, PHLF was observed in none and 13 patients according to respectively 50-50 and ISGLS criteria. FLRV%, FLRV%BSA, FLRV%weight and FLRV-BWR significantly correlated with FLR function (P<0.001), with Spearman's correlation coefficients of 0.680, 0.704, 0.698, and 0.711, respectively. No difference was observed between the areas under the curve of FLRV%, FLRV%BSA, FLRV%weight and FLR-BWR (all P=ns). Overall, the percentages of patients misclassified by FLRV%, FLRV%BSA, FLRV%weight (thresholds: 30%) and FLR-BWR (threshold: 0.5) versus FLR function (threshold: 2.69%/min/m2) were 23.8% (95% CI: 15.9-33.3%), 18.8% (95% CI: 11.7-27.8%), 17.8% (95% CI: 11-26.7%), and 31.7% (95% CI: 22.8-41.7%), respectively. FLR volume metrics wrongly classified 1-13.9% of patients with sufficient FLR function (i.e., ≥2.69%/min/m2), and 9.9-30.7% of patients with insufficient FLR function. FLRV-BWR was the most and the least reliable measure to identify patients with sufficient and insufficient FLR function, respectively. CONCLUSIONS: Despite significant correlations, the discrepancy rates between FLR volume and function metrics speaks in favor of implementing 99mTc-mebrofenin HBS in the work-up before liver preparation.

Study of oxaliplatin penetration into ovaries of patients treated with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases of colorectal and appendiceal origin using mass spectrometry imaging.

OBJECTIVES: Platinum salts are commonly used in hyperthermic intraperitoneal chemotherapy (HIPEC) for digestive tract cancer treatment. During HIPEC with oxaliplatin for peritoneal metastases (PMs) treatment, the ovaries are directly exposed to the drug, questioning about ovarian resection and the potential impact of the drug on ovarian functionality, especially in young women of childbearing age. The goal of this work is to understand unwanted damages to the ovaries during HIPEC therapy by the determination of the concentration and distribution of platinum in ovaries in order to address its potential toxicity. METHODS: Mass spectrometry imaging techniques, matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP MS), were used to study the penetration of oxaliplatin in ovaries after HIPEC treatment. RESULTS: MALDI-MS allowed the localization of an oxaliplatin-derivative (m/z 456.2) at the periphery of the ovaries. The quantitative LA-ICP MS maps confirmed the localization of elemental platinum as well as in the central part of ovaries from patients who received a previous platinum salt-based chemotherapy. CONCLUSIONS: LA-ICP MS images showed that platinum diffusion was extended in cases of previous systemic treatment, questioning about platinum derivatives gonado-toxicity when combining the two treatments.

Oncological Outcomes after Liver Venous Deprivation for Colorectal Liver Metastases: A Single Center Experience.

Colorectal liver metastases (CRLM) are the major cause of death in patients with colorectal cancer (CRC). The cornerstone treatment of CRLM is surgical resection. Post-operative morbidity and mortality are mainly linked to an inadequate future liver remnant (FLR). Nowadays preoperative portal vein embolization (PVE) is the most widely performed technique to increase the size of the future liver remnant (FLR) before major hepatectomies. One method recently proposed to increase the FLR is liver venous deprivation (LVD), but its oncological impact is still unknown. The aim of this study is to report first short- and long-term oncological outcomes after LVD in patients undergoing right (or extended right) hepatectomy for CRLM. Seventeen consecutive patients undergoing LVD between July 2015 and May 2020 before an (extended) right hepatectomy were retrospectively analyzed from an institutional database. Post-operative and follow-up data were analyzed and reported. Primary outcomes were 1-year and 3-year overall survival (OS) and hepatic recurrence (HR). Postoperative complications occurred in 8 patients (47%). No deaths occurred after surgery. HR occurred in 9 patients (52.9%). 1-year and 3-year OS were 87% (95% confidence interval [CI]: ±16%) and 60.3%, respectively (95% CI: ±23%). Median Disease-Free Survival (DFS) was 6 months (CI 95%: 4.7-7.2). With all the limitations of a retrospective study with a small sample size, LVD showed similar oncological outcomes compared to literature reports for Portal Vein Embolization (PVE).

The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery.

Importance: Studies on the prognostic role of hyperthermic intraperitoneal chemotherapy (HIPEC) in pseudomyxoma peritonei (PMP) are currently not available. Objectives: To evaluate outcomes after cytoreductive surgery (CRS) and HIPEC compared with CRS alone in patients with PMP. Design, Setting, and Participants: This cohort study analyzed data from the Peritoneal Surface Oncology Group International (PSOGI) registry, including 1924 patients with histologically confirmed PMP due to an appendiceal mucinous neoplasm. Eligible patients were treated with CRS with or without HIPEC from February 1, 1993, to December 31, 2017, and had complete information on the main prognostic factors and intraperitoneal treatments. Inverse probability treatment weights based on the propensity score for HIPEC treatment containing the main prognostic factors were applied to all models to balance comparisons between the CRS-HIPEC vs CRS-alone groups in the entire series and in the following subsets: optimal cytoreduction, suboptimal cytoreduction, high- and low-grade histologic findings, and different HIPEC drug regimens. Data were analyzed from March 1 to June 1, 2018. Interventions: HIPEC including oxaliplatin plus combined fluorouracil-leucovorin, cisplatin plus mitomycin, mitomycin, and other oxaliplatin-based regimens. Main Outcomes and Measures: Overall survival, severe morbidity (determined using the National Cancer Institute Common Terminology for Adverse Events, version 3.0), return to operating room, and 30- and 90-day mortality. Differences in overall survival were compared using weighted Kaplan-Meier curves, log-rank tests, and Cox proportional hazards multivariable models. A sensitivity analysis was based on the E-value from the results of the main Cox proportional hazards model. Differences in surgical outcomes were compared using weighted multivariable logistic models. Results: Of the 1924 patients included in the analysis (997 [51.8%] men; median age, 56 [interquartile range extremes (IQRE), 45-65] years), 376 were in the CRS-alone group and 1548 in the CRS-HIPEC group. Patients with CRS alone were older (median age, 60 [IQRE, 48-70] vs 54 [IQRE, 44-63] years), had less lymph node involvement (14 [3.7%] vs 119 [7.7%]), received more preoperative systemic chemotherapy (198 [52.7%] vs 529 [34.2%]), and had higher proportions of high-grade disease (179 [47.6%] vs 492 [31.8%]) and suboptimal cytoreduction residual disease (grade 3, 175 [46.5%] vs 117 [7.6%]). HIPEC was not associated with a higher risk of worse surgical outcomes except with mitomycin, with higher odds of morbidity (1.99; 95% CI, 1.25-3.19; P = .004). HIPEC was associated with a significantly better overall survival in all subsets (adjusted hazard ratios [HRs], 0.60-0.68, with 95% CIs not crossing 1.00). The weighted 5-year overall survival was 57.8% (95% CI, 50.8%-65.7%) vs 46.2% (95% CI, 40.3%-52.8%) for CRS-HIPEC and CRS alone, respectively (weighted HR, 0.65; 95% CI, 0.50-0.83; P < .001; E-value, 2.03). Such prognostic advantage was associated with oxaliplatin plus fluorouracil-leucovorin (HR, 0.42; 95% CI, 0.19-0.93; P = .03) and cisplatin plus mitomycin (HR, 0.57; 95% CI, 0.42-0.78; P = .001) schedules. Conclusions and Relevance: In this cohort study, HIPEC was associated with better overall survival when performed after CRS in PMP, generally without adverse effects on surgical outcomes.