Developing a hyperthermic intraperitoneal chemotherapy (HIPEC) gynecologic oncology program: a Canadian experience.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for epithelial ovarian cancer following cytoreductive surgery. The intraperitoneal spread of the disease makes the peritoneal cavity an ideal target for drug delivery. HIPEC has shown promising results in improving overall survival in epithelial ovarian cancer patients when performed during interval cytoreductive surgery. Recent studies have provided level 1 evidence supporting increased overall survival in stage III ovarian cancer patients treated with HIPEC during interval cytoreduction. Meta-analyses have further confirmed the survival improvement in women receiving HIPEC. Despite its inclusion in guidelines, many centers have been hesitant to implement HIPEC programs due to perceived obstacles, such as increased morbidity, cost, and resource requirements. Studies have shown that morbidity rates are acceptable in selected patients, and the addition of HIPEC to cytoreductive surgery is cost effective. Therefore, the main barrier to implementing HIPEC programs is related to resource requirements and logistics, but with proper preparation, these challenges can be overcome. Establishing a successful HIPEC program requires institutional support, a knowledgeable and dedicated team, adequate resources and equipment, and proper training and audit. This review aims to provide evidence based information to guide the development of successful HIPEC programs, including preoperative, anesthetic, and surgical considerations. It also reviews the different equipment and protocols for the perfusion and common postoperative events.

Hyperthermic Intraperitoneal Chemotherapy and Interval Debulking Surgery in Conjunction With Elective Cesarean Delivery.

BACKGROUND: Ovarian cancer is rare during pregnancy. For patients beyond 20 weeks of gestation who choose to continue the pregnancy, neoadjuvant chemotherapy may be initiated, followed by interval debulking surgery. Hyperthermic intraperitoneal chemotherapy (HIPEC) may be used with interval debulking surgery for stage III epithelial ovarian cancer, but data are lacking on its administration in the peripartum period. CASE: We illustrate the case of a 40-year-old patient diagnosed with stage III epithelial ovarian cancer at 27 weeks of gestation who underwent neoadjuvant chemotherapy followed by cesarean delivery at term along with interval debulking surgery and HIPEC. The intervention was well tolerated and resulted in the birth of a healthy neonate. The postoperative period was unremarkable, and the patient is disease-free after 22-months of follow-up. CONCLUSION: We demonstrate the feasibility of peripartum HIPEC. Optimal oncologic care should not be jeopardized by the peripartum state of an otherwise healthy patient.

Sensory acceptability of antioxidant-based formulations dedicated to mitigate heterocyclic aromatic amines in cooked meat.

In a previous work, we studied the inhibition of heterocyclic aromatic amine formation by natural ingredients rich in antioxidants: caper, oregano, wine and green tea. This present work aimed to assess the sensory impact of the addition of these ingredients in ground beef patties. The best liked formulations were determined by a hedonic scoring. Caper and oregano were not significantly different from the standard, the most appreciated, due to their congruency with cooked meat. Direct dissimilarity assessment was performed to evaluate the overall, gustative and odor differences between formulations. Olfactive differences were evidenced as key drivers of these differences. Standard and caper were close while oregano was found significantly different from them. A fast sensory profiling permitted to evidence that aromatic plant note was discriminant for oregano formulation. Gas chromatography-mass spectrometry/multibooth olfactometry identified the distinctive odor-active compounds of the formulations as pyrazines and sulfide for oregano formulation and ester for caper formulation.

A Canadian single-centre experience with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for abdominal malignancies.

BACKGROUND: Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has recently shown promise for the treatment of patients with various types of peritoneal carcinomatosis (PC). However, it is an extensive procedure that is associated with a variety of morbidities. We evaluated the safety and clinical outcomes of CRS-HIPEC performed at our centre. METHODS: Patients with abdominal malignancies who underwent CRS-HIPEC between February 2005 and December 2018 at the Centre hospitalier de l'Université de Montréal (CHUM) were retrospectively reviewed. RESULTS: A total of 141 patients were identified (66 with appendiceal cancer, 62 with colorectal cancer, 10 with mesothelioma and 3 with small intestinal tumours). The median age was 55 years. Median overall survival (OS) was not reached for patients with appendiceal tumours; it was 38.3 months for colorectal cancers. Among patients with colorectal cancer, survival was significantly better for those who received intraperitoneal HIPEC with oxaliplatin (74.9 mo) compared with mitomycin C (29.1 mo) (p = 0.006). Complete cytoreductive surgery and low peritoneal carcinomatosis index were associated with the highest overall survival in patients with appendiceal tumours and those with colorectal tumours. CONCLUSION: CRS-HIPEC can be performed with acceptable morbidity in patients with PC. These results validate the outcomes of previously reported trials, but further prospective trials are warranted to determine which patients will most benefit from the addition of HIPEC to CRS.

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for small bowel neuroendocrine tumors with peritoneal metastasis.

BACKGROUND: Up to 20% of patients with small-bowel neuroendocrine tumors (SB-NETs) may present with peritoneal carcinomatosis (PM). Surgical cytoreduction (CRS) has been proposed as an adequate management as it confers a survival benefit in selected patients. The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to CRS in this context may be an option but data on its added benefits is lacking. METHODS: A search was performed in the prospective multicenter international collaborative database of the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working groups, and patients who underwent a surgical treatment (CRS or CRS with HIPEC) for a SB-NET with PM were identified and compared. RESULTS: Between 2002 and 2016, a total of 67 patients were identified as having a CRS for SB-NET, with 36 receiving HIPEC during surgery. Median postoperative follow-up was 34 months. The peritoneal cancer index (PCI) and the completeness of cytoreduction score (CCR-score) were higher in the CRS-HIPEC group. More grade III-IV complications occurred in this group as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Despite a tendency toward a better progression/recurrence-free survival in patients receiving HIPEC, no significant differences were noted between the CRS and CRS-HIPEC groups in terms of postoperative recurrence. CONCLUSIONS: HIPEC does not seem to provide additional benefits in terms of postoperative evolution and survival in patients with SB-NET undergoing CRS. It is associated with higher morbidity. It may possibly lead to an improved recurrence-free survival, but further reports are required to confirm this assumption.

An International Registry of Peritoneal Carcinomatosis from Appendiceal Goblet Cell Carcinoma Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

PURPOSE: Peritoneal carcinomatosis from appendiceal goblet cell carcinoma (A-GCC) is a rare and aggressive form of appendiceal tumor. Cytoreductive surgery (CRS) and hyperthermic intra peritoneal chemotherapy (HIPEC) was reported as an interesting alternative regarding survival compared to surgery without HIPEC and/or systemic chemotherapy. Our aim was to evaluate the impact of CRS and HIPEC for patients presenting A-GCC through an international registry. METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with A-GCC tumor and peritoneal metastases who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI). The post-operative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 83 patients. After a median follow-up of 47 months, the median overall survival (OS) was 34.6 months. The 3- and 5-year OS was 48.5% and 35.7%, respectively. Patients who underwent complete macroscopic CRS had a significantly better survival than those treated with incomplete CRS. The 5-year OS was 44% and 0% for patients who underwent complete, and incomplete CRS, respectively (HR 9.65, p < 0.001). Lymph node involvement and preoperative chemotherapy were also predictive of a worse prognosis. There were 3 postoperative deaths, and 30% of the patients had major complications. CONCLUSION: CRS and HIPEC may increase long-term survival in selected patients with peritoneal metastases of A-GCC origin, especially when complete CRS is achieved. Ideally, randomized control trials or more retrospective data are needed to confirm CRS and HIPEC as the gold standard in this pathology.

Cytoreductive Surgery and Intraperitoneal Chemotherapy in Advanced Serous Epithelial Ovarian Cancer: A 14-Year French Retrospective Single-Center Study of 124 Patients.

INTRODUCTION: Ovarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases. METHODS: A prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed. RESULTS: From January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%. CONCLUSION: CRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates.

Mitigation of heterocyclic aromatic amines in cooked meat. Part I: Informed selection of antioxidants based on molecular modeling.

This work aimed to develop a method permitting an informed choice of antioxidants to reduce carcinogenic heterocyclic aromatic amine (HAA) formation during proteinaceous food cooking. Therefore, a three-step approach was developed. First, the most promising antioxidants were selected using molecular modeling approaches. For this, analog design was used to highlight the most suitable antioxidants based on their diversification potential using bioisosteric replacement. Then, structure activity relationship studies allowed drawing the relevant properties for inhibiting HAA formation and explained partly the inhibitory activity. Secondly, the approved antioxidants were tested in ground beef patties to assess their inhibitory properties against HAA formation. Resveratrol was found to be the most efficient as it totally inhibited MeIQ and reduced MeIQx and PhIP formation by 40 and 70%, respectively. Finally, natural ingredients rich in these antioxidants were evaluated. Oregano was found to totally inhibit MeIQ formation and to reduce by half MeIQx and PhIP formation.

Overall survival of pseudomyxoma peritonei and peritoneal mesothelioma patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy can be predicted by computed tomography quantified sarcopenia.

BACKGROUND: Malnutrition is associated with increased postoperative morbidity in abdominal surgery. This study aimed to determine if sarcopenia and/or abdominal fat composition could predict postoperative outcomes for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for pseudomyxoma peritonei (PMP) and peritoneal mesothelioma (PM). METHODS: All patients who underwent a complete CRS-HIPEC for PMP and PM, between January 2009 and September 2017, were retrospectively studied. Preoperative computed tomography (CT) was used to measure the cross-sectional surface of skeletal muscle mass and adipose tissue (visceral and subcutaneous), at the level of the third lumbar vertebrae, to assess for sarcopenia and abdominal fat composition. RESULTS: Among 115 patients, 82 were treated for PMP and 33 for PM. 64 patients (55.7%) were sarcopenic on the preoperative imagery. Major postoperative complications occurred in 63 patients (54.8%), without observable difference between sarcopenic and non-sarcopenic patients (56.2% vs. 52.9%; p = 0.723). The median overall survival (OS) was 73.3 for the patients with a normal muscle mass and 57.2 months for the sarcopenic patients (p = 0.05). CONCLUSION: CT measured sarcopenia is an independent predictive factor for overall survival in patients treated for PMP and PM with CRS-HIPEC, but cannot predict postoperative morbidity.

Peritoneal Carcinomatosis of Rare Ovarian Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-Institutional Cohort from PSOGI and BIG-RENAPE.

PURPOSE: Ovarian cancer is the most common deadly cancer of gynecologic origin. Patients often are diagnosed at advanced stage with peritoneal metastasis. There are many rare histologies of ovarian cancer; some have outcomes worse than serous ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be considered for patients with recurrence. This study was designed to assess the impact of CRS and HIPEC on survival of patient with peritoneal metastasis from rare ovarian malignancy. METHODS: A prospective, multicentric, international database was retrospectively searched to identify all patients with rare ovarian tumor (mucinous, clear cells, endometrioid, small cell hypercalcemic, and other) and peritoneal metastasis who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working group. The postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 210 patients with a median follow-up of 43.5 months. Median overall survival (OS) was 69.3 months, and the 5-year OS was 57.7%. For mucinous tumors, median OS and DFS were not reached at 5 years. For granulosa tumors, median overall survival was not reached at 5 years, and median DFS was 34.6 months. Teratoma or germinal tumor showed median overall survival and DFS that were not reached at 5 years. Differences in OS were not statistically significant between histologies (p = 0.383), whereas differences in DFS were (p < 0.001). CONCLUSIONS: CRS and HIPEC may increases long-term survival in selected patients with peritoneal metastasis from rare ovarian tumors especially in mucinous, granulosa, or teratoma histological subtypes.

Peritoneal Carcinomatosis of Urachus Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An International Registry of 36 Patients.

PURPOSE: Peritoneal carcinomatosis or pseudomyxoma peritonei from urachus is a rare form of presentation, often diagnosed at an advanced state of tumor burden. Because of its rarity, little is known about its natural history, prognosis, or optimal treatment. We searched a large international multicenter database of peritoneal surface disease to identify cases of peritoneal carcinomatosis of urachus that were treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) at expert centers. The aim is to improve knowledge and understanding of the disease and standardize its treatment. METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with urachus tumor and peritoneal metastases who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI). Postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 36 patients. After median follow-up of 48 months, median overall survival (OS) was 58.5 months. Three- and 5-year OS was 55.4 and 46.2%, respectively. Patients who underwent complete macroscopic CRS had significantly better survival than those treated with incomplete CRS, with median OS not achieved and of 20.1 months, respectively [95% confidence interval (CI) 4.4-30.5, p < 0.001]. There were no postoperative deaths, and 37.9% of patients had major complications. CONCLUSION: CRS and HIPEC may increase long-term survival in selected patients with peritoneal metastases of urachus origin, especially when complete CRS is achieved.

Preoperative nutritional risk assessment in patients undergoing cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for colorectal carcinomatosis.

BACKGROUND: Malnutrition is associated with increased postoperative morbidity in colorectal surgery. This study aimed to determine if preoperative nutritional markers could predict postoperative outcomes for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal metastasis (PM) of colorectal origin. METHODS: All patients who underwent a complete CRS-HIPEC for colorectal PM between January 2009 and December 2014 were evaluated. Preoperative clinical and biological nutritional factors, including Body Mass Index (BMI), preoperative albumin and prealbumin levels were analysed. Preoperative computed tomography was used to measure the cross-sectional surface of the visceral and subcutaneous adipose tissue, at the third lumbar vertebrae, to assess the abdominal fat composition. Skeletal muscle mass was measured to assess for sarcopenia. RESULTS: Among 214 patients, 14 (6.5%) had a BMI ≥ 35 kg/m2, 90 (42%) were sarcopenic, 19 (9%) presented albumin <35 g/L and 2 (1%) had pre-albumin <20 mg/dL. Median values for visceral and subcutaneous fat surfaces were 99.2 cm2 and 198 cm2, respectively. Hypoalbuminemia was associated with worse overall survival (23 vs. 59 months, p = 0.015). The other nutritional factors did not impact overall or progression free survival after CRS-HIPEC for colorectal PM. In multivariate analysis, major post-operative complication and hypoalbuminemia were independently associated with decreased overall survival. CONCLUSIONS: Hypoalbuminemia appears as a strong predictive factor for decreased overall survival in patients presenting PM of colorectal origin undergoing CRS-HIPEC.

Postpartum hemorrhage: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF): in collaboration with the French Society of Anesthesiology and Intensive Care (SFAR).

Postpartum haemorrhage (PPH) is defined as blood loss ≥500mL after delivery and severe PPH as blood loss ≥1000mL, regardless of the route of delivery (professional consensus). The preventive administration of uterotonic agents just after delivery is effective in reducing the incidence of PPH and its systematic use is recommended, regardless of the route of delivery (Grade A). Oxytocin is the first-line prophylactic drug, regardless of the route of delivery (Grade A); a slowly dose of 5 or 10 IU can be administered (Grade A) either IV or IM (professional consensus). After vaginal delivery, routine cord drainage (Grade B), controlled cord traction (Grade A), uterine massage (Grade A), and routine bladder voiding (professional consensus) are not systematically recommended for PPH prevention. After caesarean delivery, placental delivery by controlled cord traction is recommended (grade B). The routine use of a collector bag to assess postpartum blood loss at vaginal delivery is not systematically recommended (Grade B), since the incidence of severe PPH is not affected by this intervention. In cases of overt PPH after vaginal delivery, placement of a blood collection bag is recommended (professional consensus). The initial treatment of PPH consists in a manual uterine examination, together with antibiotic prophylaxis, careful visual assessment of the lower genital tract, a uterine massage, and the administration of 5-10 IU oxytocin injected slowly IV or IM, followed by a maintenance infusion not to exceed a cumulative dose of 40IU (professional consensus). If oxytocin fails to control the bleeding, the administration of sulprostone is recommended within 30minutes of the PPH diagnosis (Grade C). Intrauterine balloon tamponade can be performed if sulprostone fails and before recourse to either surgery or interventional radiology (professional consensus). Fluid resuscitation is recommended for PPH persistent after first line uterotonics, or if clinical signs of severity (Grade B). The objective of RBC transfusion is to maintain a haemoglobin concentration (Hb) >8g/dL. During active haemorrhaging, it is desirable to maintain a fibrinogen level ≥2g/L (professional consensus). RBC, fibrinogen and fresh frozen plasma (FFP) may be administered without awaiting laboratory results (professional consensus). Tranexamic acid may be used at a dose of 1 g, renewable once if ineffective the first time in the treatment of PPH when bleeding persists after sulprostone administration (professional consensus), even though its clinical value has not yet been demonstrated in obstetric settings. It is recommended to prevent and treat hypothermia in women with PPH by warming infusion solutions and blood products and by active skin warming (Grade C). Oxygen administration is recommended in women with severe PPH (professional consensus). If PPH is not controlled by pharmacological treatments and possibly intra-uterine balloon, invasive treatments by arterial embolization or surgery are recommended (Grade C). No technique for conservative surgery is favoured over any other (professional consensus). Hospital-to-hospital transfer of a woman with a PPH for embolization is possible once hemoperitoneum is ruled out and if the patient's hemodynamic condition so allows (professional consensus).

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex.

Calcium (Ca(2+)) is a secondary messenger in cells and Ca(2+) flux initiated from endoplasmic reticulum (ER) stores via inositol 1,4,5-triphosphate (IP3) binding to the IP3 receptor (IP3R) is particularly important for the activation and function of immune cells. Previous studies demonstrated that genetic deletion of selenoprotein K (Selk) led to decreased Ca(2+) flux in a variety of immune cells and impaired immunity, but the mechanism was unclear. Here we show that Selk deficiency does not affect receptor-induced IP3 production, but Selk deficiency through genetic deletion or low selenium in culture media leads to low expression of the IP3R due to a defect in IP3R palmitoylation. Bioinformatic analysis of the DHHC (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) family of enzymes that catalyze protein palmitoylation revealed that one member, DHHC6, contains a predicted Src-homology 3 (SH3) domain and DHHC6 is localized to the ER membrane. Because Selk is also an ER membrane protein and contains an SH3 binding domain, immunofluorescence and coimmunoprecipitation experiments were conducted and revealed DHHC6/Selk interactions in the ER membrane that depended on SH3/SH3 binding domain interactions. DHHC6 knockdown using shRNA in stably transfected cell lines led to decreased expression of the IP3R and impaired IP3R-dependent Ca(2+) flux. Mass spectrophotometric and bioinformatic analyses of the IP3R protein identified two palmitoylated cysteine residues and another potentially palmitoylated cysteine, and mutation of these three cysteines to alanines resulted in decreased IP3R palmitoylation and function. These findings reveal IP3R palmitoylation as a critical regulator of Ca(2+) flux in immune cells and define a previously unidentified DHHC/Selk complex responsible for this process.

Fractones and other basal laminae in the hypothalamus.

The physiological role of basal laminae (BL) and connective tissue (meninges and their projections) in the adult brain is unknown. We recently described novel forms of BL, termed fractones, in the most neurogenic zone of the adult brain, the subependymal layer (SEL) of the lateral ventricle. Here, we investigated the organization of BL throughout the hypothalamus, using confocal and electron microscopy. New types of BL were identified. First, fractones, similar to those found in the lateral ventricle wall, were regularly arranged along the walls of the third ventricle. Fractones consisted of labyrinthine BL projecting from SEL blood vessels to terminate immediately beneath the ependyma. Numerous processes of astrocytes and of microglial cells directly contacted fractones. Second, another form of BL projection, termed anastomotic BL, was found between capillaries in dense capillary beds. The anastomotic BL enclosed extraparenchymal cells that networked with the perivascular cells coursing in the sheaths of adjacent blood vessels. Vimentin immunoreactivity was often detected in the anastomotic BL. In addition, the anastomotic BL overlying macrophages contained numerous fibrils of collagen. We also found that the BL located at the pial surface formed labyrinthine tube-like structures enclosing numerous fibroblast and astrocyte endfeet, with pouches of collagen fibrils at the interface between the two cell types. We suggest that cytokines and growth factors produced by connective tissue cells might concentrate in BL, where their interactions with extracellular matrix proteins might contribute to their effects on the overlying neural tissue, promoting cytogenesis and morphological changes and participating in neuroendocrine regulation.