Association between polyunsaturated fatty acids in adipose tissue and mortality of colorectal cancer patients.

INTRODUCTION: Nutritional intake and dysregulation of fatty acid metabolism play a role in the progression of various tumors, but the consumption of fatty acids is difficult to assess accurately with dietary questionnaires. Biomarkers can objectively assess intake, storage and bioavailability. OBJECTIVE: We studied the association between the polyunsaturated fatty acid (PUFA) composition of abdominal subcutaneous adipose tissue (good indicator of dietary intake over 2-3 years) and all-cause mortality. METHODS: In the multicenter AGARIC study, samples from 203 patients with colorectal cancer (CRC) undergoing curative surgery, were harvested from subcutaneous adipose tissue, which were then analyzed for PUFA composition. RESULTS: After a median follow-up of 45 months, 76 patients died. These patients were more often men (72.4% versus 57.5%, P = 0.04), diabetic (32.9% versus 13.4%, P = 0.001), old (median: 74.5 versus 66.6 years, P < 0.001) and with high alcohol consumption (47.4% versus 30.7%, P = 0.005). An increased risk of death was observed with higher levels of 20:2 ω-6 (hazard ratiotertile3 vstertile1 (HRT3vsT1) 2.12; 95% confidence interval (CI) 1.01-4.42; p-trend = 0.04), 22:4 ω-6 (HRT3vsT1 = 3.52; 95% CI = 1.51-8.17; p-trend = 0.005), and 22:5 ω-6 (HRT3vsT1 = 3.50; 95% CI = 1.56-7.87; p-trend = 0.002). Conversely, the risk of death seemed lower when higher concentrations of 18:3 ω-6 (HRT3vsT1 = 0.52; 95% CI = 0.27-0.99; p-trend = 0.04) and the essential fatty acid, α-linolenic acid 18:3 ω-3 (HRT3vsT1 = 0.47; 95% CI = 0.24-0.93; p-trend = 0.03) were observed. CONCLUSION: The risk of death was increased in CRC patients with higher concentrations of certain ω-6 PUFAs and lower concentrations of α-linolenic acid in their subcutaneous adipose tissue. These results reflect dietary habits and altered fatty acid metabolism. Our exploratory results warrant confirmation in larger studies with further exploration of the mechanisms involved.

Enteral versus parenteral nutrition in the conservative treatment of upper gastrointestinal fistula after surgery: a multicenter, randomized, parallel-group, open-label, phase III study (NUTRILEAK study).

BACKGROUND: Postoperative upper gastrointestinal fistula (PUGIF) is a devastating complication, leading to high mortality (reaching up to 80%), increased length of hospital stay, reduced health-related quality of life and increased health costs. Nutritional support is a key component of therapy in such cases, which is related to the high prevalence of malnutrition. In the prophylactic setting, enteral nutrition (EN) is associated with a shorter hospital stay, a lower incidence of severe infectious complications, lower severity of complications and decreased cost compared to total parenteral nutrition (TPN) following major upper gastrointestinal (GI) surgery. There is little evidence available for the curative setting after fistula occurrence. We hypothesize that EN increases the 30-day fistula closure rate in PUGIF, allowing better health-related quality of life without increasing the morbidity or mortality. METHODS/DESIGN: The NUTRILEAK trial is a multicenter, randomized, parallel-group, open-label phase III trial to assess the efficacy of EN (the experimental group) compared with TPN (the control group) in patients with PUGIF. The primary objective of the study is to compare EN versus TPN in the treatment of PUGIF (after esophagogastric resection including bariatric surgery, duodenojejunal resection or pancreatic resection with digestive tract violation) in terms of the 30-day fistula closure rate. Secondary objectives are to evaluate the 6-month postrandomization fistula closure rate, time of first fistula closure (in days), the medical- and surgical treatment-related complication rate at 6 months after randomization, the fistula-related complication rate at 6 months after randomization, the type and severity of early (30 days after randomization) and late fistula-related complications (over 30 days after randomization), 30-day and 6-month postrandomization mortality rate, nutritional status at day 30, day 60, day 90 and day 180 postrandomization, the mean length of hospital stay, the patient's health-related quality of life (by self-assessment questionnaire), oral feeding time and direct costs of treatment. A total of 321 patients will be enrolled. DISCUSSION: The two nutritional supports are already used in daily practice, but most surgeons are reluctant to use the enteral route in case of PUGIF. This study will be the first randomized trial testing the role of EN versus TPN in PUGIF. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03742752. Registered on 14 November 2018.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis in the Elderly: A Case-Controlled, Multicenter Study.

OBJECTIVE: This study was designed to identify factors associated with morbidity and mortality in patients older than 70 years who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC). BACKGROUND: Major surgery is associated with higher morbidity and mortality in elderly patients. For PC, CRS and HIPEC is the only current potential curative therapy, but the risks inherent to this patient population have called its benefits into question. METHODS: We retrospectively analyzed a multi-center database from 1989 to 2015. All patients who underwent CRS and HIPEC for PC were selected and patients older than 70 years were matched 1:4 with a younger cohort according to cancer origin, peritoneal cancer index (PCI), and completeness of cytoreduction. Major morbidity and mortality were analyzed. RESULTS: Of 2328 patients, 188 patients older than aged 70 years were matched with 704 younger patients. Patients older than aged 70 years demonstrated a higher American Society of Anesthesiologist score (≥ASA III 10.8 vs. 6.6 %, p = 0.008). There was no difference in overall 90-day morbidity (≥70: 45.7 % vs. <70: 44.5 %; p = 0.171); however, patients older than 70 years had significantly more cardiovascular complications (13.8 vs. 9.2 %, p = 0.044). Differences between the older and younger cohorts failed to reach significance for 90-day mortality (5.4 and 2.7 %, respectively; p = 0.052), and failure-to-rescue (11.6 and 6.1 %, respectively; p = 0.078). In multivariate analysis, PCI > 7 (95 % CI 1.051-5.798, p = 0.038) and HIPEC duration (95 % CI 1.106-6.235, p = 0.028) were independent factors associated with morbidity in elderly patients. CONCLUSIONS: CRS and HIPEC appear feasible for selected patients older than aged 70 years, albeit with a higher risk of medical complications associated with increased mortality.

Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin Increases the Risk of Postoperative Hemorrhagic Complications: Analysis of Predictive Factors.

BACKGROUND: Treatment of peritoneal carcinomatosis (PC) using cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is recommended as curative treatment for selected patients. Modalities of HIPEC remain heterogeneous and HIPEC using oxaliplatin (HIPEC-Ox) appears to increase the risk of postoperative hemorrhagic complications (HCs). OBJECTIVE: The aim of this study was to assess the risk of HCs after CRS combined with HIPEC-Ox versus other drugs, and to determine predictive factors for HCs after HIPEC-Ox. METHODS: Data from 701 patients included in the National French Registry who were treated with CRS and HIPEC at 24 centers between 1998 and 2007 were used to evaluate the incidence of HCs following HIPEC with or without oxaliplatin. Overall, 771 patients treated with HIPEC-Ox at five French specialty centers were then analyzed to determine factors associated with the occurrence of HCs. RESULTS: The overall incidence of HCs was 9.8 %. When used with HIPEC, oxaliplatin significantly and independently increased the rate of HCs (15.7 vs. 2.6 % for other drugs; p = 0.004, odds ratio 32.4). Among the 771 patients who underwent HIPEC-Ox, HCs occurred in 14.3 % of patients. The only independent risk factor for HCs was an extended PC with a Peritoneal Cancer Index (PCI) >12 (p = 0.040). CONCLUSION: HIPEC-Ox increases the risk of HCs compared with HIPEC with other drugs. The potential oncologic benefit of oxaliplatin and the risk of HCs should be considered in patients with PC who have a high PCI, as well as in at-risk patients.

High pressure enhances the effect of hyperthermia in intraperitoneal chemotherapy with oxaliplatin: an experimental study.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) achieve good results in selected patients with peritoneal carcinomatosis. High intra-abdominal pressure could enhance the penetration of chemotherapy drugs. The aim of this study was to compare the effects of high pressure and hyperthermia when used separately and when combined in terms of blood and tissue absorption of oxaliplatin in a swine model of intraperitoneal chemotherapy. METHODS: Four groups of 5 pigs each underwent laparotomy and open intraperitoneal chemotherapy with oxaliplatin at a constant concentration (150 mg/L) for 30 minutes in normothermia and atmospheric pressure (group 1), or hyperthermia (42°C) and atmospheric pressure (group 2), or normothermia and high pressure (25 cm H2O) (group 3), or hyperthermia and high pressure (group 4). High pressure was achieved thorough a water column over the abdomen. Systemic absorption and abdominal tissue mapping of the penetration of oxaliplatin in each group were studied. RESULTS: Blood concentrations of oxaliplatin were similar in the different groups. Hyperthermia achieved higher concentrations in visceral surfaces (P = 0.0014), but not in parietal surfaces. High pressure enhanced diffusion of the drug in both the visceral and parietal peritoneum (P = 0.0058 and P = 0.0044, respectively). The combination of hyperthermia and high pressure significantly increased the penetration of oxaliplatin and achieved the highest tissue concentrations (10.39 mg/kg vs 5.48 mg/kg; P = 0.00001 in the visceral peritoneum, and 66.16 mg/kg vs 35.62 mg/kg; P = 0.0003 in the parietal peritoneum). CONCLUSIONS: Open high-pressure HIPEC with oxaliplatin is feasible in the pig. Hyperthermia enhances diffusion in the visceral peritoneum, whereas high pressure is effective in the visceral and parietal peritoneum. The combination of the two achieves the highest tissue concentrations of oxaliplatin.

Childbearing after hyperthermic intraperitoneal chemotherapy: results from an international survey.

BACKGROUND: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) can improve survival in selected patients with primary or secondary peritoneal malignancies. With the opportunity for long-term survival, questions about the impact of those procedures in fertility in women of childbearing age can be raised. MATERIALS AND METHODS: An international survey was performed among all teams participating in the International Peritoneal Surface Malignancy Group in order to collect data about pregnancies and their outcome in women having undergone previous CRS with adjuvant HIPEC. RESULTS: There were 7 pregnancies reported after CRS and HIPEC in women treated for peritoneal malignancies. All these women conceived spontaneously, most of them within 2 years after the procedure. They delivered most often by vaginal way after an uneventful pregnancy. Their newborns were healthy, except 1 case of congenital diaphragmatic hernia requiring emergent surgery. There were 2 additional uneventful pregnancies reported after the diagnosis of pseudomyxoma peritonei and before CRS and HIPEC, with the support of the medical team. Another woman having undergone oocytes retrieval and embryo cryopreservation prior to the surgery was mother of twins after the procedure via a surrogate mother. CONCLUSION: Childbearing after cytoreductive surgery and heated intraperitoneal chemotherapy is possible in women conserving their genital organs after the procedure. The question of fertility should be considered and discussed in women in reproductive age prior to cytoreductive surgery and heated intraperitoneal chemotherapy. Different options could be offered in this setting. Multidisciplinary decision making involving surgical oncologists and fertility specialists is important.

Comparison of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a murine model of peritoneal carcinomatosis.

BACKGROUND: The best method to deliver intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis from ovarian cancer is not well defined. The aim of this study was to assess the ability of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a rat model of peritoneal carcinomatosis. METHODS: Four groups of 5 BDIX rats with ovarian peritoneal carcinomatosis underwent IPC with 30 mg/l of cisplatin according to the following conditions: normothermia at 37° for 1 or 2 hours, hyperthermia at 42°C for 1 hour or normothermia at 37°C for 2 hours with 2 mg/l adrenaline. Tissue platinum content was measured by atomic absorption spectroscopy. The effect of hyperthermia, adrenaline and the duration of exposure to the drug was measured in vivo (tissue concentration of platinum in tumor, abdominal and extra abdominal tissues) and in vitro (cytotoxicity on human ovarian cancer cells). RESULTS: In vitro, hyperthermia and longer exposure enhanced the accumulation and the cytotoxic effect of cisplatin on cancer cells. In vivo, only the 2 hours treatment with adrenaline resulted in increased platinum concentrations. The rats treated with adrenaline showed significantly lower concentrations of cisplatin in extra peritoneal tissues than those treated with hyperthermia. CONCLUSION: Adrenaline is more effective than hyperthermia in order to enhance the intratumoral concentration of cisplatin in rats with peritoneal carcinomatosis from ovarian origin. It may also decrease the systemic absorption of the drug.

Which method to deliver hyperthermic intraperitoneal chemotherapy with oxaliplatin? An experimental comparison of open and closed techniques.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) achieves good results in selected patients with peritoneal carcinomatosis. There are two main procedures to deliver this therapy: the open abdomen and the closed abdomen techniques. A true comparison of the two techniques has never been performed. The aim of this study was to compare blood and abdominal tissue concentrations of oxaliplatin after open and closed techniques to deliver HIPEC. METHODS: Nine pigs underwent HIPEC at 42-43 degrees C for 30 min with oxaliplatin (400 mg/m(2)) according to two techniques: closed (three animals) or open (six animals). The open technique used either an external heater with a pump (three animals) or an intra-abdominal heating cable (three animals) to achieve hyperthermia. Temperature homogeneity, systemic absorption, and abdominal tissue mapping of the penetration of oxaliplatin with each technique were studied. Two additional pigs underwent hyperthermia with dyes instead of oxaliplatin to depict the distribution of the liquid within the abdomen with both techniques. RESULTS: Hyperthermia was satisfactory with both techniques. The closed technique achieved higher temperatures within the diaphragmatic area, while the open technique obtained higher temperatures in the mid and lower abdomen (P < 0.001 for both comparisons). The systemic absorption of oxaliplatin was higher with the open technique (P < 0.04 for all comparisons), as was the accumulation within the abdominal cavity. The operating time for the two techniques was not greatly different. CONCLUSIONS: Intraperitoneal hyperthermia can be achieved with both techniques. The open technique had far higher systemic absorption and abdominal tissue penetration of oxaliplatin than the closed technique.

Closed hyperthermic intraperitoneal chemotherapy with open abdomen: a novel technique to reduce exposure of the surgical team to chemotherapy drugs.

BACKGROUND: Exposure of the surgical team to toxic drugs during hyperthermic intraperitoneal chemotherapy (HIPEC) remains a matter of great concern. During closed-abdomen HIPEC, operating room staff are not exposed to drugs, but the distribution of the heated liquid within the abdomen is not optimal. With open-abdomen HIPEC, the opposite is true. Although the open-abdomen method is potentially more effective, it has not become a standard procedure because of the risk of exposure of members of the team to drugs. METHODS: We present a new technique (closed HIPEC with open abdomen) which ensures protection against potentially contaminating exposure to liquids, vapours and aerosols, and allows permanent access to the whole abdominal cavity. Its principle is to extend the abdominal surgical wound upwards with a sort of "glove-box". The cutaneous edges of the laparotomy are stapled to a latex "wall expander". The expander is draped over a special L-section metal frame placed above the abdomen. A transparent cover containing a "hand-access" port, like those used in laparoscopic surgery, is fixed inside the frame. RESULTS: In 10 patients, this device proved to be hermetic for both liquids and vapours. Intra-abdominal temperature was maintained between 42 and 43 degrees C during most of the procedure. The whole abdominal cavity was accessible to the surgeon, allowing optimal exposure of all peritoneal surfaces. CONCLUSION: This technique allows optimal HIPEC, while limiting the potential toxic effects for the surgical, medical and paramedical teams.