Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. METHODS: We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed. FINDINGS: Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). INTERPRETATION: Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. FUNDING: Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.

Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study.

BACKGROUND: Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. METHODS: We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m2, or oxaliplatin 300 mg/m2 plus irinotecan 200 mg/m2, plus intravenous fluorouracil 400 mg/m2), or mitomycin-HIPEC (mitomycin 35 mg/m2) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394. FINDINGS: Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0-54·8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61-1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. INTERPRETATION: Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. FUNDING: French National Cancer Institute.

The Challenging Diagnosis of Non-Community-Acquired Pneumonia in Non-Mechanically Ventilated Subjects: Value of Microbiological Investigation.

BACKGROUND: Early recognition and an attempt at obtaining microbiological documentation are recommended in patients with non-community-acquired pneumonia (NCAP), whether hospital-acquired (HAP) or health care-associated (HCAP). We aimed to characterize the clinical features and microbial etiologies of NCAP to assess the impact of microbiological investigation on their management. METHODS: This was a prospective 1-y study in a university hospital with 141 non-mechanically ventilated subjects suspected of having HAP (n = 110) or HCAP (n = 31). RESULTS: Clinical criteria alone poorly identified pneumonia (misdiagnosis in 50% of cases). Microbiological confirmation was achievable in 80 subjects (57%). Among 79 microorganisms isolated, 28 were multidrug-resistant aerobic Gram-negative bacilli and group III Enterobacteriaceae and 6 were methicillin-resistant Staphylococcus aureus. Multidrug-resistant aerobic Gram-negative bacilli accounted for one third of the microorganisms in early-onset HAP and for 50% in late-onset HAP. Methicillin-resistant S. aureus was most often recovered from subjects with HCAP. Inappropriate empirical antibiotics were administered to 36% of subjects with confirmed pneumonia. Forty subjects were admitted to the ICU, 13 (33%) of whom died. Overall, 39 subjects (28%) died in the hospital. CONCLUSIONS: Integrating the microbiological investigation in the complex clinical diagnostic workup of patients suspected of having NCAP is mandatory. Respiratory tract specimens should be obtained whenever possible for appropriate management.

Prophylactic laparoscopic cholecystectomy in adult sickle cell disease patients with cholelithiasis: A prospective cohort study.

INTRODUCTION: Prophylactic laparoscopic cholecystectomy remains controversial and has been discussed for selected subgroups of patients with asymptomatic cholelithiasis who are at high risk of developing complications such as chronic haemolytic conditions. Cholelithiasis is a frequent condition for patients with sickle cell disease (SCD). Complications from cholelithiasis may dramatically increase morbidity for these patients. Our objective was to evaluate the effectiveness of prophylactic cholecystectomy in SCD patients with asymptomatic gallbladder stones. METHODS: From January 2000 to June 2014, we performed 103 laparoscopic cholecystectomies on SCD patients. Fifty-two patients had asymptomatic cholelithiasis. The asymptomatic patients were prospectively enrolled in this study, and all underwent a prophylactic cholecystectomy with an intraoperative cholangiography. The symptomatic patients were retrospectively studied. Upon admission, all patients were administered specific perioperative management including intravenous hydration, antibiotic prophylaxis, oxygenation, and intravenous painkillers, as well as the subcutaneous administration of low-molecular-weight heparin. During the same period, 51 patients with SCD underwent a cholecystectomy for symptomatic cholelithiasis. We compared these 2 groups in terms of postoperative mortality, morbidity, and hospital stay. RESULTS: There were no postoperative deaths or injuries to the bile ducts in either group. In the asymptomatic group, we observed 6 postoperative complications (11.5%), and in the symptomatic group, there were 13 (25.5%) postoperative complications. DISCUSSION: Regarding the SCD complications, we observed 1 case (2%) of acute chest syndrome in an asymptomatic cholelithiasis patient, while there were 3 cases (6%) in the symptomatic group. Vaso-occlusive crisis was observed in 1 patient (2%) with asymptomatic cholelithiasis, and in 4 patients (8%) in the other group. The mean hospital stay averaged 5.8 (4-17) days for prophylactic cholecystectomy and 7.96 (4-18) days for the comparative symptomatic group. CONCLUSIONS: Postoperative complications related to SCD were less frequent for asymptomatic patients who had a laparoscopic prophylactic cholecystectomy. This intervention, if performed with perioperative specific management, is safe and helps avoid emergency operations for acute complications including cholecystitis, choledocholithiasis, and cholangitis. For SCD patients, a prophylactic cholecystectomy reduces hospital stays.

Rapidly progressive kidney failure induced by fungal mycelia obstructing indwelling ureteral stents.

Antibiotics reduce the commensal flora in the gut, thereby facilitating the overgrowth of undesirable microorganisms such as Candida albicans. Here, we report the case of a 48-year-old woman with a history of obstructive uropathy consecutive to a radiation therapy, in whom both indwelling ureteral stents were rapidly occluded by fungal mycelia, resulting in a rapidly progressive kidney failure. Ascendant infection by C albicans had occurred after a 2- week course of antibiotics, prescribed for a perforative peritonitis also due to radiation-induced colitis. As shown by iterative CT scans made before (at the time of the diagnosis of peritonitis) and after the antibiotic course, kidney failure was explained by a sudden and bilateral pyelocaliceal dilation, due to the obstruction of the ureteral stents. Fungal mycelia were objectivised during the replacement procedure. Intravenous fluconazole was started, and renal function recovered ad integrum with the relief of the obstruction.