PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy.

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts-a hematotoxicity marker-and serum creatinine-a nephrotoxicity marker-were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m2. The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m2 with an IPEC duration of 1-2 h and an 1-h duration is favored for doses between 100 and 120 mg/m2. Graphical abstract.

A Rare Case of Adult Acute Disseminated Encephalomyelitis Associated with Primary Epstein-Barr Virus Infection.

We report a rare case of acute disseminated encephalomyelitis (ADEM) secondary to a primary Epstein-Barr (EBV) infection, in a 22-year-old male. Symptomatic infectious mononucleosis and ADEM are both quite uncommon conditions in this age group. LEARNING POINTS: ADEM is a very rare CNS disorder; it is more common in childhood but can also be described in adults.The clinical evaluation must focus on the presence of recent signs of infection or vaccination.A normal cerebral scan does not rule out the disease and MRI must be performed to confirm the diagnoses.

Impact of biological agents on the prevalence of chemotherapy associated liver injury (CALI): Multicentric study of patients operated for colorectal liver metastases.

BACKGROUND: The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM). METHODS: One hundred patients with CRLM having undergone at least one liver segment resection were prospectively included, and chemotherapy data recorded. Specimens were reviewed by a single pathologist and CALI were described. Prevalence of CALI was compared to our previous experience published in 2013. NRH diagnosis was performed on reticulin special stain, by contrast to our previous study. Postoperative outcome was analysed. RESULTS: Bevacizumab was more frequently administrated in patients of the present study: 53/100 (53%) compared to 20/151 (13%), p < 0.0001. Overall, in the present series, SOS was only observed in 28/100 (28%) patients compared to 116/151 (77%) in 2013 (p < 0.001). When looking specifically to patients receiving Bevacizumab with Folfox, we observed a reduced SOS prevalence compared to Folfox alone (p = 0.008). A higher prevalence of NRH was found in the present study, related to increased detection accuracy, but in patients receiving Bevacizumab in association with Folfox, this prevalence was also reduced compared to Folfox alone (p = 0.03). Both SOS and NRH were associated with severe complications (p = 0.008 and p = 0.005, respectively) and postoperative liver insufficiency (p < 0.001 and p < 0.01, respectively). CONCLUSIONS: The routine use of Bevacizumab in association with Folfox significantly reduced CALI prevalence, in turn linked to severe postoperative complications.

Rectal cancer treatment in a teaching hospital.

BACKGROUND: Rectal adenocarcinomas surgery morbidity and mortality might be impaired by neoadjuvant therapy. We performed this retropsective study to be compared with the PROCARE study running afterwards. METHODS: We performed a retrospective study of 95 patients operated on for rectal adenocarcinoma in a single institution during the period of 2007-2009. We used logistic regression to estimate the relationship between possible predictive parameters of anastomotic leakage (AL). RESULTS: The laparoscopic approach is favored in 63.1% of the cases with a conversion rate of 11.6%, mainly in man (6 out of 7). For low rectal cancer though, laparotomy was the first choice (92.3%). From a carcinological point of view, laparoscopy allowed a complete tumor resection according to the PME (n = 27) and TME (n = 26) standards. Multivariate analysis revealed that women, lower BMI, lower rectum tumor, laparoscopic surgery, neoadjuvant treatment and anal suture were associated with higher risk of AL. The mean hospital stay was 15.4 days (3-46 days) with an in-hospital mortality rate of 3.1%. Adjuvant chemotherapy was completed in 42.1% of the patients. Despite these treatments, we registered a recurrence rate of 26.6%. Of these, 72% were distally localized and 12% exclusively locally. Among the patients operated on by laparoscopy, there was one local recurrence and one local with distant metastases (3.7%). The one- and three-year survival rates were 91.5% and 80.4%, respectively. CONCLUSIONS: Our study showed a higher rate of AL than expected (18%). In our series recorded in PROCARE-Home, our leak rate has dropped to 10%. It may be indicating a positive effect of PROCARE.

Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial.

BACKGROUND: Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours. METHODS: Patients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778. FINDINGS: Between June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35). INTERPRETATION: In patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula. FUNDING: Funding Johnson & Johnson Medical Devices, Belgium.

Laparoscopic repair of paraesophageal hernia. Long-term follow-up reveals good clinical outcome despite high radiological recurrence rate.

OBJECTIVE: The purpose of this report is to evaluate and compare the long-term objective and subjective outcome after laparoscopic paraesophageal hernia repair (LPHR). BACKGROUND: Short-term symptomatic results of LPHR are often excellent. However, a high recurrence rate is detected at objective radiographic follow-up. METHODS: Retrospective review of a prospectively gathered database of consecutive patients undergoing LPHR with and without reinforced crural repair at a single institution. Subjective and objective outcomes were assessed by using a structured symptoms questionnaire, Gastrointestinal Quality-of-Life Index, satisfaction score, and barium esophagogram. RESULTS: From September 1991 to September 2005, LPHR was performed in 85 patients (median age, 66 years) with (25 patients) and without (60 patients) reinforced crural repair. Two patients (3%) underwent laparoscopic reoperation, for severe dysphagia and for symptomatic recurrence, respectively. Subjective outcome, available for 64 patients (75%), improved significantly at median follow-up of 118 months with a postoperative median Gastrointestinal Quality-of-Life Index score of 116. Radiographic recurrence (median follow-up, 99 months) occurred in 23 (66%) of the 35 patients, independently of age at operation, type of paresophageal hiatal hernias, and crural reinforcement, and showed no impact on quality of life. CONCLUSIONS: Although providing excellent symptomatic results, long-term objective evaluation of LPHR reveals a high recurrence rate even with reinforced cruroplasty. A tailored, lengthening gastroplasty and reinforced cruroplasty based on objective intraoperative evaluation, and not only on surgeon's personal judgment, may be the answer to recurrences.

Antireflux transoral incisionless fundoplication using EsophyX: 12-month results of a prospective multicenter study.

BACKGROUND: A novel transoral incisionless fundoplication (TIF) procedure using the EsophyX system with SerosaFuse fasteners was designed to reconstruct a full-thickness valve at the gastroesophageal junction through tailored delivery of multiple fasteners during a single-device insertion. The safety and efficacy of TIF for treating gastroesophageal reflux disease (GERD) were evaluated in a prospective multicenter trial. METHODS: Patients (n = 86) with chronic GERD treated with proton pump inhibitors (PPIs) were enrolled. Exclusion criteria included an irreducible hiatal hernia > 2 cm. RESULTS: The TIF procedure (n = 84) reduced all hiatal hernias (n = 49) and constructed valves measuring 4 cm (2-6 cm) and 230 degrees (160 degrees -300 degrees ). Serious adverse events consisted of two esophageal perforations upon device insertion and one case of postoperative intraluminal bleeding. Other adverse events were mild and transient. At 12 months, aggregate (n = 79) and stratified Hill grade I tight (n = 21) results showed 73% and 86% of patients with >or=50% improvement in GERD health-related quality of life (HRQL) scores, 85% discontinuation of daily PPI use, and 81% complete cessation of PPIs; 37% and 48% normalization of esophageal acid exposure; 60% and 89% hiatal hernia reduction; and 62% and 80% esophagitis reduction, respectively. More than 50% of patients with Hill grade I tight valves had a normalized cardia circumference. Resting pressure of the lower esophageal sphincter (LES) was improved significantly (p < 0.001), by 53%. EsophyX-TIF cured GERD in 56% of patients based on their symptom reduction and PPI discontinuation. CONCLUSION: The 12-month results showed that EsophyX-TIF was safe and effective in improving quality of life and for reducing symptoms, PPI use, hiatal hernia, and esophagitis, as well as increasing the LES resting pressure and normalizing esophageal pH and cardia circumference in chronic GERD patients.

Laparoscopic pancreatic resection: results of a multicenter European study of 127 patients.

BACKGROUND: The reported experience with laparoscopic pancreatic resections (LPR) remains limited to case reports or small series of patients. METHODS: A retrospective multicenter study was conducted in 25 European surgical centers concerning their experience with LPR. Detailed questionnaires were used, focusing on patients, tumors, operative data, and late outcome. RESULTS: During the study period, 127 patients with presumed pancreatic neoplasms were enrolled in this series. Final diagnoses included benign pancreatic diseases in 111 patients (87%; insulinoma: 22, neuroendocrine neoplasm: 20, mucinous cystadenoma: 26, serous cystadenoma: 21, chronic pancreatitis: 11, others: 11), and 16 patients (13%) had malignant pancreatic diseases (insulinoma: 3, neuroendocrine neoplasm: 5, ductal adenocarcinoma: 4, cystadenocarcinoma: 2, renal metastases: 2). Five patients with presumed benign pancreatic disease had malignancy at final pathology. The median tumor size was 30 mm (range, 5-120 mm); 89% of tumors were located in the left pancreas. Laparoscopically successful procedures included 21 enucleations, 24 distal splenopancreatectomies, 58 distal pancreatectomies with splenic preservation, and 3 pancreatoduodenal resections. The overall conversion rate was 14%. There were no postoperative deaths. The rate of overall postoperative pancreatic-related complications was 31%, including a 17% rate of clinical pancreatic fistula. The surgical reoperation rate was 6.3%. In laparoscopically successful operations, the median postoperative hospital stay was 7 days (range, 3-67 days), decreased compared with patients requiring conversion to open pancreatectomy. During a median follow-up of 15 months (range, 3-47 months), 23% of the patients with pancreatic malignancies had tumor recurrence. Late outcome was satisfactory in all patients with benign diseases. CONCLUSIONS: LPR is feasible and safe in selected patients with presumed benign and distal pancreatic tumors. The management of the pancreatic stump remains a challenge. The role of LPR for pancreatic malignancies remains controversial.