Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice.

BACKGROUND AND AIMS: Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of postoperative liver failure, known as the small-for-size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in an SFSS liver remnant initiated early angiogenesis, improving the vascular architecture, safeguarding against liver failure, and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS and their impact on hepatocyte function and subsequent liver failure. APPROACH AND RESULTS: Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered posthepatectomy survival rates. The early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony-stimulating factor in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and endothelial progenitor cell recruitment but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of Adeno-associated virus serotype 8-thyroxine-binding globulin-hepatocyte nuclear factor 4 alpha virus for hepatocyte-specific overexpression of hepatocyte nuclear factor 4 alpha, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of hepatocyte nuclear factor 4 alpha overexpression and granulocyte colony-stimulating factor treatment rescued survival after SFSS-setting hepatectomy. CONCLUSIONS: In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS hepatectomy, it is essential to adopt a 2-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.

Budget-Friendly Generation, Biochemical Analyses, and Lentiviral Transduction of Patient-Derived Colon Organoids.

For the past decade, three-dimensional (3D) culture models have been emerging as powerful tools in translational research to overcome the limitations of two-dimensional cell culture models. Thanks to their ability to recapitulate the phenotypic and molecular heterogeneity found in numerous organs, organoids have been used to model a broad range of tumors, such as colorectal cancer. Several approaches to generate organoids exist, with protocols using either pluripotent stem cells, embryonic stem cells, or organ-restricted adult stem cells found in primary tissues, such as surgical resections as starting material. The latter, so-called patient-derived organoids (PDOs), have shown their robustness in predicting patient drug responses compared to other models. Because of their origin, PDOs are natural offspring of the patient tumor or healthy surrounding tissue, and therefore, have been increasingly used to develop targeted drugs and personalized therapies. Here, we present a new protocol to generate patient-derived colon organoids (PDCOs) from tumor and healthy tissue biopsies. We emphasize budget-friendly and reproducible techniques, which are often limiting factors in this line of research that restrict the development of this 3D-culture model to a small number of laboratories worldwide. Accordingly, we describe efficient and cost-effective techniques to achieve immunoblot and high-resolution microscopy on PDCOs. Finally, a novel strategy of lentiviral transduction of PDCOs, which could be applied to all organoid models, is detailed in this article. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Establishment of PDCOs from biopsies Basic Protocol 2: Long-term maintenance and expansion of PDCOs in BME domes Basic Protocol 3: Cryopreservation and thawing of PDCOs Basic Protocol 4: Lentiviral transduction of PDCOs Basic Protocol 5: Immunoblot and evaluation of variability between donors Basic Protocol 6: Immunofluorescence labeling and high-resolution microscopy of PDCOs Basic Protocol 7: Transcriptomic analyses of PDCOs by RT-qPCR.

Effective multimodal management of a giant adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare and aggressive tumour. The only curative treatment is surgery with negative margins. In most series, the average lesion size ranges from 5.5 to 15 cm. METHODS: We report the case of a 27-year-old female with hyperandrogenism and Cushing syndrome due to a right adrenocortical carcinoma of 19.7 cm. RESULTS: The tumour abutting on liver and vena cava and the presence two nodules in liver required extensive surgery including a right posterior sectionectomy and an en bloc resection of the adrenal mass together with the right kidney and the gallbladder. The vena cava was also resected with a reconstruction using a pericardial patch since it was invaded on its border. Pathological examination confirmed an adrenocortical carcinoma, with tumour invasion of vessels, tumour capsule, vena cava and two metastases in the liver (pT4N0M1). All margins were negative. Three months after surgery, two lung nodules, cardio-phrenic and internal mammary adenomegalies were noticed on a PET/CT scan, justifying the initiation of chemotherapy, alongside with mitotane. After a 10-month follow-up, CT scan was stable excepted for a lung nodule growing from 4 to 7 mm. Targeted stereotaxic radiotherapy was then administered. Twenty-two months after surgery, the patient has improved considerably and all signs of hyperandrogenism and Cushing syndrome have resolved. CONCLUSION: This case of adrenocortical carcinoma illustrates one of the largest tumours among those reported. It demonstrates the feasibility and effectiveness of a multimodal approach in its treatment even if it is giant and at high risk.

Preoperative treatment of benign insulinoma: diazoxide or somatostatin analogues?

Surgery is the ideal treatment of insulinoma. However, systemic therapy may be required to prevent severe preoperative hypoglycaemia, when surgery is contraindicated, delayed or refused and in case of unresectable metastatic disease. Diazoxide is commonly used but is not always effective and can cause serious side effects. Somatostatin analogues (octreotide and lanreotide) may be an alternative option. We report the case of a 27-year-old patient with insulinoma in whom diazoxide was compared with lanreotide before operation. A diagnosis of insulinoma was made on the basis of a fasting test and a 2 cm tumour confirmed in the body of the pancreas, with a high uptake of 111-In-pentreotide. Diazoxide was initiated and increased to a maximal tolerated dose of 450 mg/day. Because of dyspnoea and persisting hypoglycaemia, diazoxide was shifted to lanreotide 120 mg. All symptoms resolved without hypoglycaemia. According to the EORTC quality score of life, the score without treatment, under diazoxide, under lanreotide and after surgery were respectively 84.7, 73.3, 90.9 and 99.1. Thus, providing a positive Octreoscan, somatostatin analogues may be a safe, effective and well-tolerated option in patients with insulinoma refractory and/or intolerant to diazoxide or with a high risk of fluid retention.

Occurrence of sporadic medullary thyroid carcinoma in Graves' disease in association with a RET proto-oncogene mutation.

BACKGROUND: Graves' disease may be associated with thyroid cancer, particularly differentiated thyroid cancer. Medullary thyroid cancer (MTC) is less common. The occurrence of sporadic MTC in Graves' disease in the presence of a RET proto-oncogene has never been reported. CLINICAL PRESENTATION: A 63-year-old woman was referred for Graves' disease. A thyroid ultrasound disclosed five nodules, one of which was classified as Eu-Tirads 5 with a size of 6.7 × 6.5× 11 mm. Fine needle aspiration was reported as Bethesda class IV follicular neoplasm of a Hürthle cell subtype. Calcitonin level was found to be elevated. A total thyroidectomy confirmed the diagnosis of MTC and a bilateral cervical lymphadenectomy was performed, with four lymph nodes being infiltrated by MTC. Genetic testing revealed a M918T mutation in the RET proto-oncogene. CONCLUSION: MTC may occur in Graves' disease, especially if a nodule is present. In this case, genetic testing should always be performed even if MTC is sporadic. Increased incidence of thyroid cancer in autoimmune thyroid diseases, as well as the link existing between autoimmunity, inflammation and carcinogenesis, leads us to hypothesize that the association here reported is not coincidental.

Presacral Myelolipoma: The Usefulness of a 99mTc-Albumin Nanocolloid Scintigraphy.

Myelolipoma is a rare mesenchymal tumor consisting of adipose tissue and hematopoietic cells. Found usually in the adrenal region, however, few cases have been reported in extra-adrenal regions, most frequently in the presacral region. It is important to recognize such tumor, as it can attain massive size and causes pressure symptoms, and needs to be differentiated from malignant tumors, including liposarcomas. Although CT and MRI can suggest a diagnosis of myelolipoma, these are not conclusive. The hematopoietic cells are enhanced by a Tc-albumin nanocolloid scintigraphy and help to distinguish myolipoma from other entities.

Incidence and Prognosis of Biliary Tract and Gallbladder Cancers in a Belgian Academic Hospital.

BACKGROUND: Biliary tract and gallbladder cancers are rare tumors with a poor prognosis (except the ampulla type). The evolution of hepatobiliary cancer incidence varies widely around the world. According to the Belgian Cancer Registry, the number of hepatobiliary cancers has increased every year since 2004. MATERIALS AND METHODS: This retrospective study included patients diagnosed with cholangiocarcinoma, ampulla cancer, or gallbladder cancer at the university hospital, CHU UCL, Godinne site, in Namur, Belgium, between 1997 and 2017. The evolution of cancer incidence was evaluated with the Mann-Kendall method, by analyzing 7 consecutive 3-year periods. We calculated survival with the Kaplan-Meier method, and we determined prognostic factors with the log-rank test and Cox models. RESULTS: Between 1997 and 2017, we included 128 patients that were newly diagnosed in our center. According to the Mann-Kendall test, the evolution of the incidence of these cancers in our hospital increased significantly over the study period (Sen's slope = 7; p = 0.003). The 1-year overall survival was 53.0 ± 4.7%. Poor prognostic factors included age, cancer stage, local cancer extension, and metastatic disease. The independent prognostic factors of survival were age (p = 0.002), ampulla cancer (p < 0.001), and metastatic disease (p < 0.001). CONCLUSIONS: We found that the incidence of biliary tract and gallbladder cancers increased over a period of 20 years in our center. Further investigations are needed to determine the reasons for this increase. Although new therapies are emerging, the prognosis remains poor for these cancers. Determining risk factors might promote the development of preventive approaches.

Servier in oncology: bringing innovation to patients.

Interview conducted with Claude P Bertrand, PharmD, PhD, Executive Vice President of Servier Research and Development, Chief Scientific Officer, Servier, France. Claude Bertrand speaks to Roshaine Wijayatunga, Senior Editor: Oncology. Dr Claude Bertrand graduated in pharmacy (PharmD) from Strasbourg University, France, and obtained his PhD in Strasbourg with research in the fields of immunopharmacology and neurogenic inflammation. After a 2-year postdoctoral appointment at the University of California, San Francisco, USA, Claude joined the allergy and asthma unit at Ciba-Geigy (later Novartis) in Basel, Switzerland. In 1996, he moved to the Inflammatory Disease Unit at Roche Bioscience, CA, USA, where he became the head of the in vivo pharmacology group and was responsible for supporting projects in rheumatology and respiratory diseases. In 1999, he was recruited as Director of Biology for Inflammation, GI and Pain at Parke-Davies, which later became part of Pfizer where he headed drug discovery. In 2004, Dr Bertrand joined AstraZeneca as Vice President of Discovery for Respiratory and Inflammation Research at Alderley Park, UK, and, in 2005, he was appointed Global Senior Vice President for Respiratory and Inflammation Research Area overseeing research and development activities at three sites in the UK and Sweden. In 2009, Dr Bertrand joined Ipsen, France, as Executive Vice President, Chief Scientific Officer, and from June 2011 was the Executive Vice President for Research and Development, Chief Scientific Officer with a focus on oncology, neurology and endocrinology. In March 2017, he was appointed General Director R&D, Chief Scientific Officer at Servier and has recently been promoted to Executive Vice President R&D. As such, he joined the Executive Committee on 1 November 2018. Claude sits on the Board of Directors of Eclosion2 and ABIVAX, and is also part of the Scientific Advisory Board of MEDALIS. He was the President of ARIIS from 2011 to 2016. Since 2014, he has been on the Board of Hcéres. Claude has published more than 70 papers in peer-reviewed journals, authored 20 chapters and presented more than 100 communications at scientific meetings. Since 1996, he has been a visiting lecturer for PhD student programs at universities in London, Strasbourg, Nancy, Rennes, Orléans and Paris.

Hypoxia protects the liver from Small For Size Syndrome: A lesson learned from the associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure in rats.

Portal hyperperfusion and "dearterialization" of the liver remnant are the main pathogenic mechanisms for Small For Size syndrome (SFSS). Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces rapid remnant hypertrophy. We hypothesized a similar increase in portal pressure/flow into the future liver remnant in ALPPS and SFSS-setting hepatectomies. In a rodent model, ALPPS was compared to SFSS-setting hepatectomy. We assessed mortality, remnant hypertrophy, hepatocyte proliferation, portal and hepatic artery flow, hypoxia-induced response, and liver sinusoidal morphology. SFSS-hepatectomy rats were subjected to local (hepatic artery ligation) or systemic (Dimethyloxalylglycine) hypoxia. ALLPS prevented mortality in SFSS-setting hepatectomies. Portal hyperperfusion per liver mass was similar in ALLPS and SFSS. Compared to SFSS, efficient arterial perfusion of the remnant was significantly lower in ALPPS causing pronounced hypoxia confirmed by pimonidazole immunostaining, activation of hypoxia sensors and upregulation of neo-angiogenic genes. Liver sinusoids, larger in ALPPS, collapsed in SFSS. Induction of hypoxia in SFSS reduced mortality. Hypoxia had no impact on hepatocyte proliferation but contributed to the integrity of sinusoidal morphology. ALPPS hemodynamically differ from SFSS by a much lower arterial flow in ALPPS's FLR. We show that the ensuing hypoxic response is essential for the function of the regenerating liver by preserving sinusoidal morphology.

Associating liver partition and portal vein ligation for staged hepatectomy: establishment of an animal model with insufficient liver remnant.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows extended hepatectomy in patients with an extremely small future liver remnant (FLR). Current rodent models of ALPPS do not include resection resulting in insufficient-for-survival FLR, or they do incorporate liver mass reduction prior to ALPPS. Differences in FLR volume and surgical procedures could bias our understanding of physiological and hemodynamic mechanisms. We aimed to establish a rat ALPPS model with minimal FLR without prior parenchymal resection. In rodents, the left median lobe (LML) represents 10% of total liver. Partial hepatectomy (PHx) sparing LML and pericaval parenchyma represents our reference 87% resection. The first step in the procedure is either portal vein ligation (PVL) corresponding to ligation of all but the LML portal branches, or PVL with transection between the left and right median lobe segments (PVLT), and is defined as ALPPS stage-1. Second, ligated lobes were removed: PVL-PHx represents a conventional 2-stage hepatectomy, while PVLT followed by PHx is a strict reproduction of human ALPPS. In Group A, liver hypertrophy was analyzed after PVL (n = 38), PVLT (n = 47), T (n = 10), and sham (n = 10); In group B, mortality and FLR hypertrophy was assessed after PHx (n = 42), Sham-PHx (n = 6), PVL-PHx (n = 37), and PVLT-PHx (n = 45). In group A, PVLT induced rapid FLR hypertrophy compared to PVL (p < 0,05). Hepatocyte proliferation was higher in PVLT remnants (p < 0,05). In group B, PHx had a 5-day mortality rate of 84%. Sham operation prior to PHx did not improve survival (p = 0.23). In both groups, major fatalities occurred within 48 h after resection. PVL or PVLT prior to PHx reduced mortality to 33.3% (p = 0,007) or 25% (p = 0.0002) respectively, with no difference between the 2 two-stage procedures (p = 0.6). 7-day FLR hypertrophy was higher after the PVLT-PHx compared to PVL-PHx and PHx (p = 0.024). Our model reproduces human ALPPS with FLR that is insufficient for survival without liver resection prior to the stage-1 procedure. It offers an appropriate model for analyzing the mechanisms driving survival rescue and increased hypertrophy.

Laparoscopic ultrasonography as an alternative to intraoperative cholangiography during laparoscopic cholecystectomy.

AIM: To assess the role of laparoscopic ultrasound (LUS) as a substitute for intraoperative cholangiography (IOC) during cholecystectomy. METHODS: We present a MEDLINE and PubMed literature search, having used the key-words "laparoscopic intraoperative ultrasound" and "laparoscopic cholecystectomy". All relevant English language publications from 2000 to 2016 were identified, with data extracted for the role of LUS in the anatomical delineation of the biliary tract, detection of common bile duct stones (CBDS), prevention or early detection of biliary duct injury (BDI), and incidental findings during laparoscopic cholecystectomy. Data for the role of LUS vs IOC in complex situations (i.e., inflammatory disease/fibrosis) were specifically analyzed. RESULTS: We report data from eighteen reports, 13 prospective non-randomized trials, 5 retrospective trials, and two meta-analyses assessing diagnostic accuracy, with one analysis also assessing costs, duration of the examination, and anatomical mapping. Overall, LUS was shown to provide highly sensitive mapping of the extra-pancreatic biliary anatomy in 92%-100% of patients, with more difficulty encountered in delineation of the intra-pancreatic segment of the biliary tract (73.8%-98%). Identification of vascular and biliary variations has been documented in two studies. Although inflammatory disease hampered accuracy, LUS was still advantageous vs IOC in patients with obscured anatomy. LUS can be performed before any dissection and repeated at will to guide the surgeon especially when hilar mapping is difficult due to fibrosis and inflammation. In two studies LUS prevented conversion in 91% of patients with difficult scenarios. Considering CBDS detection, LUS sensitivity and specificity were 76%-100% and 96.2%-100%, respectively. LUS allowed the diagnosis/treatment of incidental findings of adjacent organs. No valuable data for BDI prevention or detection could be retrieved, even if no BDI was documented in the reports analyzed. Literature analysis proved LUS as a safe, quick, non-irradiating, cost-effective technique, which is comparatively well known although largely under-utilized, probably due to the perception of a difficult learning curve. CONCLUSION: We highlight the advantages and limitations of laparoscopic ultrasound during cholecystectomy, and underline its value in difficult scenarios when the anatomy is obscured.

[Pharmacist involvement in supporting care in patients receiving oral anticancer therapies: A situation report in French cancer centers]. / Implication du pharmacien dans l'accompagnement des patients sous anticancéreux oraux : état des lieux dans les centres de lutte contre le cancer (CLCC).

INTRODUCTION: The increasing prescription of oral anticancer therapies has significantly changed inpatient care to outpatient care. This transformation requires an excellent coordination between different professionals to ensure healthcare channel security. METHOD: We performed a prospective study in 18 French cancer centers from March to April 2016. The aim of this study was to identify resources deployed to support patients receiving oral anticancer therapies and to assess pharmacist's involvement. RESULTS: More than half of the centers have developed patient education program and/or practice pharmaceutical consultations. In total, 54.5% have deployed an oral anticancer drugs program and the pharmacist is involved in multidisciplinary teams. In total, 44.4% of the centers have developed hospital-to-community coordination actions but all of them highlight the time-consuming character of those programs. DISCUSSION: Administrative burdens are seriously hindering patient education program's development. Multidisciplinary consultations can offer an attractive alternative because of easy implementation modalities. Finally, hospital-to-community coordination actions seem hard to implement and require harmonization of communication practices, and need more technical and financial means.

Painful thyroid nodule, a misleading presentation of subacute thyroiditis.

Typical presentation of subacute thyroiditis (SAT) is an anterior neck pain radiating up to the jaw and ear, often associated with asthenia and fever. Biology shows hyperthyroidism and inflammation. The thyroid uptake is low at scintigraphy. However, the clinical presentation of SAT may be misleading. We report two cases of SAT whose initial manifestation was a painful thyroid nodule suspected of malignancy. In both cases, ultrasound feature was a heterogeneous, hypoechoic, ill-defined area with a low vascularization on colour Doppler. These areas were interpreted by radiologist as nodules. Surgery was then considered. Such a presentation should be known by clinicians to prevent unnecessary surgery.

Post-Chernobyl incidence of papillary thyroid cancer among Belgian children less than 15 years of age in April 1986: a 30-year surgical experience.

OBJECTIVE: We raised the question of a possible relationship in Belgium between the occurrence of papillary thyroid carcinoma (PTC) and age of children (<15 years) at the time of the Chernobyl nuclear plant accident in April 1986. SETTING: Referral university centre for endocrine surgery. MATERIAL AND METHODS: Thirty-year prospective study of the experience of a surgical team with PTC since the Chernobyl accident, taken out of 2349 patients operated on for any thyroid lesions from April 1986 to April 2015, comparing the incidence of PTC by age groups. MAIN OUTCOME MEASUREMENT: Comparison of PTC incidence in patients >15 years (group A) and children <15 years (group B) in April 1986. RESULTS: Out of a total of 2349 patients having undergone thyroid surgery for all types of lesions during 30 year after Chernobyl and born before April 1986, 2164 were >15 years of age at the time of the nuclear accident (group A) and 175 developed PTC (8.1%) compared to 36 PTC (19.5%) that occurred in 185 children <15 years of age (group B) in April 1986 (p < 0.001). CONCLUSIONS: Radiation exposure affected residents of countries (including Belgium) well beyond Ukraine and Belarus. This was demonstrated by a 1990 meteorological report. Over 30 years, there has been a persistent higher incidence of PTC among Belgian children below the age of 15 years at the time of the Chernobyl accident. This relationship with age has even been strengthened by the implementation of more sophisticated immunohistochemical biomarkers diagnostic technology since April 2011.

A systematic review of the predictive value of (18)FDG-PET in esophageal and esophagogastric junction cancer after neoadjuvant chemoradiation on the survival outcome stratification.

PURPOSE: We studied the predictive value of [(18) F]fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) for assessing disease-free (DFS) and overall survival (OS) in esophageal and esophagogastric junction cancer. MATERIALS AND METHODS: A literature search (PUBMED/MEDLINE, EMBASE, Cochrane) was performed to identify full papers with (18)FDG-PET and survival data, using indexing terms and free text words. Studies with >10 patients with locally advanced esophageal cancer, presenting sequential or at least one post-adjuvant treatment (18)FDG-PET data and Kaplan-Meier survival curves with >6 months median follow-up period were included. We performed a meta-analysis for DFS and OS using the hazard ratio (HRs) as outcome measure. Sources of heterogeneity study were also explored. RESULTS: We identified 26 eligible studies including a total of 1,544 patients (average age 62 years, 82% males). The TNM distribution was as follows: stage I 7%, II 24%, III 53% and IV 15%. The pooled HRs for complete metabolic response versus no response were 0.51 for OS (95% CI, 0.4-0.64; P < 0.00001) and 0.47 for DFS (95% CI, 0.38-0.57; P < 0.00001), respectively. No statistical heterogeneity was present. To explore sources of clinical heterogeneity, we also realised subgroup and regression analyses. Taken into account the moderate correlation between OS and DFS (ρ = 0.54), we used joint bivariate random regression model. These analyses did not show a statistically significant impact of study characteristics and PET modalities on the pooled outcome estimates. CONCLUSION: Despite methodological and clinical heterogeneity, metabolic response on (18)FDG-PET is a significant predictor of long-term survival data.

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.

The treatment of peritoneal carcinomatosis of colorectal cancer with complete cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) with oxaliplatin: a Belgian multicentre prospective phase II clinical study.

BACKGROUND: Up to 25% of patients with metastatic colorectal cancer (CRC) present with peritoneal carcinomatosis (PC) as the only site of metastases. Complete cytoreductive surgery (CCRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) aims for locoregional disease control and long-term survival. Oxaliplatin is effective for treating advanced CRC. This study assesses the safety and efficacy of CCRS with HIPEC with oxaliplatin for patients with PC of CRC. METHODS: A Belgian prospective multicenter registry was performed to monitor perioperative morbidity and assess mortality, disease-free survival (DFS), and overall survival (OS). RESULTS: Forty-eight consecutive patients underwent CCRS (R0/1) with HIPEC (male/female ratio 17/31, median age 60 years, range 24-76 years). Median PC index was 11 (range 1-22). Median operation time was 460 (range 125-840) min, with a median blood loss of 475 (range 2-6,000) ml. Thirty-day mortality was 0%. Complication rate (any grade) was 52.1%. Anastomotic leakage occurred in 10.4% of patients, bleeding in 6.3%, and bowel perforation in 2.1%. Median hospital stay was 20 (range 5-65) days. At median follow-up of 22.7 (range 3.2-55.7) months, OS was 97.9% [95% confidence interval (CI) 86.1-99.7] at 1 year and 88.7% (95% CI 73.6-95.4) at 2 years. DFS at 1 year was 65.8% (95% CI 52.3-76.2) and 45.5% (95% CI 34.3-55.9) at 2 years. Median time until recurrence was 19.8 months (95% CI 12-upper limit not defined). Only after dichotomizing PC index was a significant difference in OS found between low and high PC index. CONCLUSIONS: CCRS followed by HIPEC with oxaliplatin for PC from CRC can be implemented with acceptable morbidity. Long-term DFS and OS can be achieved in selected patients.

Relationship between phosphodiesterase type 4 inhibition and anti-inflammatory activity of CI-1044 in rat airways.

The anti-inflammatory effects of CI-1044 and of the other selective PDE4 inhibitors rolipram and cilomilast were investigated in Brown-Norway (BN) rats, against lipopolysaccharide-induced tumor necrosis factor alpha (TNFalpha) production in whole blood and antigen-induced lung eosinophilia. In vitro, CI-1044 inhibited TNFalpha production with an IC(50) of 0.31 microm being equipotent to Cilomilast (IC(50) = 0.26 microm) and rolipram (IC(50) = 0.11 microm). Given orally, CI-1044 inhibited ex vivo TNFalpha production with an ED(50) value of 0.4 mg/kg after single administration, whereas rolipram (ED(50) = 1.4 mg/kg) and cilomilast (ED(50) = 1.6 mg/kg) were less potent. In the same ex vivo setting, but given repeatedly, CI-1044 led to an ED(50) of 0.5 mg/kg corresponding to a plasma concentration of 82.6 ng/mL (0.22 microm). In vivo, CI-1044 prevented TNFalpha release with an ED(50) of 1 mg/kg p.o. and inhibited ovalbumin-induced lung eosinophilia following single or repeated oral administration with an ED(50) of 3.25 and 4.8 mg/kg p.o., respectively, suggesting the absence of pharmacological tolerance. CI-1044 in this model was equipotent to rolipram (81% inhibition at 10 mg/kg) but better than cilomilast (25% inhibition at 10 mg/kg). Finally, CI-1044 (10 mg/kg) inhibited inflammatory cell recruitment with a long duration of action (up to 8 h) and was still active when given post-challenge. Our data show that CI-1044 is an orally active PDE4 inhibitor that may be used as an anti-inflammatory therapy in lung inflammatory diseases.

Oxidative stress is an important component of airway inflammation in mice exposed to cigarette smoke or lipopolysaccharide.

1. It was proposed previously that oxidative stress is a main component of the inflammatory process in chronic obstructive pulmonary disease (COPD). Thus, in the present study, we investigated the inflammatory response in mice deficient for the p47(phox) subunit of NADPH oxidase (p47 KO) exposed to cigarette smoke (CS). 2. Exposure of mice to CS elicited an increase in the number of macrophages and neutrophils and levels of interleukin (IL)-6, keratinocyte-derived chemokine (KC/CXCL1) and monocyte chemoattractant protein-1 (MCP1/CCL2) in bronchoalveolar lavage fluid (BALF), which were lower in p47 KO mice compared with control mice. In contrast, 24 h after lipopolysaccharide (LPS) exposure, the number of macrophages and neutrophils, as well as KC/CXCL1 levels, in BALF was significantly greater in p47 KO mice compared with control mice. 3. The present study has shown that airway inflammation is decreased in p47 KO mice after exposure to CS, but not LPS, suggesting that oxidative stress is involved in the pathogenesis of airway inflammation associated with COPD.