Catherine Brezault

Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis

Rubbia‐Brandt L, Lauwers G Y, Wang H, Majno P E, Tanabe K, Zhu A X, Brezault C, Soubrane O, Abdalla E K, Vauthey J‐N, Mentha G & Terris B
(2010) Histopathology56, 430–439
Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin‐associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis

Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome.

Background/Objective:Oxaliplatin-based chemotherapy induces sinusoidal obstruction syndrome (SOS) lesions in the nontumorous liver parenchyma, which may increase the risk of liver resection for colorectal liver metastases. The objective of this study was to evaluate the accuracy of aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 scoring systems to predict chemotherapy-associated liver injury and to correlate the severity of sinusoidal injury with postoperative outcome. Methods:Between 1998 and 2007, 78 patients were operated for colorectal liver metastases after preoperative oxaliplatin-based chemotherapy. Grading of steatosis and SOS in the nontumorous liver parenchyma was obtained in these patients. Univariate analysis of 18 preoperative factors to predict SOS occurrence was performed as well as multivariate analysis. Relevance of preoperative platelet count level, transaminase levels, and fibrosis scoring systems were evaluated to predict high grade lesions of SOS using a receiving operative curve analysis. Ninety-day mortality and morbidity were studied according to SOS severity in 51 patients who underwent major liver resection. Results:Overall, pathologic examination showed high-grade lesions of SOS (SOS 2/3) in 46 (59%) patients. Univariate analysis showed that a low preoperative platelet count, elevated preoperative aspartate aminotransferase, short interval between chemotherapy and surgery were significant factors associated with high-grade lesions of SOS. Multivariate analysis showed that only the APRI score was an independent predictive factor for severe SOS. Receiving operative curve analysis revealed that the cut-off value predicting high-grade lesions of SOS with the best accuracy was an APRI score of 0.36 (area under the curve, 0.85; sensitivity, 87%; specificity, 69%). After major liver resection (n = 51), SOS 2/3 (n = 38) was associated with postoperative hepatic dysfunction (26/38 in SOS 2/3 vs. 3/13 in SOS 0/1; P = 0.004) and ascites (P = 0.03). Conclusion:A low preoperative platelet count and high APRI score seem to be the most reliable indicators to predict SOS severity.

Gene expression Profiling Provides Insights into Pathways of Oxaliplatin Related Sinusoidal Obstruction Syndrome in Humans

Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS. Mol Cancer Ther; 10(4); 687–96. ©2011 AACR.

Helpfulness of the combination of acetic acid and FICE in the detection of Barrett's epithelium and Barrett's associated neoplasias

AIM To investigate the mucosal morphology in Barretts oesophagus by chromo and magnifying endoscopy. METHODS A prospective pilot study at a tertiary medical centre was conducted to evaluate the use of acetic acid pulverisation combined with virtual chromoendoscopy using Fujinon intelligent chromoendoscopy (FICE) for semiological characterization of the mucosal morphology in Barretts oesophagus and its neoplastic complications. Upper endoscopy using high definition white light, 2% acid acetic pulverisation and FICE with high definition videoendoscopy were performed in 20 patients including 18 patients who presented with aspects of Barretts oesophagus at endoscopy examination. Two patients used as controls had normal endoscopy and histological results. Prospectively, videos were watched blind from histological results by three trained FICE technique endoscopists. RESULTS The videos of patients with high-grade dysplasia showed an irregular mucosal pattern in 14% using high definition white light endoscopy and in 100% using acid acetic-FICE combined. Videos did not identify irregular vascular patterns using high definition white light endoscopy, while acid acetic-FICE combined visualised one in 86% of cases. CONCLUSION Combined acetic acid and FICE is a promising method for screening high-grade dysplasia and early cancer in Barretts oesophagus.

Feasibility of Gemcitabine plus Oxaliplatin in Advanced Hepatocellular Carcinoma Patients with Child-Pugh B Cirrhosis

Purpose: Sorafenib improves survival in advanced hepatocellular carcinoma (HCC), but the demonstration of its efficacy and safety is limited to Child-Pugh A cirrhotic patients. The biweekly combination of gemcitabine and oxaliplatin (GEMOX) is safe and widely used in patients with advanced malignancies. We aimed to evaluate the feasibility of GEMOX in HCC patients with Child-Pugh B cirrhosis ineligible for sorafenib. Methods: The medical records of cirrhotic patients with advanced HCC receiving the GEMOX regimen between July 2006 and November 2011 were retrospectively reviewed. Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was safety. Secondary evaluation criteria were the presence of muscle wasting (sarcopenia), response rate, progression-free survival and overall survival (OS). Results: Patients with Child-Pugh A (group A, n = 17) or Child-Pugh B cirrhosis (group B, n = 15) received a total of 169 cycles (median 4, range 1–16/patient). Eight patients in each group had sarcopenia. Common toxicities were thrombocytopenia (25 and 14 in groups A and B, respectively; p = 0.65) and peripheral neuropathy (44 and 54% in groups A and B, respectively; p = 1). Neither febrile neutropenia nor toxic death occurred. One patient in each group experienced grade 3 oesophageal varices bleeding. The response and disease control rates were 18% (95% CI 0–35.8) and 58.8% (95% CI 35.4–82.2) in group A, and 27% (95% CI 4.3–49.1) and 60.0% (95% CI 35.2–84.8) in group B. The median progression-free survival and OS did not differ between the two groups, but median OS was significantly shorter in sarcopenic patients. Conclusions: The GEMOX regimen appears feasible in HCC patients with Child-Pugh B cirrhosis and exerts anti-tumour activity. These data need to be confirmed in a prospective study.

Quality control of colonoscopy procedures : A prospective validated method for the evaluation of professional practices applicable to all endoscopic units

OBJECTIVES To produce valid information, an evaluation of professional practices has to assess the quality of all practices before, during and after the procedure under study. Several auditing techniques have been proposed for colonoscopy. The purpose of this work is to describe a straightforward original validated method for the prospective evaluation of professional practices in the field of colonoscopy applicable in all endoscopy units without increasing the staff work load. METHODS Pertinent quality-control criteria (14 items) were identified by the endoscopists at the Cochin Hospital and were compatible with: findings in the available literature; guidelines proposed by the Superior Health Authority; and application in any endoscopy unit. Prospective routine data were collected and the methodology validated by evaluating 50 colonoscopies every quarter for one year. RESULTS The relevance of the criteria was assessed using data collected during four separate periods. The standard checklist was complete for 57% of the colonoscopy procedures. The colonoscopy procedure was appropriate according to national guidelines in 94% of cases. These observations were particularly noteworthy: the quality of the colonic preparation was insufficient for 9% of the procedures; complete colonoscopy was achieved for 93% of patients; and 0.38 adenomas and 0.045 carcinomas were identified per colonoscopy. CONCLUSION This simple and reproducible method can be used for valid quality-control audits in all endoscopy units. In France, unit-wide application of this method enables endoscopists to validate 100 of the 250 points required for continuous medical training. This is a quality-control tool that can be applied annually, using a random month to evaluate any changes in routine practices.

Feasibility of gemcitabine and oxaliplatin in patients with advanced biliary tract carcinoma and a performance status of 2.

The use of gemcitabine and oxaliplatin is well documented in selected patients with advanced biliary tract carcinoma (BTC), but little is known on the feasibility of systemic treatments in patients with a performance status (PS) of 2. We retrospectively examined the medical records of consecutive BTC patients with a PS of 2 receiving gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 every 2 weeks from January 2003 to December 2011 in our institution. Body composition was analysed by computed tomography scan to detect sarcopenia. The primary evaluation criterion was safety. The secondary evaluation criteria were the response rate, progression-free survival (PFS) and overall survival (OS). Twenty-eight patients (median age: 63 years, range 41–83) received a total of 175 cycles (median per patient: 6, range 2–12). Ten patients (35.7%) had sarcopenia on the pretreatment computed tomography scan. The most frequent toxicities were thrombocytopenia (grades 2–4: n=4, 14.3%), peripheral neuropathy (grades 2–3: n=9, 32.1%) and cholangitis (n=4, 14.3%). The best response was a partial response in 10.7% of patients [95% confidence interval (CI): 0–22.2] and stable disease in 42.9% of patients. The median PFS and OS were 4.6 (95% CI: 2.5–6.3) and 7.5 (95% CI: 5.2–9.5) months, respectively. The median PFS and OS were significantly longer in patients without sarcopenia: 7.0 months (95% CI: 4.4–8.0) vs. 2.2 months (95% CI: 2.0–2.5), P less than 0.01, and 10.4 months (95% CI: 7.5–11.6) vs. 4.9 months (95% CI: 3.7–5.2), P less than 0.01, respectively. In our experience, gemcitabine–oxaliplatin was feasible and induced effective palliation in PS2 patients with advanced BTC. Further studies are warranted to confirm these findings.

The predictive and prognostic value of the Glasgow Prognostic Score in metastatic colorectal carcinoma patients receiving bevacizumab.

The Glasgow Prognostic Score (GPS), based on C-reactive protein and albumin levels, has shown its prognostic value in metastatic colorectal carcinoma (mCRC) patients receiving conventional cytotoxic therapy. Bevacizumab, a monoclonal antibody to vascular epidermal growth factor, improves the overall survival in mCRC. The aim of the present study was to assess the prognostic value of GPS in mCRC patients receiving antivascular epidermal growth factor therapy. From August 2005 to August 2012, consecutive patients with mCRC who received chemotherapy plus bevacizumab were eligible for the present analysis. The clinical stage, C-reactive protein, albumin and the Eastern Cooperative Oncology Group performance status were recorded at the time of initiation of bevacizumab. Patients received 5-fluorouracil-based chemotherapy plus bevacizumab in accordance with the digestive oncology multidisciplinary staff proposal and in line with the French recommendations for the treatment of mCRC. Eighty patients were eligible (colon n=59, rectum n=21), with a median follow-up of 14 months (range 1–58 months). Chemotherapy given with bevacizumab and 5-fluorouracil was oxaliplatin (n=41, 51%) or irinotecan (n=27, 34%). At baseline, 56, 31 and 13% of patients had a GPS of 0 (n=45), 1 (n=25) and 2 (n=10), respectively. The median progression-free survival in these groups was 10.1, 6.5 and 5.6 months (P=0.16), respectively. The median overall survival was 20.1, 11.4 and 6.5 months, respectively (P=0.004). Our study confirmed the prognostic value of GPS in mCRC patients receiving chemotherapy plus bevacizumab. Given the poor survival observed in patients with an GPS of 2, studies dedicated to these patients could identify optimal treatment modalities.

A Rare Hematological Adverse Event Induced by Bevacizumab: Severe Thrombocytopenia

BACKGROUND Bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, is approved for the treatment of various malignancies, and its hematological toxicities are considered infrequent. METHODS A colorectal cancer patient receiving chemotherapy (5-fluorouracil and oxaliplatin) plus bevacizumab developed acute, severe thrombocytopenia. We postulated that this thrombocytopenia could be directly triggered by bevacizumab. RESULTS A man with stage IV colorectal cancer and synchronous liver metastasis had received 10 cycles of FOLFOX plus bevacizumab (5 mg/kg) without significant hematological toxicity. Due to thrombocytopenia, oxaliplatin was withdrawn after cycle 11. On cycle 12, shortly after bevacizumab infusion and before 5-fluorouracil infusion, the patient developed fever, lower limbs purpura, grade 1 proctorrhagia, and epistaxis. Platelets had decreased from 105,000/mm(3) to 3000/mm(3) within 1 hour after bevacizumab infusion. Flow cytometry identified platelet-associated immunoglobulins. Despite 2 apheresis-derived platelet transfusions, oral corticotherapy, and gamma globulin infusions, thrombocytopenia persisted, but was finally successfully treated with a peptibody thrombopoietin mimetic, which was introduced 28 days after the last bevacizumab infusion. CONCLUSIONS Clinicians should keep in mind that bevacizumab can induce acute and potentially severe immune-mediated thrombocytopenia.

Cervical extravasation of bevacizumab

Monoclonal antibodies such as bevacizumab are widely used in medical oncology, either alone or in combination with chemotherapy. No specific recommendations on the management of monoclonal antibodies extravasation exist. Incidence rates vary considerably. Estimates of 0.5-6% have been reported in the literature. Also, patient-associated and procedure-associated risk factors of extravasation are multiple, such as bolus injections or poorly implanted central venous access. We report on an 86-year-old woman with colon cancer with liver metastasis who was treated with 5-fluorouracil, folinic acid, and bevacizumab. Extravasation occurred during chemotherapy infusion because of a catheter migration of the port outside of the superior vena cava, causing cervical pain without skin modifications. Diagnosis was confirmed with the appearance of clinical right cervical tumefaction and cervicothoracic computed tomography scan indicated a perijugular hypodense collection, corresponding to the extravasation. Conservative management was proposed. The patient recovered within 3 weeks from all symptoms. Physicians should be aware that in cases of bevacizumab extravasation, a nonsurgical approach might be effective.