A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. PATIENTS AND METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial.

BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology.

BACKGROUND: Cholangiocarcinomas are uncommon tumours with a poor prognosis, that frequently present epidermal growth factor receptor overexpression. METHODS: In a multi-centre phase II trial, patients with unresectable cholangiocarcinoma, naïve to chemotherapy, received Cetuximab (400 mg/m(2) at week 1, then 250 mg/m(2)/week) and Gemcitabine (1 g/m(2) on day 1, 8 and 15 every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Moreover, we assessed the impact of KRAS status and skin toxic effect on efficacy. RESULTS: Forty-four patients (41% locally advanced/59% metastatic) were enrolled. Median age was 61.5 years; ECOG PS was 0 (68%) or 1. Six months PFS reached 47%. Median OS was 13.5 months [95% confidence interval (CI) 9.8-31.8 months]. Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were haematological (52.2%), skin rash (13.6%) and fatigue (11.4%). KRAS mutations were found in 7 of 27 patients and had no influence on PFS. Skin toxic effect ≥grade 2 was associated with increased PFS (P = 0.05). CONCLUSION(S): Our study met its primary end point, suggesting that Gemcitabine-Cetuximab has activity in cholangiocarcinoma. KRAS status was not associated with PFS, unlike skin toxic effect, which could be used as a surrogate marker for efficacy. ClinicalTrials.gov Identifier: NCT00747097.

Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.

BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.

Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I-II study.

BACKGROUND: The prognosis of pancreaticobiliary tumors is poor. The aim was to assess the feasibility of radiotherapy (RT) and concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma. PATIENTS AND METHODS: Twenty-two patients with locally advanced pancreatic (n = 17) or biliary tract cancer (n = 5) were included. They received two cycles of gemcitabine/oxaliplatin followed by 5 weeks of RT in combination with a weekly fixed dose gemcitabine and an escalating dose of oxaliplatin from 40 up to 70 mg/m(2). National Cancer Institute-Common Toxicity Criteria 3.0 was used to score weekly the treatment-related toxicity. RESULTS: The patients treated at a dose of 40 mg/m(2) of oxaliplatin had no dose-limiting toxicity. At 50 mg/m(2), two patients developed grade 4 thrombocytopenia. Nine patients received 60 mg/m(2), one developed grade 4 thrombocytopenia. Grade 4 thrombocytopenia in two patients and grade 3 diarrhea in one patient were observed with 70 mg/m(2). Median time to progression was 8 months and median overall survival was 17 months. CONCLUSIONS: RT in combination with gemcitabine and oxaliplatin is feasible in patients with locally advanced pancreaticobiliary cancer. The reported time to progression underlines the potential activity of this regimen. The dose of 60 mg/m(2) of oxaliplatin can be considered as the recommended dose.

Prognostic factors and prognostic index for chemonaïve and gemcitabine-refractory patients with advanced pancreatic cancer.

BACKGROUND: Gemcitabine monotherapy is the cornerstone of the treatment of patients suffering from advanced pancreatic cancer (PC). For a few years, new chemotherapeutic agents and combinations have been under validation. The use of such treatment makes it necessary to determine factors that could predict survival time. PATIENTS AND METHODS: To identify factors that predict survival time in chemonaïve patients with advanced PC and after gemcitabine failure, a retrospective analysis was performed on patients with advanced PC coming from phase II and III studies and treated with gemcitabine-based first-line chemotherapy. RESULTS: Ninety-nine patients (median age 66 years, range 27-87) suffering from pathologically proven unresectable or metastatic adenocarcinoma of the pancreas were reviewed. Median overall survival time for the whole population was 251 days and progression-free survival in first- and second-line treatment was 108 and 67 days, respectively. The Cox regression analysis identified aspartate transaminase >53 IU/l, weight loss > or =10% and Karnofsky performance status <90 as significant independent negative prognostic factors in first-line and CA 19-9 >400 IU/ml and albumin < or =3.5 mg/dl in second-line chemotherapy. A prognostic index was calculated from the regression coefficients for each independent prognostic factor and used to classify the patients in 3 different groups with good, intermediate and poor prognosis. The prognosis index in chemonaïve and gemcitabine-refractory patients was (Karnofsky performance status x 0.52) + (weight loss x 1.10) + (aspartate transaminase x 0.82) and (albumin x 1.40) + (CA 19-9 x 0.74), respectively. CONCLUSIONS: Predictive factors could be identified in first- and second-line treatments, although they require prospective validation before they could be used in the design and analysis of future clinical trials.

Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study.

Gemcitabine and oxaliplatin (GEMOX) are active as first-line therapy against advanced pancreatic cancer. This study aims to evaluate the activity and tolerability of this combination in patients refractory to standard gemcitabine (GEM). A total of 33 patients (median age of 57) were included with locally advanced and metastatic evaluable diseases, who had progressed during or following GEM therapy. The GEMOX regimen consisted of 1000 mg m(-2) of GEM at a 100-min infusion on day 1, followed on day 2 by 100 mg m(-2) of oxaliplatin at a 2-h infusion; a cycle that was given every 2 weeks. All patients received at least one cycle of GEMOX (median 5; range 1-29). Response by 31 evaluable patients was as follows: PR: 7/31(22.6%), s.d. > or = 8 weeks: 11/31(35.5%), s.d. < 8 weeks: 1/31(3.2%), PD: 12/31(38.7%). Median duration of response and TTP were 4.5 and 4.2 months, respectively. Median survival was 6 months (range 0.5-21). Clinical benefit response was observed in 17/31 patients (54.8%). Grade III/IV non-neurologic toxicities occurred in 12/33 patients (36.3%), and grade I, II, and III neuropathy in 17(51%), 3(9%), and 4(12%) patients, respectively. GEMOX is a well-tolerated, active regimen that may provide a benefit to patients with advanced pancreatic cancer after progression following standard gemcitabine treatment.

Raltitrexed plus gemcitabine (TOMGEM) in advanced pancreatic cancer. Results of a Belgian multicentre phase II study.

OBJECTIVES: This multicenter phase II study was designed to determine the activity and tolerance of gemcitabine and raltitrexed in advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Thirty-three chemonaive patients with measurable disease received the TOMGEM regimen consisting of Raltitrexed 3 mg/m(2) in 15 min followed by Gemcitabine 1,000 mg/m(2) in 30 min on day 1, Gemcitabine alone 1,000 mg/m(2) on day 8 and repeated on day 21. RESULTS: Thirty-three patients (median age: 62; locally advanced/metastatic disease: 5/28) were enrolled; the total number of cycles administered was 173 (median: 4). There were 10 partial response (confirmed), 2 stable disease (SD) >/=24 weeks, 7 SD <24 weeks, and 14 progressive disease for a response rate of 30.3% (95% CI: 14-46%); a clinical benefit was observed in 8/30 patients assessed (30%); median duration of response was 9.1 months. National Cancer Institute Common Toxicity Criteria grade III or IV neutropenia/thrombocytopenia were observed in 42 and 12% of the patients, respectively. Relevant nonhematological toxicities (grade III-IV) were rare although one toxic death was observed. Median time to progression was 2.8 months; one-year survival was 21%; median survival was 4.7 months. CONCLUSION: Our data suggest that the combination of raltitrexed/gemcitabine is a very convenient regimen with an acceptable toxicity, and is active in advanced pancreatic cancer.

[The medical gastroenterology department]. / Le Service de Gastro-Entérologie Médicale.

The present paper summarizes the various themes of research which have been developed in the department of medical gastroenterology since it was created in 1977. These include: in pancreatology, the study of chronic pancreatitis pathogenesis, acute pancreatitis pathogenesis and immunomodulation, endoscopic treatment of chronic pancreatitis, the development of new imaging techniques of the bile ducts and the pancreas, as well as the treatment of pancreatic cancer and benign or malignant biliary diseases. in hepatology, the immunomodulation of liver cirrhosis, especially alcoholic liver disease, the modulation of experimental acute and chronic hepatitis, the study of liver ischemia-reperfusion. Clinical hepatology has focused on liver transplantation, prognosis factors of chronic liver disease and treatment of portal hypertension and viral hepatitis. in gut diseases, the treatment of gastro-oesophageal reflux and its complications, the therapeutic endoscopy of the upper and lower GI and the prevention, as well as the treatment, of colon cancer, the pathogenesis and the immunopharmacology of inflammatory bowel diseases and the clinical enteral and parenteral nutrition.

[Individual screening for colorectal cancer: which strategy for which patient?]. / Dépistage individuel du cancer colorectal: quelle stratégie pour quel patient?

Currently, more than 4,000 newly colorectal cancer are diagnosed each year in Belgium. The individual average-risk for developing colorectal cancer is about 5%. 90% of colorectal cancer occurred after the age of 50, and in 70% of the cases in patients without particular risk factors (average-risk population). Personal and/or familial history of colorectal adenoma, colorectal cancer, inflammatory bowel disease localised to the colon, familial polyposis syndrome or Hereditary Non Polyposis Colorectal Cancer (HNPCC) increase the risk of colorectal cancer. An individual appropriate screening of high-risk patients and average-risk asymptomatic patients older than 50, together with endoscopic resection of adenoma decrease the incidence and the mortality of colorectal cancer. Usual screening methods are fecal occult blood testing which is not proven to be efficient alone for individual screening (but still recommended for general population's screening), sigmoidoscopy (which has to be completed by a colonoscopy, if lesions founded), and colonoscopy. Virtual colonoscopy and genetic testing need further evaluation. Currently, colonoscopy seems to be the goldstandard method providing complete examination of the whole colon and being the most cost-effective method. Screening strategy should be decided on an individual basis considering the patient's benefit with respect to the informed consent.

[Preoperative evaluation of rectal cancer]. / Evaluation préopératoire du cancer du rectum.

For a patient with a rectal tumor, the preoperative staging should answer four questions: Is the rectal tumor unique? Is the patient operable? Are there distal metastases? What is the loco-regional extension? The loco-regional extension is well evaluated by the echo-endoscopy while the involvement of the surrounding organs is better assessed by CT-scan or resonance magnetic imaging.

[Screening for colorectal cancer by endoscopy: rectosigmoidoscopy or coloscopy?]. / Dépistage du cancer colorectal par endoscopie: rectosigmoidoscopie ou coloscopie?

Screening for colorectal cancer is almost uniformly recommended for average-risk asymptomatic persons aged 50 years and older and it may substantially reduce its relative mortality. However, consensus is lacking about the type of screening test. Flexible sigmoidoscopy followed by colonoscopy in the presence of adenoma(s), detect 70% of the neoplasms and should be recommended for adults aged 50 years and older. Colonoscopy with polypectomy may ultimately become the preferred strategy after 60 years and certainly in the presence of alarm signs and personal or familial risks for colorectal cancer.

[Treatment of colorectal cancer: a resolute multidisciplinary approach]. / Le traitement du cancer colorectal: une approche résolument multidisciplinaire.

Significant developments have been occurred in the field of colorectal cancer treatments over these last years, surgery clearly remaining the only curative therapy. Optimalized surgical approaches, such as total mesorectum excision, aggressive resections of liver metastases and development of innovative techniques of local destruction of hepatic lesions using radiofrequency attempt to prolong survival. New chemotherapeutic and biological agents, associated with a better knowledge of tumor biology open promising perspectives with regards to an increasing of survival, an improvement of quality of life and the possibility to resect curatively liver metastases initially unresectable, after neoadjuvant chemotherapy. The present paper aims to review the therapeutic approaches at the different stages of the disease and strongly insists on the multidisciplinary strategy required for an optimal management and a global view of colorectal cancer, shared by the surgeon, the gastroenterologist and/or the oncologist and the radiotherapist.

Cold liver ischemia-reperfusion injury critically depends on liver T cells and is improved by donor pretreatment with interleukin 10 in mice.

Kupffer cells are thought to mediate most of the deleterious effects of liver ischemia-reperfusion injury. The role of liver T cells and the impact of resident cell deactivation by interleukin 10 (IL-10) have never been addressed. Using a model of ex vivo liver cold ischemia and reperfusion, we assessed liver injury, tumor necrosis factor (TNF) and interferon gamma (IFN-gamma) release from livers of balb/c mice, nude mice, nude mice reconstituted with T cells, and gadolinium balb/c pretreated mice. The anti-inflammatory cytokine IL-10 was then used to define the best strategy of administration potentially able to modulate ischemia-reperfusion injury. For this purpose IL-10 was administered to the donor before liver harvesting, in the preservation medium during cold ischemia or during reperfusion. TNF and IFN-gamma were released time dependently and paralleled liver injury after reperfusion of cold preserved livers. Reperfused livers from nude or gadolinium pretreated mice disclosed a dramatic decrease in TNF and IFN-gamma release. Tissue injury was reduced by 51% in the absence of T cells and by 88% when Kupffer cells were deactivated. This effect was reverted by T-cell transfer to nude mice. Only donor pretreatment with IL-10 or IL-10 infusion during reperfusion led to a significant decrease in liver injury, TNF, and IFN-gamma release (-66% or -41%, -95% or -94%, and -70% or -70%, respectively). In conclusion, liver resident T cells are critically involved in cold ischemia-reperfusion injury and pretreatment of the donor with IL-10 decreases liver injury and the release of T-cell- and macrophage-dependent cytokines.

CD4(+ )T cells play an important role in acute experimental pancreatitis in mice.

BACKGROUND & AIMS: Few data are available on the potential role of T lymphocytes in experimental acute pancreatitis. The aim of this study was to characterize their role in the inflammatory cascade of acute pancreatitis. METHODS: To type this issue, acute pancreatitis was induced by repeated injections of cerulein in nude mice and in vivo CD4(+) or CD8(+) T cell-depleted mice. The role of T lymphocyte-costimulatory pathways was evaluated using anti-CD40 ligand or anti-B7-1 and -B7-2 monoclonal blocking antibodies. The role of Fas-Fas ligand was explored using Fas ligand-targeted mutant (generalized lymphoproliferative disease) mice. Severity of acute pancreatitis was assessed by serum hydrolase levels and histology. Intrapancreatic interleukin 12, interferon gamma, Fas ligand, and CD40 ligand messenger RNA were detected by reverse-transcription polymerase chain reaction. Intrapancreatic T lymphocytes were identified by immunohistochemistry. RESULTS: In control mice, T cells, most of them CD4(+) T cells, are present in the pancreas and are recruited during acute pancreatitis. In nude mice, histological lesions and serum hydrolase levels are significantly decreased. T-lymphocyte transfer into nude mice partially restores the severity of acute pancreatitis and intrapancreatic interferon gamma, interleukin 12, and Fas ligand gene transcription. The severity of pancreatitis is also reduced by in vivo CD4(+) (but not CD8(+)) T-cell depletion and in Fas ligand-targeted mutant mice. Blocking CD40-CD40 ligand or B7-CD28 costimulatory pathways has no effect on the severity of pancreatitis. CONCLUSIONS: T lymphocytes, particularly CD4(+) T cells, play a pivotal role in the development of tissue injury during acute experimental pancreatitis in mice.

N-acetylcysteine decreases severity of acute pancreatitis in mice.

Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (pO2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP- 1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.

Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice.

The role of the anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in the mouse model of liver injury induced by carbon tetrachloride (CCl4). To address the role of endogenous IL-10 production, acute hepatitis was induced by CCl4 in C57Bl/6 IL-10 gene knock out (KO) and wild-type (WT) mice. After CCl4 challenge, serum and liver levels of tumor necrosis factor-alpha (TNF-) and serum levels of transforming growth factor-beta 1 (TGF-beta1) increased and were significantly higher in IL-10 KO mice, whereas IL-6 serum levels were only slightly increased compared with WT mice. At histological examination, the livers disclosed a significantly more prominent neutrophilic infiltration in IL-10 KO mice 12 and 24 hours after CCl4 injection. In contrast, hepatocyte necrosis, evaluated by histological examination and serum alanine aminotransferase levels, was only marginally affected. The proliferative response of hepatocytes, assessed by the proliferating cell nuclear-antigen labeling index, was significantly increased in IL-10 KO mice, compared with WT mice 48 hours after CCl4 injection. Finally, repeated CCl4 injections led to more liver fibrosis in IL-10 KO mice after 7 weeks. In conclusion, endogenous IL-10 marginally affects the hepatocyte necrosis although it controls the acute inflammatory burst induced by CCl4. During liver repair, it limits the proliferative response of hepatocytes and the development of fibrosis.