Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma.

This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy.

Case Report: Exacerbation of varices following atezolizumab plus bevacizumab treatment of hepatocellular carcinoma: A case series and literature review.

Recently, a combined regimen of atezolizumab and bevacizumab (AB) treatment has been approved as a first-line treatment in patients with advanced hepatocellular carcinoma (HCC), contributing to prolonged survival. However, we often encounter cases where treatment must be discontinued due to the occurrence of adverse events. One of these events, which is often fatal, is gastrointestinal bleeding. To clarify the clinical effects of gastrointestinal bleeding after AB treatment, we evaluated patients with HCC who were treated with AB at our institution. Of the 105 patients, five treated with AB developed gastrointestinal bleeding, necessitating treatment discontinuation. Additionally, we encountered two cases where exacerbation of varicose veins was observed, and AB therapy could be continued by preventive treatment of varices. In conclusion, an appropriate follow-up is required during treatment with AB to prevent possible exacerbation of varicose veins.

Feasibility and safety of a novel indwelling catheter system via the femoral artery for intermittent transarterial therapy for treating malignant liver tumors.

PURPOSE: An indwelling arterial access system via the brachial artery, System-i, has been previously reported. We have modified the technique for the femoral artery approach. This study aimed to evaluate the feasibility and safety of the modified System-i for patients with malignant liver tumors. MATERIALS AND METHODS: The modified System-i is an indwelling catheter that provides vascular access for inserting a microcatheter without repeated punctures to the femoral artery. Between 2018 and 2020, the system was implanted for 50 patients with malignant liver tumors. We used the system for patients with difficulty in inserting the conventional indwelling catheter system. To place the system, a side-holed catheter was implanted in the femoral artery, and the tip of the catheter was placed in the superficial femoral artery through the contralateral iliac artery. Using this system, transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy was performed. A shaped high-flow microcatheter and a non-tapered microcatheter were used with the system. The technical aspects and outcomes of the system were also assessed. RESULTS: Implantation of the system was successful in all patients. The median implantation time was 40 min. The main reason for implantation was obstruction or stenosis of the hepatic artery. Among the 50 patients, 11 (22%) showed complications, of which four had major complications/class C based on the SIR criteria. CONCLUSION: The modified System-i is a safe system that can be a feasible repeated interventional radiological treatment via the femoral approach. We need to evaluate the efficacy of this system in the treatment of advanced cancers in the future. The modified System-i is a novel indwelling catheter system that allows vascular access to perform intermittent transarterial therapy, such as transcatheter arterial chemoembolization and hepatic arterial infusion chemotherapy via the femoral approach. In this study, we report the technical details and safety of the system.

First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study.

BACKGROUND AND AIMS: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice.

BACKGROUND: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. MATERIALS AND METHODS: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs). RESULTS: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs. CONCLUSION: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

How, Why and Where it Hurts-Breaking Down Pain Syndrome Among Nursing Home Patients With Dementia: A Cross-Sectional Analysis of the COSMOS Trial.

BACKGROUND: Between 40%-60% of nursing home patients with dementia suffer from chronic and acute pain despite increasing their analgesic drug prescription. AIMS: Determine the locations and intensity of pain and the association between quality of life (QoL) and four stratified pain-analgesic groups: (1) pain-analgesics treatment; (2) pain-no analgesics; (3) no pain-analgesics treatment; and (4) no pain-no analgesics. DESIGN: Multicenter, multicomponent cluster randomized controlled Communication, Systematic assessment and treatment of pain, Medication review, Occupational therapy, and Safety - an effectiveness (COSMOS) trial. PARTICIPANTS: At baseline, 723 nursing home patients were enrolled; 463 were completely evaluated for the presence of pain and included in the cross-sectional analyses. METHODS: Data were collected using the following tests: Cognitive function (Mini-Mental-State Evaluation [MMSE]); Quality of Life in Late stage of Dementia (QUALID); Dementia-Specific QoL (QUALIDEM); Mobilization-Observation-Behavior-Intensity-Dementia Pain Scale (MOBID-2); and number of analgesic drug prescriptions. Analysis of covariance (ANCOVA) was used to compare pain and QoL across pain-analgesics groups. RESULTS: The majority of participants (78%) had moderate-to-severe dementia, were female (74%), and a mean age of 86.7 years. Almost 44% reported clinically significant pain, whereas 69% had ≥2 pain locations, especially in the musculoskeletal system. Some 33.5% of participants had pain receiving analgesics, 10% had pain with no analgesics, and 27% had no pain receiving analgesics. Patients evaluated with clinically significant pain intensity scores had lower QoL (<.001) compared with assessments relying on different pain locations. CONCLUSION: Untreated musculoskeletal and multi-located pain is still common in nursing home patients with dementia. A significant share without pain receive analgesics. Proper pain assessment and regular re-assessment are prerequisites for the prescribing and deprescribing of analgesics. Pain intensity scores are more significantly connected to QoL. This must be stressed when evaluating pain and QoL.

Alternating Lenvatinib and Trans-Arterial Therapy Prolongs Overall Survival in Patients with Inter-Mediate Stage HepatoCellular Carcinoma: A Propensity Score Matching Study.

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT (n = 41) or non-AT group (n = 72) according to the post LEN treatment. Overall survival (OS) was calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Factors associated with AT were evaluated using a decision tree analysis. After PSM, there were no significant differences in age, sex, etiology, or albumin-bilirubin (ALBI) score/grade between groups. The survival rate of the AT group was significantly higher than that of the non-AT group (median survival time; not reached vs. 16.3 months, P = 0.01). Independent factors associated with OS were AT and ALBI grade 1 in the Cox regression analysis. In the decision tree analysis, age and ALBI were the first and second splitting variables for AT. In this study, we show that AT may improve prognosis in patients with intermediate-stage HCC. Moreover, alternating LEN and trans-arterial therapy may be recommended for patients below 70 years of age with ALBI grade 1.

Lenvatinib prolongs the progression-free survival time of patients with intermediate-stage hepatocellular carcinoma refractory to transarterial chemoembolization: A multicenter cohort study using data mining analysis.

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria.

Clinical Significance of Adverse Events for Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study.

We sought to investigate the clinical profile(s) associated with the discontinuation of lenvatinib (LEN) due to severe adverse events (DLSAE) in patients with unresectable hepatocellular carcinoma (HCC). This retrospective study enrolled 177 patients with HCC treated with LEN. Independent factors associated with DLSAE were advanced age, albumin-bilirubin (ALBI) grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2. The overall survival (OS) in the group that did not require DLSAE was significantly longer compared to the group that did require DLSAE (median survival time (MST): not reached vs. 12.8 months, p < 0.001). Moreover, advanced age was the most important variable for DLSAE in a decision tree analysis. Hypertension and hand-foot-skin-reaction (HFSR) were also significantly associated with longer survival, and the occurrence of hypertension was the earliest predictor for improved prognosis, while appetite loss and development of grade ≥ 3 fatigue were predictive of a poor prognosis. We concluded that the appearance of hypertension has potential as an early surrogate marker to predict improved prognosis. Moreover, careful management to avoid discontinuation of treatment leads to longer survival in patients receiving LEN.

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability toward Adverse Events.

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study.

We aimed to investigate the impact of the controlling nutritional status (CONUT) score, an immuno-nutritional biomarker, on the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). This retrospective study enrolled 164 patients with HCC and treated with LEN (median age 73 years, Barcelona Clinic Liver Cancer (BCLC) stage B/C 93/71). Factors associated with overall survival (OS) were evaluated using multivariate and decision tree analyses. OS was calculated using the Kaplan-Meier method and analyzed using the log-rank test. Independent factors for OS were albumin-bilirubin grade 1, BCLC stage B, and CONUT score <5 (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.58-5.31, p < 0.001). The CONUT score was the most important variable for OS, with OS rates of 70.0% and 29.0% in the low and high CONUT groups, respectively. Additionally, the median survival time was longer in the low CONUT group than in the high CONUT group (median survival time not reached vs. 11.3 months, p < 0.001). The CONUT score was the most important prognostic variable, rather than albumin-bilirubin grade and BCLC stage, in patients with HCC treated with LEN. Accordingly, immuno-nutritional status may be an important factor in the management of patients with HCC treated with LEN.

Case: Authentic multimodal therapy and liver resection for an initially unresectable intrahepatic cholangiocarcinoma.

INTRODUCTION: Although curative resection is an outstanding prognostic factor of intrahepatic cholangiocarcinoma (ICC), certain segments remain unresectable. The standard therapy for initially unresectable ICC is uncertain. In this case report, we reported the feasibility of multimodal chemotherapy and curative resection. CASE: A 59-year-old Asian woman with back pain was referred to the hospital by her family physician regarding liver mass visible on ultrasonography. At admission, the carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were high, and images showed characteristic signs of ICC with intrahepatic metastases and invasions to on the right Glisson's sheath. Multimodal therapy was applied to the ICC, which could not be resected at first. The therapy comprised hepatic arterial chemoembolization with drug-eluting beads (DEB-TACE), angiographic subsegmentectomy (AS), and systemic chemotherapy. Downstaging of the ICC, which results in curative resection, was planned due to non-normalization of the tumor markers, and pathological analysis revealed complete remission. At 34 months after the surgery, the patient was alive without relapse. DISCUSSION: Recently, chemotherapy and/or an interventional approach were reported to be feasible, although unresectable advanced ICC has a poor prognosis. Some studies have reported that multimodal chemotherapy and R0 resection of initially unresectable ICC can prolong survival time. However, some reports have shown high morbidity and mortality associated with initially unresectable ICC treated with multimodal chemotherapy and R0 resection. Our study resulted in complete remission without complications. CONCLUSION: Multimodal chemotherapy and hepatic curative resection on locally advanced ICC are feasible treatment approaches for initially unresectable ICC.

Transient stasis of pancreatic fluid flow together with mild injury of the pancreatic duct cause chronic pancreatitis.

BACKGROUND: Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas. AIMS: The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury. METHODS: Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 µl/100 g body weight of 0.01% agarose (group A), 40 µl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography. RESULTS: In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42. CONCLUSIONS: Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts.

Animal models of chronic pancreatitis.

Animal models for CP in rats can be classified into 2 groups: one is noninvasive or nonsurgical models and the other is invasive or surgical models. Pancreatic injury induced by repetitive injections of supramaximal stimulatory dose of caerulein (Cn) or by intraductal infusion of sodium taurocholate (NaTc) recovered within 14 days, whereas that caused by repetitive injection of arginine or by intraductal infusion of oleic acid was persistent. However, the destroyed acinar tissues were replaced by fatty tissues without fibrosis. Transient stasis of pancreatic fluid flow by 0.01% agarose and minimum injury of the pancreatic duct by 0.1% NaTc solution induced progressive pancreatic injury although one alone is insufficient to cause persistent pancreatic injury. However, the damaged tissue was replaced by fatty tissue without fibrosis. Continuous pancreatic ductal hypertension (PDH) caused diffuse interlobular and intralobular fibrosis closely resembling human CP.

Excellent outcomes with angiographic subsegmentectomy in the treatment of typical hepatocellular carcinoma: a retrospective study of local recurrence and long-term survival rates in 120 patients with hepatocellular carcinoma.

BACKGROUND: The authors successfully adopted an interesting and effective treatment for hepatocellular carcinoma (HCC) referred to as angiographic subsegmentectomy (AS). This treatment involved simultaneous embolization of the peripheral feeding artery and the portal vein. The result was that almost all of the HCC and peripheral liver parenchyma developed complete anatomic necrosis. METHODS: To determine the effectiveness of this method, the authors retrospectively studied the local recurrence rates of 49 solitary HCCs and the long-term survival rates of 120 patients with HCC between 2000 and 2008. RESULTS: The results indicated that, in 31 small, solitary HCCs (<2.0 cm), the local recurrence rate was only 9.6%; and, in 10 slightly larger HCCs (<3.0 cm), the local recurrence rate was only 10%. The 5-year, 8-year, and 10-year survival rates for patients with stage I and stage I/Child-Pugh grade A HCC were 74.27% and 77.65%, 53.05% and 51.76%, and 53% and 51.76%, respectively; and the 5-year, 8-year, and 10-year survival rates for patients with stage II and stage II/Child-Pugh grade A HCC were 66.21% and 71.41%, 39.9% and 39.60%, and 29.92% and 25%), respectively. There were no severe complications. CONCLUSIONS: AS should be investigated further as potential first-line therapy for the treatment of patients with stage I and II HCC.

Preferential increase of extracellular matrix expression relative to transforming growth factor beta1 in the pancreas during the early stage of acute hemorrhagic pancreatitis in rats.

OBJECTIVES: To elucidate the role of transforming growth factor (TGF) beta1 and extracellular matrix (ECM) after acute necrotizing pancreatitis, we studied the regulation of TGF-beta1 and ECM after induction of pancreatitis. METHODS: We examined the serial changes of levels of plasma TGF-beta1 by enzyme-linked immunoassay and expression of TGF-beta1 and ECM by Northern and Western blot analyses, respectively, in the pancreas after induction of sodium taurocholate-induced acute pancreatitis. RESULTS: Plasma total (active and inactive) TGF-beta1 levels at 3 hours after induction of pancreatitis were significantly increased compared with baseline values. The levels of TGF-beta1 messenger RNA (mRNA) were unaltered by day 2. Levels of fibronectin mRNA at 3 hours after induction of pancreatitis were already higher than the baseline values. Latency-associated peptide-TGF-beta1 showed a peak on day 7. Thus, the expression of ECM mRNA increased earlier than that of TGF-beta1 mRNA. CONCLUSIONS: These results suggest that the increase in plasma TGF-beta1 concentration probably results from the elevated secretion of TGF-beta1 from several cells and/or the redistribution of TGF-beta1 protein and that the increase in expression of ECM probably is associated with the activation of TGF-beta1. It is conceivable that both increased plasma concentration and focal activation of TGF-beta1 play an important role in ECM production during the early stage of acute pancreatitis.

High glucose activates rat pancreatic stellate cells through protein kinase C and p38 mitogen-activated protein kinase pathway.

OBJECTIVE: Hyperglycemia is implicated in fibrosis in many organs. Exocrine and endocrine pancreas are closely linked both anatomically and physiologically, and pathological conditions in the exocrine gland can cause impairment of endocrine function and vice versa. Chronic pancreatitis causes pancreatic fibrosis and sometimes results in diabetes mellitus. Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrogenesis. However, the effects of high glucose concentrations on PSC activation have not been fully elucidated. METHODS: Cultured PSCs were incubated in the presence of various concentrations of glucose. Pancreatic stellate cell proliferation, alpha-smooth muscle actin (alpha-SMA) expression, and collagen production were determined by colorimetric conversion assay, Western blot analysis, and Sirius red dye binding assay, respectively. RESULTS: High glucose concentrations significantly increased PSC proliferation, alpha-SMA expression, and collagen type I production in PSCs. High glucose concentrations activated protein kinase C (PKC) in PSCs, and PKC inhibitor GF109203X inhibited glucose-stimulated PSC proliferation, alpha-SMA expression, and collagen secretion. High glucose also activated p38 mitogen-activated protein kinase (MAPK) in PSCs, and p38 MAPK inhibitor SB203580 inhibited glucose-stimulated collagen secretion. CONCLUSIONS: Our results indicate that high glucose concentrations stimulate PSC activation via PKC-p38 MAP kinase pathway and suggest that high glucose may aggravate pancreatic fibrosis.

Persistent destruction of the basement membrane of the pancreatic duct contributes to progressive acinar atrophy in rats with experimentally induced pancreatitis.

BACKGROUND AND AIMS: The imbalance between synthesis and degradation of extracellular matrix (ECM) proteins is a characteristic feature in chronic pancreatitis. We evaluated the relationship between type IV collagen structure in the basement membrane (BM) and the development of acinar atrophy or the regeneration from acinar injury. METHODS: Three different models of pancreatitis were induced in rats by repetitive intraperitoneal injections of 500 mg/100 g body weight of arginine (Arg) or 20 microg/kg body weight of caerulein (Cn) or a single retrograde intraductal infusion of 40 microL/100 g body weight of 3% sodium taurocholate (NaTc). We examined the changes in type IV collagen structure by immunostaining, and the serial changes in the gelatinolytic activity of pro- and active matrix metalloproteinase-2 by zymography in these models of pancreatitis. RESULTS: The pancreas appeared to be histologically normal on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc, whereas 85% to 90% of acinar tissue was replaced by fatty tissue and dilated pancreatic ducts on day 54 after the first intraperitoneal Arg injection. Immunoreactivity for type IV collagen appeared as a discontinuous line along the BM of ducts, vessels, tubular complexes, and acinar cells on day 40 in Arg-induced pancreatitis, whereas it was detected as a continuous line along the BM on day 35 in Cn-induced pancreatitis and on day 42 in NaTc-induced pancreatitits. Gelatinolytic activity of active MMP-2 increased significantly from day 13 to day 40 after the first intraperitoneal Arg injection, whereas it decreased to the baseline level on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc. CONCLUSIONS: Our findings indicate that a long-term increase in gelatinolytic activity of active MMP-2 in Arg-induced pancreatitis causes continuous disorganization of type IV collagen in the BM and progressive acinar atrophy, whereas a transient increase in gelatinolytic activity of active MMP-2 is involved in the regeneration of type IV collagen structure in the BM and recovery from acinar injury.

Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice.

Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.