Proton beam stereotactic body radiotherapy and hypofractionated therapy with pencil beam scanning is safe and effective for advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma: A single center experience.

Background: Proton beam therapy (PBT) is a non-surgical treatment that spares adjacent tissues compared to photon radiation and useful for Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). We present a single center experience in HCC and iCCA treated with Pencil Beam Scanning (PBS) PBT. Methods: Forty-four consecutive patients (22 patients in each group) receiving PBT were included and reviewed. PBT was delivered with hypofractionated or stereotactic body radiation therapy (SBRT) using PBS. Tumor size was approximated by clinical target volume (CTV). Outcomes were evaluated with Kaplan-Meier and liver toxicity was determined by MELD-Na and albumin-bilirubin (ALBI) grade. Results: Median follow up was 38.7 months, fourteen (35%) had multifocal disease and median CTV was 232.5cc. Four (9%) and 40 (91%) patients received SBRT and hypofractionated radiation, respectively. Two year overall survival was statistically higher for HCC (entire group: 68.9% months [95% CI: 61.3 - 76.3%]; iCCA: 49.8% [95% CI: 38.5% - 61.1%]; HCC: 89.4% [95% CI: 82.3 - 96.5%]; P <0.005). There was no statistical difference in progression-free survival or freedom from local failure. Biologically Equivalent Dose (BED) was greater than or equal to 80.5Gy in 37 (84%) patients. All iCCA patients had stable or improved ALBI grade following treatment. ALBI grade was stable in 83% of HCC patients and average MELD-Na score remained stable. Tumor size, pretreatment liver function, and total radiation dose were not associated with liver toxicity. Conclusions: PBT for unresectable HCC and iCCA is safe and effective, even for large and multifocal tumors. Liver function was preserved even in those with baseline cirrhosis in this advanced population with large tumors.

Impact of Inflammatory Bowel Disease Subtypes on the Post-liver Transplant Outcomes of Patients with Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: Liver transplant patients with primary sclerosing cholangitis often present with concurrent inflammatory bowel disease. The effect of comorbid conditions on post-transplant prognosis was evaluated. METHODS: The 2005-2019 United Network of Organ Sharing Standard Transplant Analysis and Research database was used to identify patients with primary sclerosing cholangitis. Patients were categorized as having Crohn's Disease, ulcerative colitis, unclassified inflammatory bowel disease, or no inflammatory bowel disease. Baseline characteristics were assessed between cohorts, and outcomes were examined using Cox regression. Outcomes included all-cause mortality, graft failure, infection-induced mortality, and organ system-delineated mortality. Supplementary analyses with unique exclusion and stratification criteria were also performed. RESULTS: Among 2829 patients undergoing transplant, 1360 were considered to have ulcerative colitis, 372 were considered to have Crohn's Disease, and 69 were considered to have an unclassified form of inflammatory bowel disease. Primary sclerosing cholangitis patients with some form of inflammatory bowel disease had no increased risk for any outcomes. However, patients with ulcerative colitis had lower risks of general infectious (aHR 0.65 95%CI 0.44-0.95) and sepsis-induced (aHR 0.56 95%CI 0.35-0.91) mortality, whereas patients with Crohn's Disease had higher risks of sepsis-induced mortality (aHR 2.13 95%CI 1.22-3.70). Supplementary analyses showed effect modification by abdominal surgery history and era. CONCLUSION: The type of inflammatory bowel disease in liver transplant patients with primary sclerosing cholangitis was found to portend risk difference for infection-induced mortality, with ulcerative colitis found to be protective and Crohn's Disease predictive of increased mortality secondary to infectious etiologies. These associations warrant further investigation.

A Systematic Review of Crohn's Disease Case Definitions in Administrative or Claims Databases.

BACKGROUND: We sought to review Crohn's disease (CD) case definitions that use diagnosis, procedure, and medication claims. METHODS: We searched PubMed and Embase from inception through January 31, 2022, using terms related to CD, inflammatory bowel disease, administrative claims, or validity. Each article was scrutinized by 2 authors independently screening and abstracting data. Collected data included participant characteristics, case definition characteristics, and case definition validity. When diagnostic accuracy was provided for multiple case definitions, we extracted the case definition selected by the authors. All diagnostic accuracy characteristics were captured. RESULTS: We identified 30 studies that evaluated a case definition using claims data to identify CD patients. The most common case definition included counts of diagnosis codes (57%) followed by a combination of diagnosis codes and medications (20%). All but 1 study validated the case definition with a medical chart review. In 2 studies, the patient's primary care provider completed a survey to confirm disease status. The positive predictive value of the case definitions ranged from 18% (≥1 code at a single U.S. health plan) to 100% (≥1 code plus a relevant prescription at a U.S. hospital). More complex case definitions (eg, ≥1 code + prescription or ≥2 codes) had lower variability in positive predictive value (≥80%) and specificity (≥85%) than the ≥1 code requirement. CONCLUSIONS: Health services researchers should validate case definitions in their research cohorts. When such validation cannot be performed, we recommend using a more complex case definition. Studies without a validated CD case definition should use sensitivity analyses to confirm the robustness of their results.

This systematic review of Crohn's disease (CD) case definitions identified that complex case definitions such as ≥1 diagnosis code + ≥1 prescription had desirable diagnostic accuracy properties.

Pseudomembranous colitis: Not always Clostridium difficile.

Although Clostridium difficile infection is the cause of most cases of pseudomembranous colitis, clinicians should consider less common causes, especially if pseudomembranes are seen on endoscopy but testing remains negative for C difficile or if presumed C difficile infection does not respond to treatment. Histologic review of colonic mucosal biopsy specimens can provide clues to the underlying cause.

Withaferin-A Reduces Acetaminophen-Induced Liver Injury in Mice.

Withaferin-A (WA) has anti-oxidant activities however, its therapeutic potential in acetaminophen (APAP) hepatotoxicity is unknown. We performed a proof-of-concept study to assess the therapeutic potential of WA in a mouse model that mimics APAP-induced liver injury (AILI) in humans. Overnight fasted C57BL/6NTac (5-6 wk. old) male mice received 200 mg/kg APAP intraperitoneally (i.p.). After 1 h mice were treated with 40 mg/kg WA or vehicle i.p., and euthanized 4 and 16 h later; their livers were harvested and serum collected for analysis. At 4 h, compared to vehicle-treated mice, WA-treated mice had reduced serum ALT levels, hepatocyte necrosis and intrahepatic hemorrhage. All APAP-treated mice had reduced hepatic glutathione (GSH) levels however, reduction in GSH was lower in WA-treated when compared to vehicle-treated mice. Compared to vehicle-treated mice, livers from WA-treated mice had reduced APAP-induced JNK activation, mitochondrial Bax translocation, and nitrotyrosine generation. Compared to vehicle-treated mice, WA-treated mice had increased hepatic up-regulation of Nrf2, Gclc and Nqo1, and down-regulation of Il-6 and Il-1ß. The hepatoprotective effect of WA persisted at 16 h. Compared to vehicle-treated mice, WA-treated mice had reduced hepatocyte necrosis and hepatic expression of Il-6, Tnf-α and Il-1ß, increased hepatic Gclc and Nqo1 expression and GSH levels, and reduced lipid peroxidation. Finally, in AML12 hepatocytes, WA reduced H2O2-induced oxidative stress and necrosis by preventing GSH depletion. Collectively, these data show mechanisms whereby WA reduces necrotic hepatocyte injury, and demonstrate that WA has therapeutic potential in AILI.

M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury.

The role of muscarinic receptor subtypes in modulating acute liver injury is unknown. We detected M1 muscarinic receptor (M1R) expression in human and murine hepatocytes, and investigated the consequences of M1R deficiency on acute liver injury in vivo and inhibiting M1R activation on hepatocyte injury in vitro. Age-matched wild-type (WT) and M1R-deficient (Chrm1(-/-)) male mice were injected intraperitoneally with 200mg/kg acetaminophen (APAP) and euthanized 0, 2, 4, 16, 24, and 36h later. Biochemical and histological parameters indicated that liver injury peaked within 16h after APAP treatment and resolved by 24h. Compared to WT, M1R-deficient mice had reduced intrahepatic hemorrhage and hepatocyte necrosis, reflected by an attenuated rise in serum alanine aminotransferase levels. Livers of M1R-deficient mice showed reduced hepatocyte DNA fragmentation and attenuated expression of injury cytokines (Il-1α, Il-1ß, Il-6, and Fasl). In all mice hepatic glutathione levels decreased after APAP injection, but they recovered more quickly in M1R-deficient mice. During the course of APAP-induced liver injury in M1R-deficient compared to WT mice, hepatic Nrf-2, Gclc, and Nqo1 expressions increased and nitrotyrosine generation decreased. APAP metabolic pathways were not altered by M1R deficiency; expression of hepatic Cyp2e1, Cyp1a2, Cyp3a11, Cyp3a13, Car, and Pxr was similar in Chrm1(-/-) and WT mice. Finally, treatment of murine AML12 hepatocytes with a novel M1R antagonist, VU0255035, attenuated H2O2-induced oxidative stress, prevented GSH depletion, and enhanced viability. We conclude that M1R modify hepatocyte responses to oxidative stress and that targeting M1R has therapeutic potential for toxic liver injury.

Portal hypertensive gastropathy and colopathy.

Portal hypertensive gastropathy (PHG) and colopathy (PHC) are considered complications of portal hypertension. Both entities are clinically relevant because they may cause insidious blood loss or even acute massive gastrointestinal hemorrhage. Endoscopic evaluation is necessary for the diagnosis of PHG and PHC. The existence of different endoscopic criteria for PHG and PHC makes consensus difficult and results in a broad range of reported prevalence. Therapy targeted at reduction of portal pressure and mucosal blood flow has been used to treat acute bleeding; nonselective ß-blockers are the most frequently used agents. Further studies are needed to clarify the natural history, pathogenesis, and treatment of PHG and PHC.

Hemorrhagic ascites. Clinical presentation and outcomes in patients with cirrhosis.

BACKGROUND & AIMS: Hemorrhagic ascites can pose diagnostic and therapeutic dilemmas in patients with cirrhosis. We aimed at exploring the characteristics and outcomes of patients with cirrhosis and hemorrhagic ascites. METHODS: The records of all patients with cirrhosis and ascites, who underwent paracentesis between 2003 and 2010 at Parkland Memorial Hospital, were retrospectively reviewed. Hemorrhagic ascites was defined as an ascitic fluid red blood cell (RBC) count ≥ 10,000/µl. We compared each patient with 3 age- and gender-matched controls (cirrhotic patients with ascites and an ascitic RBC count <10,000/µl). Survival curves were generated using Kaplan-Meier plots and compared using the log rank test. RESULTS: 1113 cirrhotic patients underwent paracentesis; 214 (19%) had hemorrhagic ascites. Patients with hemorrhagic ascites had higher rates of spontaneous bacterial peritonitis (p <0.001), acute kidney injury (AKI, p <0.001), and were more likely to require intensive care unit (ICU)-level care (p=0.01) compared to patients without hemorrhagic ascites. Patients with hemorrhagic ascites had a higher mortality than controls at one month (87% vs. 72%), 1 year (72% vs. 50%) and 3 years (61% vs. 41%). Using multivariate regression analysis, hemorrhagic ascites was also an independent predictor of mortality (HR 1.34, 95% CI 1.07-1.68) after adjusting for the model for end-stage liver disease score (HR 1.04, 1.03-1.05), ICU-level care (HR 2.02, 1.63-2.51) and presence of hepatocellular carcinoma (HR 2.27, 1.61-3.19). CONCLUSIONS: Patients with hemorrhagic ascites had a significantly higher rate of ICU care, AKI, and mortality than patients with portal hypertension and ascites but without hemorrhagic ascites. We conclude that hemorrhagic ascites is a marker of advanced liver disease and poor outcome.