Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

Feasibility of a Palliative Care Intervention within Routine Care of Hepatocellular Carcinoma: A Pilot Randomized Controlled Trial.

Background: Patients with hepatocellular cancer (HCC) are at risk for poor quality of life (QoL) and high symptom burden, coupled with limited treatment options. Palliative care (PC) can play an important role in reducing the suffering of this population, but remains underutilized. Aim: To demonstrate feasibility of an outpatient PC intervention within HCC care. Methods: This is a pilot randomized controlled trial conducted at an academic center. All stages of HCC patients (except Barcelona Clinic Liver Cancer stage D) with a scheduled hepatology appointment were eligible. Patients were randomized to receive PC intervention or usual care (control arm). In the PC arm, patients received PC from a PC provider at enrollment and at three months from the baseline visit, in addition to continued standard of care. Control arm received only standard care. All patients completed FACT-Hep (Functional Assessment of Cancer Therapy-Hepatobiliary Cancer) and modified Edmonton Symptom Assessment Scale at baseline and at three-month visit. Descriptive statistics were utilized to summarize questionnaires, and change in QoL and symptoms from baseline to three months were compared between the two study groups. Results: Of the 109 approached, 57 patients (52.3%) consented to enroll, and 52 (91%) completed the study. QoL and symptom burden assessments demonstrated impaired QoL and high symptom burden in both arms of the study. At least 50% of enrolled patients in each arm had some degree of fatigue, pain, sleep disturbance, and appetite loss, at baseline. Post-intervention, symptom burden and QoL improved in the intervention arm and remained same or worsened in the control group. All FACT-Hep scores decreased numerically among controls and increased numerically among patients in the PC intervention group. Conclusion: Outpatient PC intervention within routine HCC care is feasible, and can potentially improve QoL and symptoms.

Follow Up Imaging in Hepatocellular Cancer Ultrasound Screening Exams With Poor Visualization Scores.

OBJECTIVES: The Ultrasound Liver Imaging Reporting and Data Systems (LI-RADS) provides standardized terminology and reporting for ultrasound (US) examinations performed for hepatocellular cancer (HCC) screening. However, there are no recommendations regarding follow up imaging for visualization scores with suboptimal visualization. Therefore, the aim of this study is to examine follow up imaging practices in the setting of US studies scored as B (moderate limitations) and C (severe limitations). METHODS: A single center retrospective analysis of studies from 2017 to 2021 with HCC US screening visualization scores of B and C was performed. Follow up imaging with US, CT, or MRI within 6 months with visualization score B or C on initial US were included. RESULTS: Five hundred and sixty HCC US studies with suboptimal imaging were reviewed. Of those with follow up imaging, patients with a visualization score of B underwent US in more than half (58%) of the cases while those with visualization score of C underwent more CT/MRI studies (62.5%, P = .12) Patients with visualization score of B had more MRI exams performed (55%) while patients with a visualization score of C underwent more CT exams (70%, P = .16). CONCLUSIONS: Currently, there are no guidelines instructing follow up imaging on HCC screening ultrasounds with poor visualization, and the data suggests that providers have taken a heterogeneous approach. This suggests a need for society recommendations on how to approach HCC screening ultrasounds in patients with suboptimal studies.

Correction: Biophotonic detection of high order chromatin alterations in field carcinogenesis predicts risk of future hepatocellular carcinoma: A pilot study.

[This corrects the article DOI: 10.1371/journal.pone.0197427.].

Biophotonic detection of high order chromatin alterations in field carcinogenesis predicts risk of future hepatocellular carcinoma: A pilot study.

PURPOSE: Hepatocellular carcinoma (HCC) results from chronic inflammation/cirrhosis. Unfortunately, despite use of radiological/serological screening techniques, HCC ranks as a leading cause of cancer deaths. Our group has used alterations in high order chromatin as a marker for field carcinogenesis and hence risk for a variety of cancers (including colon, lung, prostate, ovarian, esophageal). In this study we wanted to address whether these chromatin alterations occur in HCC and if it could be used for risk stratification. EXPERIMENTAL DESIGN: A case control study was performed in patients with cirrhosis who went on to develop HCC and patients with cirrhosis who did not develop cancer. We performed partial wave spectroscopic microscopy (PWS) which measures nanoscale alterations on formalin fixed deparaffinized liver biopsy specimens, 17 progressors and 26 non-progressors. Follow up was 2089 and 2892 days, respectively. RESULTS: PWS parameter disorder strength Ld were notably higher for the progressors (Ld = 1.47 ± 0.76) than the non-progressors (Ld = 1.00 ± 0.27) (p = 0.024). Overall, the Cohen's d effect size was 0.907 (90.7%). AUROC analysis yielded an area of 0.70. There was no evidence of confounding by gender, age, BMI, smoking status and race. CONCLUSIONS: High order chromatin alterations, as detected by PWS, is altered in pre-malignant hepatocytes with cirrhosis and may predict future risk of HCC.

Evidence-based review of gastrointestinal bleeding in the chronic kidney disease patient.

Patients with end-stage renal disease are more likely to suffer from gastrointestinal (GI) problems, including bleeding from upper and lower sources. Peptic ulcer disease is the most common cause of upper GI bleeding, and although there is some debate in the literature regarding whether the frequency of ulcer disease is higher in patients with kidney disease, it is well established that outcomes are worse in patients with compromised renal function. Angioectasias can be found throughout the GI tract and are another common cause of bleeding; management can be divided into localized endoscopic therapy and systemic hormonal treatment, or surgery for refractory cases. The most frequent causes of lower GI bleeding in this population, in addition to angioectasias, are diverticulosis, hemorrhoids, and ischemic colitis.

Does a personal or family history of malignancy preclude the use of immunomodulators and biologics in IBD.

The medical treatment for inflammatory bowel disease (IBD) has improved over the past 20 years. Although the routine use of immunomodulators and biologic agents in the treatment of IBD in the modern era has been a great achievement, these medicines are associated with rare but serious adverse events. In addition to the infectious complications, there are data to suggest that some of these agents are associated with higher rates of malignancy. In a patient with a history of cancer, or a family history of cancer, the gastroenterologist must be prepared to answer questions about the oncogenic potential of these agents. Thiopurines have been associated with a small increased risk of lymphoma in patients with IBD. In addition, an association with skin cancer has been established. Methotrexate is generally considered safe in patients with a history of cancer. There may be a small risk of lymphoma and possibly skin cancer with anti-tumor necrosis factor agents, but determining the cancer risk of these medications is difficult as they are often used in combination with thiopurines. In general, a family history of cancer should not influence a patient's medical regimen. Treatment for a patient with a personal history of cancer must be individualized and take into account the type and stage of cancer, time since completion of therapy, and the opinion of an oncologist.

Decreased virus population diversity in p53-null mice infected with weakly oncogenic Abelson virus.

The Abelson murine leukemia virus (Ab-MLV), like other retroviruses that contain v-onc genes, arose following a recombination event between a replicating retrovirus and a cellular oncogene. Although experimentally validated models have been presented to address the mechanism by which oncogene capture occurs, very little is known about the events that influence emerging viruses following the recombination event that incorporates the cellular sequences. One feature that may play a role is the genetic makeup of the host in which the virus arises; a number of host genes, including oncogenes and tumor suppressor genes, have been shown to affect the pathogenesis of many murine leukemia viruses. To examine how a host gene might affect an emerging v-onc gene-containing retrovirus, we studied the weakly oncogenic Ab-MLV-P90A strain, a mutant that generates highly oncogenic variants in vivo, and compared the viral populations in normal mice and mice lacking the p53 tumor suppressor gene. While variants arose in both p53+/+ and p53-/- tumors, the samples from the wild-type animals contained a more diverse virus population. Differences in virus population diversity were not observed when wild-type and null animals were infected with a highly oncogenic wild-type strain of Ab-MLV. These results indicate that p53, and presumably other host genes, affects the selective forces that operate on virus populations in vivo and likely influences the evolution of oncogenic retroviruses such as Ab-MLV.