Liver Transplantation for Unresectable Colorectal Liver Metastasis: Perspective and Review of Current Literature.

The treatment of unresectable colorectal liver metastasis (CRLM) has previously been limited to palliative chemotherapy. Traditionally, the role of liver transplant has not been associated with sufficient survival to justify a patient undergoing a major operation with the associated requirement for postoperative immunosuppression. With improvements in chemotherapy options, a certain subset of patients can experience stable disease for years, which has prompted investigation into the role of liver transplant in these patients. Several recent studies have shown promising results in well-selected patients, with posttransplant survival approaching that of liver transplant recipients for other diseases. Here, we present a review of the data and current protocols for liver transplant for unresectable CRLM.

Regulatory T cell: a double-edged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is becoming a leading cause of end-stage liver disease globally. Metabolic-dysfunction-associated steatohepatitis (MASH) represents a progressive inflammatory manifestation of MASLD. MASH underlies a versatile and dynamic inflammatory microenvironment, accompanied by aberrant metabolism and ongoing liver regeneration, establishing itself as a significant risk factor for hepatocellular carcinoma (HCC). The mechanisms underlying the escape and survival of malignant cells within the extensive inflammatory microenvironment of MASH remain elusive. Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and preventing excessive immune responses in the liver. Paradoxically, Tregs have been implicated in inhibiting tumour-promoting inflammation and facilitating the evasion of cancer cells. Recent studies have unveiled distinct behaviours of Tregs at different stages of MASLD, suggesting a dual role in the pathogenesis. In this review, we explore the fate of Tregs from MASLD to HCC, offering recent insights into potential targets for clinical intervention.

Differential Expression and Diagnostic Value of MUC5AC Glycoforms in Pancreatic Ductal Adenocarcinoma.

We explored the differential expression and diagnostic value of two significant Mucin 5AC (MUC5AC) glycoforms, less-glycosylated immature (IM) and heavily-glycosylated mature (MM), in neoplastic diseases (NpD), including pancreatic ductal adenocarcinoma (PDA) and neuroendocrine tumors (NET), and non-neoplastic (non-NpD) diseases. Commercially available tissue microarray (TMA) was constructed from 96 patients, including 38 primary PDA (PT), 5 metastatic lesions (ML), 11 NET, and the rest being non-NpD tissues. Immunohistochemistry for MUC5AC was performed using CHL2 and 45M1 clones for IM and MM isoforms, respectively. MUC5AC (both glycoforms) are not detected in non-NpD. In MUC5AC-positive neoplastic tissues, IM was localized to the cytoplasm (Cy) while MM was identified in apical (Ap) and extracellular (Ec) regions too. One ML positive (omentum) in the TMA expressed both. For PDA vs. non-PDA, the sensitivity (SN) was higher with MM ± IM (71%) than MM (47%) or IM (65%)-alone. The specificity (SP) was 100% with MM-alone, which dropped with the addition of IM (96%) or IM-alone (93%). For NpD vs. non-NpD, the SN (MM + IM-59%, IM-55%, MM-37%) was inferior, and SP was 100% for both glycoforms (MM ± IM). The combination of MUC5AC glycoforms has high SP and reasonable SN to diagnose PDA. They have the potential to be a reliable diagnostic marker and should be investigated further in more extensive studies.

Interventions to Improve Surveillance for Hepatocellular Carcinoma in High-Risk Patients: A Scoping Review.

PURPOSE: Hepatocellular carcinoma (HCC) is most often a sequela of chronic liver disease or chronic hepatitis B infection. Among high-risk patients, surveillance for HCC every 6 months is recommended by international guidelines. However, rates of HCC surveillance are suboptimal (11-64%). Barriers at the patient, provider, and healthcare delivery system levels have been identified. METHODS: We performed a systemic scoping review to identify and characterize interventions to improve HCC surveillance that has previously been evaluated. Searches using key terms in PubMed and Embase were performed to identify studies examining interventions designed to improve the surveillance rate for HCC in patients with cirrhosis or chronic liver disease that were published in English between January 1990 and September 2021. RESULTS: Included studies (14) had the following study designs: (1) randomized clinical trials (3, 21.4%), (2) quasi-experimental (2, 14.3%), (3) prospective cohort (6, 42.8%), and (4) retrospective cohort (3, 21.4%). Interventions included mailed outreach invitations, nursing outreach, patient education with or without printed materials, provider education, patient navigation, chronic disease management programs, nursing-led protocols for image ordering, automated reminders to physicians and nurses, web-based clinical management tools, HCC surveillance databases, provider compliance reports, radiology-led surveillance programs, subsidized HCC surveillance, and the use of oral medications. It was found that HCC surveillance rates increased after intervention implementation in all studies. CONCLUSION: Despite improvements in HCC surveillance rates with intervention, compliance remained suboptimal. Further analysis of which interventions yield the greatest increases in HCC surveillance, design of multi-pronged strategies, and improved implementation are needed.

Phosphorylation of IWS1 by AKT maintains liposarcoma tumor heterogeneity through preservation of cancer stem cell phenotypes and mesenchymal-epithelial plasticity.

Chemotherapy remains the mainstay of treatment for patients with advanced liposarcoma (LPS), but response rates are only 25% and the overall survival at 5 years is dismal at 20-34%. Translation of other therapies have not been successful and there has been no significant improvement in prognosis for nearly 20 years. The aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the aggressive clinical behavior LPS and in resistance to chemotherapy, but the precise mechanism remains elusive and efforts to target AKT clinically have failed. Here we show that the AKT-mediated phosphorylation of the transcription elongation factor IWS1, promotes the maintenance of cancer stem cells in both cell and xenograft models of LPS. In addition, phosphorylation of IWS1 by AKT contributes to a "metastable" cell phenotype, characterized by mesenchymal/epithelial plasticity. The expression of phosphorylated IWS1 also promotes anchorage-dependent and independent growth, cell migration, invasion, and tumor metastasis. In patients with LPS, IWS1 expression is associated with reduced overall survival, increased frequency of recurrence, and shorter time to relapse after resection. These findings indicate that IWS1-mediated transcription elongation is an important regulator of human LPS pathobiology in an AKT-dependent manner and implicate IWS1 as an important molecular target to treat LPS.

Prognostic factors in patients receiving surgery and radiation therapy for retroperitoneal sarcoma: A machine-learning analysis.

BACKGROUND: The addition of radiation therapy to surgery for retroperitoneal sarcoma remains controversial. Improved patient selection may help identify optimal candidates for multimodality treatment. The aim of this analysis was to define prognostic factors among patients who receive radiation therapy and surgery to aid in patient selection for multimodal therapy. METHODS: Patients who received radiation therapy and underwent curative-intent resection for retroperitoneal sarcoma between 2004 and 2016 were identified from a national cohort in the United States (National Cancer Database). A machine-based classification and regression tree model was used to generate similar groups of patients relative to overall survival based on preoperative factors. RESULTS: A total of 1,443 patients received radiation therapy in addition to surgery. Median age was 61 years old and 55.0% were female. Most patients (66%) received care at an academic or integrated network cancer program. With a median follow-up of 84 months, receipt of radiation therapy was not associated with improved overall survival (P = .81). Classification and regression tree analysis revealed a significant association between overall survival and American Joint Committee on Cancer stage group, age, tumor histology, and Charlson comorbidity score. Application of these parameters via machine learning stratified patients into 5 cohorts with distinct survival outcomes. In the most favorable cohort (Cohort 1: American Joint Committee on Cancer stage group ≤II, age ≤61, histology including fibrosarcoma, well differentiated liposarcoma, myxoid liposarcoma, and leiomyosarcoma), the 5-year overall survival was 81.7% and median overall survival was not reached; in the least favorable cohort (Cohort 6: American Joint Committee on Cancer stage group >II, age >68) where the 5-year survival was 41.3% and median overall survival was 45.2 months (P < .001 versus Cohort 1). CONCLUSION: In the absence of a defined survival benefit, patients with advanced American Joint Committee on Cancer stage group, older age, and medical comorbidities have relatively unfavorable overall survival after combined modality therapy and therefore stand the least to gain from the addition of radiation therapy to surgery. In contrast, younger patients with good performance status and retroperitoneal sarcoma histologies with a higher propensity for local recurrence may have the greatest opportunity to benefit from radiation therapy.

Patient-, Provider-, and System-Level Barriers to Surveillance for Hepatocellular Carcinoma in High-Risk Patients in the USA: a Scoping Review.

PURPOSE: Hepatocellular carcinoma has a dismal prognosis, except in patients diagnosed early who are candidates for potentially curative therapies. Most HCC cases develop in patients with chronic liver disease. Therefore, expert society guidelines recommend surveillance every 6 months with ultrasound with or without serum alpha-fetoprotein for high-risk patients. However, fewer than 20% of patients in the USA undergo appropriate surveillance. METHODS: A systematic scoping review was performed with the objective of identifying barriers to screening among high-risk patients in the USA including mapping key concepts in the relevant literature, identifying the main sources and types of evidence available, and identifying gaps in the literature. A total of 43 studies published from 2007 to 2021 were included. Data were extracted and a conceptual framework was created. RESULTS: Assessment of quantitative studies revealed poor surveillance rates, often below 50%. Three categories of barriers to surveillance were identified: patient-level, provider-level, and system-level barriers. Prevalent patient-level barriers included financial constraints, lack of awareness of surveillance recommendations, and scheduling difficulties. Common provider-level barriers were lack of provider awareness of guidelines for surveillance, difficulty accessing specialty resources, and time constraints in the clinic. System-level barriers included fewer clinic visits and rural/safety-net settings. Proposed interventions include improved patient/provider education, patient navigators, increased community/academic collaboration, and EMR-based reminders. CONCLUSION: Based on these findings, there is a crucial need to implement and evaluate proposed interventions to improve HCC surveillance.

Congenital Absence of the Portal Vein.

A 59-year-old woman presented with abdominal bloating, elevated alkaline phosphatase and transaminases, and computed tomography abdomen/pelvis demonstrating large right-sided hepatic masses. A percutaneous fine needle aspiration demonstrated hepatocellular neoplasm concerning for hepatocellular carcinoma. Preoperative imaging demonstrated possible porto-caval shunt. She underwent uneventful right hepatic lobectomy with confirmation of porto-systemic shunt. Congenital porto-systemic shunt, or Abernethy malformation, is rare and is associated with congenital cardiac and gastrointestinal abnormalities. Additionally, congenital porto-systemic shunt is associated with increased risk of hepatic neoplasms including hepatocellular carcinoma. Recommended surveillance for these patients is not well defined.

Disparities in Care Access to Liver-Directed Therapy Among Medicare Beneficiaries with Colorectal Cancer Liver Metastasis.

BACKGROUND: Liver-directed therapies (LDT) are important components of the multidisciplinary care of patients with colorectal cancer liver metastases (CRCLM) that contribute to improved long-term outcomes. Factors associated with receipt of LDT are poorly understood. PATIENTS AND METHODS: Patients > 65 years old diagnosed with CRCLM were identified within the Medicare Standard Analytic File (2013-2017). Patients with extrahepatic metastatic disease were excluded. Mixed-effects analyses were used to assess patient factors associated with the primary outcome of LDT, defined as hepatectomy, ablation, and/or hepatic artery infusion chemotherapy (HAIC), as well as the secondary outcome of hepatectomy. RESULTS: Among 23,484 patients with isolated CRCLM, only 2004 (8.5%) received LDT, although resectability status could not be determined for the entire cohort. Among patients who received LDT, 61.7% underwent hepatectomy alone, 28.1% received ablation alone, 8.5% underwent hepatectomy and ablation, and 1.8% received HAIC either alone (0.8%) or in combination with hepatectomy and/or ablation (0.9%). Patient factors independently associated with lower odds of LDT included older age, female sex, Black race, greater comorbidity burden, higher social vulnerability index, primary rectal cancer, synchronous liver metastasis, and further distance from a high-volume liver surgery center (p < 0.05). Results were similar for receipt of hepatectomy. CONCLUSIONS: Despite the well-accepted role of LDT for CRCLM, only a small proportion of Medicare beneficiaries with CRCLM receive LDT. Increasing access to specialized centers with expertise in LDT, particularly for Black patients, female patients, and those with higher levels of social vulnerability or long travel distances, may improve outcomes for patients with CRCLM.

BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis.

Cancer therapies trigger diverse cellular responses, ranging from apoptotic death to acquisition of persistent therapy-refractory states such as senescence. Tipping the balance toward apoptosis could improve treatment outcomes regardless of therapeutic agent or malignancy. We find that inhibition of the mitochondrial protein BCL-xL increases the propensity of cancer cells to die after treatment with a broad array of oncology drugs, including mitotic inhibitors and chemotherapy. Functional precision oncology and omics analyses suggest that BCL-xL inhibition redirects the outcome of p53 transcriptional response from senescence to apoptosis, which likely occurs via caspase-dependent down-modulation of p21 and downstream cytostatic proteins. Consequently, addition of a BCL-2/xL inhibitor strongly improves melanoma response to the senescence-inducing drug targeting mitotic kinase Aurora kinase A (AURKA) in mice and patient-derived organoids. This study shows a crosstalk between the mitochondrial apoptotic pathway and cell cycle regulation that can be targeted to augment therapeutic efficacy in cancers with wild-type p53.

Constitutively Active Androgen Receptor in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression.

Surgical resection rates after neoadjuvant therapy for localized pancreatic ductal adenocarcinoma: meta-analysis.

BACKGROUND: Neoadjuvant therapy is increasingly being used before surgery for localized pancreatic cancer. Given the importance of completing multimodal therapy, the aim of this study was to characterize surgical resection rates after neoadjuvant therapy as well as the reasons for, and long-term prognostic impact of, not undergoing resection. METHODS: A systematic review and meta-analysis of prospective trials and high-quality retrospective studies since 2010 was performed to calculate pooled resection rates using a generalized random-effects model for potentially resectable, borderline resectable, and locally advanced pancreatic cancer. Median survival times were calculated using random-effects models for patients who did and did not undergo resection. RESULTS: In 125 studies that met the inclusion criteria, neoadjuvant therapy consisted of chemotherapy (36.8 per cent), chemoradiation (15.2 per cent), or chemotherapy and radiation (48.0 per cent). Among 11 713 patients, the pooled resection rates were 77.4 (95 per cent c.i. 71.3 to 82.5), 60.6 (54.8 to 66.1), and 22.2 (16.7 to 29.0) per cent for potentially resectable, borderline resectable, and locally advanced pancreatic cancer respectively. The most common reasons for not undergoing resection were distant progression for resectable and borderline resectable cancers, and local unresectability for locally advanced disease. Among 42 studies with survival data available, achieving surgical resection after neoadjuvant therapy was associated with improved survival for patients with potentially resectable (median 38.5 versus 13.3 months), borderline resectable (32.3 versus 13.9 months), and locally advanced (30.0 versus 14.6 months) pancreatic cancer (P < 0.001 for all). CONCLUSION: Although rates of surgical resection after neoadjuvant therapy vary based on anatomical stage, surgery is associated with improved survival for all patients with localized pancreatic cancer. These pooled resection and survival rates may inform patient-provider decision-making and serve as important benchmarks for future prospective trials.

Patient Preferences for Neoadjuvant Therapy in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Physicians are increasingly recommending neoadjuvant therapy (NT) before surgery for pancreatic ductal adenocarcinoma (PDAC). However, patient preferences for and opinions regarding NT are poorly understood. METHODS: Survivors and caregivers from a national PDAC patient advocacy organization completed an online survey assessing preferences for NT versus surgery first (SF) and factors influencing their decision making. RESULTS: Among 54 participants, 74.1% had a personal history of PDAC. While most patients preferred SF for resectable disease, NT was the preferred treatment approach for borderline resectable, locally advanced, and resectable cancers with high carbohydrate antigen 19-9. The most important factor influencing patient decision making regarding NT was its impact on overall survival while the least important was published national guidelines. The most preferred rationale for NT was ability to downstage to surgical resection and early treatment of micrometastatic disease. CONCLUSIONS: Among a national cohort of PDAC survivors and caregivers, the majority preferred SF for resectable PDAC, whereas NT was preferred when the resectability of a tumor was in question. The impact of NT on quantity and quality of life, as well as the likelihood of achieving surgical resection, was most highly valued by participants.

The Hepatic Pre-Metastatic Niche.

Primary tumors can communicate with the liver to establish a microenvironment that favors metastatic colonization prior to dissemination, forming what is termed the "pre-metastatic niche" (PMN). Through diverse signaling mechanisms, distant malignancies can both influence hepatic cells directly as well as recruit immune cells into the PMN. The result is a set of changes within the hepatic tissue that increase susceptibility of tumor cell invasion and outgrowth upon dissemination. Thus, the PMN offers a novel step in the traditional metastatic cascade that could offer opportunities for clinical intervention. The involved signaling molecules also offer promise as biomarkers. Ultimately, while the existence of the hepatic PMN is well-established, continued research effort and use of innovative models are required to reach a functional knowledge of PMN mechanisms that can be further targeted.

Incidence and Risk Factors for New-Onset Diabetes Mellitus After Surgical Resection of Pancreatic Cystic Lesions: A MarketScan Study.

OBJECTIVES: There is a paucity of literature evaluating new-onset diabetes mellitus (NODM) after resection of pancreatic cystic lesions (PCLs). We sought to characterize the incidence and risk factors associated with NODM after partial pancreatectomy for PCLs. METHODS: We utilized the IBM MarketScan Database (2012-2018) to identify all nondiabetic adults who underwent partial pancreatectomy for PCLs. Patients with any other pancreatic disease were excluded. We performed Kaplan-Meier analysis and multivariable Cox proportional hazards regression to define the incidence and risk factors of postoperative NODM. RESULTS: Among 311 patients, the overall risk (95% confidence interval) of NODM was 9.1% (6.3-12.9%), 15.1% (11.3-20.2%), and 20.2% (15.3-26.4%) at 6, 12 and 24 months, respectively. Multivariable analysis (adjusted hazard ratio; 95% confidence interval) revealed that older age (1.97; 1.04-3.72; 55-64 vs 18-54 years), obesity (2.63; 1.35-5.12), hypertension (1.79; 1.01-3.17), and cardiovascular disease (2.54; 1.02-6.28) were independent predictors of NODM. Rates of NODM were similar after distal pancreatectomy versus pancreaticoduodenectomy. CONCLUSIONS: Within 2 years, 1 in 5 patients without any other pancreatic disease will develop NODM after partial pancreatectomy for PCLs. Those with advanced age, metabolic syndrome features, and/or cardiovascular disease may benefit from preoperative counseling and intensive postoperative monitoring, education, and treatment for diabetes mellitus.