Targeted therapies in hepatocellular carcinoma: Past, present, and future

Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC

A comprehensive review on mutation breeding milestones in cereals: Conventional to advanced molecular approaches to achieve sustainable goals in trait improvement

The grass family includes the annual common grasses known as cereals. The 5 main types of cereals are rice, wheat, barley, rye and oats. As a result of their high vitamin (20-80%) and fiber content (90%), these grains can help treat conditions like type II diabetes, complex metabolic syndrome, obesity, gastrointestinal disorders, and high cholesterol. Cereals have inspired a long history of research into their genetics, development, and evolution due to their significance in both economic and scientific terms. They need to be improved because they play a big part in global food production and crop quality is declining. The crop improvement can be done by incorporating desired features from non-adapted landraces/wild resources. That induced mutagenesis has made a significant contribution to crop improvement initiatives by producing mutant varieties with better and desired genetic modifications in the crop plants mainly in agronomically significant features. The mutants produced by the induction of physical and chemical mutagens were highly useful. The notable traits obtained by the induced mutations are semidwarfness and early maturity in rice varieties, disease resistance in barley, salinity, and drought tolerance in wheat, and lodging and disease resistance in oat and rye. In this review, we focused on identifying and developing elite mutants, their genetic function, and their utilization in future breeding programs for various traits in cereal crops

Intra-operative point-of-procedure delineation of oral cancer margins using optical coherence tomography.

ObjectivesSurgical margin status is a significant determinant of treatment outcome in oral cancer. Negative surgical margins can decrease the loco-regional recurrence by five-fold. The current standard of care of intraoperative clinical examination supplemented by histological frozen section, can result in a risk of positive margins from 5 to 17 percent. In this study, we attempted to assess the utility of intraoperative optical coherence tomography (OCT) imaging with automated diagnostic algorithm to improve on the current method of clinical evaluation of surgical margin in oral cancer.Materials and methodsWe have used a modified handheld OCT device with automated algorithm based diagnostic platform for imaging. Intraoperatively, images of 125 sites were captured from multiple zones around the tumor of oral cancer patients (n = 14) and compared with the clinical and pathologic diagnosis.ResultsOCT showed sensitivity and specificity of 100%, equivalent to histological diagnosis (kappa, ĸ = 0.922), in detection of malignancy within tumor and tumor margin areas. In comparison, for dysplastic lesions, OCT-based detection showed a sensitivity of 92.5% and specificity of 68.8% and a moderate concordance with histopathology diagnosis (ĸ = 0.59). Additionally, the OCT scores could significantly differentiate squamous cell carcinoma (SCC) from dysplastic lesions (mild/moderate/severe; p ≤ 0.005) as well as the latter from the non-dysplastic lesions (p ≤ 0.05).ConclusionThe current challenges associated with clinical examination-based margin assessment could be improved with intra-operative OCT imaging. OCT is capable of identifying microscopic tumor at the surgical margins and demonstrated the feasibility of mapping of field cancerization around the tumor

Liver transplantation for hepatocellular carcinoma: Management after the transplant

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153700/1/ajt15697.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153700/2/ajt15697_am.pd

Provider Attitudes Toward Risk-Based Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis in the United States.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patients HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patients HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients estimated HCC risk, instead of our current one-size-fits all strategy

Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: a multicenter study

BACKGROUND: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). AIMS: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. METHODS: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. RESULTS: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein \u3e10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08). CONCLUSIONS: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels

Early Antibiotic Exposure Is Not Detrimental to Therapeutic Effect from Immunotherapy in Hepatocellular Carcinoma

BACKGROUND AND RATIONALE: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. METHODS: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. RESULTS: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). CONCLUSIONS: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Positron Emission Tomography With Computed Tomography as a Diagnostic and Prognostic Biomarker for Hepatocellular Carcinoma: Ready for Prime Time?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155518/1/lt25775.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155518/2/lt25775_am.pd

Overview of immunosuppression in liver transplantation

Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease. Beginning with the revolutionary discovery of cyclosporine in the 1970s, immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or via T cell depletion. They are used as induction therapy in the immediate peri- and post-operative period, as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon