TKIs beyond immunotherapy predict improved survival in advanced HCC.

PURPOSE: For patients with advanced HCC, predictors of immunotherapy response are scarce, and the benefits of tyrosine kinase inhibitor (TKI) treatment after immunotherapy are unclear. We explored whether clinical features, such as target lesion response, immune-mediated toxicity, or subsequent TKI therapy predict immunotherapy response. METHODS: We retrospectively studied 77 patients with advanced HCC receiving immunotherapy. Patient characteristics and outcomes were assessed using various statistical methods, including the log-rank test and Kaplan-Meier methods. Cox proportional hazard modeling was used for multivariable survival analysis. RESULTS: For all patients, median overall survival (mOS) was 13 months (95% CI 8-19), and median progression-free survival (mPFS) was 6 months (95% CI 4-10). Patients with partial response (PR) and stable disease (SD) compared to progressive disease (PD) had prolonged mPFS (27 vs. 5 vs. 1 month(s), p < 0.0001) and mOS (not met vs. 11 vs. 3 months, p < 0.0001). Patients with vs. without immune-mediated toxicities trended towards longer mPFS (9 vs. 4 months p = 0.133) and mOS (17 vs. 9 months; p = 0.095). Patients who did vs. did not receive a tyrosine kinase inhibitor (TKI) after immunotherapy had a significantly improved mOS (19 vs. 5 months, p = 0.0024)). Based on multivariate modeling, the hazard ratio (HR) of overall survival (OS) of patients receiving TKI vs. no TKI was 0.412 (p = 0.0043). CONCLUSION: We show that disease control predicts prolonged mOS and mPFS. Furthermore, TKI therapy administered after immunotherapy predicts prolonged mOS in patients with advanced HCC.

Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up ~7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not amenable to curative therapy. For these patients, chemotherapy has been the mainstay treatment, providing an inadequate overall survival of less than one year. Despite the boom in targeted therapies over the past decade, only a few targeted agents have been approved in BTCs (i.e., IDH1 and FGFR inhibitors), perhaps in part due to its relatively low incidence. This review will explore current data on PARP inhibitors (PARPi) used in homologous recombination deficiency (HRD), particularly with respect to BTCs. Greater than 28% of BTC cases harbor mutations in genes involved in homologous recombination repair (HRR). We will summarize the mechanisms for PARPi and its role in synthetic lethality and describe select genes in the HRR pathway contributing to HRD. We will provide our rationale for expanding patient eligibility for PARPi use based on literature and anecdotal evidence pertaining to mutations in HRR genes, such as RAD51C, and the potential use of reliable surrogate markers of HRD.

Prevalence of Premenstrual Dysphoric Disorder among Female Students of a Medical College in Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Premenstrual dysphoric disorder is a severe form of premenstrual syndrome that impairs quality of life and carries an increased risk of suicidal attempts. Hormonal changes may underlie these symptoms. The present study was conducted to find out the prevalence of premenstrual dysphoric disorder among female students of a medical college in Nepal. METHODS: This descriptive cross-sectional study was conducted among 266 healthy young females in a medical college of Nepal from 21st June 2021 to 31st August 2021 with approval from the Institutional Review Committee 51/2021. Convenience sampling was done. Self-rated questionnaire of premenstrual symptoms screening tool was used to evaluate premenstrual dysphoric disorder. The Premenstrual Symptoms Screening Tool reflects and translates categorical Diagnostic and Statistical Manual of Mental Disorders-IV criteria into a rating scale with degrees of severity. Data were analyzed using the Statistical Package for Social Sciences version 16. Point estimate at 95% confidence interval was calculated along with frequency and proportion for the binary data. RESULTS: Out of 266 female students, we found that the prevalence of premenstrual dysphoric disorder was 10 (3.8%) (1.50-6.10 at 95% Confidence Interval). CONCLUSIONS: The prevalence of premenstrual dysphoric disorder in our study was found to be higher when compared to other similar studies.

Risk factors for bleeding hepatocellular adenoma in a United States cohort.

BACKGROUND & AIMS: Known risk factors for hepatocellular adenoma (HCA) bleeding are size >5 cm, growth rate, visible vascularity, exophytic lesions, ß-catenin and Sonic Hedgehog activated HCAs. Most studies are based on European cohorts. The objective of this study is to identify additional risk factors for HCA bleeding in a US cohort. METHODS: Retrospective chart review was performed on patients diagnosed with HCA on magnetic resonance imaging (n = 184) at an academic tertiary institution. Clinical, pathological, and imaging data were collected. Primary outcomes measured were HCA bleeding and malignancy. Statistical analysis was performed with SAS 9.4 using Chi-Square, Fisher's exact test, sample t test, non-parametric Wilcoxon test, and logistic regression. RESULTS: After excluding patients whose pathology showed focal nodular hyperplasia and non-adenoma lesions, follow-up data were available for 167 patients. 16% experienced microscopic or macroscopic bleeding and 1.2% had malignancy. HCA size predicted bleeding (P < .0001) and no patients with lesion size <1.8 cm bled. In unadjusted analysis, hepatic adenomatosis (≥10 lesions) trended towards 2.8-fold increased risk of bleeding. Of patients with a single lesion that bled, 77% bled from a lesion >5 cm. In patients with multiple HCAs that bled, 50% bled from lesions <5 cm. In patients with multiple adenomas, size (P = .001) independently predicted bleeding and hepatic steatosis trended towards increased risk of bleeding (P = .05). CONCLUSIONS: In a large US cohort, size predicted increased risk of HCA bleeding while hepatic adenomatosis trended towards increased risk of bleeding. In patients with multiple HCAs, size predicted bleeding and hepatic steatosis trended toward increased risk of bleeding.

Study of Body Mass Index among Medical Students of a Medical College in Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Changes in the lifestyle, food habits, lack of nutritious diet, stress, physical inactivity increases the body mass index among adults. Excess weight gain is an important risk factor for non-communicable diseases such as heart disease, stroke, diabetes, and some cancers (endometrial, breast, colon). Thus, this study aims to find out body mass index of medical students of a medical college in Nepal. METHODS: This descriptive cross-sectional study was conducted in the department of physiology of a tertiary care center from August 2019 to February 2020 after taking ethical clearence from Institutional Review Committee (Reference number 192/19). Height and weight were recorded and body mass index was then being calculated. Data entry was done in Microsoft Excel and analyzed using Statistical Package for the Social Sciences version 22. RESULTS: Out of 266 medical students, 39 (15%) were overweight and 32 (12%) were underweight with mean body mass index 26.60±1.99kg/m2 and 17.13±1.19kg/m2 respectively. Mean body mass index of males was 21.76±3.06kg/m2 and that of females was 21.70±2.96 kg/m2. CONCLUSIONS: Comparing with a similar study done in Nepal previously, we found a higher prevalence of overweight in medical students whereas majority of medical students had normal weight. Factors affecting body mass index in medical students should be explored further.

Influence of Body Mass Index, Handedness and Gender on Ruler Drop Method Reaction Time among Adults.

BACKGROUND: The interval between stimulus and response is called reaction time. It measures the sensorimotor function and performance of an individual. It involves stimulus processing, decision making and response programming. Many factors such as age, gender, handedness, physical fitness, sleep, fatigue, distraction, personality type and type of stimulus have been shown to affect reaction time. Thus the aim of this study was to assess the effect of body mass index, handedness and gender on reaction time. METHODS: A cross-sectional study was conducted in the Department of Physiology, Kathmandu University School of Medical Sciences, from October 2019 to December 2019, among 113 student volunteers. Height and weight were recorded and body mass index was then calculated. In ruler drop method, the students were made to sit with their forearm resting on a flat horizontal table surface, with their open hand at the edge of the surface. When the examiner suspended and released the ruler vertically the students were instructed to catch it as quickly as possible. RESULTS: Females had a faster reaction time than males when testing either hand (178.46±17.56 Vs 195.99±15.67; right hand) and (184.25±17.02 Vs 199.57±15.91; left hand). In females, right hand responded faster than left hand. In both gender, reaction time was faster in normal weight compared to overweight individuals but it was statistically insignificant. CONCLUSIONS: Females responded faster than males. Right hand had shorter reaction time than left hand in females. Reaction time was insignificantly prolonged in overweight individuals.

Autonomic Influence on Heart Rate for Deep Breathing and Valsalva Maneuver in Healthy Subjects.

INTRODUCTION: The Autonomic nervous system is responsible for regulation and integration of visceral functions. Disturbance of autonomic nervous system play crucial role in pathogenesis and clinical course of many diseases. In the present study deep breathing test and valsalva maneuver have been described to monitor parasympathetic function genderwise. METHODS: A cross-sectional study was conducted among 100 subjects, aged 18-25 years, from May to November 2017, in exercise physiology laboratory, Kathmandu University School of Medical Sciences, Chaukot, Kavre. Electrocardiograph recorded by AD instrument was used to calculate the resting heart rate and the heart rate response to deep breathing test and valsalva maneuver. RESULTS: Heart rate response to deep breathing test (31.69±14.79 Vs. 36.08±18.65, P=0.195) and valsalva ratio (1.59±0.39 Vs. 1.69±0.54, P=0.314) tend to be higher in female than male subjects but not significant. The resting heart rate of females was significantly higher than that of males (84.37 ± 11.08 Vs. 78.43 ± 12.06, P<0.05). Heart rate was significantly increased during and decreased after valsalva maneuver in both male and female subjects. CONCLUSIONS: This study concludes that both deep breathing test and valsalva maneuver activates parasympathetic system inhealthy subjects. And also dominant parasympathetic activity was found in female comparison to male subjects.

Portal Vein Thrombosis: Imaging the Spectrum of Disease With an Emphasis on MRI Features.

OBJECTIVE: The purpose of this article is to review the classic and uncommon imaging findings of portal vein thrombosis (PVT) (acute, chronic, congenital, and septic thrombus) as visualized on multiple modalities, with an emphasis on MRI findings. Additional aims are to understand the imaging of obliterative portal venopathy and its clinical significance, appreciate morphologic changes of the biliary system that may accompany PVT, and recognize changes in liver enhancement patterns seen with PVT related to the hepatic arterial buffer response. The review also addresses morphologic changes of the liver that may occur after PVT, including nodular regenerative hyperplasia, central hepatic hypertrophy, and peripheral fibrosis that may stimulate cirrhosis, as well as the importance of portal vein mapping and the diagnostic findings and clinical significance of tumor within the portal vein in the liver transplant population. CONCLUSION: PVT may be a complication of liver cirrhosis, but it may also occur as a primary vascular disorder without liver disease. PVT can result in portal hypertension and may present with variceal bleeding or hypersplenism. Radiologists should be familiar with the imaging of PVT in patients of various ages and in different clinical scenarios. PVT can influence hepatic perfusion, the shape of the bile ducts, and liver architecture. Bland PVT and tumor-related PVT have major implications for hepatic transplant.

Prevalence of Color Blindness in Undergraduates of Kathmandu University.

INTRODUCTION: Color blindness is X-linked recessive inherited disorder that occurs mostly in males and is transmitted through females. Many people with color blindness may remain undetected. Thus the present study aims to evaluate the incidence of color blindness among undergraduates of Kathmandu University. METHODS: A cross-sectional study was conducted among 825 undergraduates, aged 17-25 years, from June to August 2018, in Kathmandu University, Kavre, Nepal. The Ishihara plates were used to evaluate the color vision of students under natural day light condition. RESULTS: Study revealed that 24 (2.9%) undergraduates were color blind which include 24 male (5%) and no female. Among the color blind, five (20.3%), three (12.5%), two (8.33%) and 14 (58.33%) males were the victims of deuteranomaly, deuteranopia, protanomalia and total color blindness respectively. Color blindness is prevalent among the Brahmin 10 (3.9%), followed by Chettri 10 (2.72%) and Newar 4 (2.24%). CONCLUSIONS: Prevalence of color blindness is found to be higher in males than females. Total color blindness is the most prevalent in our study. Screening enables the students to become aware of limitations and devise ways of overcoming them.

Evidence Supporting LI-RADS Major Features for CT- and MR Imaging-based Diagnosis of Hepatocellular Carcinoma: A Systematic Review.

The Liver Imaging Reporting and Data System (LI-RADS) standardizes the interpretation, reporting, and data collection for imaging examinations in patients at risk for hepatocellular carcinoma (HCC). It assigns category codes reflecting relative probability of HCC to imaging-detected liver observations based on major and ancillary imaging features. LI-RADS also includes imaging features suggesting malignancy other than HCC. Supported and endorsed by the American College of Radiology (ACR), the system has been developed by a committee of radiologists, hepatologists, pathologists, surgeons, lexicon experts, and ACR staff, with input from the American Association for the Study of Liver Diseases and the Organ Procurement Transplantation Network/United Network for Organ Sharing. Development of LI-RADS has been based on literature review, expert opinion, rounds of testing and iteration, and feedback from users. This article summarizes and assesses the quality of evidence supporting each LI-RADS major feature for diagnosis of HCC, as well as of the LI-RADS imaging features suggesting malignancy other than HCC. Based on the evidence, recommendations are provided for or against their continued inclusion in LI-RADS. © RSNA, 2017 Online supplemental material is available for this article.

Interreader Reliability of LI-RADS Version 2014 Algorithm and Imaging Features for Diagnosis of Hepatocellular Carcinoma: A Large International Multireader Study.

Purpose To determine in a large multicenter multireader setting the interreader reliability of Liver Imaging Reporting and Data System (LI-RADS) version 2014 categories, the major imaging features seen with computed tomography (CT) and magnetic resonance (MR) imaging, and the potential effect of reader demographics on agreement with a preselected nonconsecutive image set. Materials and Methods Institutional review board approval was obtained, and patient consent was waived for this retrospective study. Ten image sets, comprising 38-40 unique studies (equal number of CT and MR imaging studies, uniformly distributed LI-RADS categories), were randomly allocated to readers. Images were acquired in unenhanced and standard contrast material-enhanced phases, with observation diameter and growth data provided. Readers completed a demographic survey, assigned LI-RADS version 2014 categories, and assessed major features. Intraclass correlation coefficient (ICC) assessed with mixed-model regression analyses was the metric for interreader reliability of assigning categories and major features. Results A total of 113 readers evaluated 380 image sets. ICC of final LI-RADS category assignment was 0.67 (95% confidence interval [CI]: 0.61, 0.71) for CT and 0.73 (95% CI: 0.68, 0.77) for MR imaging. ICC was 0.87 (95% CI: 0.84, 0.90) for arterial phase hyperenhancement, 0.85 (95% CI: 0.81, 0.88) for washout appearance, and 0.84 (95% CI: 0.80, 0.87) for capsule appearance. ICC was not significantly affected by liver expertise, LI-RADS familiarity, or years of postresidency practice (ICC range, 0.69-0.70; ICC difference, 0.003-0.01 [95% CI: -0.003 to -0.01, 0.004-0.02]. ICC was borderline higher for private practice readers than for academic readers (ICC difference, 0.009; 95% CI: 0.000, 0.021). Conclusion ICC is good for final LI-RADS categorization and high for major feature characterization, with minimal reader demographic effect. Of note, our results using selected image sets from nonconsecutive examinations are not necessarily comparable with those of prior studies that used consecutive examination series. © RSNA, 2017.

MRI features of primary rare malignancies of the liver: A report from four university centres.

PURPOSE: To determine if rare primary malignancies of the liver may have consistent features on magnetic resonance imaging (MRI). MATERIALS AND METHODS: This IRB-compliant retrospective study reviewed the records from the pathology departments of four university centres over an 11-year period from 2005-2016 to identify rare primary malignant tumours, which were cross-referenced with MRI records. MRI studies of these patients were reviewed to determine if these tumours exhibited consistent and distinctive features. RESULTS: Sixty patients were identified with rare primary liver tumours. The following distinctive features and frequency of occurrence were observed: mixed hepatocellular carcinoma-cholangiocarcinoma showed regions of wash-out in 7/19 of patients; 6/6 of fibrolamellar carcinomas demonstrated large heterogeneous lesions with large heterogeneous central scars; epithelioid haemangioendothelioma larger than 2 cm showed target-like enhancement in late-phase enhancement in 9/13; sarcomas excluding angiosarcoma had central necrosis in 3/9 and haemorrhage in 5/9; angiosarcomas showed centripedal progressive nodular enhancement in 3/6 and showed regions of haemorrhage in 3/6; and 7/7 of primary hepatic lymphomas showed encasement of vessels. CONCLUSION: Although helpful features for the differentiation of rare primary malignancies of the liver are identified, no MRI features appear to be specific and therefore histopathological confirmation is usually required for definitive diagnosis. KEY POINTS: • No MRI features appear to be specific for rare primary liver malignancies. • Haemorrhage is a helpful sign in diagnosis of primary hepatic sarcomas. • Angiosarcomas may show progressive nodular enhancement towards the centre mimicking haemangioma. • Vessel encasement is a helpful sign in diagnosis of primary hepatic lymphoma.

Primary Hepatic Neoplasms of Vascular Origin: Key Imaging Features and Differential Diagnoses With Radiology-Pathology Correlation.

OBJECTIVE: This article describes, illustrates, and correlates imaging and pathologic features of primary vascular mesenchymal neoplasms of the liver, which arise from the vascular endothelium and perivascular epithelioid cells. CONCLUSION: Familiarity with the spectrum of benign, malignant-potential and malignant vascular neoplasms, and nonneoplastic mimickers allows consideration in the differential diagnosis of enhancing hepatic masses. Understanding relevant pathologic features facilitates recognition of key imaging features, specifically dynamic contrast enhancement patterns on CT and MRI, which provide a useful classification system.

Regorafenib in advanced hepatocellular carcinoma (HCC): considerations for treatment.

PURPOSE: We report our institutional observations of ten patients with advanced hepatocellular carcinoma (HCC) (seven and three were Child-Pugh class A and B, respectively) who received compassionate regorafenib therapy between June 2016 and January 2017. These patients did not fit the rigid criteria of a clinical trial and represented the use of regorafenib in an everyday clinic situation. METHODS: Regorafenib (160 mg P.O. daily) was administered to patients on a 4-week cycle (3 weeks on, 1 week off) until disease progression (assessed using mRECIST criteria) or discontinuation secondary to toxicity (assessed using CTCAE criteria). Relevant clinical data were abstracted from patient medical records and reviewed retrospectively. RESULTS: The median duration of patient treatment was 6.6 weeks, and the median time to disease progression was 12.5 weeks. Most common treatment emergent adverse events were fatigue, diarrhea, and hand-foot skin reaction. Elevated AST and ALT were the most commonly observed laboratory-assessed adverse events, which reached grade 3 status in the Child-Pugh class B patients only. We observed intolerance to regorafenib treatment in one patient who had previously received a liver transplant. We also saw lithium toxicity in one patient receiving long-term lithium treatment, suggesting a potential and unexpected drug-drug interaction with regorafenib. CONCLUSIONS: Taken together, our observations indicate that regorafenib is beneficial in the treatment of patients with advanced HCC who progressed on or demonstrated intolerance to sorafenib therapy; however, careful selection and close monitoring of patients is necessary to maximize the benefit while minimizing the toxicities of regorafenib treatment.

Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC.

Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3(+) and CD8(+) cells and clinical outcome. High densities of both CD3(+) and CD8(+) T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3(+) and CD8(+) cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6-21.8] for CD3(+) and 3.9 (95% CI, 1.1-14.1) for CD8(+) Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419-30. ©2016 AACR.

Pancreaticoduodenectomy hospital resource utilization in octogenarians.

BACKGROUND: Although pancreaticoduodenectomy (PD) is feasible in patients greater than or equal to 80 years, little is known about the potential strain on resource utilization. METHODS: Outcomes and inpatient charges were compared across age cohorts (I: ≤70, II: 71 to 79, III: ≥80 years) in 99 patients who underwent PD (2005 to 2013) at our institution. The generalized linear modeling approach was used to estimate the impact of age. RESULTS: Perioperative complications were equivalent among cohorts. Increasing age was associated with intensive care unit use, increased length of stay (LOS), and the likelihood of discharge to a skilled facility. After controlling for covariates, hospital charges were significantly higher in Cohort III (P = .006) and Cohort II (P = .035) when compared with Cohort I. However, hospital charges between Cohorts II and III were equivalent (P = .374). Complications (P = .005) and LOS (P < .001) were associated with higher hospital charges. CONCLUSIONS: Increasing age was associated with increased intensive care unit, LOS, and discharge to skilled facilities. However, octogenarians had equivalent PD charges and outcome measures when compared with septuagenarians and future studies should validate these findings in larger national studies.

Pseudolymphoma (reactive lymphoid hyperplasia) of the liver: A clinical challenge.

Reactive lymphoid hyperplasia (RLH), also known as pseudolymphoma or nodular lymphoid lesion of the liver is an extremely rare condition, and only 51 hepatic RLH cases have been described in the literature since the first case was described in 1981. The majority of these cases were asymptomatic and incidentally found through radiological imaging. The precise etiology of hepatic RLH is still unknown, but relative high prevalence of autoimmune disorder in these cases suggests an immune-based liver disorder. Imaging features of hepatic RLH often suggest malignant lesions such as hepatocellular carcinoma and cholangiocarcinoma. In this report, we discuss two cases of hepatic RLH in patients with autoimmune hepatitis. We also present pathologic and magnetic resonance imaging findings, including one case utilizing a hepatocellular contrast agent, Eovist. Definitive diagnosis of hepatic RLH often requires surgical excision.

Phase II study of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma.

PURPOSE: To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC). METHODS: This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1-7 and 150 mg/m(2) TMZ PO daily on days 1-5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03. RESULTS: We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months. CONCLUSION: The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit. CLINICALTRIALS. GOV IDENTIFIER: NCT01205828.