Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors

Although therapeutic options are gradually improving, the overall prognosis for patients with hepatocellular carcinoma (HCC) is still poor. Gene therapy-based strategies are developed to complement the therapeutic armamentarium, both in early and late-stage disease. For efficient delivery of transgenes with antitumor activity, vectors demonstrating preferred tumor tropism are required. Here, we report on the natural tropism of adeno-associated virus (AAV) serotype 2 vectors for HCC. When applied intravenously in transgenic HCC mouse models, similar amounts of vectors were detected in the liver and liver tumor tissue. In contrast, transduction efficiency, as indicated by the level of transgene product, was moderate in the liver but was elevated up to 19-fold in mouse tumor tissue. Preferred transduction of HCC compared to hepatocytes was confirmed in precision-cut liver slices from human patient samples. Our mechanistic studies revealed that this preference is due to the improved intracellular processing of AAV2 vectors in HCC, resulting, for example, in nearly 4-fold more AAV vector episomes that serve as templates for gene transcription. Given this background, AAV2 vectors ought to be considered to strengthen current—or develop novel—strategies for treating HCC.

Prospective Evaluation of Raised Liver Transaminases in Asymptomatic Patients Attending OPD in a Tertiary Care Hospital

Background: Liver diseases are a cause of worldwide morbidity .The course is usually long and has no signs before the development of late stage disease. The only indicative markers are liver enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT) during asymptomatic period. There is a paucity of data from our subcontinent regarding the prevalence, risk factors and etiology of asymptomatic chronically raised liver enzymes.The aim of the study was to determine the prevalence, risk factors and etiology associated with unexplained chronically raised liver transaminases in patients attending OPD in a tertiary care hospital.Methods:This was a prospective study conducted in the Department of Gastroenterology, MMIMSR, Mullana from July 2019-Dec 2020 in 50 patients who presented with chronically raised liver enzymes. Detailed comprehensive history, physical examination and investigation was done to identify etiology and risk factors associated with raised liver enzymes.Results:566 patients were screenedfor inclusion in the study. The prevalence of raised transaminases in asymptomatic patients was 9.4%. NAFLD was the most common etiology of raised liver transaminases, seen in 70 % of patients followed by Hepatitis C and Hepatitis B. Dyslipidemia was the most important risk factor associated with NAFLD.Conclusion:NAFLD should be kept in mind while dealing patients with unexplained transaminitis. Earlier detection could help halt the progression to chronic liver disease.

Health-related quality of life among cervical cancer patients at Kenyatta National Hospital

Background Previous study showed that health-related quality of life (HRQoL) was adversely affected during treatment of cervical cancer, with a worsening global score. Therefore, this study aimed to determine the HRQoL of cervical cancer patients at Kenyatta National Hospital. Methods A cross-sectional study design was employed among cervical cancer patients. All eligible consecutive samples of 103 cervical cancer patients were included in the study. Following consent, patients were interviewed using The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire 30 (EORTC QLQ-30) and Cervical Cancer Module CX24 (EORTC QLQ-CX24). The data were entered and analyzed using the SPSS version 20.0 software. Univariate and multivariate binary logistic regression analysis was employed to investigate the predictors of HRQoL. A p-value of ≤ 0.05 was considered statistically significant. Results The majority (69%) of the patients had a poor overall quality of life while 31% of study participants had a good quality of life. Patients with early-stage disease were 7.3 times (AOR = 7.3, 95% CI = 2.4–21.7, p = 0.000) more likely to have a good HRQoL than patients with advanced-stage disease. Patients with no comorbidities were 3.1 times (COR = 3.1, 95% CI = 1.1–9.1, p = 0.037) more likely to have a good HRQoL than patients with comorbidities. Conclusion The overall HRQoL among cervical cancer patients was poor in the setting. Advanced stage of disease and presence of comorbidities were the significant predictors of poor quality of life.

NOX4 inhibition promotes the remodeling of dystrophic muscle

The muscular dystrophies (MDs) are genetic muscle diseases that result in progressive muscle degeneration followed by the fibrotic replacement of affected muscles as regenerative processes fail. Therapeutics that specifically address the fibrosis and failed regeneration associated with MDs represent a major unmet clinical need for MD patients, particularly those with advanced stage disease progression. The current study investigates targeting NAD(P)H oxidase (NOX) 4 as a potential strategy to reduce fibrosis and promote regeneration in disease-burdened muscle that models Duchenne muscular dystrophy (DMD). NOX4 is elevated in the muscles of dystrophic mice and DMD patients, localizing primarily to interstitial cells located between muscle fibers. Genetic and pharmacological targeting of NOX4 significantly reduces fibrosis in dystrophic respiratory and limb muscles. Mechanistically, NOX4 targeting decreases the number of fibrosis-depositing cells (myofibroblasts) and restores the number of muscle-specific stem cells (satellite cells) to their physiological niche, thereby, rejuvenating muscle regeneration. Furthermore, acute inhibition of NOX4 is sufficient to induce apoptotic clearing of myofibroblasts within dystrophic muscle. These data indicate that targeting NOX4 is an effective strategy to promote the beneficial remodeling of disease-burdened muscle representative of DMD and, potentially, other MDs and muscle pathologies.

New Frontiers in the Medical Therapy of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. Summary: After controversial results of monotherapy, ICPIs have been mainly investigated in association with anti-angiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPIs-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first line treatment, the second line scenario relies mainly on tyrosine kinase inhibitors, which however, have not been formally trialed after ICPIs. Key messages: In this review we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

Trends in the Incidence and Treatment of Early-Onset Pancreatic Cancer

Background: Early-onset pancreatic cancer (EOPC) is relatively uncommon. It is unclear if the incidence of EOPC is evolving and how these patients are treated. Methods: We conducted a retrospective, population-based study using SEER 2004–2016. We evaluated annual age-adjusted incidence rate (AAIR), stage at presentation, and race/ethnicity among 7802 patients plus treatment patterns in 7307 patients (excluding neuroendocrine tumors) younger than 50. Results: The AAIR was higher in males while the rate increased faster in females. The AAIR was highest in Non-Hispanic Black patients and increased for all races/ethnicities over time. The percentage of patients diagnosed with distant-stage disease decreased over time but increased for localized-stage disease. Hispanic patients made up a larger proportion of patients over time compared to other groups. For localized-stage disease, primary surgery alone was the most utilized modality of therapy. For regional-stage disease, chemotherapy with radiation was the most utilized modality from 2004–2010, whereas chemotherapy alone was the most utilized from 2011–2016. For distant-stage disease, chemotherapy alone was the most utilized and used increasingly over time. Patients with EOPC received radiation and chemotherapy at similar rates to, and underwent surgery more frequently, than patients 50–69. Conclusions: The AAIR of EOPC increased over time, faster so in females. Groups who experience a higher burden of pancreatic cancer, particularly African Americans, experienced a higher burden of EOPC. Treatment of localized and regional-stage disease did not follow standard treatment guidelines for pancreatic cancer. Our findings indicate that EOPC patients received more treatment than their older counterparts.

Treatment Outcomes and Relative Dose Intensity of Chemotherapy in Slovene Patients With Advanced Hodgkin Lymphoma

This retrospective study was undertaken to investigate the association of relative dose intensity (RDI) with the outcome of Hodgkin lymphoma (HL) patients with advanced stage disease receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). A total of 114 HL patients treated between 2004 and 2013 were enrolled for evaluation. RDI calculations were based on a Hryniuk's model. The association of variables with overall survival (OS) and progression-free survival (PFS) was analysed using univariate and multivariate Cox proportional hazards models. The median age of patients was 39 years, majority of patients were males and had stage IV disease. Fifty-four patients received ABVD and 60 received BEACOPP chemotherapy with 24 and 4 deaths, respectively. Patients in BEACOPP group were significantly younger with lower Charlson comorbidity index (CCI) in comparison with ABVD group, making the comparison of groups impossible. In ABVD group, RDI was not significantly associated with OS (p=0.590) or PFS (p=0.354) in a multivariate model where age was controlled. The low number of events prevented the analysis in the BEACOPP group. Patients' age was strongly associated with both OS and PFS: all statistically significant predictors for OS and PFS from univariate analyses (chemotherapy regimen, CCI, RDI) lost its effect in multivariate analyses where age was controlled. Based on our observations, we can conclude that RDI is not associated with the OS or PFS after the age is controlled, neither in all patients combined nor in individual chemotherapy groups.

Factors Associated with Surgery Among South Asian American and Non-Hispanic White Women with Breast Cancer

South Asian American (SA) women are diagnosed with more aggressive breast cancer than non-Hispanic White (NHW) women. Understanding the factors associated with the types of surgery received by these women sheds light on disease management in these culturally distinct populations. We used data on age at diagnosis, stage, grade, estrogen and progesterone receptors, and surgery from 4,590 SA and 429,030 NHW breast cancer cases in the Surveillance, Epidemiology and End Results (SEER) program. We used logistic regression with surgery as the binary outcome (subcutaneous, total, or radical mastectomy (STRM) versus partial mastectomy, no, unknown or other (PNUM)) and included additive effects of all the variables and interactions of age, stage, grade, and estrogen and progesterone receptors with race/ethnicity. Type I error of 5% was used to assess statistical significance of the effects. SA were significantly more likely than NHW cases to receive STRM relative to PNUM surgery among women diagnosed at or after age 50 years and having localized stage disease (Odds Ratio (OR) = 1.27, 95% Confidence Interval (CI) = 1.06 – 1.52). Further, SA were significantly less likely than NHW cases to receive STRM relative to PNUM surgery among those diagnosed before age 50 years and having regional or distant stage disease (OR = 0.75, 95% CI = 0.59 – 0.95 for age at diagnosis < 40 years; OR = 0.77, 95% CI = 0.62 – 0.95 for age at diagnosis 40-49 years). The type of surgery received by SA and NHW women differ according to age at diagnosis and disease stage. KEYWORDS: Breast Cancer; Surgery; Cancer Health Equity; Disease Characteristics; South Asian American; Non-Hispanic White; Logistic Regression; Interaction

Emerging Roles of Calcium Signaling in the Development of Non-Alcoholic Fatty Liver Disease

The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca2+ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca2+ is intricately compartmentalized, and the Ca2+ flow is tightly controlled by a network of Ca2+ transport and buffering proteins. Impaired Ca2+ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca2+ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca2+ signaling as a potential therapeutic approach.