Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .

BBIBP-CorV (Sinopharm) vaccination- induced immunity is affected by age, gender and prior COVID-19 and activates responses to spike and other antigens

Long-term solutions against SARS-CoV-2 infections require understanding of immune protection induced by different vaccine COVID-19 formulations. We investigated humoral and cellular immunity induced by Sinopharm (BBIBP-CorV) in a region of high SARS-CoV-2 seroprevalence. Levels of IgG antibodies to SARS-CoV-2 spike protein and its receptor-binding domain (RBD) were determined 24-weeks. Cellular immunity was investigated using a commercially available IFN-{gamma} release assay to SARS-CoV-2 spike (Ag1 and 2) and extended genome antigens (Ag3). Increasing IgG seropositivity to Spike protein and RBD was observed post-vaccination. Seropositivity was reduced in those over 50 years and raised in females and those with prior COVID-19. After 20 weeks post-vaccination, only one third of participants had positive T cell responses to SARS-CoV-2 antigens. Prior COVID-19 impacted IFN{gamma} responses, with reactivity enhanced in those infected earlier. The frequency of IFN{gamma} responses was highest to extended genome antigen set. Overall, BBIBP-CorV- induced antibody responses were impacted by age, gender and prior COVID-19. Cellular immunity was present in a limited number of individuals after 20 weeks but was enhanced by prior infection. This suggests the need for booster vaccinations in older individuals. BBIBP-CorV-induced cellular activation is broader than to spike, requiring further study to understand how to monitor vaccine effectiveness.

Optimizing risk factors influence Intensive Care stay after Hyperthermic Intraperitoneal Chemotherapy? An observational cohort study.

BACKGROUND: It may be necessary to admit patients receiving Hyperthermic Intraperitoneal Chemotherapy (HIPEC) to the intensive care unit (ICU). They were required to evaluate the length of ICU stay (LOS) following HIPEC, as well as their survival rates and risk factors that influence LOS. METHODS: 74 HIPEC patients were observed after being admitted to the ICU. Their assignments were made based on their LOS at the ICU. Short stay group, patients who stayed in the ICU for three days or less (S-group) and patients who stayed for three days or longer (L-group). RESULTS: Survival rates for both groups were comparable. After HIPEC, they exhibited intraoperative hypotension (P = 0.015), hyopthermia (P = 0.014), and hyperglycemia (P = 0.010). Additionally, patients in group L underwent longer surgeries (P = 0.013), lost more blood (P = 0.043), and required more transfusions (P = 0.001). Subjects in group-L had higher SOFA, fentanyl, and vasopressor requirements (all P 0.001), higher ALT and AST levels, disrupted K, lower Na, and higher INR levels (all P 0.001), as well as a higher APACHE II score (P = 0.007). Preoperative BUN had an independent risk factor for LOS of 0.861; (95% CI), (0.742- 0.999); P = 0.048; and crystalloid transfusion had an independent risk factor of 1.000; (95% CI), (0.999- 1.000); P = 0.003. CONCLUSIONS: Transfusions of crystalloids and BUN were independent risk factors for extended LOS. ICU LOS had no impact on survival. All measures should be taken to control hemostasis in vulnerable HIPEC participants.

SARS-CoV-2 Variants of Concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron coincident with consecutive pandemic waves in Pakistan

Identification and monitoring of SARS-CoV-2 Variants of Concern/Interest (VOC/VOIs) is essential to guide public health measures. We report the surveillance of VOCs circulating in Karachi during the pandemic between April 2021 and February 2022. We screened 2150 SARS-CoV-2 PCR positive samples received at the AKUH Clinical Laboratories. VOC was identified using a PCR-based approach targeting lineage-specific mutations using commercially available assays. Of the SARS-CoV-2 PCR positive samples, 81.7% had VOC/VOI, while 18.3% were undetermined. Alpha variants were predominant at 82.5% and 40.3% of the cases in April and May 2021. Beta variants increased in May (29%) and June (42%) and then reduced to 6% by July. Gamma variant cases were at 14.5% and 9% in May and June, respectively. Delta variants first detected in May, increased to comprise 66% of all variants by July, remaining dominant in August, September, October, and November 2021 at 88%, 91%, 91% and 85% respectively. Omicron (BA.1) variants emerged in December, rising to 42% of cases with an increase to 81% by January 2022 and then reducing to 45% in February 2022. Delta variant prevalence was coincident with increased hospital admissions and mortality. The Omicron variant surge was associated with increased daily infections but limited COVID-19 severity. We highlight the predominance of the VOCs identified through a rapid PCR based approach. As this is important to inform a public health response, we propose that a mutation targeted approach can be a rapid, lower cost solution to aid tracking of known VOCs during pandemic waves.

Life-Threatening Intraparenchymal Hemorrhage of Steroid-Induced Hepatic Adenomas in a Healthy Man.

Hepatocellular adenomas are uncommon benign epithelial tumors of the liver that are associated with several risk factors such as anabolic androgens and oral contraceptive pills. They may present as incidental findings, with abdominal pain or hemorrhage. This case report details the presentation and management of a life-threatening hepatocellular adenomas hemorrhage in a seemingly healthy 28-year-old man. After initial conservative management, a clinical deterioration prompted urgent reevaluation and successful embolization of the liver through transarterial embolization. As oral contraceptive pills use and anabolic steroid abuse have become more prevalent in recent decades, we may begin to see more of these presentations.

Transcriptomic profiling of disease severity in patients with COVID-19 reveals role of blood clotting and vasculature related genes

COVID-19 caused by SARS-CoV-2 manifests as a range of symptoms. Understanding the molecular mechanisms responsible for immuno-pathogenesis of disease is important for treatment and management of COVID-19. We examined host transcriptomes in moderate and severe COVID-19 cases with a view to identifying pathways that affect its progression. RNA extracted from whole blood of COVID-19 cases was analysed by microarray analysis. Moderate and severe cases were compared with healthy controls and differentially regulated genes (DEGs) categorized into cellular pathways. DEGs in COVID-19 cases were mostly related to host immune activation and cytokine signaling, pathogen uptake, host defenses, blood and vasculature genes, and SARS-CoV-2- and other virus-affected pathways. The DEGs in these pathways were increased in severe compared with moderate cases. In a severe COVID-19 patient with an unfavourable outcome we observed dysregulation of genes in platelet homeostasis and cardiac conduction and fibrin clotting with disease progression. COVID-19 morbidity is associated with cytokine activation, cardiovascular risk and thrombosis. We identified DEGs related to dysregulation of blood clotting and homeostasis, platelet activation pathways and to be associated with disease progression. These can be biomarkers of disease progression and also potential targets for treatment interventions in COVID-19.

Prolonged Unexplained Hypoxemia as Initial Presentation of Cirrhosis: A Case Report.

BACKGROUND Hepatopulmonary syndrome (HPS) is a pulmonary complication of advanced liver disease with dyspnea as the predominant presenting symptom. The diagnosis of HPS can often be missed due to its nonspecific presentation and the presence of other comorbidities. CASE REPORT We present an interesting case of an obese 43-year-old man who presented with progressive, unexplained hypoxemia and shortness of breath in the absence of any symptoms or signs of chronic liver disease. After extensive cardiopulmonary investigations, he was diagnosed with severe HPS as a result of non-alcoholic steatohepatitis (NASH) leading to cirrhosis. He subsequently underwent successful hepatic transplantation and continues to improve at 12-month follow-up. CONCLUSIONS HPS needs to be considered in the differential diagnosis of unexplained hypoxemia. Given its poor prognosis, early diagnosis is warranted and treatment with liver transplantation is the preferred choice.

Spontaneous Hepatitis B Seroclearance upon Development of Hepatocellular Carcinoma.

The spontaneous seroclearance of hepatitis B upon development of a hepatocellular carcinoma (HCC) is extremely rare. To date, there has been one published case series reporting hepatitis B seroconversion following HCC resection. We describe two novel cases of spontaneous hepatitis B seroclearance following the development of HCC, prior to resection. Following resection, specimens were HBsAg- and HBcAg-negative in both tumor and peritumor tissues. Although the precise mechanism of this is poorly understood, nonuniform integration of hepatitis B virus DNA within the liver could lead to selective tumorigenesis of HBsAg-producing cells, explaining the observed clearance of serum HBsAg with the development of HCC.

Improving prognosis for patients with hepatocellular carcinoma in Ireland 1994-2008.

OBJECTIVES: The incidence of hepatocellular carcinoma (HCC) is increasing in low-prevalence countries such as the USA, UK and Ireland. Over the past two decades, diagnostic techniques have improved and new treatments have been introduced. The aim of this study was to determine whether there has been an impact on hepatoma mortality in Ireland. METHODS: Anonymized cancer registration data from the National Cancer Registry of Ireland were used to investigate patient characteristics and trends in treatment and survival for Irish patients diagnosed with histologically confirmed HCC between 1994 and 2008. Analyses were carried out according to sex, age, stage of disease treatment received and period of incidence. RESULTS: The incidence of HCC in Ireland increased steadily from 1994 to 2008. The median overall survival was 580 days for the entire cohort, with 1, 2, 3 and 5-year survivals of 56, 46, 39 and 36%, respectively. One-year cause-specific survival improved from 38% during 1994-1998, to 51% during 1999-2002 and to 66% during 2003-2007. Five-year cause-specific survival also improved over time from 19 to 34 to 38%, respectively. Surgery was associated with 1, 2, 3 and 5-year survivals of 92, 82, 78 and 78%, respectively. CONCLUSION: This is the first population-based report of incidence, treatment patterns and outcomes of HCC in Ireland. Prognosis improved over time in this biopsy-proven cohort of patients with HCC. This improvement in survival seemed to be largely because of the effect of surgical interventions.

Liver transplantation in Ireland.

The Irish National Liver Transplant program commenced in 1993 in St. Vincent's University Hospital in Dublin. It is an adult-only program and is the only liver transplant program in Ireland. Pediatric recipients are referred to King's College Hospital in the United Kingdom. To date, almost 1000 adult liver transplants have been performed. Current 1-year patient survival is 93%, and 5-year survival is 79%. The program is fully funded by the government health service. There is a close collaboration with the United Kingdom Organ Donation and Transplant Directorate, and there is an arrangement for organ sharing for super-urgent transplants. Traditionally, organ donation rates have been high in Ireland. However, demand for liver transplant has increased over the past 20 years, and waiting lists are now lengthening. Deceased cardiac death donation is now being considered, but there are no plans for living related donor liver transplant. Donor coordinators have recently been appointed to the major hospitals in Ireland, and it is hoped that this initiative will lead to an increase in organ donation rates. Liver Transplantation 22 1014-1018 2016 AASLD.