Outcomes in the Asian subgroup of the phase III randomised HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: In the global, phase III HIMALAYA study in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib; durvalumab was noninferior to sorafenib. HBV is the predominant HCC aetiology in most of Asia vs. HCV or nonviral aetiologies in Western countries and Japan. This analysis evaluated safety and efficacy outcomes for STRIDE and durvalumab monotherapy vs. sorafenib, in HIMALAYA participants enrolled in Asia, excluding Japan. METHODS: In HIMALAYA, participants were randomised to STRIDE, durvalumab, or sorafenib. The Asian subgroup in this analysis included participants enrolled in Hong Kong, India, South Korea, Taiwan, Thailand, and Vietnam. OS, objective response rate (ORR; per Response Evaluation Criteria in Solid Tumors, version 1.1), and safety were assessed in the Asian subgroup and in an exploratory subgroup of participants in Hong Kong and Taiwan. RESULTS: The Asian subgroup included 479 participants randomised to STRIDE (n=156), durvalumab (n=167), or sorafenib (n=156). OS was improved for STRIDE vs. sorafenib (HR 0.68; 95% CI 0.52-0.89]). The OS HR for durvalumab vs. sorafenib was 0.83 (95% CI 0.64-1.06). In Hong Kong and Taiwan (n=141), OS HRs for STRIDE vs. sorafenib and durvalumab vs. sorafenib were 0.44 (95% CI 0.26-0.77) and 0.64 (95% CI 0.37-1.08), respectively. In the Asian subgroup, ORR (including unconfirmed responses) was numerically higher for STRIDE (28.2%) and durvalumab (18.6%) vs. sorafenib (9.0%), and Grade 3/4 treatment-related adverse events were numerically lower for STRIDE (19.9%) and durvalumab (13.3%) vs. sorafenib (30.5%). CONCLUSIONS: STRIDE improved outcomes vs. sorafenib in the Asian subgroup. These results support the benefits of STRIDE for participants with uHCC globally, including the Asia-Pacific region. CLINICAL TRIAL NUMBER: NCT03298451 IMPACT AND IMPLICATIONS: The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival (OS), including long-term OS, vs. sorafenib, and that durvalumab monotherapy was noninferior to sorafenib in participants with unresectable hepatocellular carcinoma (uHCC). However, there are differences in the aetiology and clinical practices related to HCC in parts of Asia, compared to Western countries and Japan, which could lead to differences in treatment outcomes between these regions. The results of this analysis demonstrate the benefits of STRIDE for participants in the Asia-Pacific region, consistent with the full, global study population. Overall, these findings continue to support the use of STRIDE in a diverse population, reflective of uHCC globally.

Effect of Curcuma longa (Turmeric), as an intra-canal medicament, on inter-appointment endodontic pain in patients with symptomatic irreversible pulpitis: A randomized controlled clinical trial.

Inter-appointment pain (IAP) is a subtype of postoperative pain which occurs between endodontic appointments. It may begin within a few hours after the first appointment and may continue for several days. Apart from mechanical instrumentation and thorough irrigation, intracanal medicaments play a central role in the disinfection of root canals and thus decreasing IAP. The aim of this study was to evaluate the effect of Curcuma Longa as an intracanal medicament on IAP in patients with symptomatic irreversible pulpitis (SIP). One hundred healthy adult patients having SIP in one of their single-rooted maxillary or mandibular teeth participated in this randomized, parallel, single-blinded clinical trial. After thorough biomechanical preparation, the root canals were randomly medicated with one of the following medicaments, Control (no medicament), Calcium Hydroxide, triple antibiotic paste (TAP), and Curcuma Longa. The pain was recorded using Visual analog scale at 4 h, 24 h, and every day until the seventh day. Data were analyzed using Kruskal-Wallis, Mann-Whitney U, and Wilcoxon signed-rank tests. No statistical difference in pain scores was observed between Calcium Hydroxide, TAP or Curcuma Longa groups. It can be concluded that Curcuma Longa, Calcium hydroxide, and TAP are equally effective in controlling IAP.

Brolucizumab-associated intraocular inflammation in Indian patients by VRSI study group.

CONTEXT: Concerns about brolucizumab's (Pagenax®) association with intraocular inflammation (IOI) limit its use despite its cost-effectiveness and efficacy. This multicentric study analyzes IOI incidence across 21 tertiary eyecare centers in India since its introduction in October 2020. PURPOSE: To determine the real-world incidence rate of IOI in Indian patients secondary to intravitreal brolucizumab across 21 tertiary eye care centers in India. SETTINGS AND DESIGN: Retrospective multicentric, survey-based study. METHODS: Data including number of patients treated, clinical indications, side effects encountered, and IOI case details was collected via Google Forms in 21 Indian tertiary eye care centers since October 2020. Mean, median, frequency, and standard deviation were calculated for statistical analysis. RESULTS: All centers used pro re nata protocol for brolucizumab injections with a minimum injection interval of 8 weeks. The incidence of IOI was 0.79% (21 events out of 2655 eyes). Treatment indications included idiopathic polypoidal choroidal vasculopathy, neovascular age-related macular degeneration, diabetic macular edema, and off-label uses. IOI was experienced after the first injection (57%) in majority of cases with a median onset of 14 days (range: 1-65 days). IOI was mild in 28.5%, moderate in 33%, and severe in 38% of cases. Eighteen out of 21 IOI eyes recovered preinjection best corrected visual acuity or better. CONCLUSIONS: Our study found a lower IOI incidence (0.79%) with brolucizumab (Pagenax) in Indian patients compared to previously reported literature. IOI events were mostly mild to moderate, and post-treatment, most patients improved or maintained BCVA. Larger prospective multicentric studies with PRN dosing protocol are needed to confirm these findings.

Applications of Organoids in Advancing Drug Discovery and Development.

Organoids are small, self-organizing three-dimensional cell cultures that are derived from stem cells or primary organs. These cultures replicate the complexity of an organ, which cannot be achieved by single-cell culture systems. Organoids can be used in testing of new drugs instead of animals. Development and validation of organoids is thus important to reduce the reliance on animals for drug testing. In this review, we have discussed the developmental and regulatory aspects of organoids and highlighted their importance in drug development. We have first summarized different types of culture-based organoid systems such as submerged Matrigel, micro-fluidic 3D cultures, inducible pluripotent stem cells, and air-liquid interface cultures. These systems help us understand the intricate interplay between cells and their surrounding milieu for identifying functions of target receptors, soluble factors, and spatial interactions. Further, we have discussed the advances in humanized severe-combined immunodeficiency mouse models and their applications in the pharmacology of immune-oncology. Since regulatory aspects are important in using organoids for drug development, we have summarized FDA and EMA regulations on organoid research to support pre-clinical studies. Finally, we have included some unique studies highlighting the use of organoids in studying infectious diseases, cancer, and fundamental biology. These studies also exemplify the latest technological advances in organoid development resulting in improved efficiency. Overall, this review comprehensively summarizes the applications of organoids in early drug development during discovery and pre-clinical studies.

Novel peptide inhibitor of human tumor necrosis factor-α has antiarthritic activity.

The inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein-protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells, as observed in immunofluorescence and gel mobility-shift assays. Furthermore, the peptide protected against joint damage in the collagen-induced arthritis (CIA) mouse model, as revealed in the micro focal-CT scans. In conclusion, this TNFα antagonist would be helpful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an antiarthritic drug.

Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma.

PURPOSE: In the phase III HIMALAYA study (ClinicalTrials.gov identifier: NCT03298451) in unresectable hepatocellular carcinoma (uHCC), the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen significantly improved overall survival versus sorafenib, and durvalumab monotherapy was noninferior to sorafenib. Patient-reported outcomes (PROs), a secondary outcome from HIMALAYA, are reported here. METHODS: Participants were randomly assigned to receive STRIDE, durvalumab, or sorafenib. PROs were assessed (preplanned secondary outcome) using the European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire and the 18-item HCC module. Time to deterioration (TTD), change from baseline and improvement rate in global health status/quality of life (GHS/QoL), functioning, and disease-related symptoms were analyzed. RESULTS: In total, 1,171 participants were randomly assigned to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389) and were evaluable for PRO assessments. Across treatment arms, compliance rates for PROs were >77% at baseline and >70% overall. Baseline scores were comparable across treatment arms. TTD in GHS/QoL, physical functioning, fatigue, appetite loss, and abdominal pain was numerically longer for both STRIDE and durvalumab versus sorafenib. Clinically meaningful deterioration in PROs was not observed in any treatment arm. However, TTD in nausea and abdominal swelling was numerically longer for STRIDE versus sorafenib, and the likelihood of clinically meaningful improvement in GHS/QoL, role, emotional and social functioning, and disease-related symptoms was greater with STRIDE and durvalumab versus sorafenib. PROs with STRIDE and durvalumab were generally similar. CONCLUSION: Compared with sorafenib, STRIDE and durvalumab were associated with clinically meaningful, patient-centered GHS/QoL, functioning, and symptom benefits in people with uHCC. These findings support the benefits of the STRIDE regimen compared with sorafenib for a diverse population reflective of the global uHCC population.

Design and Characterization of Citronella Oil-Loaded Micro-Emulgel for the Treatment of Candida Albicans Infection.

The purpose of the current study was to prepare and evaluate a citronella oil-loaded microemulsion-based micro-emulgel for the treatment of Candida albicans. The primary objective was to use the skin to transfer hydrophobic medications into the bloodstream. The formulation included cinnamon oil as an antifungal oil and citronella oil as an active pharmaceutical ingredient, respectively. Tween 80 and PEG 200 were used as the surfactant and co-surfactant, respectively, to create phase diagrams. Carbopol 940, one of the frequently used polymers, was investigated for its ability to prepare gel formulations. The optimized (F3) batch contained the highest percentage (87.05 ± 0.03%) of drug content and, according to the statistics provided, had the highest drug release rate of around 87.05% within 4 h. The Korsmeyer-Peppas model with n value of 0.82, which is in the range 0.5-1, had the highest r2 value, indicating that release following non-Fickian/anomalous diffusion provided a better dimension for all of the formulations. The optimized (F3) formulation had stronger antifungal activity in comparison to other formulations. This leads to the conclusion that citronella oil can be made into a micro-emulgel, which may improve its release in aqueous systems while maintaining a high level of drug release at the target site.

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

WHAT IS THIS SUMMARY ABOUT?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Immunosuppression Monitoring-What Clinician Needs to Know?

The liver is well known for its immunotolerance, but rejection without immunosuppression is frequently encountered post liver transplantation, especially in humans.1 Indeed, the amount of immunosuppression required post liver transplant is less compared to other organ transplants like kidney, heart, and intestine.2 Reports of successful weaning of immunosuppression have been reported but are not practiced for fear of unwanted alloimmune response leading to rejection. Life-long immunosuppression is needed in most patients for graft survival but is associated with side effects like renal dysfunction, metabolic abnormalities, or risk of de novo malignancies. Also, the appropriate dose of immunosuppression to achieve adequate graft function and prevention of toxicities is very important. One shoe does not fit all. There are significant individual variations in response and side effect profile. Also, the level of immunosuppression varies with the underlying liver disease like autoimmune disease requires higher immunosuppression. Thus, monitoring the adequate immunosuppression with the minimization of drug toxicity is imperative post-transplant. Unfortunately, the current methods for immunosuppression monitoring rely on testing the immunosuppressive drug levels rather than the immune system activity. We have discussed the concept of alloreactivity, available methods of immunosuppression and drug monitoring and investigational methods in this review.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

Drug Repurposing During The COVID-19 Pandemic: Lessons For Expediting Drug Development And Access.

The COVID-19 pandemic created a large, sudden unmet public health need for rapid access to safe and effective treatments. Against this backdrop, policy makers and researchers have looked to drug repurposing-using a drug previously approved for one indication to target a new indication-as a means to accelerate the identification and development of COVID-19 treatments. Using detailed data on US clinical trials initiated during the pandemic, we examined the trajectory and sources of drug repurposing initiatives for COVID-19. We found a rapid increase in repurposing efforts at the start of the pandemic, followed by a transition to greater de novo drug development. The drugs tested for repurposing treat a wide range of indications but were typically initially approved for other infectious diseases. Finally, we documented substantial variation by trial sponsor (academic, industry, or government) and generic status: Industry sponsorship for repurposing occurred much less frequently for drugs with generic competitors already on the market. Our findings inform drug repurposing policy for both future emerging diseases and drug development in general.

Structural clarity is brought to adhesion G protein-coupled receptor tethered agonism.

An elusive problem in the adhesion G protein-coupled receptor (AGPCR) field is full understanding of the activation mechanisms of the 33-member receptor class. With the recent solution of active-state structures of nearly one quarter of AGPCRs, clarity has been brought to how AGPCRs are activated in response to endogenous full agonists. AGPCRs are self-activated via a tethered peptide agonist (TA) that transitions from a concealed or encrypted location to a decrypted state that binds to a typical GPCR orthosteric binding pocket. Here, we summarize the key milestones that led to the discovery of the AGPCR TA activation mechanism and discuss how extracellular shear forces may initiate TA decryption in physiological contexts. We compare the new active-state AGPCR structures and note that the orthosteric site-engaged TAs adopt a remarkably similar partial α-helical hook-like conformation, despite divergence of overall receptor similarity. Further, we contrast the TA-bound AGPCR structures to a partially active AGPCR structure to highlight the transitions AGPCRs may undergo during activation. Finally, we provide commentary on the validity of alternative AGPCR activation mechanisms.

Unilateral Purtscher-like retinopathy post-COVID-19.

A 32-year-old male with no known systemic illness presented with unilateral Purtscher-like retinopathy in his left eye 2 weeks after recovering from a severe COVID-19 infection. Fundus examination revealed areas of intraretinal whitening and few cotton wool spots. Multimodal imaging findings were consistent with embolic occlusion of capillaries seen in Purtscher-like retinopathy. The case highlights the effect of virus-directed coagulation cascade activation leading to unilateral microvasculopathy in our patient. The case adds to the spectrum of COVID-19 retinopathy and presses that retina screening strategies should be established for patients suffering from or recovering from severe COVID-19 infection.

Continuous Remote Patient Monitoring in Patients With Heart Failure (Cascade Study): Protocol for a Mixed Methods Feasibility Study.

BACKGROUND: Heart failure (HF) is a prevalent chronic disease and is associated with increases in mortality and morbidity. HF is a leading cause of hospitalizations and readmissions in the United States. A potentially promising area for preventing HF readmissions is continuous remote patient monitoring (CRPM). OBJECTIVE: The primary aim of this study is to determine the feasibility and preliminary efficacy of a CRPM solution in patients with HF at NorthShore University HealthSystem. METHODS: This study is a feasibility study and uses a wearable biosensor to continuously remotely monitor patients with HF for 30 days after discharge. Eligible patients admitted with an HF exacerbation at NorthShore University HealthSystem are being recruited, and the wearable biosensor is placed before discharge. The biosensor collects physiological ambulatory data, which are analyzed for signs of patient deterioration. Participants are also completing a daily survey through a dedicated study smartphone. If prespecified criteria from the physiological data and survey results are met, a notification is triggered, and a predetermined electronic health record-based pathway of telephonic management is completed. In phase 1, which has already been completed, 5 patients were enrolled and monitored for 30 days after discharge. The results of phase 1 were analyzed, and modifications to the program were made to optimize it. After analysis of the phase 1 results, 15 patients are being enrolled for phase 2, which is a calibration and testing period to enable further adjustments to be made. After phase 2, we will enroll 45 patients for phase 3. The combined results of phases 1, 2, and 3 will be analyzed to determine the feasibility of a CRPM program in patients with HF. Semistructured interviews are being conducted with key stakeholders, including patients, and these results will be analyzed using the affective adaptation of the technology acceptance model. RESULTS: During phase 1, of the 5 patients, 2 (40%) were readmitted during the study period. The study completion rate for phase 1 was 80% (4/5), and the study attrition rate was 20% (1/5). There were 57 protocol deviations out of 150 patient days in phase 1 of the study. The results of phase 1 were analyzed, and the study protocol was adjusted to optimize it for phases 2 and 3. Phase 2 and phase 3 results will be available by the end of 2022. CONCLUSIONS: A CRPM program may offer a low-risk solution to improve care of patients with HF after hospital discharge and may help to decrease readmission of patients with HF to the hospital. This protocol may also lay the groundwork for the use of CRPM solutions in other groups of patients considered to be at high risk. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36741.

GeneMiner: A Classification Approach for Detection of XSS Attacks on Web Services.

According to OWASP 2021, cross-site scripting (XSS) attacks are increasing through specially crafted XML documents. The attacker injects a malicious payload with a new pattern and combination of scripts, functions, and tags that deceits the existing security mechanisms in web services. This paper proposes an approach, GeneMiner, encompassing GeneMiner-E to extract new features and GeneMiner-C for classification of input payloads as malicious and nonmalicious. The proposed approach evolves itself to the changing patterns of attack payloads and identifies adversarial XSS attacks. The experiments have been conducted by collecting data from open source and generating various combinations of scripts, functions, and tags using an incremental genetic algorithm. The experimental results show that the proposed approach effectively detects newly crafted malicious XSS payloads with an accuracy of 98.5%, which is better than the existing classification techniques. The approach learns variations in the existing attack sample space and identifies the new attack payloads with reduced efforts.

Retinal vasoocclusive spectrum following COVID-19.

The coagulation abnormalities and thromboembolic complications of coronavirus 2 (SARS-CoV-2) are now a well-established fact. The hypercoagulable state, the tendency for thromboembolism, and a cytokine surge state have been the exclusive reasons for multiorgan failure and other morbidities that have been regularly reported in COVID-19 patients. Ocular involvement in patients with active disease and those who have recovered is uncommon but not rare. We report a case series of four patients with CRVO, BRVO, CRAO, and vitreous hemorrhage in patients with proven COVID-19 infection and no other systemic ailments. The case series also tries to correlate the elevated D-dimer values, which signify a plausible prothrombotic state with the vaso-occlusive phenomenon in the retina leading to significant visual morbidity.

LONGITUDINAL SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF EXTRAFOVEAL POLYPS AFTER COMBINATION THERAPY.

PURPOSE: To study the efficacy of swept source optical coherence tomography angiography (SSOCTA) to longitudinally follow-up patients with extrafoveal polyps post-laser photocoagulation and anti-vascular endothelial growth factor injection. METHODS: Observational case series. Four patients diagnosed as polypoidal choroidal vasculopathy with extrafoveal polyps on multimodal imaging were followed up serially on SSOCT, en face and cross-sectional SSOCTA at a month and then 3 monthly for a year. Indocyanine green angiography was repeated at 4 months and 1 year. RESULTS: Anatomical regression of extrafoveal polyps was documented on a combination of en face and cross-sectional SSOCTA, 3 months post-laser photocoagulation and anti-vascular endothelial growth factor. Regression of polyps was maintained at the 12-month follow-up visit in all cases. Changes in branching vascular network morphology post-treatment were well-delineated on en face SSOCTA. Swept source optical coherence tomography angiography findings correlated well with the gold standard indocyanine green angiography. CONCLUSION: Swept source optical coherence tomography angiography is an effective noninvasive imaging modality to diagnose and longitudinally follow-up extrafoveal polyps postintervention. Laser photocoagulation with anti-vascular endothelial growth factor achieved regression of polyps in all cases and this was maintained over 12 months.