Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting. METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders. RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group. CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

INTRODUCTION: Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. METHODS: Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. RESULTS: Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. CONCLUSION: In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

BACKGROUND: Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. METHODS: This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. RESULTS: The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. CONCLUSION: Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Clinico-epidemiological presentations and management of Nipah virus infection during the outbreak in Kozhikode district, Kerala state, India 2023.

India experienced its sixth Nipah virus (NiV) outbreak in September 2023 in the Kozhikode district of Kerala state. The NiV is primarily transmitted by spillover events from infected bats followed by human-to-human transmission. The clinical specimens were screened using real-time RT-PCR, and positive specimens were further characterized using next-generation sequencing. We describe here an in-depth clinical presentation and management of NiV-confirmed cases and outbreak containment activities. The current outbreak reported a total of six cases with two deaths, with a case fatality ratio of 33.33%. The cases had a mixed presentation of acute respiratory distress syndrome and encephalitis syndrome. Fever was a persistent presentation in all the cases. The Nipah viral RNA was detected in clinical specimens until the post-onset day of illness (POD) 14, with viral load in the range of 1.7-3.3 × 104 viral RNA copies/mL. The genomic analysis showed that the sequences from the current outbreak clustered into the Indian clade similar to the 2018 and 2019 outbreaks. This study highlights the vigilance of the health system to detect and effectively manage the clustering of cases with clinical presentations similar to NiV, which led to early detection and containment activities.

Recent development in the synthesis of imidazo[1,5-a]indole derivatives: an in-depth overview.

In the realm of nitrogen-fused heterocycles, imidazo[1,5-a]indole and its derivatives are recognized as privileged structural patterns in various pharmaceutical drugs and biologically active natural products, emphasizing their significance. This review comprehensively explores the synthetic strategies for constructing imidazo[1,5-a]indole scaffolds, with a particular focus on transition metal-catalyzed methodologies. The primary highlighted method is [4 + 1] annulation, along with other notable approaches such as C-H activation/cyclization, enantioselective C-H annulation, intramolecular hydroamination, and double cyclization processes.

Cost-effectiveness analysis under multiple effectiveness outcomes: A probabilistic approach.

Probability based criteria are proposed for the assessment of cost-effectiveness of a new treatment compared to a standard treatment when there are multiple effectiveness measures. Depending on the preferences of a policy maker, there are several options to define such criteria. Two such metrics are investigated in detail. One metric is defined as the conditional probability that a new treatment is more effective with respect to the multiple effectiveness measures for patients having lower costs under the new treatment. A second metric is defined as the conditional probability that a new treatment is less costly for patients having greater health benefits under the new treatment. The metrics offer considerable flexibility to a policy maker as thresholds for cost and effectiveness can be incorporated into the metrics. Parametric confidence limits are developed using a percentile bootstrap approach assuming multivariate normality for the joint distribution of the log(cost) and effectiveness measures. A non-parametric estimation procedure is also developed using the theory of U-statistics. Numerical results indicate that the proposed confidence limits accurately maintain coverage probabilities. The methodologies are illustrated using a study on the treatment of type two diabetes. Code implementing the proposed methods are provided in the supporting information.

Rectangular multivariate normal prediction regions for setting reference regions in laboratory medicine.

Reference intervals are among the most widely used medical decision-making tools and are invaluable in the interpretation of laboratory results of patients. Moreover, when multiple biochemical analytes are measured on each patient, a multivariate reference region (MRR) is needed. Such regions are more desirable than separate univariate reference intervals since the latter disregard the cross-correlations among variables. Traditionally, assuming multivariate normality, MRRs have been constructed as ellipsoidal regions, which cannot detect componentwise extreme values. Consequently, MRRs are rarely used in actual practice. In order to address the above drawback of ellipsoidal reference regions, we propose a procedure to construct rectangular MRRs under multivariate normality. The rectangular MRR is computed using a prediction region criterion. However, since the population correlations are unknown, a parametric bootstrap approach is employed for computing the required prediction factor. Also addressed in this study is the computation of mixed reference intervals, which include both two-sided and one-sided prediction limits, simultaneously. Numerical results show that the parametric bootstrap procedure is quite accurate, with estimated coverage probabilities very close to the nominal level. Moreover, the expected volumes of the proposed rectangular regions are substantially smaller than the expected volumes obtained from Bonferroni simultaneous prediction intervals. We also explore the computation of covariate-dependent MRRs in a multivariate regression setting. Finally, we discuss real-life applications of the proposed methods, including the computation of reference ranges for the assessment of kidney function and for components of the insulin-like growth factor system in adults.

Stage IA melanoma follow-up: Exploring the level of confidence of South Australian general practitioners in undertaking surveillance skin checks including considerations for shared care.

BACKGROUND: The literature highlights the role of Australian general practitioners (GP) in the management of skin cancers. With melanoma incidences on the rise, there have been discussions into whether lower-risk stage IA patients could safely be followed up by their GPs for annual surveillance full skin examinations (FSE). This study explores the level of confidence of South Australian (SA) GPs in undertaking FSEs including factors that could support discussions around shared care between GPs and dermatology units for lower-risk patients. METHODS: An online survey was designed and distributed to SA GPs via email, newsletters and social media between 5 December 2021 and 30 January 2022. Descriptive statistics were used to describe survey responses. Pearson's Chi-squared analysis was used to investigate associations between key variables of interest and explanatory variables. Logistic regression analysis was used to model odds ratios for associations between the dependent variable and independent variables. RESULTS: A total of 135 responses were obtained. Forty-four per cent of GPs were comfortable undertaking annual FSEs, 41% were uncomfortable and 15% were unsure. Scope of work, >20 years experience and additional training had statistically significant relationships (p < 0.05). Dermoscopy and detecting melanoma recurrences were reported to be skills with lower levels of confidence. With regards to shared care, 77% indicated that they would feel supported undertaking FSEs if rapid access referral pathways were allocated for patients who developed suspicious lesions. Preferred upskilling modalities included, face-to-face sessions in a dermatology unit (39%), dermatologist run webinars (25%) and certificate courses (20%). CONCLUSIONS: At present, there is a subset of SA GPs who are comfortable undertaking FSEs and therefore could be engaged in shared care with specialists. Further considerations have to be made in the areas of upskilling and supporting the workforce to enhance engagement in shared care.

Rectangular tolerance regions and multivariate normal reference regions in laboratory medicine.

Reference intervals are widely used in the interpretation of results of biochemical and physiological tests of patients. When there are multiple biochemical analytes measured from each subject, a multivariate reference region is needed. Because of their greater specificity against false positives, such reference regions are more desirable than separate univariate reference intervals that disregard the cross-correlations between variables. Traditionally, under multivariate normality, reference regions have been constructed as ellipsoidal regions. This approach suffers from a major drawback: it cannot detect component-wise extreme observations. In the present work, procedures are developed to construct rectangular reference regions in the multivariate normal setup. The construction is based on the criteria for tolerance intervals. The problems addressed include the computation of a rectangular tolerance region and simultaneous tolerance intervals. Also addressed is the computation of mixed reference intervals that include both two-sided and one-sided limits, simultaneously. A parametric bootstrap approach is used in the computations, and the accuracy of the proposed methodology is assessed using estimated coverage probabilities. The problem of sample size determination is also addressed, and the results are illustrated using examples that call for the computation of reference regions.

Surface Modification of Bi2O3 Nanoparticles with Biotinylated ß-Cyclodextrin as a Biocompatible Therapeutic Agent for Anticancer and Antimicrobial Applications.

Bismuth oxide nanoparticles with appropriate surface chemistry exhibit many interesting properties that can be utilized in a variety of applications. This paper describes a new route to the surface modification of bismuth oxide nanoparticles (Bi2O3 NPs) using functionalized beta-Cyclodextrin (ß-CD) as a biocompatible system. The synthesis of Bi2O3 NP was done using PVA (poly vinyl alcohol) as the reductant and the Steglich esterification procedure for the functionalization of ß-CD with biotin. Ultimately, the Bi2O3 NPs are modified using this functionalized ß-CD system. The particle size of the synthesized Bi2O3 NPs is found to be in the range of 12-16 nm. The modified biocompatible systems were characterized using different characterization techniques such as Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and Differential Scanning Calorimetric analysis (DSC). Additionally, the antibacterial and anticancerous effects of the surface-modified Bi2O3 NP system were also investigated.

One goal: Health for all; Post-COVID public health initiatives.

WHO's theme on its 75th year, "Health for All", is both appropriate and meaningful on account of the unfinished agenda of primary health care (PHC), the Sustainable Development Goals, and the aftermath of the COVID-19 pandemic. The Kerala experience of the pandemic amply demonstrated that the application of these PHC principles helped to address diverse aspects of physical, mental, and social dimensions. The need for 'internalization' of One Health principles and operational strategies cannot be over-emphasized.

Endovascular management of cerebral venous thrombosis: a tertiary-centre experience.

Background: Stroke related to cerebral venous thrombosis (CVT) is uncommon, with untoward lethal outcomes. Systemic anticoagulation is the treatment of choice. However, some patients can be resistant to this treatment. Endovascular management with thrombolysis and mechanical thrombectomy can be a viable option in such cases. Material and methods: We retrospectively reviewed the endovascular management used for CVT in 8 patients who failed to respond to standard anticoagulation therapy between December 2017 and December 2022 in our institute. Clinical profile, imaging parameters, endovascular procedure details, and outcomes in terms of angiographic findings and clinical follow-up were analysed. Results: In this period, a total of 8 patients underwent mechanical thrombectomy. The procedure was successful in all cases (8/8 = 100%), and 50% of them showed near total/complete recanalization; Perforation of the cortical veins was noted in 2 cases (~25%). Among the 8 patients, one died (1/8 = 12.5%) due to cardiac aetiology; the remaining 7 patients (87.5%) showed good clinical outcome with a modified Rankin Scale score 0 to 2. Conclusion: Catheter-directed thrombolysis with mechanical thromboaspiration is a safe and effective treatment for cerebral venous sinus thrombosis not responding to anticoagulation.

Substance use related cluster headache: A case series.

BACKGROUND: Essential oils (EOs) with pro-convulsant properties are known to cause seizures and may worsen migraine. Here we report five cases of cluster headache (CH) secondary to the usage of toothpastes containing pro-convulsant EOs. METHODS: Patients were identified from the headache clinics of three tertiary care hospitals in south India. Detailed history, examination, and brain magnetic resonance imaging were done in all patients. CH was diagnosed according to the International Classification of Headache Disorders, 3rd edition. Descriptive statistics were used to analyze data. RESULTS: We had five cases of EO-related CH (EORCH), from February 2020 to August 2021; three females and two males, with age ranging from 19 to 54 years. Three had new onset CH, while two had previous cluster attacks which had become refractory to medications for the past 1 year. The toothpastes contained EOs of camphor, eucalyptus, sage, thujone, clove, and fennel in various combinations. These toothpastes were used for a period of at least 3 months in those with new onset CH and for 12 months or more by those with chronic CH. After stopping the usage of these toothpastes, the CH attacks resolved completely within 5-10 days in all patients. In one patient we re-challenged with the same toothpaste and got the CH attack after a period of 2 months. None of the patients had recurrence of CH attacks at follow-up, ranging from 1 to 2 years. CONCLUSION: EOs with pro-convulsive properties may trigger and sustain CH. Physicians may consider inquiring about the exposure to these pro-convulsant EOs in patients with CH and may consider advising the discontinuation of products like toothpastes containing them as a possible means of CH remission.

Auditory Brainstem Response in Children with Thalassemia Major under Chelating Therapy.

The present study compared the Auditory Brainstem Response (ABR) of children with thalassemia major and typically developing children. A total of 16 children participated in this study. Group I included 8 children with thalassemia major regularly undergoing blood transfusions and chelating therapy. Group II included 8 age and gender-matched typically developing children. All children in both groups had hearing sensitivity within normal limits. The Auditory Brainstem Response (ABR) was recorded monaurally for click stimuli from both ears. Results showed that the mean latencies of peaks of ABR were similar in both groups. The mean peak amplitude of peaks I and V of the ABR were different between groups, but it was not statistically significant. The present study showed no abnormality in the latency and amplitude of peaks of the ABR in children with thalassemia major with hearing sensitivity within normal limits.

INSTRuCT: Protocol, Infrastructure, and Governance.

Background and Purpose: Very few large scale multicentric stroke clinical trials have been done in India. The Indian Council of Medical Research funded INSTRuCT (Indian Stroke Clinical Trial Network) as a task force project with the objectives to establish a state-of-the-art stroke clinical trial network and to conduct pharmacological and nonpharmacological stroke clinical trials relevant to the nation and globally. The purpose of the article is to enumerate the structure of multicentric stroke network, with emphasis on its scope, challenges and expectations in India. Methods: Multiple expert group meetings were conducted by Indian Council of Medical Research to understand the scope of network to perform stroke clinical trials in the country. Established stroke centers with annual volume of 200 patients with stroke with prior experience of conducting clinical trials were included. Central coordinating center, standard operating procedures, data and safety monitoring board were formed. Discussion: In first phase, 2 trials were initiated namely, SPRINT (Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India) and Ayurveda treatment in the rehabilitation of patients with ischemic stroke in India (RESTORE [Rehabilitation of Ischemic stroke Patients in India: A Randomized controlled trial]). In second phase, 4 trials have been approved. SPRINT trial was the first to be initiated. SPRINT trial randomized first patient on April 28, 2018; recruited 3048 patients with an average of 128.5 per month so far. The first follow-up was completed on May 27, 2019. RESTORE trial randomized first patient on May 22, 2019; recruited 49 patients with an average of 3.7 per month so far. The first follow-up was completed on August 30, 2019. Conclusions: In next 5 years, INSTRuCT will be able to complete high-quality large scale stroke trials which are relevant globally. REGISTRATION: URL: http://www.ctri.nic.in/; Unique Identifier: CTRI/2017/05/008507.

Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia.

Ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.

Direct Synthesis of Tri-/Difluoromethyl Ketones from Carboxylic Acids by Cross-Coupling with Acyloxyphosphonium Ions.

A simple and straightforward approach to the synthesis of trifluoromethyl and difluoromethyl ketones from widely available carboxylic acids is disclosed. The transformation utilizes an acyloxyphosphonium ion as the active electrophile, conveniently generated in situ from the carboxylic acid substrate by using commodity chemicals. The utility of the reaction system is exemplified by its chemoselectivity, with tolerance to a variety of important functional groups. The late-stage functionalization of carboxylic acid active pharmaceutical ingredients and pharmaceutically relevant compounds is also discussed.

Current developments in the synthesis of 4-chromanone-derived compounds.

The chroman-4-one framework is a significant structural entity that belongs to the class of oxygen-containing heterocycles. It acts as a major building block in a large class of medicinal compounds, and synthetic compounds exhibit a broad variety of remarkable biological and pharmaceutical activities. Several studies have been performed to improve the methodologies of 4-chromanone-derived compounds. This review focuses on the major synthetic methods of preparation reported on chroman-4-one derivatives from 2016 to 2021.

Intraoperative Three-dimensional Imaging of Ventricular Septal Defects in Children Using Epicardial Echocardiography: A Novel Approach.

OBJECTIVE: To assess the feasibility and accuracy of intraoperative three-dimensional (3D) epicardial en face images of ventricular septal defects (VSD) in children using the 3D transesophageal echocardiography (TEE) probe as an epicardial probe. DESIGN: This was a prospective nonrandomized blinded observational study. SETTING: The study was conducted at a single tertiary cardiac care center. PARTICIPANTS: Fifty pediatric patients, weighing between 5.0 kg and 20 kg, who were scheduled for elective surgical closure of their VSDs, prospectively were recruited for this study. INTERVENTIONS: Epicardial 3D images were acquired using the full-volume mode. VSD location and size were determined from the 3D data sets using multiplanar reconstruction mode (QLAB 9) by a blinded investigator. The accuracy in terms of location and size was compared with surgical findings. MEASUREMENTS AND MAIN RESULTS: In 50 study subjects, 54 VSDs were located by epicardial 3D echocardiography (3DE): 12 perimembranous, 17 inlet, eight muscular, 15 malaligned, and two outlet. Average image acquisition time was 4.96 (±1.47) minutes. Average image reconstruction time was 6.18 (±1.93) minutes. Good en face views of the VSD could be rendered in all patients (100% feasibility). The highest image quality was for perimembranous and malaligned VSDs. The location of VSD by 3DE corresponded precisely with surgical findings (100% accuracy). With linear regression analysis, excellent correlation was observed between the diameters measured by surgery and that measured by 3DE from the right ventricle side (r2 = 0.97, p < 0.001). CONCLUSIONS: The authors' study demonstrated that diagnostic quality 3D en face images of VSD can be obtained intraoperatively using 3D epicardial echocardiography. The short acquisition and reconstruction times make this technique clinically applicable.

Nivolumab-induced hepatitis: A rare side effect of an immune check point inhibitor.

Immune checkpoint inhibitors have ushered in a new era in cancer management. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor. This inhibits suppression of the T-cell activity, which can in turn cause increased killing of cancer cells. This alteration in the activity of the T cells can cause them to lose their ability to identify host cells and leads to immune-related adverse effects (irAE). Nivolumab-induced hepatotoxicity is rare and accounts for 3-6% of all irAE. We present a case of nivolumab-induced hepatitis. A woman who was treated for recurrent renal cell carcinoma presented with hepatitis. Workup for other causes was negative and the hepatitis was attributed to the administration of nivolumab. She was started on oral steroids followed which she initially improved. However, she later presented with massive upper gastrointestinal bleeding secondary to gastroduodenal ulcers and subsequently developed acute tubular necrosis and passed from the complications. Immune checkpoint inhibitors have proven to be a promising approach in the management of a wide array of neoplasms by immunomodulation. As these agents are becoming standard of therapy in the management of cancers, a heightened vigilance in the diagnosis of irAE is warranted. With heightened vigilance, early recognition can lead to decreased mortality and morbidity.