Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase 1 multicenter study of BMS-986365 in patients with progressive mCRPC. PATIENTS AND METHODS: Patients who progressed on androgen deprivation therapy, ≥ 1 ARPI, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (Part A) and expansion (Part B) of BMS-986365 up to 900 mg twice daily (BID). Primary objectives were safety, tolerability, and to define maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS). RESULTS: Parts A and B enrolled 27 and 68 patients, respectively. In Part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events (TRAEs) were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A MTD was not reached and RP2D selection is ongoing. Across Part B three highest doses (400-900 mg BID, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% CI) was 6.3 months (5.3-12.6), including 8.3 months (3.8-16.6) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5-not evaluable) versus 5.5 months (2.7-8.3), respectively. Efficacy was observed in patients with AR ligand binding domain (LBD) WT or with AR LBD mutations. CONCLUSIONS: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with potentially higher benefit in chemotherapy-naïve patients. These data show BMS-986365's potential to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

Acinic cell carcinoma of the parotid gland: A diagnostic dilemma on cytology.

INTRODUCTION: Acinic cell carcinoma (ACC) represents 1-6% of parotid gland neoplasms. CASE REPORT: We report cytomorphological features of two uncommon variants of acinic cell carcinoma. The first case was an eleven-year-old female with a nodular mass in parotid and the FNA smears demonstrated a lymphoepithelial lesion composed of epithelial tumour cells with features of acinar cells in a lymphoid background. The second case was a 62-year-old male with a large parotid mass. The FNA smears revealed presence of extracellular, acellular amyloid-like material with tumour cells arranged in follicles. DISCUSSION: Awareness of cytomorphological features of these unusual variants of acinic cell carcinoma may help to avoid diagnostic pitfall.

Cytokeratin 20 immunocytochemistry on urine sediments: A potential low-cost adjunct to cytology in the diagnosis of low-grade urothelial carcinoma.

BACKGROUND: Urine cytology is the corner-stone for the diagnosis of urothelial neoplasia; however, a substantial proportion of low-grade carcinomas are reported as inconclusive owing to scant cellularity and subtle cytological features. Biomarkers applied on urine sediment smears of such patients are likely to be clinically relevant. Access to Food and Drug Administration approved urinary biomarkers in resource limited setting is poor. Detection of cytokeratin 20 (CK20) in urine sediments, although still a research tool, is a promising marker as immunocytochemistry is performed regularly in several Indian laboratories. OBJECTIVE: We tested the clinical utility of CK20 immunocytochemistry as a potential low-cost adjunct to urine cytology in diagnosis of low-grade urothelial carcinoma. One hundred and fifty fresh, voided urine specimens from 42 cases of biopsy proven urothelial neoplasia (14 high grade, 28 combined low-grade [n=26]) and low malignant potential [n=2]), and 20 non-neoplastic lesions were included in the study sample. RESULTS: Confident diagnosis of malignancy was possible in five (17.8%) low-grade malignancies. Thirteen of 16 (81.3%) low-grade malignancies with inconclusive cytology showed positive CK20 expression. This reduced the proportion of low-grade cases with inconclusive cytology from 57.1% to 10.7% (P=.021). In addition, we could correctly classify one case of bladder lithiasis with false positive urine cytology. Discrepant CK20 staining (positive) was seen in one patient with acute cystitis. CONCLUSIONS: CK20 expression in non-umbrella cells is a robust marker of urinary bladder carcinoma. It has potential clinical utility for identification of low-grade urothelial malignancy with inconclusive cytological diagnosis.

Applications of ultrasonography in respiratory intensive care.

Emerging evidence suggests that ultrasonography of lung is a fast, inexpensive, widely available bed-side diagnostic tool which is useful for quick and early diagnosis of respiratory diseases. It is useful in the differential diagnosis of pulmonary infiltrates and has good accuracy in identifying consolidation and alveolar-interstitial syndrome. This technique can also be useful in the immediate evaluation of patients with dyspnoea or acute respiratory failure in the respiratory intensive care unit and helps in monitoring treatment response. Ultrasonography of lung has also been found to be useful in the diagnosis of pulmonary embolism, traumatic lung contusion and lung consolidation as well. There is a need for developing specific guidelines for establishing the standards of training and education regarding lung ultrasonography in India.

Prevalance of tuberculosis amongst healthcare workers, working in DOTS/sputum microscopy centre in two different districts of state of Uttarakhand & Uttar Pradesh of India.

BACKGROUND & OBJECTIVE: The Healthcare workers (HCWs) who work in DOTS/Sputum microscopy centre are exposed to higher risk of contacting tuberculosis (TB) comparatively to other health workers who are serving the other health sectors. The HCWs in DOTS are more exposed due to direct contact with patients suffering from TB or through sharing the infected air space with the infectious patients. The aim of the study is to know the prevalance of TB disease amongst the HCWs who are working in DOTS cum Sputum Microscopy Centre's under RNTCP in two different districts of state of Uttar Pradesh (UP) and Uttarakhand (UK) of india. METHODS: The prospective cross-sectional study is conducted in two districts of different states having high burden of TB disease in UP and low burden of TB disease in UK state. All 100% (130) staff i.e. Medical officers, Sputum microscopy technicians, DOTS providers of DOTS cum Sputum Microscopy centre's of both selected Ghaziabad (UP) and Dehradun (UK) districts are covered in the study. RESULTS: The 4.6% (6) healthcare workers of both the districts were taking ATT at the time of interview and 13.8% (18) HCWs had taken the ATT in past. The 62.5% (15) HCWs i.e 55.5% (5) from Dehradun district and 66.6% (10) from Ghaziabad district preferred to have a ATT from the private medical store inspite of taking DOTS with assumption of low efficacy of drugs and high toxicity. The 58.33% (14) HCWs ie 55.5% (5) staff members of DOTS/sputum microscopy centre in Dehradun & 60.0% (9) staff members of DOTS/sputum microscopy centre in Ghaziabad district had not notified about the status of their disease to the health care authority due the assumption that they may be asked to leave the job or to go on a long unpaid leave. CONCLUSION: The 18.4% (24) HCWs of both the district got TB disease during their working in DOTS/Sputum microscopy centre and 4.6% (6) HCWs of both the districts were taking the ATT at the time of interview.

Prevalence of onychomycosis in patients with diabetes mellitus: A cross-sectional study from a tertiary care hospital in North India.

Background Though diabetes mellitus (DM) is a well-recognised risk factor for onychomycosis (OM), the epidemiology of OM in diabetic patients remains largely unexplored, especially from the Indian subcontinent. Aims and objectives To estimate the prevalence of OM in diabetic patients, to identify and analyse risk factors, and correlate the severity of nail changes with glycemic control (HBA1c). Methods This cross-sectional, analytical study involved 300 diabetic patients. Patients with the clinical diagnosis of OM, supplanted by at least two of the four tests (KOH, culture, onychoscopy and nail histopathology) were considered cases of OM. Demographic and haematological profile was analysed using chi-square test/ Fischer's exact test. Logistic regression was applied to assess the independent risk factors. Results The prevalence of OM in DM patients was 34% (102/300) and significant risk factors included; age >60 years, male gender, closed shoes, disease duration >5 years, high BMI (>25) and lack of awareness about nail changes. Distal and lateral subungual OM (78%) was the commonest presentation followed by proximal subungual OM, superficial OM and total dystrophic OM. Correlation between HbA1c and the number of nails involved was found to be significant. Limitation As cases were recruited from a hospital setting, there could be chances of Berksonian bias. Conclusion The prevalence of OM in diabetic patients is high and the severity of nail changes correlates with HbA1C levels. It is important to diagnose OM early in order to treat and prevent complications.

Genomic revolution: Transforming tuberculosis diagnosis and treatment with the use of Whole Genome Sequencing - A consensus statement.

Tuberculosis (TB) is a preventable, treatable, and curable disease. However, in 2020, 9∙9 million people were estimated to have developed tuberculosis, and 1.5 million people were estimated to have died from it. Whereas in India, 2.6 million were diagnosed with TB and 436,000 succumbed to TB in 2019. India (26%) is the major contributor to the global drop in TB cases. The COVID-19 pandemic has substantially reduced access to services for the diagnosis and treatment of TB, resulting in an increase in deaths and a reversal in global progress. [1] Presently, TB incidence is falling at a rate of 2% per year, obstructed mainly by the rearing pandemic of drug-resistant tuberculosis (DRTB). Particularly concerning is multi-drug resistant TB (MDRTB), defined as resistance towards isoniazid (INH) and rifampicin (RIF). [2] The World Health Organization (WHO) targeted to reduce worldwide TB incidence by 90% until 2035. (1) Early initiation of effective treatment based on susceptibility patterns of the Mycobacterium tuberculosis complex (MTBC) is considered key to successful TB control in countries with high DRTB incidence. Worldwide MDRTB treatment outcomes are poor, with cure rates less than 60% (2) due to the lack of comprehensive Drug Susceptibility Testing (DST) in most high MDRTB burden countries. This is leading to the inadequate anti-TB activity of the provided regimens (3-5), unlike regimens advised for DST assure optimal results. (6) In addition to resistances to the established regimens, the resistance to the newer DRTB drugs is increasing. On World TB Day 2022, Academy of Advanced Medical Education, Thyrocare Technologies Limited and HyastackAnalytics - IITB along with expert pulmonologist and renowned physicians from India convened for an advisory board meeting in Delhi on 20th March 2022 to discuss the role of Whole Genome Sequencing (WGS) in the diagnosis and management of TB. Objectives and specific topics relating to WGS in MDRTB were discussed, each expert shared their views, which led to a group discussion with a commitment to putting the patient first, and increasing their collective efforts, the organizations recognized that it is possible to make this goal a reality. The organizations involved in the discussion have declared their commitment to engaging in collaborative efforts to tackle DRTB detection efficiently. They advocate for strengthening access to WGS TB services, controlling and preventing TB, improving surveillance and drug resistance management, and investing in research and development. This Round Table serves as a framework to build on and ensure that the goal of ending TB is achievable with WGS services wherever needed. Post discussion, a uniform consensus was said to be arrived if more than 80% board members agreed to the statement. The present paper is the outcome of aspects presented and discussed in the advisory board meeting.

Drug resistant tuberculosis among elderly: Challenges.

The article deals with challenges faced by the geriatric populations while on MDR treatment. Risk factors like tobacco use, low socio-economic status, previous disease, longer delays in seeking treatment and reduced mobility are some of the challenges while initiating MDR treatment. Other issues like drug-related adverse events and increased co-morbidity pose a major challenge while treating patients. Susceptibility among the geriatric age group includes various anatomical and physiological changes including nutritional deficiencies and co morbidities.

Utilization of health care services by elderly for respiratory diseases including TB - Challenges.

Progressive functional decline of all body organ systems in association with decreased immunity makes elderly vulnerable to all types of diseases including respiratory diseases. Advances in medical fields have resulted in increasing proportion of elderly globally. Healthcare demands of elderly population are complex. Provision of healthcare services for this continuously increasing population subgroup & ensuring their adequate utilization is full of challenges. These are demographic, socioeconomic, financial, physical accessibility, quality of healthcare services, attitudinal & transportation related. Large size of this subgroup with special healthcare needs in context of limited available resources of middle income country like India is the biggest challenge. Poor educational status & socioeconomic condition of Indian elderly, dependence on family, absence of formal social security & healthcare security complicates situation further. Condition of elderly females is particularly worse. In view of poor physical ability with often associated physical disability makes accessibility of healthcare services also significant factor. Overcoming negative attitudinal factors prevalent in Indian elderly & make them utilize available healthcare services is another huge challenge. Quality of healthcare services in form of availability of required expertise & equipments, attitude of healthcare providers towards elderly patients & convenience in utilization of these services also play an important role. Special provisions in TB control program for elderly in view of their complex needs, high prevalence, morbidity & mortality are also required.

Indian Guidelines on Nebulization Therapy.

Inhalational therapy, today, happens to be the mainstay of treatment in obstructive airway diseases (OADs), such as asthma, chronic obstructive pulmonary disease (COPD), and is also in the present, used in a variety of other pulmonary and even non-pulmonary disorders. Hand-held inhalation devices may often be difficult to use, particularly for children, elderly, debilitated or distressed patients. Nebulization therapy emerges as a good option in these cases besides being useful in the home care, emergency room and critical care settings. With so many advancements taking place in nebulizer technology; availability of a plethora of drug formulations for its use, and the widening scope of this therapy; medical practitioners, respiratory therapists, and other health care personnel face the challenge of choosing appropriate inhalation devices and drug formulations, besides their rational application and use in different clinical situations. Adequate maintenance of nebulizer equipment including their disinfection and storage are the other relevant issues requiring guidance. Injudicious and improper use of nebulizers and their poor maintenance can sometimes lead to serious health hazards, nosocomial infections, transmission of infection, and other adverse outcomes. Thus, it is imperative to have a proper national guideline on nebulization practices to bridge the knowledge gaps amongst various health care personnel involved in this practice. It will also serve as an educational and scientific resource for healthcare professionals, as well as promote future research by identifying neglected and ignored areas in this field. Such comprehensive guidelines on this subject have not been available in the country and the only available proper international guidelines were released in 1997 which have not been updated for a noticeably long period of over two decades, though many changes and advancements have taken place in this technology in the recent past. Much of nebulization practices in the present may not be evidence-based and even some of these, the way they are currently used, may be ineffective or even harmful. Recognizing the knowledge deficit and paucity of guidelines on the usage of nebulizers in various settings such as inpatient, out-patient, emergency room, critical care, and domiciliary use in India in a wide variety of indications to standardize nebulization practices and to address many other related issues; National College of Chest Physicians (India), commissioned a National task force consisting of eminent experts in the field of Pulmonary Medicine from different backgrounds and different parts of the country to review the available evidence from the medical literature on the scientific principles and clinical practices of nebulization therapy and to formulate evidence-based guidelines on it. The guideline is based on all possible literature that could be explored with the best available evidence and incorporating expert opinions. To support the guideline with high-quality evidence, a systematic search of the electronic databases was performed to identify the relevant studies, position papers, consensus reports, and recommendations published. Rating of the level of the quality of evidence and the strength of recommendation was done using the GRADE system. Six topics were identified, each given to one group of experts comprising of advisors, chairpersons, convenor and members, and such six groups (A-F) were formed and the consensus recommendations of each group was included as a section in the guidelines (Sections I to VI). The topics included were: A. Introduction, basic principles and technical aspects of nebulization, types of equipment, their choice, use, and maintenance B. Nebulization therapy in obstructive airway diseases C. Nebulization therapy in the intensive care unit D. Use of various drugs (other than bronchodilators and inhaled corticosteroids) by nebulized route and miscellaneous uses of nebulization therapy E. Domiciliary/Home/Maintenance nebulization therapy; public & health care workers education, and F. Nebulization therapy in COVID-19 pandemic and in patients of other contagious viral respiratory infections (included later considering the crisis created due to COVID-19 pandemic). Various issues in different sections have been discussed in the form of questions, followed by point-wise evidence statements based on the existing knowledge, and recommendations have been formulated.

Study of different methods of susceptibility testing of M. tuberculosis.

This communication is on a multi-centre collaborative study carried out by New Delhi Tuberculosis (NDTB) Centre, Delhi, to compare the different methods of drug susceptibility testing (DST) of Mycobacterium tuberculosis for Streptomycin, Rifampicin, Isoniazid and Ethambutol in various accredited laboratories 40 samples (selected by simple random sampling technique) from sputum positive out-patients presenting between December 2004 and January 2005 were collected at New Delhi Tuberculosis Centre from 24 males and 16 females (age ranging from 18 to 55 years) were taken up for culture and susceptibility testing. The proportion method of DST done at NDTB Centre was taken as standard for comparing the other methods after it was found to have a good agreement with the proportion method performed at Tuberculosis Research Centre, Chennai (Kappa coefficient 0.75 to 1). All 40 sub-cultures were processed for DST by the resistance ratio and proportion methods at NDTB Centre. Also, the 40 sub-cultures were sent to Central JALMA Institute for Leprosy (JALMA), Agra that used the resistance ratio method and 25 sub-cultures were transported to National Institute of Communicable Diseases (NICD), Delhi for performing the Bactec 460TB method. The resistance ratio and proportion methods were compared both intra-laboratory (NDTB Centre) and inter-laboratory (NDTB Centre and JALMA). The sensitivity and specificity of the resistance ratio method compared to the proportion method both inter and intra-laboratory, were very high for all the drugs (except Ethambutol inter-laboratory). This was corroborated by the good agreement between the resistance ratio performed at the two centres. Bactec 460TB method, on the other hand, did not have acceptable measures of validity (sensitivity and specificity) compared to the proportion method for Streptomycin and Ethambutol. Both resistance ratio method & proportion method are comparable and either can be used for making clinical decisions. But Bactec 460 method, despite yielding early results loses out on validity.

Latent TB (LTBI) treatment: Challenges in India with an eye on 2025: "To Treat LTBI or not to treat, that is the question".

Latent tuberculosis infection (LTBI) is defined as a consistent immune response to Mycobacterium tuberculosis antigens without evidence of clinically evident active tuberculosis (TB). Diagnosis and treatment for LTBI are important for TB, especially in high-risk populations especially in high prevalent country like India. Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are used to diagnose LTBI. Therefore an unequivocal policy /of diagnosis and treatment of LTBI will serve to ameliorate the standards of the Indian health scenario and bring the TB infection to the propinquity of its ultimate elimination.

Lessons to be learnt from 100 year old 1918 influenza pandemic viz a viz 2019 corona pandemic with an eye on NTEP.

The article is about the 1918 H1N1 flu pandemic also called the "Spanish flu" which killed 50 million plus people worldwide, and the coronavirus pandemic (Covid-19) which has spread in the world at an alarming pace. As of now there are 11,327,790 cases and 532,340 deaths globally. Aim of this article is to draw conclusions and share knowledge from both the pandemics and apply these lessons in other health programmes.

Morbidity and mortality trends of Covid 19 in top 10 countries.

The present article highlights morbidity and mortality trends of Covid 19 in the last 3 months in top 10 countries of the world. In spite of efforts being undertaken, all countries are showing an increasing trend in terms of morbidity and mortality. The order of countries in terms of mortality and morbidity has changed in the last 3 months. Various efforts are being undertaken by WHO and other agencies world over including the vaccine development initiative.

Covid-19 and social stigma: Role of scientific community.

COVID-19 has led to stigma and discrimination among various groups of people in different populations. Healthcare workers caring for those affected by COVID-19,3 people who have recovered from COVID-19,4 those belonging to lower socioeconomic groups, those having particular religious and racial identities have all been at the receiving end of the discrimination. COVID-19 has led to reinforcement of preexisting stereotypes against various groups. For instance, in Italy, in weeks before the national lockdown started, a state of emergency was declared but everyday life was going on as always, the sentiment toward the Chinese community changed: their restaurants were left empty, more and more parents did not want their children to go to school if they had a Chinese classmate, and a high-profile politician said on TV that 'we have all seen them eat live mice'.

White paper on Ivermectin as a potential therapy for COVID-19.

A group of senior doctors with vast clinical experience met on 19th July'20 under the aegis of Academy of Advanced Medical Education. The panel looked at Ivermectin, one of the old molecule and evaluated it's use in COVID 19 (Novel Coronavirus Disease 2019) management. After critical panel discussion, all the attending doctors came to a conclusion that Ivermectin can be a potential molecule for prophylaxis and treatment of people infected with Coronavirus, owing to its anti-viral properties coupled with effective cost, availability and good tolerability and safety.

Molecular Detection of Aspergillus in Sputum of Patients with Lower Respiratory Tract Infections.

BACKGROUND: Raised incidences of respiratory tract infections due to fungal agents in immunocompetent individuals are a cause of concern due to the unavailability of rapid diagnostic methods. MATERIALS AND METHODS: Sputum and serum samples were collected from patients having lower respiratory tract infections (LRTIs), serum samples were screened for the presence of anti Aspergillus antibodies and sputum samples were homogenized and processed for identification of Aspergillus by conventional methods and further subjected to polymerase chain reaction (PCR) using genus-specific ITS 4-5 primers. RESULTS: PCR identified Aspergillus in 28% sputum samples, which was high as compared to conventional methods. CONCLUSION: Simple conventional PCR technique proves to be useful screening in for early identification of Aspergillus colonization in patients with LRTI, which can prevent irreversible damage in their lungs by fungal invasion.

Direct detection of mycobacterial species in pulmonary specimens by two rapid amplification tests, the gen-probe amplified mycobacterium tuberculosis direct test and the genotype mycobacteria direct test.

Nucleic acid amplification tests have improved tuberculosis diagnostics considerably. This study evaluates a new amplification test, the GenoType Mycobacteria Direct (GTMD) test, for detection of the Mycobacterium tuberculosis complex, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, and Mycobacterium malmoense directly in 61 sputum samples. Thirty (49.2%) samples were auramine smear positive, and 31 (50.8%) were smear negative. The GTMD results were compared to the Gen-Probe Amplified M. tuberculosis Direct (MTD) test results, using culturing and sequencing of the 16S rRNA gene as reference methods. The GTMD test could identify 28 of 29 samples containing the M. tuberculosis complex and was negative in a sputum sample containing M. intracellulare. The overall sensitivity and specificity results were 93.3% and 90.0% for the GTMD test, respectively, and 93.1% and 93.5% for the MTD test, respectively. The GTMD test is rapid and can be easily included in routine clinical laboratories for the direct detection of the M. tuberculosis complex in smear-positive sputum samples as an adjunct to microscopy and culture. Further studies are needed to evaluate the performance of the GTMD test for the detection of atypical mycobacteria.

Journey of tuberculosis control in India.

NTP was pilot tested in Anantapur district of Andhra Pradesh during 1961 and thereafter the programme was launched throughout the country. In 1992, the Government of India together with the World Health Organization (WHO) and Swedish International Development Agency (SIDA) reviewed the National TB Programme and concluded that it suffered from managerial weakness, inadequate funding, over-reliance on x-ray, non-standard treatment regimens, low rates of treatment completion and lack of systematic information on treatment outcomes. Programme review showed that only 30% of patients were diagnosed and only 30% of those treated successfully. Based on the findings and recommendations of the review in 1992, the GOI evolved a revised strategy and launched the Revised National TB Control Programme (RNTCP).