An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.

Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) levels in ∼10%-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis and identified tyrosine kinase KIT as highly enriched. Furthermore, high to moderate levels of KIT expression were detected in ∼85% of SPINK1-positive PCa specimens. We show KIT signaling orchestrates SPINK1-mediated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/ß-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling led to restoration of AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide distinct treatment modalities for advanced-stage SPINK1-positive patients.

Outcome of Patients on Prolonged V-V ECMO at a Tertiary Care Center in India.

Introduction: Extracorporeal membrane oxygenation (ECMO) is a life-support system that provides cardiopulmonary support. With recent advances, the duration of ECMO has increased but data on the outcomes of prolonged V-V ECMO are limited and inconsistent. Materials and methods: It is a retrospective observational study done at a tertiary care center in Kolkata to study the outcome of patients receiving prolonged V-V ECMO defined as >14 days. Observation: A total of 22 patients received prolonged ECMO support. Fifteen patients (68.2%) had severe coronavirus disease-2019 (COVID-19). The mean duration of invasive mechanical ventilation (IMV) before ECMO was 5 days. Baseline PaO2/FiO2 (p/f) ratio was 82 and Murray score was 3.5. The mean duration of ECMO support was 27.18 days (SD: 11.59). Five patients (22.7%) had minor bleeding and one patient had oxygenator failure. Survival at hospital discharge was seven patients (31.8%). Conclusion: Duration of ECMO support alone should not represent a basis for decision making to decide futility or continuation of ECMO support. Prolonged ECMO in acute respiratory distress syndrome (ARDS) has minor complications and can lead to recovery in almost one-third of the patients. How to cite this article: Goel K, Chakraborty A, Goel A. Outcome of Patients on Prolonged V-V ECMO at a Tertiary Care Center in India. Indian J Crit Care Med 2023;27(11):790-794.

COVID-19 - a potential trigger for MOGAD-associated optic neuritis: a case report and literature review.

SARS-CoV-2 affects the nervous system directly by neurotoxic action, by binding to angiotensin-converting enzyme-2 (ACE2) receptors or indirectly by inducing cytokine storm leading to disruption of the blood-brain barrier, immunological mediation, increasing blood coagulation and as a trigger for autoimmune-mediated demyelinating injuries in the central nervous system. In COVID-19 neuro-ophthalmological manifestations are not so common. Optic neuritis is the result of optic nerve inflammation and has varied causes. In many patients, signs of inflammation are not visible on the fundus, and it usually manifests as papillitis-anterior neuritis, retrobulbar neuritis or visible optic nerve oedema. We are reporting a case of a middle-aged adult diagnosed with myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis of the right eye post-COVID-19 disease. Routine biochemical and haematological investigations, including electrolytes and hepatic and renal functions, were normal. In cerebrospinal fluid (CSF) - glucose 63.8 mg/dL, protein 39.1 mg/dL and ADA - 1 µ/L. No oligoclonal bands of immunoglobulin G (IgG) were seen on high-resolution electrophoresis. Serum Anti-MOG-antibodies were positive. A gadolinium-contrast magnetic resonance imaging (MRI) of the brain and orbits shows post-contrast enhancement in the superior aspect of the right intraconal soft tissue. The right optic nerve appears bulky and heterogeneous with peripheral post-contrast enhancement along its entire length suggestive of neuritis. A diagnosis of MOG antibody-positive optic neuritis was made, and the patient was treated with an injection of Methylprednisolone with intravenous immunoglobulin. Each day, the evaluation of the right eye showed remarkable improvement from finger counting to 6/6 vision. The patient was discharged on the 9th day of admission. We can conclude that early diagnosis was essential for improving the long-term outcome of the patient.

Guidelines for endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA): Joint Indian Chest Society (ICS)/Indian Association for Bronchology (IAB) recommendations.

Over the past decade, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become an indispensable tool in the diagnostic armamentarium of the pulmonologist. As the expertise with EBUS-TBNA has evolved and several innovations have occurred, the indications for its use have expanded. However, several aspects of EBUS-TBNA are still not standardized. Hence, evidence-based guidelines are needed to optimize the diagnostic yield and safety of EBUS-TBNA. For this purpose, a working group of experts from India was constituted. A detailed and systematic search was performed to extract relevant literature pertaining to various aspects of EBUS-TBNA. The modified GRADE system was used for evaluating the level of evidence and assigning the strength of recommendations. The final recommendations were framed with the consensus of the working group after several rounds of online discussions and a two-day in-person meeting. These guidelines provide evidence-based recommendations encompassing indications of EBUS-TBNA, pre-procedure evaluation, sedation and anesthesia, technical and procedural aspects, sample processing, EBUS-TBNA in special situations, and training for EBUS-TBNA.

A study on the morbid histopathological changes in COVID-19 patients with or without comorbidities using minimally invasive tissue sampling.

COVID-19 causes morbid pathological changes in different organs including lungs, kidneys, liver, and so on, especially in those who succumb. Though clinical outcomes in those with comorbidities are known to be different from those without-not much is known about the differences at the histopathological level. To compare the morbid histopathological changes in COVID-19 patients between those who were immunocompromised (Gr 1), had a malignancy (Gr 2), or had cardiometabolic conditions (hypertension, diabetes, or coronary artery disease) (Gr 3), postmortem tissue sampling (minimally invasive tissue sampling [MITS]) was done from the lungs, kidney, heart, and liver using a biopsy gun within 2 hours of death. Routine (hematoxylin and eosin) and special staining (acid fast bacilli, silver methanamine, periodic acid schiff) was done besides immunohistochemistry. A total of 100 patients underwent MITS and data of 92 patients were included (immunocompromised: 27, malignancy: 18, cardiometabolic conditions: 71). In lung histopathology, capillary congestion was more in those with malignancy, while others like diffuse alveolar damage, microthrombi, pneumocyte hyperplasia, and so on, were equally distributed. In liver histopathology, architectural distortion was significantly different in immunocompromised; while steatosis, portal inflammation, Kupffer cell hypertrophy, and confluent necrosis were equally distributed. There was a trend towards higher acute tubular injury in those with cardiometabolic conditions as compared to the other groups. No significant histopathological difference in the heart was discerned. Certain histopathological features were markedly different in different groups (Gr 1, 2, and 3) of COVID-19 patients with fatal outcomes.

Neuroleptic malignant syndrome in a case of extra-pontine myelinolysis: On the horns of dilemma.

Osmotic demyelination syndrome (ODS) and neuroleptic malignant syndrome (NMS) lead to severe neurological sequalae. Though currently thought to be different syndromes, literature suggests a relation between the two. We present the case of a 45-year-old male who was found to have chronic severe hyponatremia and underwent rapid correction of sodium and developed parkinsonism features. Magnetic resonance imaging (MRI) confirmed extrapontine myelinolysis (a type of ODS). The patient received haloperidol for agitated behavior and developed new features of rigidity, fever, tachycardia and elevated creatine phosphokinase (CPK) levels and thus neuroleptic malignant syndrome was suspected to overlap with ODS. We report this case highlighting the difficulty in differentiating the between ODS and NMS and their relationship.

Steroids in COVID-19: Tailor-made or "one size fits all"?

Since the RECOVERY trial, steroids have endorsed by all guidelines for treating moderate-severe COVID-19. The prescribed dose is 6mg dexamethasone or its equivalents for 10 days. However, in clinical practice, there are numerous occasions where the role of steroids cannot be extrapolated from current evidence: patients on immunosuppression, patients with persistent oxygen requirement after ten days of therapy, etc. We highlight the existing caveats and the need for further research and discussion.

Clinico-pathological features in fatal COVID-19 infection: a preliminary experience of a tertiary care center in North India using postmortem minimally invasive tissue sampling.

OBJECTIVES: To study the histopathology of patients dying of COVID-19 using post-mortem minimally invasive sampling techniques. METHODS: This was a single-center observational study conducted at JPNATC, AIIMS. Thirty-seven patients who died of COVID-19 were enrolled. Post-mortem percutaneous biopsies were taken from lung, heart, liver, kidney and stained with hematoxylin and eosin. Immunohistochemistry was performed using CD61 and CD163. SARS-CoV-2 virus was detected using IHC with primary antibodies. RESULTS: The mean age was 48.7 years and 59.5% were males. Lung histopathology showed diffuse alveolar damage in 78% patients. Associated bronchopneumonia was seen in 37.5% and scattered microthrombi in 21% patients. Immunopositivity for SARS-CoV-2 was observed in Type II pneumocytes. Acute tubular injury with epithelial vacuolization was seen in 46% of renal biopsies. Seventy-one percent of liver biopsies showed Kupffer cell hyperplasia and 27.5% showed submassive hepatic necrosis. CONCLUSIONS: Predominant finding was diffuse alveolar damage with demonstration of SARS-CoV-2 protein in the acute phase. Microvascular thrombi were rarely identified in any organ. Substantial hepatocyte necrosis, Kupffer cell hypertrophy, microvesicular, and macrovesicular steatosis unrelated to microvascular thrombi suggested that liver might be a primary target of COVID-19.