COVID-19 and Cancer: A Comparison of the Two Important Pandemic Waves in an Indian Cancer Patients' Cohort.

Ullas BatraIt is well known that patients with cancer are at an increased risk of severe COVID-19. There are no reports that depict the differences in outcomes in cancer patients between the two waves of the pandemic. This is a real-world experience aimed at characterizing the differences in demographics, clinical features, treatment details, and outcomes in COVID-19-positive cancer patients between the two pandemic waves. This was a prospective study of all COVID-19-positive cancer patients attending our specialty out-patient department at Rajiv Gandhi Cancer Institute and Research Centre between March 2020 and November 2020 (1st wave) and April 2021 and June 2021 (second wave). All patients diagnosed to have COVID-19 by real-time polymerase chain reaction (RT-PCR) with a biopsy-proven solid organ malignancy attending the medical oncology out-patient department were included during both the waves. A total of 300 patients with proven SARS-CoV-2 infection by either RT-PCR or cartridge based nucleic acid amplification test were encountered, of which 123 were encountered during the first wave of the pandemic and 177 during the second wave. The case fatality rate of the first wave was 9.8%, with a 15-day case fatality rate of 5.6%, whereas for the second wave, it was 13% and 7.2%, respectively. Twelve patients succumbed to COVID-19 disease in the first wave and 23 succumbed in the second. There were no statistically significant correlations; however, the death in the second wave tended to occur more in younger male patients, with comorbidities and history of smoking. There was no relation with ongoing cancer-directed treatment or chemotherapy. Our study is unique in comparing characteristics of the two most important COVID-19 waves and treatment patterns in cancer patients from a single center. The second wave showed a higher CFR, hospital admission rate, and higher frequency of respiratory complications; however, there was no relation to cancer-directed therapy and COVID-19, thus reiterating the fact that cancer treatment should not be halted in the event of a COVID-19 infection.

AI-based pipeline for early screening of lung cancer: integrating radiology, clinical, and genomics data.

Background: The prognosis of lung carcinoma has changed since the discovery of molecular targets and their specific drugs. Somatic Epidermal Growth Factor Receptor (EGFR) mutations have been reported in lung carcinoma, and these mutant proteins act as substrates for targeted therapies. However, in a resource-constrained country like India, panel-based next-generation sequencing cannot be made available to the population at large. Additional challenges such as adequacy of tissue in case of lung core biopsies and locating suitable tumour tissues as a result of innate intratumoral heterogeneity indicate the necessity of an AI-based end-to-end pipeline capable of automatically detecting and learning more effective lung nodule features from CT images and predicting the probability of the EGFR-mutant. This will help the oncologists and patients in resource-limited settings to achieve near-optimal care and appropriate therapy. Methods: The EGFR gene sequencing and CT imaging data of 2277 patients with lung carcinoma were included from three cohorts in India and a White population cohort collected from TCIA. Another cohort LIDC-IDRI was used to train the AIPS-Nodule (AIPS-N) model for automatic detection and characterisation of lung nodules. We explored the value of combining the results of the AIPS-N with the clinical factors in the AIPS-Mutation (AIPS-M) model for predicting EGFR genotype, and it was evaluated by area under the curve (AUC). Findings: AIPS-N achieved an average AP50 of 70.19% in detecting the location of nodules within the lung region of interest during validation and predicted the score of five lung nodule properties. The AIPS-M machine learning (ML) and deep learning (DL) models achieved AUCs ranging from 0.587 to 0.910. Interpretation: The AIPS suggests that CT imaging combined with a fully automated lung-nodule analysis AI system can predict EGFR genotype and identify patients with an EGFR mutation in a cost-effective and non-invasive manner. Funding: This work was supported by a grant provided by Conquer Cancer Foundation of ASCO [2021IIG-5555960128] and Pfizer Products India Pvt. Ltd.

Cell-penetrating protein-recognizing polymeric nanoparticles through dynamic covalent chemistry and double imprinting.

Molecular recognition of proteins is key to their biological functions and processes such as protein-protein interactions (PPIs). The large binding interface involved and an often relatively flat binding surface make the development of selective protein-binding materials extremely challenging. A general method is reported in this work to construct protein-binding polymeric nanoparticles from cross-linked surfactant micelles. Preparation involves first dynamic covalent chemistry that encodes signature surface lysines on a protein template. A double molecular imprinting procedure fixes the binding groups on the nanoparticle for these lysine groups, meanwhile creating a binding interface complementary to the protein in size, shape, and distribution of acidic groups on the surface. These water-soluble nanoparticles possess excellent specificities for target proteins and sufficient affinities to inhibit natural PPIs such as those between cytochrome c (Cytc) and cytochrome c oxidase (CcO). With the ability to enter cells through a combination of energy-dependent and -independent pathways, they intervene apoptosis by inhibiting the PPI between Cytc and the apoptotic protease activating factor-1 (APAF1). Generality of the preparation and the excellent molecular recognition of the materials have the potential to make them powerful tools to probe protein functions in vitro and in cellulo.

Inroads into saline-alkaline stress response in plants: unravelling morphological, physiological, biochemical, and molecular mechanisms.

MAIN CONCLUSION: This article discusses the complex network of ion transporters, genes, microRNAs, and transcription factors that regulate crop tolerance to saline-alkaline stress. The framework aids scientists produce stress-tolerant crops for smart agriculture. Salinity and alkalinity are frequently coexisting abiotic limitations that have emerged as archetypal mediators of low yield in many semi-arid and arid regions throughout the world. Saline-alkaline stress, which occurs in an environment with high concentrations of salts and a high pH, negatively impacts plant metabolism to a greater extent than either stress alone. Of late, saline stress has been the focus of the majority of investigations, and saline-alkaline mixed studies are largely lacking. Therefore, a thorough understanding and integration of how plants and crops rewire metabolic pathways to repair damage caused by saline-alkaline stress is of particular interest. This review discusses the multitude of resistance mechanisms that plants develop to cope with saline-alkaline stress, including morphological and physiological adaptations as well as molecular regulation. We examine the role of various ion transporters, transcription factors (TFs), differentially expressed genes (DEGs), microRNAs (miRNAs), or quantitative trait loci (QTLs) activated under saline-alkaline stress in achieving opportunistic modes of growth, development, and survival. The review provides a background for understanding the transport of micronutrients, specifically iron (Fe), in conditions of iron deficiency produced by high pH. Additionally, it discusses the role of calcium in enhancing stress tolerance. The review highlights that to encourage biomolecular architects to reconsider molecular responses as auxiliary for developing tolerant crops and raising crop production, it is essential to (a) close the major gaps in our understanding of saline-alkaline resistance genes, (b) identify and take into account crop-specific responses, and (c) target stress-tolerant genes to specific crops.

Chemotherapy for Salivary Gland Malignant Carcinoma : Meta-analysis and Systemic Review.

 The primary form of treatment for salivary gland cancer is surgical resection. Radiation therapy is used as adjuvant therapy in cases of aggressive tumours, currently patients with recurrent or metastatic cancer who are not suitable for surgery or radiation are most often treated with chemotherapy. PRISMA guidelines for systematic reviews were followed to evaluate salivary gland malignancies involving cytotoxic chemotherapy and biologic agents. An electronic literature search of Medline, PubMed, Scopus, etc. was performed and relevant articles were selected based on the inclusion criteria. Cytotoxic chemotherapies and biologic drugs such as anti HER - 2, anti-EGFR and anti-C-Kit are used to treat salivary gland cancer. Although most trials have respond poorly to standard chemotherapy with short durability and significant toxicity. Most of the research has focused on ACC and the use of combination therapy with cisplastin in conjunction with other treatments has been found to improve overall survival rate. Due to the limited patient population it was difficult to assess the efficacy of chemotherapy, which achieved very modest results. There are potential molecular targets such as HER2,NTRK and targeted treatments are becoming more popular. However to further explore potential treatment alternatives SGC patients should be enrolled in clinical trials.

Outcomes of intravitreal anti-VEGF injections and panretinal photocoagulation in preretinal hemorrhage secondary to proliferative diabetic retinopathy involving the fovea.

PURPOSE: To evaluate the outcome of intravitreal anti-vascular endothelial growth factor (VEGF) injections and panretinal photocoagulation (PRP) in fovea involving preretinal hemorrhage (PRH) secondary to proliferative diabetic retinopathy (PDR). METHODS: Retrospective non-comparative cross-sectional series of patients diagnosed with fovea involving PRH secondary to PDR at our institute from March 2019 to October 2021 who were treated with combination treatments of intravitreal anti-VEGF and PRP and have completed a minimum 6-month follow-up. The primary outcome measure was serial changes in the visual acuity (VA) and PRH regression from the fovea. Secondary outcome measures were the quantitative assessment of the size of PRH, its association with VA improvement and time to regression, and the proportion of patients who underwent surgery for poor response. RESULTS: In total, 22 eyes of 21 patients showed regression of PRH from the foveal center at 33.6 days, and complete regression was seen at 140.7 days. The average number of anti-VEGF injections required for clearance of PRH from the fovea was 1.6. Mean LogMAR visual acuity improved from 0.54 at baseline to 0.32 at 4 weeks and 0.18 at 6 months ( P < 0.01). Three eyes (13.6%) required vitrectomy surgery during follow-up. The mean area of PRH as measured by Image J analysis was 14.78 mm 2 at baseline, 8.97 mm 2 at 4 weeks, and 1.25 mm 2 at 3 months ( P < 0.01). No statistically significant difference was seen between the size of PRH and PRH clearance time and VA improvement. No systemic side effects were observed following the intravitreal injections during follow-up. CONCLUSION: Intravitreal anti-VEGF injections and PRP were found to be effective and safe treatment methods for fovea involving PRH secondary to PDR. Long-term studies are warranted to assess the long-term efficacy.

Investigation of Anterior Teeth Fractures Among Students Aged Between 8 and 13 Years in Hyderabad, India.

Introduction Trauma involving anterior teeth stands as a prevalent type of dental injury among school-age children, impacting physical, psychological, and social well-being. This study aimed to assess the occurrence of fractures in anterior teeth among school children in Hyderabad and its associated risk factors. Materials and methods This research incorporated a cross-sectional analysis, involving 2046 children in the age group of 8 to 13 years from different schools in Hyderabad City. Alongside clinical evaluations, all participants completed a questionnaire regarding traumatic dental injuries.  Results Results indicated a prevalence rate of 8.5%, notably higher among younger boys. Factors such as lip competence coverage, increased overjet, and malocclusion with maxillary incisor proclination were associated with a heightened risk of such injuries. The peak incidence was observed at age 12, with fractures involving enamel and dentin being the most common type, predominantly affecting the maxillary central incisors. Conclusion The findings emphasize the significance of educational programs aimed at enhancing awareness and understanding of dental injuries among parents, students, and school staff.

Remote at-home wearable-based gait assessments in Progressive Supranuclear Palsy compared to Parkinson's Disease.

BACKGROUND: Wearable sensors can differentiate Progressive Supranuclear Palsy (PSP) from Parkinson's Disease (PD) in laboratory settings but have not been tested in remote settings. OBJECTIVES: To compare gait and balance in PSP and PD remotely using wearable-based assessments. METHODS: Participants with probable PSP or probable/clinically established PD with reliable caregivers, still able to ambulate 10 feet unassisted, were recruited, enrolled, and consented remotely and instructed by video conference to operate a study-specific tablet solution (BioDigit Home ™) and to wear three inertial sensors (LEGSys™, BioSensics LLC, Newton, MA USA) while performing the Timed Up and Go, 5 × sit-to-stand, and 2-min walk tests. PSPRS and MDS-UPDRS scores were collected virtually or during routine clinical visits. RESULTS: Between November, 2021- November, 2022, 27 participants were screened of whom 3 were excluded because of technological difficulties. Eleven PSP and 12 PD participants enrolled, of whom 10 from each group had complete analyzable data. Demographics were well-matched (PSP mean age = 67.6 ± 1.3 years, 40% female; PD mean age = 70.3 ± 1.8 years, 40% female) while disease duration was significantly shorter in PSP (PSP 14 ± 3.5 months vs PD 87.9 ± 16.9 months). Gait parameters showed significant group differences with effect sizes ranging from d = 1.0 to 2.27. Gait speed was significantly slower in PSP: 0.45 ± 0.06 m/s vs. 0.79 ± 0.06 m/s in PD (d = 1.78, p < 0.001). CONCLUSION: Our study demonstrates the feasibility of measuring gait in PSP and PD remotely using wearable sensors. The study provides insight into digital biomarkers for both neurodegenerative diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04753320, first posted Febuary 15, 2021.

Anaesthetic and Surgical Considerations in Post COVID-19 Patients Requiring Head and Neck Surgery.

As the cases of COVID-19 have declined, the number of patients who have recovered from the dreaded disease is reporting for elective or emergency surgeries. Surgical planning in patients who have recovered from COVD-19 requires special considerations because of the morbidity and mortality associated with the infection and its devastating after-effects. There is a distinct paucity of literature on guidelines and protocols to follow in the perioperative management of these patients. With the help of experience gained over the past 2 years of the 'COVID-19 era', we have been able to establish important recommendations, guidelines and useful protocols during perioperative management of COVID-recovered patients. These protocols include important anesthetic and surgical considerations, which are both practical as well as implementable and are also in cognizance with government-laid down advisories. Although SARS-CoV-2 infection primarily affects the pulmonary and cardiac systems, it has the potential for serious and severely affect multiple organs and various other body systems in erratic and unpredictable manner. All of these factors can have significant implications that make the perioperative management of post-COVID-19 patients, difficult and challenging. Considering the far-reaching and long-lasting effects of this infection on the human body, the protocols and recommendations presented in this article can serve as a valuable guide for clinicians to effectively manage the surgical patient and help reduce perioperative complications attributable to COVID-19 infection.

SARS-CoV-2 ORF6 protein targets TRIM25 for proteasomal degradation to diminish K63-linked RIG-I ubiquitination and type-I interferon induction.

Evasion and antagonism of host cellular immunity upon SARS-CoV-2 infection provide replication advantage to the virus and contribute to COVID-19 pathogenesis. We explored the ability of different SARS-CoV-2 proteins to antagonize the host's innate immune system and found that the ORF6 protein mitigated type-I Interferon (IFN) induction and downstream IFN signaling. Our findings also corroborated previous reports that ORF6 blocks the nuclear import of IRF3 and STAT1 to inhibit IFN induction and signaling. Here we show that ORF6 directly interacts with RIG-I and blocks downstream type-I IFN induction and signaling by reducing the levels of K63-linked ubiquitinated RIG-I. This involves ORF6-mediated targeting of E3 ligase TRIM25 for proteasomal degradation, which was also observed during SARS-CoV-2 infection. The type-I IFN antagonistic activity of ORF6 was mapped to its C-terminal cytoplasmic tail, specifically to amino acid residues 52-61. Overall, we provide new insights into how SARS-CoV-2 inhibits type-I IFN induction and signaling through distinct actions of the viral ORF6 protein.

Dissecting the Molecular Basis of Host Leucine-Rich Repeat Containing 15 Mediated Interaction with Receptor Binding Domain of SARS-CoV-2 Spike Protein: A Computational Approach.

The detection of leucine-rich repeat containing 15 (LRRC15) as a connecting link with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the possibility of its involvement in differential restriction activity of SARS-CoV-2 pathways. However, the structure-function mechanism of LRRC15 involving the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and their mode of interaction is largely unknown. Using state-of-the-art AlphaFold2 and all-atom molecular dynamics simulations, our findings provide evidences of alternative binding modes of RBD with LRR units of LRRC15 having varied affinities. Contribution of both the receptor binding regions in RBD, including receptor binding motif in accommodating the LRR domain, towards the C-terminal region, emphasizes its differential role in modulating host cell receptiveness for SARS-CoV-2, the innate immune system, as well as antiviral tone. However, further experimental validations are necessary for unravelling the unknown mechanism and distinctive features of this host receptor in the COVID-19 pandemic, involving both the transmembrane as well as cytoplasmic domain.

Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson's disease.

INTRODUCTION: Distinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical care/prognostication. METHODS: We recruited 21 participants with PSP(n = 11) or PD(n = 10) with reliable caregivers. Standardized passage reading, counting, and sustained phonation were recorded on the BioDigit Home tablet (BioSensics LLC, Newton, MA USA), and speech features from the assessments were analyzed using the BioDigit Speech platform (BioSensics LLC, Newton, MA USA). An independent t-test was performed to compare each speech feature between PSP and PD participants. We also performed Spearman's correlations to evaluate associations between speech measures and clinical scores (e.g., PSP rating scales and MoCA). In addition, the model's performance in classifying PSP and PD was evaluated using Rainbow passage reading analysis. RESULTS: During Rainbow passage reading, PSP participants had a significantly slower articulation rate (2.45(0.49) vs 3.60(0.47) words/minute), lower speech-to-pause ratio (2.33(1.08) vs 3.67(1.18)), intelligibility dynamic time warping (DTW, 0.26(0.19) vs 0.53(0.26)), and similarity DTW (0.43(0.27) vs 0.67(0.13)) compared to PD participants. PSP participants also had longer pause times (17.24(5.47) vs 8.45(3.13) sec) and longer total signal times (52.44(6.67) vs (36.67(6.73) sec) when reading the passage. In terms of the phonation 'a', PSP participants showed a significant higher spectral entropy, spectral centroid, and spectral spread compared to PD participants and no differences were found for phonation 'e'. PD participants had more accurate reverse number counts than PSP participants (14.89(3.86) vs 7.36(4.67)). PSP Rating Scale (PSPRS) dysarthria (r = 0.79, p = 0.004) and bulbar item scores (r = 0.803, p = 0.005) were positively correlated with articulation rate in reverse number counts. Correct reverse number counts were positively correlated with total Montreal Cognitive Assessment scores (r = 0.703, p = 0.016). Machine learning models using passage reading-derived measures obtained an AUC of 0.93, and the sensitivity/specificity in correctly classifying PSP and PD participants were 0.95 and 0.90, respectively. CONCLUSION: Our study demonstrates the feasibility of differentiating PSP from PD using a digital health technology platform. Further multi-center studies are needed to expand and validate our initial findings.

Plant Essential Oils as Biopesticides: Applications, Mechanisms, Innovations, and Constraints.

The advent of the "Green Revolution" was a great success in significantly increasing crop productivity. However, it involved high ecological costs in terms of excessive use of synthetic agrochemicals, raising concerns about agricultural sustainability. Indiscriminate use of synthetic pesticides resulted in environmental degradation, the development of pest resistance, and possible dangers to a variety of nontarget species (including plants, animals, and humans). Thus, a sustainable approach necessitates the exploration of viable ecofriendly alternatives. Plant-based biopesticides are attracting considerable attention in this context due to their target specificity, ecofriendliness, biodegradability, and safety for humans and other life forms. Among all the relevant biopesticides, plant essential oils (PEOs) or their active components are being widely explored against weeds, pests, and microorganisms. This review aims to collate the information related to the expansion and advancement in research and technology on the applications of PEOs as biopesticides. An insight into the mechanism of action of PEO-based bioherbicides, bioinsecticides, and biofungicides is also provided. With the aid of bibliometric analysis, it was found that ~75% of the documents on PEOs having biopesticidal potential were published in the last five years, with an annual growth rate of 20.51% and a citation per document of 20.91. Research on the biopesticidal properties of PEOs is receiving adequate attention from European (Italy and Spain), Asian (China, India, Iran, and Saudi Arabia), and American (Argentina, Brazil, and the United States of America) nations. Despite the increasing biopesticidal applications of PEOs and their widespread acceptance by governments, they face many challenges due to their inherent nature (lipophilicity and high volatility), production costs, and manufacturing constraints. To overcome these limitations, the incorporation of emerging innovations like the nanoencapsulation of PEOs, bioinformatics, and RNA-Seq in biopesticide development has been proposed. With these novel technological interventions, PEO-based biopesticides have the potential to be used for sustainable pest management in the future.

Acid-Functionalized Artificial Enzymes with Tunable Selectivity for Vinyl Ether Hydrolysis.

Enzymes often employ catalytic groups with a medium or low intrinsic activity for highly challenging catalytic tasks. In this work, we report nanoparticle catalysts with accurately positioned carboxylic acids through either a covalent or noncovalent imprinting technique. The rationally designed active site allows the catalysis to be highly selective or quite unselective with respect to the substrate. With the proper catalyst, the hydrolysis proceeds smoothly in neutral water or even a slightly basic solution at room temperature.

Picolinic acid is a broad-spectrum inhibitor of enveloped virus entry that restricts SARS-CoV-2 and influenza A virus in vivo.

The COVID-19 pandemic highlights an urgent need for effective antivirals. Targeting host processes co-opted by viruses is an attractive antiviral strategy with a high resistance barrier. Picolinic acid (PA) is a tryptophan metabolite endogenously produced in mammals. Here, we report the broad-spectrum antiviral activity of PA against enveloped viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), flaviviruses, herpes simplex virus, and parainfluenza virus. Mechanistic studies reveal that PA inhibits enveloped virus entry by compromising viral membrane integrity, inhibiting virus-cellular membrane fusion, and interfering with cellular endocytosis. More importantly, in pre-clinical animal models, PA exhibits promising antiviral efficacy against SARS-CoV-2 and IAV. Overall, our data establish PA as a broad-spectrum antiviral with promising pre-clinical efficacy against pandemic viruses SARS-CoV-2 and IAV.

Unusual case of Trigeminal Neuralgia Associated with Poland -Moebius Syndrome.

Moebius Syndrome is a rare congenital neurological condition characterized by paralysis of several cranial nerves, commonly the VI(Abducens) and VII(Facial) cranial nerves which causes lateral gaze strabismus and internal strabismus & classical mask like appearance respectively. Other cranial nerves such as V, VII, IX, X, XI, XII are rarely affected. Von Graefe and German neurologist Moebius (1888), after whom the syndrome was eventually named, provided the earliest descriptions of it. Although the etiopathogenesis is unknown, it appears to occur sporadically in the majority of cases, and some documented cases show hereditary predisposition. This paper presents a rare instance of trigeminal neuralgia associated with Moebius syndrome. According to the author's research, this is the first case of Poland Moebius syndrome with trigeminal neuralgia documented from India.

Rapid regression of idiopathic multifocal choroiditis with intravitreal methotrexate-wide-field optical coherence tomography angiography-based study.

Wide-field optical coherence tomography angiography (OCTA) results in a patient of idiopathic multifocal choroiditis successfully treated with intravitreal methotrexate injections.

Tri-modality therapy in advanced esophageal carcinoma: long-term results and insights from a developing world, institutional cohort.

OBJECTIVE: To evaluate treatment outcomes in patients from a low-middle income country (LMIC) with esophageal carcinoma who underwent esophagectomy after neoadjuvant chemoradiation (NACRT/S). METHODS: Between 2010 and 2020, 254 patients (median follow-up: 53 months) met our inclusion criteria. Out-of-field nodal regions were determined by reviewing individual radiotherapy plans. Cox regression modelling was performed to analyze overall survival (OS) and recurrence-free survival (RFS), while pathological complete response (pCR) prediction utilized Poisson regression. RESULTS: The median OS was 71.4 months (interquartile range: 19.6-∞), RFS did not reach the median and pCR rate was 46%. On multivariable Cox regression, BMI [0.93 (0.89-0.98); 0.94 (0.89-0.99)] and absence of out-of-field node with extranodal extension (ENE)[0.22 (0.09-0.53); 0.30 (0.12-0.75)] influenced OS and RFS, respectively. Age [1.03 (1.01-1.06)], nodal stage [cN2-3 vs cN0: 2.67 (1.08-6.57)] and adventitial involvement [2.54 (1.36-4.72)] also influenced OS, while involved margins [3.12 (1.24-7.81)] influenced RFS. On multivariable Poisson regression, non-CROSS-chemotherapy regimens [0.65 (0.44-0.95)] and residual primary disease on pre-surgical imaging [0.73 (0.57-0.93)] were significantly associated with pCR. The most frequently involved in-field and out-of-field nodal regions were the periesophageal and perigastric (greater and lesser curvature) regions, respectively. CONCLUSION: NACRT/S is feasible and effective in patients from LMIC. Out-of-field ENE merits further investigation as a prognostic factor since it significantly influenced both OS and RFS. ADVANCES IN KNOWLEDGE: The results of clinical trials are replicable in LMICs. Out-of-field ENE is an independent prognostic factor for OS and RFS.

KRAS mutated Non-Small Lung Carcinoma: A Real World Context from the Indian subcontinent.

BACKGROUND: KRAS, although a common variant of occurrence (~20% of non-small-cell lung carcinoma [NSCLC]) has been untargetable, owing to the molecular structure which inherently prevents drug binding. KRAS mutations in NSCLC are associated with distinct clinical profiles including smokers and mucinous histology. KRAS G12C mutations account for ~40% KRAS altered NSCLC, but NSCLC being a geographically diverse disease, the features may be distinct in this part of the world. This is a single-center experience of KRAS-mutated NSCLC including clinical, imaging, pathologic features, and treatment patterns and outcomes. METHODS: This is a single-center retrospective study of KRAS-mutated NSCLC. The clinicopathological features and outcomes were retrieved and collated from the medical record archives of the hospital. RESULTS: Fifty (30.6%) patients with advanced-stage NSCLC with alterations in the KRAS gene were enrolled in the 163 patients who were tested for KRAS alterations. The median age was 61 years. Molecular detection revealed three main types of KRAS mutations viz-a-vis: G12C in 17 (34%), G12V in 9 (18%), and G12D in 6 (12%) patients. Comparing G12C versus the non-G12C mutated cases, co-mutations were common in the non-G12C subgroup (p < 0.05). Among the 36, who were treated at our center, all received chemotherapy as the first line with a median progression-free survival (PFS)of 5.4 months. The PFS of G12C was higher than the non-G12C subgroup (6.4 vs 3.8 months). CONCLUSION: This is the largest single-center experience from the Indian subcontinent for KRAS-mutated NSCLC with distinct clinical features. It highlights the unmet need for G12C inhibitors in our country, where prevalence is equivalent to the West.

A novel EML4-NTRK3 fusion in lung adenocarcinoma with dramatic response to entrectinib.

ABSTRACT: In-frame fusions in NTRK genes, with intact kinase domain, have been reported to occur at higher frequencies in rare tumors like infantile fibrosarcoma, congenital mesoblastic nephroma, and secretory carcinoma, whereas they occur at very low frequencies in common malignancies like NSCLC and colon cancers (0.1%-1%). Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. More than 50 fusion partners have been described, and only in-frame fusions result in constitutive ligand-independent kinase activity leading to oncogenesis. The commonly reported NTRK fusions in the lung include SQSTM1-NTRK1, ETV6-NTRK3, and SQSTM1-NTRK3. Detection of these rests on the use of conventional modalities like Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); however, accurate characterization requires direct sequencing methods. We report an interesting case of an NTRK fusion-positive NSCLC, exhibiting good response to entrectinib.