Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers.

Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.

Prolonged Corticosteroid Use Leading to Cerebral Venous Sinus Thrombosis: A Rare Association.

Partial or complete obstruction of blood flow in venous sinuses of the brain leads to a clinical condition termed cerebral venous sinus thrombosis (CVST). In most diagnosed cases, CVST has at least one risk factor identified among many postulated, and it most commonly includes acquired or inherited prothrombotic conditions. Steroid intake for intentional weight gain is prevalent in the general population, especially among new-generation bodybuilders and athletes. Excess exogenous steroids have many adverse effects, and increasing the risk of venous thromboembolism is one of them. The role of these steroids in developing CVST among such individuals has not been reported frequently in the literature. We report a case of a young male with a history of chronic exogenous steroid intake to increase his body weight, who presented with clinical features of CVST.

Implication of photic sneeze reflex in ophthalmology.

Background: Photic sneeze reflex (PSR) also known as autosomal dominant compelling helioophthalmic outburst is a rare condition characterized by uncontrolled sneezing in response to bright light. The exact mechanism causing this is poorly understood. However, various hypotheses have been proposed. Ophthalmic examination involves exposing the patient to bright light like slit lamp, indirect ophthalmoscopy, and surgical microscope, which can trigger sneezing in PSR patients. Purpose: The purpose of this video is to draw light to this rare phenomenon and its implication in ophthalmic surgery. Synopsis: A 74-year-old male patient presented with diminution of vision in left eye. On routine slit lamp and IDO examination, patient had repeated sneezing. We diagnosed him to have photic sneeze reflex. He had pseudophakic bullous keratopathy in the right eye and senile immature cataract in the left eye. Taking into consideration his one eyed status and PSR, measures were taken accordingly and cataract surgery was performed uneventfully. We describe in this video the challenges encountered with this phenomenon and approach in such cases. Highlights: In this video, we tried to give an idea about photic sneeze reflex and its theories. Also, we tried to bring out the impact of PSR on ophthalmologic practice. Video link: https://youtu.be/KMZ_PC0hzhI.

Correlation of serum SARS-CoV-2 IgM and IgG serology and clinical outcomes in COVID-19 patients: Experience from a tertiary care centre.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a pandemic for the last 2 years. Inflammatory response to the virus leads to organ dysfunction and death. Predicting the severity of inflammatory response helps in managing critical patients using serology tests IgG and IgM. AIM: To investigate the correlation of the serology (IgM and IgG) with reverse transcriptase polymerase chain reaction (RT-PCR) status, disease severity [mild to critical], intensive care unit (ICU) admission, septic shock, acute kidney injury, and in-hospital mortality. METHODS: We conducted a longitudinal study to correlate serum SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) serology with clinical outcomes in coronavirus disease 2019 (COVID-19) patients. We analyzed patient data from March to December 2020 for those who were admitted at All India Institute of Medical Sciences Rishikesh. Clinical and laboratory data of these patients were collected from the e-hospital portal and analyzed. A correlation was seen with clinical outcomes and was assessed using MS Excel 2010 and SPSS software. RESULTS: Out of 494 patients, the mean age of patients was 48.95 ± 16.40 years and there were more male patients in the study (66.0%). The patients were classified as mild-moderate 328 (67.1%), severe 131 (26.8%), and critical 30 (6.1%). The mean duration from symptom onset to serology testing was 19.87 ± 30.53 d. In-hospital mortality was observed in 25.1% of patients. The seropositivity rate (i.e., either IgG or IgM > 10 AU) was 50%. IgM levels (AU/mL) (W = 33428.000, P ≤ 0.001) and IgG levels (AU/mL) (W = 39256.500, P ≤ 0.001), with the median IgM/ IgG levels (AU/mL), were highest in the RT-PCR-Positive group compared to RT-PCR-Negative clinical COVID-19. There was no significant difference between the two groups in terms of all other clinical outcomes (disease severity, septic shock, ICU admission, mechanical ventilation, and mortality). CONCLUSION: The study showed that serology levels are high in RT-PCR positive group compared to clinical COVID-19. However, serology cannot be useful for the prediction of disease outcomes. The study also highlights the importance of doing serology at a particular time as antibody titers vary with the duration of the disease. In week intervals there was a significant correlation between clinical outcomes and serology on week 3.

Bullous Hemorrhagic Dermatosis: A Rare Benign Cutaneous Complication of Low-Molecular-Weight Heparin.

Enoxaparin-mediated bullous hemorrhagic dermatosis (BHD) is one of the rare side effects during prophylaxis of enoxaparin for various thromboembolic events. We report a case of a 74-year-old female with multiple comorbidities who developed BHD at a distant site from subcutaneous delivery of enoxaparin. Histopathological analysis confirmed the diagnosis of BHD. Discontinuation of enoxaparin resulted in the gradual resolution of the bullae formation, and the patient was started on novel oral anticoagulation with apixaban. The usual cutaneous adverse effects of enoxaparin include maculopapular rash, pruritus, skin necrosis, eczematous dermatitis, and rarely bullous hemorrhagic dermatosis. This hemorrhagic bullae dermatosis at a distant site from the administration is a relatively rare and benign side effect of enoxaparin which is an under-recognized complication of low-molecular-weight heparin.

Utility of IL-6 in the Diagnosis, Treatment and Prognosis of COVID-19 Patients: A Longitudinal Study.

COVID-19 has caused devastating effects worldwide ever since its origin in December 2019. IL-6 is one of the chief markers used in the management of COVID-19. We conducted a longitudinal study to investigate the role of IL-6 in diagnosis, treatment, and prognosis of COVID-19-related cytokine storm. Patients with COVID-19 who were admitted at AIIMS Rishikesh from March to December 2020 were included in the study. Patients with no baseline IL-6 value at admission and for whom clinical data were not available were excluded. Clinical and laboratory data of these patients were collected from the e-hospital portal and entered in an excel sheet. Correlation was seen with other inflammatory markers and outcomes were assessed using MS Excel 2010 and SPSS software. A total of 131 patients were included in the study. Of these, 74.8% were males, with mean age 55.03 ± 13.57 years, and mean duration from symptom onset being 6.69 ± 6.3 days. A total of 82.4% had WHO severe category COVID-19, with 46.56% having severe hypoxia at presentation and 61.8% of them having some comorbidity. Spearman rank correlation coefficient of IL-6 with D-dimer was 0.203, with LDH was -0.005, with ferritin was 0.3, and with uric acid was 0.123. A total of 11 patients received Tocilizumab at a mean duration from symptom onset of 18.09 days, and 100% mortality was observed. Deaths were reported more in the group with IL-6 ≥ 40 pg/mL (57.1% vs. 40.2%, p = 0.06). ICU admissions and ventilator requirement were higher in the IL-6 ≥ 40 pg/mL group (95.9% vs. 91.4%, p = 0.32 and 55.1% vs. 37.8%, p = 0.05). The study showed that IL-6 can be used as a possible "thrombotic cytokine marker". Higher values of IL-6 (≥40 pg/mL) are associated with more deaths, ICU admissions, and ventilator requirement.

Identification of a vicilin-like major allergen from Prosopis juliflora exhibiting cross- reactivity with legume food allergens.

BACKGROUND: Prosopis juliflora is a clinically relevant allergic sensitizer worldwide and shares cross-reactivity with allergens from several tree pollen and food. The present study aims to purify and immunobiochemically characterize a major allergen from Prosopis pollen. The allergen was further investigated for its cross-reactivity with legume allergens. METHODS: Prosopis extract was fractionated by Q Sepharose and Superdex 75 gel filtration column to purify the allergen. Specific IgE against purified protein was estimated via ELISA and immunoblot. The protein was subjected to mass spectrometric analysis. Glycan characterization was performed by Schiff staining and lectin binding assay followed by deglycosylation studies. The functional activity of the purified protein was evaluated by the basophil activation test. Cross-reactivity was assessed by inhibition studies with legume extracts. RESULTS: A 35 kDa protein was purified and showed 75% IgE reactivity with the patients' sera by ELISA and immunoblot. Glycan characterization of protein demonstrated the presence of terminal glucose and mannose residues. A reduction of 40% and 27% in IgE binding was observed upon chemical and enzymatic deglycosylation of the protein, respectively. The glycoprotein allergen upregulates the expression of CD203c on basophils which was significantly reduced upon deglycosylation, signifying its biological ability to activate the effector cells. The identified protein shared significant homology with Lup an 1 from the lupine bean. Immunoblot inhibition studies of the purified allergen with legume extracts underlined high cross-reactive potential. Complete inhibition was observed with peanut and common bean, while up to 70% inhibition was demonstrated with soy, black gram, chickpea, and lima bean. CONCLUSION: A 35 kDa vicilin-like major allergen was isolated from P. juliflora. The protein possesses glycan moieties crucial for IgE binding and basophil activation. Furthermore, the purified protein shows homology with Lup an 1 and exhibits cross-reactivity with common edible legume proteins.

A Novel Approach to Measuring Binocular Visual Fields in Glaucoma.

PRECIS: Combined average visual field index (VFI) is a simple, novel tool for binocular visual field which agrees with the existing binocular integrated visual field (IVF) model, as well as patient reported activity limitation in glaucoma. PURPOSE: The aim was to determine the correlation between novel models of binocular visual field with the existing IVF and glaucoma activity limitation (GAL-9). MATERIALS AND METHODS: IVFs were calculated from the monocular visual fields of 58 patients with primary glaucoma and the novel binocular visual field models termed binocular summation visual field index (BiSumVFI) and combined average visual field index (CaVFI) were derived from the VFIs of both fields. GAL-9 questionnaire was administered to the patients. The relationship between IVF and the 2 newer models of binocular fields were determined and the correlation of IVF, BiSumVFI, and CaVFI with GAL-9 was estimated. RESULTS: A very strong correlation was seen between IVF and BiSumVFI (r=-0.913, P<0.001, confidence interval: -0.958 to -0.821) and also between IVF and CaVFI (r=-0.896, P<0.001, confidence interval: -0.947 to -0.802). Linear regression analysis showed a significant R2 of 0.902 (P<0.001) to predict IVF from BiSumVFI and R2 of 0.847 (P<0.001) to predict IVF from CaVFI. IVF, BiSumVFI, and CaVFI correlated moderately and significantly with GAL-9 with correlation coefficients of 0.481, -0.499, and -0.505, respectively. CONCLUSION: The binocular summation VFI and combined average VFI models of binocular visual field are good predictors of IVF in glaucoma. They correlate well with the existing IVF model in estimating patients' perception of activity limitation in glaucoma.

Prior or concurrent radiotherapy and nivolumab immunotherapy in non-small cell lung cancer.

BACKGROUND: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. METHODS: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. RESULTS: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. CONCLUSION: RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti-PD-1 immunotherapy in NSCLC.

Accuracy and Prognostic Significance of Oncologists' Estimates and Scenarios for Survival Time in Advanced Gastric Cancer.

BACKGROUND: Worst-case, typical, and best-case scenarios for survival, based on simple multiples of an individual's expected survival time (EST), estimated by their oncologist, are a useful way of formulating and explaining prognosis. We aimed to determine the accuracy and prognostic significance of oncologists' estimates of EST, and the accuracy of the resulting scenarios for survival time, in advanced gastric cancer. MATERIALS AND METHODS: Sixty-six oncologists estimated the EST at baseline for each of the 152 participants they enrolled in the INTEGRATE trial. We hypothesized that oncologists' estimates of EST would be unbiased (∼50% would be longer or shorter than the observed survival time [OST]); imprecise (<33% within 0.67-1.33 times the OST); independently predictive of overall survival (OS); and accurate at deriving scenarios for survival time with approximately 10% of patients dying within a quarter of their EST (worst-case scenario), 50% living within half to double their EST (typical scenario), and 10% living three or more times their EST (best-case scenario). RESULTS: Oncologists' estimates of EST were unbiased (45% were shorter than the OST, 55% were longer); imprecise (29% were within 0.67-1.33 times observed); moderately discriminative (Harrell's C-statistic 0.62, p = .001); and an independently significant predictor of OS (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; p = .001) in a Cox model including performance status, number of metastatic sites, neutrophil-to-lymphocyte ratio ≥3, treatment group, age, and health-related quality of life (EORTC-QLQC30 physical function score). Scenarios for survival time derived from oncologists' estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 57% lived within half to double their EST, and 12% lived three times their EST or longer. CONCLUSION: Oncologists' estimates of EST were unbiased, imprecise, moderately discriminative, and independently significant predictors of OS. Simple multiples of the EST accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer. IMPLICATIONS FOR PRACTICE: Results of this study demonstrate that oncologists' estimates of expected survival time for their patients with advanced gastric cancer were unbiased, imprecise, moderately discriminative, and independently significant predictors of overall survival. Simple multiples of the expected survival time accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer.

Program to Improve Private Early Education (PIPE): a case study of a systems approach for scaling quality early education solutions.

FSG is a mission-driven nonprofit organization supporting leaders in creating large-scale, lasting social change. A survey conducted by FSG in 2015 across 4407 low-income families in urban India showed that 95% of them send their children to preschools, a majority of choosing affordable private preschools (APSs), as parents perceive the quality of government schools to be poor. Parents use and value rote-based methods (e.g., reciting poems) to assess their children's learning in school; however, these methods fail to measure conceptual understanding. The APS system delivers on these rote approaches using inappropriate pedagogy, leading to poor learning outcomes. Affordable high-quality activity-based preschool solutions exist and could be brought to the APS to significantly improve the classroom environment and learning outcomes. This requires changing mindsets of all actors-solution provider companies, APS owners, APS teachers, and low-income parents. We present FSG's approach to shaping demand for quality preschool services and to improve learning outcomes in urban Indian APSs through the implementation of the pilot Program to Improve Private Early Education (PIPE).

Health-related quality of life associated with regorafenib treatment in refractory advanced gastric adenocarcinoma.

BACKGROUND: The INTEGRATE phase II multinational randomized controlled trial demonstrated the activity of regorafenib on progression-free survival (PFS) in patients with refractory advanced gastric adenocarcinoma. We sought to evaluate whether these PFS gains had the potential to be offset by quality of life (QoL) impacts from treatment side effects and to thereby determine the appropriateness of continuing development to phase III. METHODS: QoL was assessed in INTEGRATE at baseline and at each 4 weeks thereafter, until discontinuation of study treatment, using the QLQ-C30, STO22, and EQ-5D questionnaires. The patient disease and treatment assessment (PTDATA) form was also provided to English-speaking participants. Randomized groups were compared on the QLQ-C30, STO22, and EQ-5D scales using a repeated-measures model; the frequency of troublesome symptoms and side effects measured by the PTDATA form; and deterioration-free survival (DFS). The prognostic value of baseline QoL information was also evaluated. RESULTS: Of the 147 eligible randomized patients, 142 consented to participate in the QoL substudy, 136 completed a baseline QoL assessment, and 95 completed at least one post-baseline QoL assessment. The DFS rate was significantly improved with regorafenib, and there was no compelling statistical evidence that regorafenib had a broad negative effect across the spectrum of QoL indices evaluated. Fatigue, anxiety, appetite loss, and pain were among the issues most commonly reported for both randomized groups. Baseline levels of pain, appetite, constipation, and physical functioning were prognostic factors for survival. CONCLUSIONS: Regorafenib improved DFS without an excessively negative effect on QoL. Progressing development to the phase III setting is warranted.

An Unusual Presentation in Urinothorax.

Urinothorax is defined as the presence of urine in the pleural cavity. Leakage from the urinary tract can cause urinoma with retroperitoneal urine collection, and secondarily, urinothorax. We report the case of a 35-year-old female who presented with dyspnoea and right-sided chest pain. Chest radiograph revealed a right-sided pleural effusion. The patient had undergone left-sided ovarian cystectomy three months ago, had sustained a left-sided ureteric injury that required ureteric stent placement. Urinothorax was suspected as a consequence of ureteric injury; pleural fluid to serum creatinine ratio was found to be greater than one, confirming the diagnosis.

Prognostic factors and treatment outcomes in patients with Small Bowel Adenocarcinoma (SBA): the Royal Marsden Hospital (RMH) experience.

BACKGROUND: SBA is a rare tumour which carries a poor prognosis. Very few data on prognostic factors and treatment outcomes are available. We conducted a retrospective analysis of patients treated for SBA at our institution. METHODS: Clinico-pathological characteristics, treatments and outcomes of all the SBA patients treated consecutively from 1996 to 2011 were retrospectively collected. The prognostic value of baseline factors was assessed using the Cox regression model. The Kaplan-Meier method was used to estimate the survival outcomes. RESULTS: Eighty-four patients with SBA were treated during the study period. Of these, 48 presented with early stage SBA, while 36 had unresectable disease. All early stage SBA patients (58.3% males; median age, 59 years) underwent resection (R0 in 44/48) and 27 (56%) received adjuvant chemotherapy. Median relapse-free survival and overall survival (OS) were 31.1 months (95% CI: 8.0-54.3) and 42.9 (95% CI: 0-94.9), respectively. In univariate analyses, poor histological differentiation (p = 0.025) and lymphovascular invasion (p = 0.003) were prognostic for OS. In the group of patients with relapsed, unresectable or metastatic disease (n = 59), systemic chemotherapy was administered in 46 cases (78%). The response rate to first line chemotherapy was 50%. Median progression-free survival and OS were 8.8 (95% CI: 5.5-12.3) and 12.8 months (95% CI: 8.4-17.2), respectively. In univariate analyses, low albumin (p = 0.041) and high platelet count (p = 0.007) were prognostic for OS. CONCLUSION: Prospective clinical trials are needed to inform the management of SBA patients. Prognostic factors evaluated in our series may be useful for patient stratification and treatment selection in future studies.

Hypersensitivity to pollen of four different species of Brassica: a clinico-immunologic evaluation in patients of respiratory allergy in India.

BACKGROUND: Rapeseed-mustard is the second most important source of edible oil in India. Several species of Brassica are grown in different parts of country for its oilseeds. OBJECTIVE: The objective was to investigate allergenicity to antigenic extracts of pollen of 4 species of Brassica. METHODS: Brassica campestris, Brassica juncea, Brassica nigra, and Brassica napus were selected for the detailed investigation. Pollen samples from each of the four species were collected from the polliniferous materials. The antigenic and allergenic profiles of these extracts were evaluated by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Skin prick test, enzyme linked immuno sorbent assay and Western blot on atopic individuals. RESULTS: Out of the 159 atopic subjects tested, 21.38% were positive to at least one or other species of Brassica pollen, with highest skin positivity (13.20%) to B. campestris extract. Raised IgE with significant linear correlation with intensity of skin reactions was obtained. Protein fractions of 20, 25, 32, 37, 56, and 90 kDa were recognized by B. campestris and B. juncea whereas 56, 76, 87, and 90 kDa were recognized by B. nigra and B. napus as major IgE binding protein fractions. The patients also showed positivity to other inhalant pollen allergens tested. CONCLUSION: IgE mediated hypersensitivity varied from 4.40% to 13.20% in Indian atopic subjects to pollen of one or the other species of Brassica. Protein fractions of 47, 56, 76, 87, and 90 kDa were identified as IgE binding by all the four species, however individual heterogeneity exists. Thus a local species may be more pertinent for immunotherapy. The major allergen needs to be further characterized.

Decreased hospital stay and significant cost savings after routine use of prophylactic gastrostomy for high-risk patients with head and neck cancer receiving chemoradiotherapy at a tertiary cancer institution.

BACKGROUND: Evidence-based nutritional and swallowing guidelines were developed to identify patients at high risk of developing malnutrition during chemoradiation for head and neck cancer. These guidelines recommended a prophylactic gastrostomy and were actively implemented at our institution in January 2007. This study assesses the effect of this policy change on patient outcomes. METHODS: This retrospective cohort study was carried out for the years before (2005) and after (2007) implementation of these guidelines. RESULTS: In all, 165 patients were treated with radical chemoradiation for head and neck cancer at our institution in the years 2005 and 2007. Gastrostomy tube complications were low. Patients in 2007 had significantly fewer hospital admissions, unexpected admissions, and a shorter mean duration of hospital stay in comparison with those in 2005. CONCLUSIONS: Prophylactic gastrostomy tubes in patients with high-risk head and neck cancer resulted in a significant decrease in hospital admissions and length of stay, and led to increased bed availability.

Challenges and opportunities in the targeting of fibroblast growth factor receptors in breast cancer.

Activation of the fibroblast growth factor receptor pathway is a common event in many cancer types. Here we review the role of fibroblast growth factor receptor signalling in breast cancer, from SNPs in FGFR2 that influence breast cancer risk and SNPs in FGFR4 that associate with breast cancer prognosis, and potential therapeutic targets such as receptor amplification and aberrant autocrine and paracrine ligand expression. We discuss the multiple therapeutic strategies in preclinical and clinical development and the current and future challenges to successfully targeting this pathway in cancer.

Preoperative and postoperative chemotherapy for gastric cancer.

Radical surgery offers the only chance of cure for patients with operable gastric cancer; however, outcomes remain generally poor due to a high rate of relapse post gastric surgery. Multimodality therapy using chemotherapy, radiation or a combination of both have been evaluated in different parts of the world to improve outcomes from surgery alone. Perioperative chemotherapy is generally preferred in Europe in contrast to postoperative chemoradiation in the US or adjuvant fluoropyrimidine chemotherapy in East Asia. Regardless of these variations, systemic chemotherapy consistently results in a survival benefit when used in multimodality treatment of operable gastric cancer.