Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Is Venous Thromboembolism Prophylaxis Needed in Patients Undergoing Knee Arthroscopy? A Prospective Observational Study.

BACKGROUND: Although rare, deep vein thrombosis is a potentially life-threatening complication of knee arthroscopy. There are scanty literature analysing deep vein thrombosis after arthroscopy in Nepal. This study aimed to identify the prevalence of deep vein thrombosis in patients undergoing knee arthroscopy without chemoprophylaxis postoperatively at 2 weeks and 6 weeks, respectively. The study also aimed to estimate the risk of deep vein thrombosis in these patients by using Caprini Risk Assessment Model. METHODS: This prospective observational study was conducted at AKB center, B and B Hospital, Gwarko, Lalitpur, over a period of 16 months. All patients who underwent arthroscopy knee surgeries fulfilling the inclusion criteria were included in the study. The primary outcome measure was the prevalence of deep vein thrombosis as diagnosed by compression color-coded ultrasonography of the popliteal vein and calf vein at 2 weeks and 6 weeks postoperatively. The secondary outcome measure was the prevalence of deep vein thrombosis in the risk groups according to Caprini Risk Assessment Model. RESULTS: Out of 612 patients who underwent arthroscopic knee surgeries during the study period, 2 patients (0.33%) developed deep vein thrombosis at 6 weeks follow-up as diagnosed with ultrasonography of the popliteal and calf veins. The prevalence rate in high-risk group was 0.33% (1 in 307) and in very high-risk group was 5.88% (1 in 17). CONCLUSIONS: There was a low prevalence of deep vein thrombosis without chemoprophylaxis following knee arthroscopy in our study. There was higher prevalence of deep vein thrombosis in very high-risk group patients, so close monitoring of such patients during follow-up is recommended.

Physiological and molecular insights into the allelopathic effects on agroecosystems under changing environmental conditions.

Allelopathy is a natural phenomenon of competing and interfering with other plants or microbial growth by synthesizing and releasing the bioactive compounds of plant or microbial origin known as allelochemicals. This is a sub-discipline of chemical ecology concerned with the effects of bioactive compounds produced by plants or microorganisms on the growth, development and distribution of other plants and microorganisms in natural communities or agricultural systems. Allelochemicals have a direct or indirect harmful effect on one plant by others, especially on the development, survivability, growth, and reproduction of species through the production of chemical inhibitors released into the environment. Cultivation systems that take advantage of allelopathic plants' stimulatory/inhibitory effects on plant growth and development while avoiding allelopathic autotoxicity is critical for long-term agricultural development. Allelopathy is one element that defines plant relationships and is involved in weed management, crop protection, and microbial contact. Besides, the allelopathic phenomenon has also been reported in the forest ecosystem; however, its presence depends on the forest type and the surrounding environment. In the present article, major aspects addressed are (1) literature review on the impacts of allelopathy in agroecosystems and underpinning the research gaps, (2) chemical, physiological, and ecological mechanisms of allelopathy, (3) genetic manipulations, plant defense, economic benefits, fate, prospects and challenges of allelopathy. The literature search and consolidation efforts in this article shall pave the way for future research on the potential application of allelopathic interactions across various ecosystems.

Late urinary toxicity and QOL with pelvic radiotherapy for high-risk prostate cancer: Dose-effect relations in the POP-RT randomized phase III trial.

PURPOSE: The POP-RT phase III randomized trial showed improved biochemical failure-free survival and metastasis-free survival with whole pelvic radiotherapy (WPRT) versus prostate-only radiotherapy (PORT) for high/very high-risk prostate cancer, albeit with worse RTOG late urinary toxicity. We report updated late urinary adverse effects and bladder dose-effect relations within this trial. MATERIALS/METHODS: Late urinary toxicity, and cumulative severity of each symptom over the follow-up period was graded using CTCAE v5.0. Bladder dosimetry in 5-Gy increments (V5, V10, V15...V65Gy, V68Gy) in the approved radiotherapy plans was compared for urinary symptoms and overall grade 2+ toxicity. Potential factors influencing urinary toxicity were tested using multivariable logistic regression analysis. Updated urinary quality of life (QOL) scores were compared between the trial arms. RESULTS: Complete combined data for late urinary symptoms and dosimetry was available for 193/224 patients. At a median follow-up of 75 months, cumulative late urinary CTCAE grade 3 toxicity was low and similar for WPRT and PORT (5.2% vs 4.1%, p=0.49), while grade 2 toxicity was 31.3% vs 22.7% respectively (p=0.12). Cumulative rates of each urinary symptom were similar between both arms. Multivariable analysis with age at diagnosis, known diabetes, tumor stage, trial arm, prior TURP, grade 2+ acute urinary toxicity, low bladder dose (V10Gy) and moderate bladder dose (V40Gy) did not identify any significant association with late urinary toxicity. Urinary QOL scores was similar between both the arms for all the symptoms. CONCLUSION: Over long term follow up, whole pelvic radiotherapy resulted in low (∼5%) and similar grade 3 cumulative urinary toxicity as prostate-only radiotherapy. The long term patient-reported QOL scores were similar. No causative factors affecting the late urinary toxicity were identified.

Deep-Learning-Based Predictive Imaging Biomarker Model for EGFR Mutation Status in Non-Small Cell Lung Cancer from CT Imaging.

PURPOSE: The authors aimed to develop and validate deep-learning-based radiogenomic (DLR) models and radiomic signatures to predict the EGFR mutation in patients with NSCLC, and to assess the semantic and clinical features that can contribute to detecting EGFR mutations. METHODS: Using 990 patients from two NSCLC trials, we employed an end-to-end pipeline analyzing CT images without precise segmentation. Two 3D convolutional neural networks segmented lung masses and nodules. RESULTS: The combined radiomics and DLR model achieved an AUC of 0.88 ± 0.03 in predicting EGFR mutation status, outperforming individual models. Semantic features further improved the model's accuracy, with an AUC of 0.88 ± 0.05. CT semantic features that were found to be significantly associated with EGFR mutations were pure solid tumours with no associated ground glass component (p < 0.03), the absence of peripheral emphysema (p < 0.03), the presence of pleural retraction (p = 0.004), the presence of fissure attachment (p = 0.001), the presence of metastatic nodules in both the tumour-containing lobe (p = 0.001) and the non-tumour-containing lobe (p = 0.001), the presence of ipsilateral pleural effusion (p = 0.04), and average enhancement of the tumour mass above 54 HU (p < 0.001). CONCLUSIONS: This AI-based radiomics and DLR model demonstrated high accuracy in predicting EGFR mutation, serving as a non-invasive and user-friendly imaging biomarker for EGFR mutation status prediction.

Semitendinosus Autograft Transplant for Medial Meniscus.

Treatment of meniscal tears has evolved over the last few decades, and preservation has now become the gold standard of treatment. Advancements in repair technique have extended the indication of repair. However, meniscectomy has to be performed in some situations. In these situations, meniscal allograft transplantation is considered the gold standard. But allografts are not available in every part of the world. Collagen implants and synthetic polymers are also advocated. But again, its limited research, availability, and high cost have restricted its widespread use. Many authors have advocated autograft transplantation, but there are no long-term results, and there is a lack of uniform surgical techniques. There is a technique described for lateral meniscus, but a medial meniscus autograft transplant technique is not very well elaborated. In this report, we aimed to describe a medial meniscus replacement technique using a hamstring autograft.

Implantless Supplementary Fixation of Anterior Cruciate Ligament in Tibia with "Make and Use" Anchor.

Supplementary fixation after anterior cruciate ligament reconstruction may be necessary in some situations. There are several methods described for supplementary fixation with their advantages and disadvantages. Anchor fixation is preferred by many because it does not require a second surgery for removal. However, anchors are costly. We described the "make and use" all-suture anchor, which can be made instantly whenever required. We modified "make and use" all-suture anchors for supplementary fixation after ACL reconstruction. This technical note aims to describe the method of supplementary fixation using the "make and use" all-suture anchor.

Clinical outcomes of ROS1-positive non-small cell lung cancer with limited access to ROS1-tyrosine kinase inhibitors (TKIs): experience from an Indian tertiary referral centre.

Introduction: ROS1 as a driver mutation is observed in approximately 1%-2% of all non-small cell lung cancer (NSCLC). Given its rarity, we share our experience regarding ROS1-positive NSCLC including the access to ROS1 tyrosine kinase inhibitors (TKIs) in a low-middle income country like India. Methods: It is a retrospective analysis of ROS1-positive NSCLC patients registered between January 2015 to December 2021 for demographics, treatment patterns and outcomes i.e., overall survival (OS) and progression free survival (PFS). Results: Baseline characteristics were available for 70 patients of 78 patients positive for ROS1 by fluorescent in situ hybridisation. Median age at presentation was 52 years, 39 (55.7%) were males, most (51, 72.86%) were non-smokers and ten patients (14.3%) had poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) i.e., PS >2 at presentation. A total of 67 patients receiving cancer directed therapy were analysed for survival. The first line (1L) therapies included - ROS1 TKIs in 38, chemotherapy in 20, epidermal growth factor receptor TKI in eight and chemotherapy-bevacizumab in one only. ROS1 TKI was provided to 20 patients as part of an assistance programme. The median OS for patients who received ROS1 TKI was not attained (95% CI 37.85-NA), while it was 8.11 (95% CI 6.31-NA) months for those who did not (HR-0.1673). The median PFS for the 1L ROS1 TKI compared to the no-TKI group was 27.07 (95% CI 24.28-NA) months versus 5.78 (95% CI 3.42-12) months (HR: 0.2047). Poor ECOG PS at presentation was the only independent prognosticator for survival. Conclusion: Using ROS1 TKI improves clinical outcomes in all-comers though statistically not significant. To further improve outcomes, future trials should pay special attention to patients with poor PS and find a way to increase the current limited access to TKI.

SALTT study: A retrospective analysis of 111 SAlivary gland tumors of Lung and Tracheobronchial Tree.

INTRODUCTION: Primary pulmonary salivary gland-type tumours (PPSGT) are rare lung neoplasms arising from submucosal seromucinous glands in the central airway. METHODS AND RESULTS: We retrospectively analysed the clinicopathological features of 111 PPSGTs diagnosed at our institute between 2003 and 2021. The mean age at diagnosis was 43.8 years(range 6-78 years) and a male-to-female ratio of 2:1. On imaging, 92 % of cases had centrally located tumours and 37.3 % were early stage. The histopathological types included 70 cases (63 %) of mucoepidermoid carcinoma (MEC), 31 cases (27.7 %) of adenoid cystic carcinoma (ADCC), two cases of myoepithelial carcinoma, one case each of acinic cell carcinoma (ACC), clear cell carcinoma (CCC), epithelial myoepithelial carcinoma (EMC) and 5 others [including adenocarcinoma of minor salivary gland origin(n = 3), carcinoma with sebaceous differentiation(n = 1) and poorly differentiated carcinoma of salivary gland type(n = 1)]. The size of the tumours found in the resection specimens ranged from 1 cm to 13 cm, with an average size of 4.9 cm. High-risk attributes such as lymphovascular invasion (LVI), perineural invasion (PNI), pleural involvement, positive resection margins, and nodal metastasis were identified in 15.3 %, 15.3 %, 13.6 %,15.2 % and 6.7 % of cases, respectively. These attributes were found to be more frequent in ADCC than in MEC. Surgery was the main treatment modality [68/84 (80 %) cases]. ADCC cases had more recurrence and distant metastasis than MEC cases. The 3- year overall-survival (OS) and recurrence-free survival(RFS) were better in patients with age lesser than 60 years(p-value <0.0001), low pT stage (p-value 0.00038) and lower grade of MEC(p-value-0.0067). CONCLUSION: It is crucial to have an acquaintance with the morphologic spectrum and immunophenotypic characteristics of PPSGT to recognize them in this unusual location. In tandem, it is crucial to differentiate them from conventional primary non-small cell lung carcinoma, as the management protocols and prognostic implications differ significantly.

Clinical Profile and Outcomes of Carcinoma Penis Patients Receiving Systemic Therapy at an Indian tertiary care Center: A Retrospective Observational Study.

BACKGROUND: Penile cancer is a rare malignancy with scant data on the impact of systemic therapy on outcomes. METHODS: Retrospective observational study of patients with a histological diagnosis of carcinoma penis treated with systemic therapy at the Tata Memorial Centre (Mumbai, India) between August 2010 and February 2018. Primary objective was overall survival (OS); secondary objectives included assessment of clinical characteristics, treatment approaches, and toxicity profiles. RESULTS: We included 91 patients with penile carcinoma who received systemic therapy at our center. Intent of therapy was curative in 71 patients (78%), and palliative in 20 (22%). Median age was 57 years (interquartile range [IQR], 50-65.5) for curatively treated patients and 58.5 years (IQR, 44-65.2) for those with advanced disease. Common presenting symptoms were lumps (70%), and pain (57%). Neoadjuvant chemotherapy (NACT) with paclitaxel + platinum was administered to 19 patients (20.9%), of which 7 (37%) attained complete or partial response. Six patients (31.5%) underwent R0 surgery post-NACT. All 71 patients underwent primary surgery; 47 (66.2%) undergoing partial penectomy. Of the 20 patients treated with palliative first-line chemotherapy, 4(20%) attained a partial response. Median OS of patients treated in curative and palliative settings was 33.8 months (95% CI, 17.2-not recorded) and 11.4 months (95% CI, 9.53-23.3), respectively. CONCLUSIONS: Patients with penile cancer treated with systemic therapy have poor outcomes. Little over a third of the patients respond to neoadjuvant chemotherapy and those with advanced disease have poor survival despite systemic therapy, emphasizing the need for early detection and optimum management of primary and nodal disease.

Dr. Google to Dr. ChatGPT: assessing the content and quality of artificial intelligence-generated medical information on appendicitis.

INTRODUCTION: Generative artificial intelligence (AI) chatbots have recently been posited as potential sources of online medical information for patients making medical decisions. Existing online patient-oriented medical information has repeatedly been shown to be of variable quality and difficult readability. Therefore, we sought to evaluate the content and quality of AI-generated medical information on acute appendicitis. METHODS: A modified DISCERN assessment tool, comprising 16 distinct criteria each scored on a 5-point Likert scale (score range 16-80), was used to assess AI-generated content. Readability was determined using the Flesch Reading Ease (FRE) and Flesch-Kincaid Grade Level (FKGL) scores. Four popular chatbots, ChatGPT-3.5 and ChatGPT-4, Bard, and Claude-2, were prompted to generate medical information about appendicitis. Three investigators independently scored the generated texts blinded to the identity of the AI platforms. RESULTS: ChatGPT-3.5, ChatGPT-4, Bard, and Claude-2 had overall mean (SD) quality scores of 60.7 (1.2), 62.0 (1.0), 62.3 (1.2), and 51.3 (2.3), respectively, on a scale of 16-80. Inter-rater reliability was 0.81, 0.75, 0.81, and 0.72, respectively, indicating substantial agreement. Claude-2 demonstrated a significantly lower mean quality score compared to ChatGPT-4 (p = 0.001), ChatGPT-3.5 (p = 0.005), and Bard (p = 0.001). Bard was the only AI platform that listed verifiable sources, while Claude-2 provided fabricated sources. All chatbots except for Claude-2 advised readers to consult a physician if experiencing symptoms. Regarding readability, FKGL and FRE scores of ChatGPT-3.5, ChatGPT-4, Bard, and Claude-2 were 14.6 and 23.8, 11.9 and 33.9, 8.6 and 52.8, 11.0 and 36.6, respectively, indicating difficulty readability at a college reading skill level. CONCLUSION: AI-generated medical information on appendicitis scored favorably upon quality assessment, but most either fabricated sources or did not provide any altogether. Additionally, overall readability far exceeded recommended levels for the public. Generative AI platforms demonstrate measured potential for patient education and engagement about appendicitis.

Serum Urate and Recurrent Gout.

Importance: Approximately 12 million adults in the US have a history of gout, but whether serum urate levels can help predict recurrence is unclear. Objective: To assess associations of a single serum urate measurement with subsequent risk of acute gout flares and subsequent risk of hospitalizations for gout among patients in the UK with a history of gout. Design, Setting, and Participants: This retrospective study included patients with a history of gout identified from the UK between 2006 and 2010 who were followed up through Primary Care Linked Data medical record linkage until 2017 and through the Hospital Episode Statistics database until 2020. Exposures: Serum urate levels at enrollment. Main Outcome and Measure: Rate of recurrent acute gout, ascertained by hospitalization, outpatient, and prescription/procedure records, and adjusted rate ratios using negative binomial regressions. Results: Among 3613 patients with gout (mean age, 60 years; 3104 [86%] men), 1773 gout flares occurred over a mean follow-up of 8.3 years. Of these, 1679 acute gout flares (95%) occurred in people with baseline serum urate greater than or equal to 6 mg/dL and 1731 (98%) occurred in people with baseline serum urate greater than or equal to 5 mg/dL. Rates of acute gout flares per 1000 person-years were 10.6 for participants with baseline urate levels less than 6 mg/dL, 40.1 for levels of 6.0 to 6.9 mg/dL, 82.0 for levels of 7.0 to 7.9 mg/dL, 101.3 for levels of 8.0 to 8.9 mg/dL, 125.3 for urate levels of 9.0 to 9.9 mg/dL, and 132.8 for levels greater than or equal to 10 mg/dL. Rate ratio of flares were 1.0, 3.37, 6.93, 8.67, 10.81, and 11.42, respectively, over 10 years (1.61 [1.54-1.68] per mg/dL). Rates of hospitalization per 1000 person-years during follow-up were 0.18 for those with baseline serum urate less than 6 mg/dL, 0.97 for serum urate of 6.0 to 6.9 mg/dL, 1.8 for serum urate of 7.0 to 7.9 mg/dL, 2.2 for serum urate of 8.0 to 8.9 mg/dL, 6.7 for serum urate of 9.0 to 9.9 mg/dL, and 9.7 for serum urate greater than or equal to 10 mg/dL. Rate ratios of hospitalization for gout, adjusting for age, sex, and race were 1.0, 4.70, 8.94, 10.37, 33.92, and 45.29, respectively (1.87 [1.57-2.23] per mg/dL). Conclusions and Relevance: In this retrospective study of patients with a history of gout, serum urate levels at baseline were associated with the risk of subsequent gout flares and rates of hospitalization for recurrent gout. These findings support using a baseline serum urate level to assess risk of recurrent gout over nearly 10 years of follow-up.

In vivo biodistribution and ototoxicity assessment of cationic liposomal-ceftriaxone via noninvasive trans-tympanic delivery in chinchilla models: Implications for otitis media therapy.

OBJECTIVES: We report the in vivo biodistribution and ototoxicity of cationic liposomal-ceftriaxone (CFX) delivered via ear drop formulation in adult chinchilla. METHODS: CFX was encapsulated in liposomes with size of ∼100 nm and surface charge of +20 mV. 100 µl liposomes or free drug was applied twice daily in both external ear canals of adult chinchillas for either 3 or 10 days. Study groups included free ceftriaxone (CFX, Day 3: n = 4, Day 10: n = 8), liposomal ceftriaxone (CFX-Lipo, Day 3: n = 4, Day 10: n = 8), and a systemic control group (Day 3: n = 4, Day 10: n = 4). Ceftriaxone delivery to the middle ear and systemic circulation was quantified by HPLC assays. Liposome transport was visualized via confocal microscopy. Auditory brainstem response (ABR) tests and cochlear histology were used to assess ototoxicity. RESULTS: Liposomal ceftriaxone (CFX-Lipo) displayed a ∼658-fold increase in drug delivery efficiency in the middle ear relative to the free CFX (8.548 ± 0.4638% vs. 0.013 ± 0.0009%, %Injected dose, Mean ± SEM). CFX measured in blood serum (48.2 ± 7.78 ng/ml) following CFX-Lipo treatment in ear was 41-fold lower compared to systemic free-CFX treatment (1990.7 ± 617.34 ng/ml). ABR tests and histological analysis indicated no ototoxicity due to the treatment. CONCLUSION: Cationic liposomal encapsulation results in potent drug delivery across the tympanic membrane to the middle ear with minimal systemic exposure and no ototoxicity.

Management of Metastatic Urothelial Carcinoma in Emerging Markets (EM): An Expert Opinion.

Urothelial carcinoma (UC) is the 10th most common cancer globally with an almost 4 times higher prevalence in men. The main risk factors for development of urothelial carcinoma are advanced age, smoking, arsenic contamination, exposure to carcinogens. Metastatic urothelial carcinoma (mUC) has overall poor prognosis with a 5-year overall survival rate of only < 5%. The standard of care comprises of platinum-based chemotherapy, but the responses are often not sustained. A working group was established with an objective to discuss the most recent clinical data on the genitourinary tumors of interest and comprised of experts across Latin America, Emerging Asia (except China, Japan, and South Korea), Africa, and the Middle East (known as Emerging Markets or EM). There is an evident disparity in terms of uneven mortality and incidence rate distribution among various regions. There is a lack and/or insufficient data on epidemiology, treatment, and outcomes in the EM. The lack of registries impacts the healthcare decisions and the lower incidence from the region might not be reflective of the true disease burden. The treatment outcomes of mUC can be improved by understanding the current disease burden and treatment approach of mUC and identifying the gaps and challenges associated with management. Hence, a literature review was developed to summarize the current disease burden and treatment approach of mUC across EM. The review also highlights the unmet needs for mUC management in EM and suggests a way forward to improve the current situation in order to better serve the patients.

Prognostic Significance of Lymph Node Density in Pathological Node Positive Urothelial Carcinoma of the Bladder -Upfront Surgery and Post Neoadjuvant Chemotherapy Cohorts.

AIM: To validate the role of lymph node density as a prognostic marker in patients undergoing primary surgery and postneoadjuvant therapy in pathological node-positive urothelial bladder carcinoma. MATERIALS AND METHODS: Retrospective analysis of 503 patients who underwent radical cystectomy from 2006 to 2019 for muscle-invasive urothelial bladder carcinoma, of which 152 patients with pathological node-positive disease were analyzed. Demographic details, pathological findings, treatment details, disease-free, and overall survival were documented. X tile program analysis was used to divide patients with positive lymph nodes into 3 groups: LD1: <= 7, LD2 :>7 to <15, LD3: >15, and the optimal cut-off value obtained was 15%. To evaluate the impact of lymph node ratio, patients with positive lymph nodes into 3 categories for each cut-off point estimation method, the application generates the histogram, Kaplan-Meier plot and calculates hazard ratio, confidence intervals and P-values. Univariate and multivariate cox regression analysis was done with a P-value of <.05, considered significant. RESULTS: One hundred fifty-two patients (30.2%) had pathological nodal metastasis, with 87 of them having perinodal extension. Ninety-six underwent primary surgery, and 56 were postneoadjuvant chemotherapy. The median follow-up was 55.42 months. 68 of the 152 node-positive patients died of the disease. Median number of lymph nodes removed was 17.11. Lymph node density divided into tertiles were LD1 <7%, LD2 7-<15%, LD3 >15% showed 5-year RFS 40.5%,29.3%, 22.6% and 5 year OS was 55.5%, 42.4%,32.1% respectively. Cox regression analysis showed that age less than 55 years ,higher tumor stage, lymphovascular invasion, and higher lymph node ratio were significant in univariate and multivariate analysis. The lymph node density cut-off value of 15% was substantial among node-positive patients (P = .027), and subgroup analysis in upfront surgery with the adjuvant treatment group and postneoadjuvant chemotherapy group was also significant (P =.021). CONCLUSION: Pathological higher T stage, Age <55 years, Lymphovascular invasion, adjuvant chemotherapy , adjuvant radiation treatment and lymph node density had prognostic significance in both cohorts of patients who underwent upfront surgery and neoadjuvant chemotherapy. Lymph node density cut-off value of <15% was prognostically significant.

Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Olanzapine is an effective antiemetic agent but it results in substantial daytime somnolence when administered at the standard dose. Our aim was to compare the efficacy of low-dose versus standard-dose olanzapine after highly emetogenic chemotherapy in patients with solid tumours. METHODS: This was a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial done in a tertiary care referral centre in India (Tata Memorial Centre, Homi Bhabha National Institute, Mumbai). Patients aged 13-75 years with an Eastern Cooperative Oncology Group performance status of 0-2, who were receiving doxorubicin-cyclophosphamide or high-dose cisplatin for a solid tumour were eligible. Patients were randomly assigned (1:1), with block randomisation (block sizes of 2 or 4) and stratified by sex, age (≥55 or <55 years), and chemotherapy regimen, to receive low-dose (2·5 mg) oral olanzapine or standard-dose (10·0 mg) oral olanzapine daily for 4 days, in combination with a triple antiemetic regimen. Study staff were masked to treatment allocation but patients were aware of their group assignment. The primary endpoint was complete control, defined as no emetic episodes, no rescue medications, and no or mild nausea in the overall phase (0-120 hours), assessed in the modified intention-to-treat (mITT) population (ie, all eligible patients who received protocol-specified treatment, excluding those who had eligibility violations and who withdrew consent after randomisation). Daytime somnolence was the safety endpoint of interest. Non-inferiority was shown if the upper limit of the one-sided 95% CI for the difference in the complete control proportions between the treatment groups excluded the non-inferiority margin of 10%. This study is registered with the Clinical Trial Registry India, CTRI/2021/01/030233, is closed to accrual, and this is the final data analysis. RESULTS: Between Feb 9, 2021, and May 30, 2023, 356 patients were pre-screened for eligibility, of whom 275 patients were enrolled and randomly assigned (134 to the 2·5 mg olanzapine group and 141 to the 10·0 mg olanzapine group). 267 patients (132 in the 2·5 mg group and 135 in the 10·0 mg group) were included in the mITT population, of whom 252 (94%) were female, 15 (6%) were male, and 242 (91%) had breast cancer. 59 (45%) of 132 patients in the 2·5 mg olanzapine group had complete control in the overall phase versus 59 (44%) of 135 in the 10·0 mg olanzapine group (difference -1·0% [one-sided 95% CI -100·0 to 9·0]; p=0·87). In the overall phase, there were significantly fewer patients in the 2·5 mg olanzapine group than in the 10·0 mg olanzapine group with daytime somnolence of any grade (86 [65%] of 132 vs 121 [90%] of 135; p<0·0001) and of severe grade on day 1 (six]5%] vs 54 [40%]; p<0·0001). INTERPRETATION: Our findings suggest that olanzapine 2·5 mg is non-inferior to 10·0 mg in antiemetic efficacy and results in reduced occurrence of daytime somnolence among patients receiving highly emetic chemotherapy and should be considered as a new standard of care. FUNDING: Progressive Ladies Welfare Association.

Review Article on Molecular Mechanism of Regulation of Hypertension by Macro-elements (Na, K, Ca and Mg), Micro-elements/Trace Metals (Zn and Cu) and Toxic Elements (Pb and As).

Hypertension (HT) is a medical condition arising due to increase in blood pressure (BP) prevalent worldwide. The balanced dietary intakes of macro-elements and micro-elements including Na, K, Ca, Mg, Zn, and Cu have been described to maintain BP in humans by regulating the osmolarity of blood, cells/tissues, prevention of generation of oxidative and nitrosative stress (OANS), and endothelial damage through their functioning as important components of renin-angiotensin-aldosterone system (RAAS), antioxidant enzyme defense system, and maintenance of blood vascular-endothelial and vascular smooth muscle cell (VSMC) functions. However, inadequate/excess dietary intakes of Na/K, Ca/Mg, and Zn/Cu along with higher Pb and As exposures recognized to induce HT through common mechanisms including the followings: endothelial dysfunctions due to impairment of vasodilatation, increased vasoconstriction and arterial stiffness, blood clotting, inflammation, modification of sympathetic activity and higher catecholamine release, increased peripheral vascular resistance, and cardiac output; increased OANS due to reduced and elevated activities of extracellular superoxide dismutase and NAD(P)H oxidase, less nitric oxide bioavailability, decrease in cGMP and guanylate cyclase activity, increase in intracellular Ca2+ ions in VSMCs, and higher pro-inflammatory cytokines; higher parathyroid and calcitriol hormones; activation/suppression of RAAS resulting imbalance in blood Na+, K+, and water regulated by renin, angiotensin II, and aldosterone through affecting natriuresis/kaliuresis/diuresis; elevation in serum cholesterol and LDL cholesterol, decrease in HDL cholesterol due to defect in lipoprotein metabolism. The present study recommends the need to review simple dietary mineral intervention studies/supplementation trials before keeping their individual dietary excess intakes/exposures in consideration because their interactions lead to elevation and fall of their concentrations in body affecting onset of HT.

2nd Window NIR Imaging of Radiation Injury Mitigation Provided by Reduced Notch-Dll4 Expression on Vasculature.

PURPOSE: Vascular endothelium plays a central role in the pathogenesis of acute and chronic radiation injuries, yet the mechanisms which promote sustained endothelial dysfunction and contribute to late responding organ failure are unclear. We employed 2nd window (> 1100 nm emission) Near-Infrared (NIR) imaging using indocyanine green (ICG) to track and define the role of the notch ligand Delta-like ligand 4 (Dll4) in mediating vascular injury in two late-responding radiosensitive organs: the lung and kidney. PROCEDURES: Consomic strains of female Salt Sensitive or SS (Dll4-high) and SS with 3rd chromosome inherited from Brown Norway, SS.BN3 (Dll4-low) rats at ages 11-12 weeks were used to demonstrate the impact of reduced Dll4 expression on long-term vascular integrity, renal function, and survival following high-dose 13 Gy partial body irradiation at 42- and 90 days post-radiation. 2nd window dynamic NIR fluorescence imaging with ICG was analyzed with physiology-based pharmacokinetic modeling and confirmed with assays of endothelial Dll4 expression to assess the role of endogenous Dll4 expression on radiation injury protection. RESULTS: We show that SS.BN3 (Dll4-low) rats are relatively protected from vascular permeability disruption compared to the SS (Dll4-high) strain. We further demonstrated that SS.BN3 (Dll4-low) rats have reduced radiation induced loss of CD31+ vascular endothelial cells, and increased Dll4 vascular expression is correlated with vascular dysfunction. CONCLUSIONS: Together, these data suggest Dll4 plays a key role in pathogenesis of radiation-induced vascular injury to the lung and kidney.

The metabolic potential of inflammatory and insulinaemic dietary patterns and risk of type 2 diabetes.

AIMS/HYPOTHESIS: Diets with higher inflammatory and insulinaemic potential have been associated with an increased risk of type 2 diabetes. However, it remains unknown whether plasma metabolomic profiles related to proinflammatory/hyperinsulinaemic diets and to inflammatory/insulin biomarkers are associated with type 2 diabetes risk. METHODS: We analysed 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study to identify the plasma metabolome related to empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), four circulating inflammatory biomarkers and C-peptide. Dietary intakes were assessed using validated food frequency questionnaires. Plasma metabolomic profiling was conducted by LC-MS/MS. Metabolomic signatures were derived using elastic net regression. Multivariable Cox regression was used to examine associations of the metabolomic profiles with type 2 diabetes risk. RESULTS: We identified 27 metabolites commonly associated with both EDIP and inflammatory biomarker z score and 21 commonly associated with both EDIH and C-peptide. Higher metabolomic dietary inflammatory potential (MDIP), reflecting higher metabolic potential of both an inflammatory dietary pattern and circulating inflammatory biomarkers, was associated with higher type 2 diabetes risk. The HR comparing highest vs lowest quartiles of MDIP was 3.26 (95% CI 2.39, 4.44). We observed a strong positive association with type 2 diabetes risk for the metabolomic signature associated with EDIP-only (HR 3.75; 95% CI 2.71, 5.17) or inflammatory biomarkers-only (HR 4.07; 95% CI 2.91, 5.69). In addition, higher metabolomic dietary index for hyperinsulinaemia (MDIH), reflecting higher metabolic potential of both an insulinaemic dietary pattern and circulating C-peptide, was associated with greater type 2 diabetes risk (HR 3.00; 95% CI 2.22, 4.06); further associations with type 2 diabetes were HR 2.79 (95% CI 2.07, 3.76) for EDIH-only signature and HR 3.89 (95% CI 2.82, 5.35) for C-peptide-only signature. The diet scores were significantly associated with risk, although adjustment for the corresponding metabolomic signature scores attenuated the associations with type 2 diabetes, these remained significant. CONCLUSIONS/INTERPRETATION: The metabolomic signatures reflecting proinflammatory or hyperinsulinaemic diets and related biomarkers were positively associated with type 2 diabetes risk, supporting that these dietary patterns may influence type 2 diabetes risk via the regulation of metabolism.