Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer.

Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.

Design of Multi-Target drugs of HDACs and other Anti-Alzheimer related Targets: Current strategies and future prospects in Alzheimer's diseases therapy.

Alzheimer disease (AD) is the most prevalent form of dementia that develops spontaneously in the elderly. It's worth mentioning that as people age, the epigenetic profile of the central nervous system cells changes, which may speed up the development of various neurodegenerative disorders including AD. Histone deacetylases (HDACs) are a class of epigenetic enzymes that can control gene expression without altering the gene sequence. Moreover, a promising strategy for multi-target hybrid design was proposed to potentially improve drug efficacy and reduce side effects. These hybrids are monocular drugs that contain various pharmacophore components and have the ability to bind to different targets at the same time. The HDACs ability to synergistically boost the performance of other anti-AD drugs, as well as the ease with which HDACs inhibitor cap group, can be modified. This has prompted numerous medicinal chemists to design a novel generation of HDACs multi-target inhibitors. Different HDACs inhibitors and other ones such as acetylcholinesterase, butyryl-cholinesterase, phosphodiesterase 9, phosphodiesterase 5 or glycogen synthase kinase 3ß inhibitors were merged into hybrids for treatment of AD. This review goes over the scientific rationale for targeting HDACs along with several other crucial targets in AD therapy. This review presents the latest hybrids of HDACs and other AD target pharmacophores.

Minimizing Incision in Living Donor Liver Transplantation: Initial Experience and Comparative Analysis of Upper Midline Incision in 115 Recipients.

Living donor liver transplantation (LDLT) needs "Mercedes Benz" or "J-shaped" incision, causing short and long-term complications. An upper midline incision (UMI) is less invasive alternative but technically challenging. Reporting UMI for recipients in LDLT vs. conventional J-shaped incision. Retrospective analysis, July 2021 to December 2022. Peri-operative details and post-transplant outcomes of 115 consecutive adult LDLT recipients transplanted with UMI compared with 140 recipients with J-shaped incision. Cohorts had similar preoperative and intraoperative variables. The UMI group had significant shorter time to ambulation (3 ± 1.6 vs. 3.6 ± 1.3 days, p = 0.001), ICU stay (3.8 ± 1.3 vs. 4.4 ± 1.5 days, p = 0.001), but a similar hospital stay (15.6±7.6 vs. 16.1±10.9 days, p = 0.677), lower incidence of pleural effusion (11.3% vs. 27.1% p = 0.002), and post-operative ileus (1.7% vs. 9.3% p = 0.011). The rates of graft dysfunction (4.3% vs. 8.5% p = 0.412), biliary complications (6.1% vs. 12.1% p = 0.099), 90-day mortality (7.8% vs. 12.1% p = 0.598) were similar. UMI-LDLT afforded benefits such as reduced pleuropulmonary complications, better early post-operative recovery and reduction in scar-related complaints in the medium-term. This is a safe, non-inferior and reproducible technique for LDLT.

Real-time lung weight measurement during clinical ex vivo lung perfusion.

BACKGROUND: Real-time lung weight (LW) measurement is a simple and non-invasive technique for detecting extravascular lung water during ex vivo lung perfusion (EVLP). We investigated the feasibility of real-time LW measurement in clinical EVLP as a predictor of transplant suitability and post-transplant outcomes. METHODS: In our clinical acellular EVLP protocol, real-time LW was measured in 117 EVLP cases from June 2019 to June 2022. The estimated LW gain at each timepoint was calculated using a scale placed under the organ chamber. The lungs were classified into four categories based on LW adjusted for height and compared between suitable and unsuitable cases. The relationship between estimated LW gain and primary graft dysfunction was also investigated. RESULTS: The estimated LW gain during the EVLP significantly correlated with the LW gain (post EVLP LW - pre EVLP LW) measured on the back table (R2=0.61, P<0.01). In the adjusted LW categories 2-4, the estimated LW gain at 0-1 h after EVLP was significantly higher in unsuitable cases than in suitable cases. The area under the curve for the estimated LW gain was ≥0.80. Primary graft dysfunction grade 0-1 had a significantly lower estimated LW gain at 60 min than grades 2-3 (-43 vs. 1 g, P<0.01). CONCLUSIONS: Real-time lung measurements can predict transplant suitability and post-transplant outcomes by the early detection of extravascular lung water during the initial 1 h of EVLP.

Cancer Trials Ecosystem in India-Ready for Prime Time?

Executing global clinical trials for cancer is a long, expensive, and complex undertaking. While selecting countries global studies, sponsors must consider several aspects including patient pool, quality of trained investigators, competing trials, availability of infrastructure, and financial investment versus returns. With a large, often treatment-naïve, and diverse patient pool, relatively low cost, good quality health care facilities in urban areas, and a robust and well-trained workforce, India offers several advantages for conducting oncology clinical trials. However, there remains challenges, including a shifting regulatory environment in recent decades. With the implementation of the New Drugs and Clinical Trial Rules in 2019, India's regulatory atmosphere seems to have stabilized. In this article, we present a review of the evolving clinical trial landscape in India, highlight the current regulatory scenario, and discuss the advantages and challenges of selecting India as a potential location for conducting global oncology clinical trials.

Variables that predict hospital stay and the outcome of Fournier gangrene at King Abdulaziz University Hospital: a retrospective study.

BACKGROUND: The aggressive nature of Fournier gangrene and the associated health issues can result in a more complex clinical course and potentially a longer hospital stay. This study aimed to assess factors that affect the length of hospital stay (LHS) and its relation to the outcome of Fournier gangrene patients. METHODS: A retrospective study was performed at King Abdulaziz University Hospital (KAUH), Saudi Arabia, on patients diagnosed with Fournier gangrene between 2017 and 2023. Data about length of hospital stay (LHS), age, BMI, clinical and surgical data and outcome was obtained. RESULTS: The mean age of the studied patients was 59.23 ± 11.19 years, the mean body mass index (BMI) was 26.69 ± 7.99 kg/m2, and the mean duration of symptoms was 10.27 ± 9.16 days. The most common presenting symptoms were swelling or induration (64%), 88% had comorbidities with diabetes mellitus (DM) (84%), and 76% had uncontrolled DM. of patients, 24% had a poly-microbial infection, with E. coli being the most common (52%). The mean length of hospital stay (LHS) was 54.56 ± 54.57 days, and 24% of patients had an LHS of more than 50 days. Longer LHS (> 50 days) was associated with patients who did not receive a compatible initial antibiotic, whereas shorter LHS was associated with patients who received Impenem or a combination of vancomycin and meropenem as alternative antibiotics following incompatibility. Reconstruction patients had significantly longer LHS and a higher mean temperature. However, none of the studied variables were found to be predictors of long LHS in the multivariate regression analysis. CONCLUSION: Knowledge of the values that predict LHS allows for patient-centered treatment and may be useful in predicting more radical treatments or the need for additional treatment in high-risk patients. Future multicenter prospective studies with larger sample sizes are needed to assess the needed variables and predictors of long LHS.

Estimation of country-specific tuberculosis resistance antibiograms using pathogen genomics and machine learning.

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis (Mtb) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa. RESULTS: Mtb isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964). CONCLUSIONS: This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.

Integration of a facile sustainable resonance Rayleigh scattering switchable-based system for feasible determination of centrophenoxine, a nootropic and antioxidant agent; application to crude materials and dosage forms.

The proposed research adheres to a certain methodology to ensure that the technique used for analyzing the centrophenoxine drug is sustainable and green. It is important to highlight that several tools that have been recently developed were utilized as potential indicators of environmental sustainability and applicability. The present research presents a novel and entirely innovative method utilizing ultrasensitive spectrofluorimetry for the detection of centrophenoxine (CPX) drug. The employed methodology in this study involved the utilization of one-step, one-pot, and direct spectrofluorimetric technique, which was found to be both efficient and environmentally sustainable in the validation and assessment of the drug. Simply, when CPX and erythrosine B reagent were combined in an acidic environment, the highly resonance Rayleigh scattering product was immediately produced. The sensitivity limits were observed to be within the range of 15-47 ng mL-1, whereas the linearity was assessed to be in the range of 50-2000 ng mL-1. The optimal settings for all modifiable parameters of the system were ascertained through an analysis of centrophenoxine-erythrosine B complexes. Moreover, the system demonstrated compliance with International Council for Harmonization (ICH) specifications without encountering any issues. The suggested process was then rated on different recent environmental safety measuring metrics to see how good it was for the environment. Fortunately, the WAC standards that combine ecological and functional elements utilizing the Green/Red/Blue (RGB 12) design also acclaimed the current analytical technique as a white one. Additionally, a new applicability evaluation tool (BAGI) was employed to estimate the practicability of the planned method in the analytical chemistry field.

The Convergence of Radiology and Genomics: Advancing Breast Cancer Diagnosis with Radiogenomics.

Despite significant progress in the prevention, screening, diagnosis, prognosis, and therapy of breast cancer (BC), it remains a highly prevalent and life-threatening disease affecting millions worldwide. Molecular subtyping of BC is crucial for predictive and prognostic purposes due to the diverse clinical behaviors observed across various types. The molecular heterogeneity of BC poses uncertainties in its impact on diagnosis, prognosis, and treatment. Numerous studies have highlighted genetic and environmental differences between patients from different geographic regions, emphasizing the need for localized research. International studies have revealed that patients with African heritage are often diagnosed at a more advanced stage and exhibit poorer responses to treatment and lower survival rates. Despite these global findings, there is a dearth of in-depth studies focusing on communities in the African region. Early diagnosis and timely treatment are paramount to improving survival rates. In this context, radiogenomics emerges as a promising field within precision medicine. By associating genetic patterns with image attributes or features, radiogenomics has the potential to significantly improve early detection, prognosis, and diagnosis. It can provide valuable insights into potential treatment options and predict the likelihood of survival, progression, and relapse. Radiogenomics allows for visual features and genetic marker linkage that promises to eliminate the need for biopsy and sequencing. The application of radiogenomics not only contributes to advancing precision oncology and individualized patient treatment but also streamlines clinical workflows. This review aims to delve into the theoretical underpinnings of radiogenomics and explore its practical applications in the diagnosis, management, and treatment of BC and to put radiogenomics on a path towards fully integrated diagnostics.

Roles of Androgen Receptor Signaling in Urothelial Carcinoma.

Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area.

Bladder Cancer, Loss of Y Chromosome, and New Opportunities for Immunotherapy.

Immune checkpoint inhibitors (ICI) have emerged as an important therapeutic approach for patients with cancers including bladder cancer (BC). This commentary describes a recent study that demonstrated that the loss of Y chromosome (LOY) and/or loss of specific genes on Y chromosome confers an aggressive phenotype to BC because of T cell dysfunction resulting in CD8+T cell exhaustion. Loss of expression of Y chromosome genes KDM5D and UTY was similarly associated with an unfavorable prognosis in patients with BC as these genes were partially responsible for the impaired anti-tumor immunity in LOY tumors. From a clinical perspective, the study showed that tumors with LOY may be susceptible to treatment with ICIs.

Application of a white and green spectrofluorimetric approach for facile quantification of amlodipine, a hypotensive drug, in batch materials, dosage forms, and biological fluids; content homogeneity testing.

The suggested study adheres to a particular protocol to ensure that the process is environmentally friendly and sustainable. It is worth mentioning that several tools have been adopted as prospective measures of the method greenness. Fortunately, the established analytical method is identified as white by the white analytical chemistry (WAC) concept, which uses the red/ green/blue color scheme (RGB 12 tool) to combine ecological and functional factors for the first time in studying of the cited drug. Amlodipine (AMD), a cardiovascular treating agent, belongs to the dihydropyridine class of oral calcium channel-blocking agents. This article presents a novel, simple, green, one-pot-processed, fast, and ultrasensitive fluorimetric approach for monitoring and assessment of AMD using molecular-size-dependent fluorescence augmentation of the light scattering-driven signal of eosin, a biological stain at a wavelength of 415 nm. This enhancement was directly proportional to the size of the produced complex. The linearity range was from 30 to 900 ng mL-1 , with corresponding sensitivity limits (detection and quantitation levels) of 9.2 and 28 ng mL-1 , respectively. The planned approach was also successfully used to track AMD content in bulk, dosage forms, and bio-fluids (human plasma and urine). The developed method's eco-friendliness was established by different eco-rating metric tools.

Hilar Anatomy in 3035 Living Liver Donors: A Novel Classification for Donor Surgery and Suitability, Hepatic Surgeries, and Hepatobiliary Interventions.

BACKGROUND: This study examines the vascular and biliary variations in 3035 liver donors. We propose a novel classification of hepatic arteries, portal veins, and bile ducts and clinically relevant donor classification. METHODS: Preoperative imaging and operative details of 3035 donors from 2005 to 2020 were reviewed. Hilar anatomical variations were identified and grouped on the basis of incidence and clinical relevance. RESULTS: Hilar structures are classified according to the numbers supplying or draining the graft: for the hepatic artery, right (R) and left (L), RA1/LA1 (1 artery), RA2/LA2 (2 arteries), and RA3/LA3 (3 arteries), respectively, further defined on the basis of the inflow trunk into C (for common hepatic artery), S (for superior mesenteric artery), and L (for left gastric artery); for the portal vein, RP1 (1 vein) and RP2 (2 veins) for the right lobe; and for the hepatic duct, RB1/LB1 (1 duct), RB2/LB2 (2 ducts), RB3 (3 right ducts), and RB4 (4 right ducts). Donors were classified on the basis of anatomical variations into 3 groups: class 1 and class 2 donors, who can donate liver with acceptable risks, and class 3 donors, who are high-risk donors because they are anatomically unacceptable ( Figures S1 to S4, SDC , http://links.lww.com/TP/C918 ). CONCLUSIONS: Defining hilar anatomical variations and donor grouping into anatomy-based clinical classes helps in operative planning of donors, hepatobiliary surgeries, and interventional procedures.

Intermittent Ex Vivo Lung Perfusion in a Porcine Model for Prolonged Lung Preservation.

BACKGROUND: Ex vivo lung perfusion expands the lung transplant donor pool and extends preservation time beyond cold static preservation. We hypothesized that repeated regular ex vivo lung perfusion would better maintain lung grafts. METHODS: Ten pig lungs were randomized into 2 groups. The control underwent 16 h of cold ischemic time and 2 h of cellular ex vivo lung perfusion. The intermittent ex vivo lung perfusion group underwent cold ischemic time for 4 h, ex vivo lung perfusion (first) for 2 h, cold ischemic time for 10 h, and 2 h of ex vivo lung perfusion (second). Lungs were assessed, and transplant suitability was determined after 2 h of ex vivo lung perfusion. RESULTS: The second ex vivo lung perfusion was significantly associated with better oxygenation, limited extravascular water, higher adenosine triphosphate, reduced intraalveolar edema, and well-preserved mitochondria compared with the control, despite proinflammatory cytokine elevation. No significant difference was observed in the first and second perfusion regarding oxygenation and adenosine triphosphate, whereas the second was associated with lower dynamic compliance and higher extravascular lung water than the first. Transplant suitability was 100% for the first and 60% for the second ex vivo lung perfusion, and 0% for the control. CONCLUSIONS: The second ex vivo lung perfusion had a slight deterioration in graft function compared to the first. Intermittent ex vivo lung perfusion created a better condition for lung grafts than cold static preservation, despite cytokine elevation. These results suggested that intermittent ex vivo lung perfusion may help prolong lung preservation.

From Incidence to Intervention: A Comprehensive Look at Breast Cancer in South Africa.

The formidable impact of breast cancer extends globally, with South Africa facing pronounced challenges, including significant disparities in breast cancer screening, treatment and survival along ethnic and socioeconomic lines. Over the last two decades, breast cancer incidence has increased and now accounts for a substantial portion of cancers in women. Ethnic disparities in terms of screening, incidence and survival exacerbate the issue, leading to delayed diagnosis among Black patients and highlighting healthcare inequities. These concerning trends underscore the urgency of enhancing breast cancer screening while mitigating treatment delays, although obstacles within the healthcare system impede progress. The intersection of breast cancer and human immunodeficiency virus (HIV) further complicates matters and particularly affects the Black population. Tackling the aforementioned disparities in breast cancer in South Africa mandates a multifaceted strategy. Robust screening efforts, particularly those targeting marginalised communities, are crucial for early detection. Concurrently, expedited treatment initiation is imperative. Addressing HIV-related complexities requires tailored interventions to ensure effective care. These multifaceted disparities require pan African research and cooperation as well as tailored interventions to enhance breast cancer care within the African region.

Utility of Cilefa Pink B, a foodstuff dye as a fluoro-substrate in the devising of the first facile green Molecular-mass-Related Fluorescence Sensor for quantifying amlodipine in batched material and dosage forms; content uniformity evaluation.

This study introduces the first and unique Molecular-mass-Related Fluorescence Sensor as the first fluorimetric strategy for determining amlodipine. An environmentally friendly, single-step, and direct spectrofluorimetric approach was utilized to evaluate the analyte. In an acidic setting, combining the amlodipine medication and the fluorescent dye Cilefa Pink B generated an instantaneous ultra-fluorescent product. An increase in dye response after adding amlodipine was proportional to the molecular weight of the generated complex, as measured at 329 nm. was the idea ofthe applied fluorimetric analysis. The complexing process increased the molecular mass from 879.86 to 1288.739 g mol-1. The medication's range of 0.050-1.00 µg mL-1 is directly correlated with this molecular massenlargement. The ideal settings for the changeable parameters of the system were established through an analysis of the response of the amlodipine-Cilefa Pink B system. Furthermore, the developed sensor complied with ICH (International Council for Harmonization) standards. The sensitivity limits were 0.0139 µg mL-1 (for the detection limit, LOD) and 0.042 µg mL-1 (for the quantification limit, LOQ). Additionally, this method effectively recovered the drug in its original and therapeutic dosage forms. Finally, the proposed process's environmental impact was also assessed through different modern greenness evaluation tools.

Neoadjuvant therapy in hormone Receptor-Positive/HER2-Negative breast cancer.

Neoadjuvant therapy is commonly used in patients with locally advanced or inoperable breast cancer (BC). Neoadjuvant chemotherapy (NACT) represents an established treatment modality able to downstage tumours, facilitate breast-conserving surgery, yet also achieve considerable pathologic complete response (pCR) rates in HER2-positive and triple-negative BC. For patients with HR+/HER2- BC, the choice between NACT and neoadjuvant endocrine therapy (NET) is still based on clinical and pathological features and not guided by biomarkers of defined clinical utility, differently from the adjuvant setting where gene-expression signatures have been widely adopted to drive decision-making. In this review, we summarize the evidence supporting the choice of NACT vs NET in HR+/HER2- BC, discussing the issues surrounding clinical trial design and proper selection of patients for every treatment. It is time to question the binary paradigm of responder vs non-responders as well as the "one size fits all" approach in luminal BC, supporting the utilization of continuous endpoints and the adoption of tissue and plasma-based biomarkers at multiple timepoints. This will eventually unleash the full potential of neoadjuvant therapy which is to modulate patient treatment based on treatment sensitivity and surgical outcomes. We also reviewed the current landscape of neoadjuvant studies for HR+/HER2- BC, focusing on antibody-drug conjugates (ADCs) and immunotherapy combinations. Finally, we proposed a roadmap for future neoadjuvant approaches in HR+/HER2- BC, which should be based on a staggered biomarker-driven treatment selection aiming at impacting long-term relevant endpoints.

CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond.

Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and is now also being tested in patients with MM. Within this context, the B-cell maturation antigen (BCMA) has emerged as a promising candidate for CAR-T-cell antigen targeting in MM. Alternative targets include SLAMF7, CD38, CD19, the signaling lymphocyte activation molecule CS1, NKG2D, and CD138. Numerous clinical studies have demonstrated the clinical efficacy of these CAR-T-cell therapies, although longitudinal follow-up reveals some degree of antigenic escape. The widespread implementation of CAR-T-cell therapy is encumbered by several barriers, including antigenic evasion, uneven intratumoral infiltration in solid cancers, cytokine release syndrome, neurotoxicity, logistical implementation, and financial burden. This article provides an overview of CAR-T-cell therapy in MM and the utilization of BCMA as the target antigen, as well as an overview of other potential target moieties.