Search

Abstract Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance frequently develops. To explore ICB resistance mechanisms, we develop Immunotherapy Resistance cell-cell Interaction Scanner (IRIS), a machine learning model aimed at identifying cell-type-specific tumor microenvironment ligand-receptor interactions relevant to ICB resistance. Applying IRIS to deconvolved transcriptomics data of the five largest melanoma ICB cohorts, we identify specific downregulated interactions, termed resistance downregulated interactions (RDI), as tumors develop resistance. These RDIs often involve chemokine signaling and offer a stronger predictive signal for ICB response compared to upregulated interactions or the state-of-the-art published transcriptomics biomarkers. Validation across multiple independent melanoma patient cohorts and modalities confirms that RDI activity is associated with CD8 + T cell infiltration and highly manifested in hot/brisk tumors. This study presents a strongly predictive ICB response biomarker, highlighting the key role of downregulating chemotaxis-associated ligand-receptor interactions in inhibiting lymphocyte infiltration in resistant tumors.

Sheng-Min Wang,1 Changsu Han,2 Soo-Jung Lee,5 Ashwin A Patkar,3 Prakash S Masand,4 Chi-Un Pae3,5 1International Health Care Center, Seoul St Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea; 2Department of Psychiatry, College of Medicine, Korea University, Seoul, Republic of Korea; 3Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 4Global Medical Education, New York, NY, USA; 5Department of Psychiatry, Bucheon St Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea Abstract: Improving medication adherence is critical to improving outcomes in patients with schizophrenia. A long-acting injectable (depot) antipsychotic is one of the most effective methods for improving treatment adherence and decreasing rehospitalization rates in patients with schizophrenia. Until recently, only three second-generation antipsychotics were available in a long-acting injectable formulation (risperidone, paliperidone, and olanzapine). In this respect, the emergence of long-acting aripiprazole injection (ALAI), approved by the US Food and Drug Administration for the treatment of schizophrenia in 2013, is timely. ALAI is a lyophilized powder of aripiprazole, and the aripiprazole molecule is unmodified. The initial and target dosage of ALAI is 400 mg once monthly, but it could be reduced to 300 mg if adverse reactions occur with 400 mg. When first administering ALAI, it is recommended to continue treatment with oral aripiprazole (10–20 mg/day) or another oral antipsychotic for 2 weeks in order to maintain therapeutic antipsychotic concentrations. The primary clearance route for ALAI is hepatic, ie, cytochrome P450 (CYP)2D6 and CYP3A4, so dose adjustment is required in poor CYP2D6 metabolizers. The efficacy of ALAI was demonstrated in three studies. A randomized controlled trial that formed the basis for approval of ALAI in the treatment of schizophrenia showed that ALAI significantly delayed time to impending relapse when compared with placebo (P

Background: Germ cell tumours (GCT) are tumours arising from primordial germ cells. Gonadal and extragonadal GCT are infrequent in childhood occurring at a rate of 2.4 cases per million children accounting for 2-3 % of paediatric malignancies with most common subtype being a matured Teratoma. Case presentation: We present a case of a 10-year-old female child who presented to the emergency department of a tertiary care centre with complaints of cough with massive expectoration of blood of approximately 200 ml in quantity which on imaging revealed a left anterior mediastinal mass which was managed by left lateral thoracotomy with a non-anatomical left sided pulmonary lobectomy which on histopathology was diagnosed to be a case of mature teratoma. Conclusion: This case report describes a unique presentation of extra-gonadal mediastinal teratoma which presented as a rare complication with rupture into the left bronchus. It emphasizes caution and a high clinical suspicion is required in managing cases of varied presentations of teratomas.

ABSTRACT Delayed time to antimicrobial susceptibility results can impact patients’ outcomes. Our study evaluated the impact of susceptibility turnaround time (TAT) and inadequate empiric antibacterial therapy (IET) in patients with bloodstream infections (BSI) caused by Enterobacterales (ENT) species on in-hospital mortality and length of stay (LOS). This retrospective, multicenter investigation which included 29,570 blood ENT-positive admissions across 161 US healthcare facilities evaluated the association between antimicrobial susceptibility testing (AST) TAT, carbapenem susceptibility, and empiric therapy on post-BSI in-hospital mortality and LOS following an ENT BSI event in adult patients. After adjusting for outcomes covariates, post-BSI in-hospital mortality was significantly higher for patients in the IET vs adequate empiric therapy (AET) group [odds ratio (OR): 1.61 (95% CI: 1.32, 1.98); P < 0.0001], and when AST TAT was >63 h [OR:1.48 (95% CI: 1.16, 1.90); P = 0.0017]. Patients with carbapenem non-susceptible (carb-NS) ENT BSI had significantly higher LOS (16.6 days, 95% CI: 15.6, 17.8) compared to carbapenem susceptible (carb-S, 12.2 days, 95% CI: 11.8, 12.6), (P < 0.0001). Extended AST TAT was significantly associated with longer LOS for TAT of 57–65 h and >65 h (P = 0.005 and P< 0.0001, respectively) compared to TAT ≤42 h (reference). Inadequate empiric therapy (IET), carb-NS, and delayed AST TAT are significantly associated with adverse hospital outcomes in ENT BSI. Workflows that accelerate AST TAT for ENT BSIs and facilitate timely and adequate therapy may reduce post-BSI in-hospital mortality rate and LOS.IMPORTANCEFor patients diagnosed with bloodstream infections (BSI) caused by Enterobacterales (ENT), delayed time to antimicrobial susceptibility (AST) results can significantly impact in-hospital mortality and hospital length of stay. However, this relationship between time elapsed from blood culture collection to AST results has only been assessed, to date, in a limited number of publications. Our study focuses on this important gap using retrospective data from 29,570 blood ENT-positive admissions across 161 healthcare facilities in the US as we believe that a thorough understanding of the dynamic between AST turnaround time, adequacy of empiric therapy, post-BSI event mortality, and hospital length of stay will help guide effective clinical management and optimize outcomes of patients with ENT infections.

Background and Aims: The International Normalised Ratio (INR), which assesses the loss of procoagulant factors in the extrinsic pathway, fails to evaluate the coagulation abnormalities comprehensively after a major liver resection, which often leads to reduced synthesis of procoagulant and anticoagulant-factors. This study was conducted with an aim to study the trend and compare the results of routine coagulation tests and thromboelastography (TEG) during the perioperative period in patients undergoing major liver resections (≥3 segments). Methods: Twenty-five patients who underwent a major liver resection were enrolled. This prospective, single-arm, interventional study was performed with the primary objective of determining the serial changes in conventional coagulation tests and TEG during the perioperative period in patients undergoing major liver resections, at the preincision period, intraoperative period, postoperatively, at 48 h and on the fifth postoperative day. Transfusion requirements of blood components were also assessed with a TEG-guided replacement strategy. Spearman rank-order correlation was used to study the relationships of coagulation tests (both TEG and conventional tests) at each time point. Results: The prothrombin time (PT)-INR was elevated in 14 patients (56%) at the intraoperative, immediate postoperative and 48-h time points in contrast to the TEG parameters, which remained normal in all patients. Blood component transfusion was avoided in 4, 11 and 10 patients at the intraoperative, immediate postoperative and 48-h time points, respectively. Conclusion: International Normalised Ratio overestimates the coagulopathy in patients undergoing major liver resection, and a thromboelastography-guided transfusion strategy reduces overall transfusion requirements. Keywords: Blood transfusion, coagulation, hepatectomy, International Normalised Ratio, perioperative outcomes, prothrombin time, thromboelastography, Author(s): Reshma Ambulkar (corresponding author) [1]; Vignesh Baskar [2]; Shraddha Patkar [3]; Aditya Kunte [3]; Vandana Agarwal [2]; Sohan Lal Solanki [2]; Jigeeshu V Divatia [2] INTRODUCTION Liver resections are [...]

Introduction: Dementia is a broad medical term that describes the progressive cognitive decline of brain function due to disease or impairment, resulting in interference with daily activities. Magnetic Resonance Imaging (MRI) is commonly used for the clinical diagnosis of dementia by identifying cerebral atrophy and structural alterations. Furthermore, Magnetic Resonance Spectroscopy (MRS) can detect biochemical abnormalities in dementia patients, which may be beneficial for early diagnosis and treatment. Aim: To provide a comprehensive protocol and a guidance tool for radiologists to effectively diagnose dementia and its subtypes {Alzheimer’s Disease (AD), frontotemporal lobe dementia, etc.} based on radiological findings coupled with volumetry, spectroscopy, and Arterial Spin Labelling (ASL) findings. Materials and Methods: A retrospective observational study was conducted in the Department of Radiology, Nanavati Max Superspeciality Hospital, Mumbai, Maharashtra, India, between June 2022 and June 2023. A total of 125 patients were analysed to observe the correlation between whole brain volume, Intracranial Volume (ICV) of different cortical regions, hippocampal atrophy, and MRS findings. Descriptive statistics were used, and results were expressed as means and standard deviations for continuous variables, and as frequencies and percentages for categorical variables. Results: Out of 125 patients, 71 (56.8%) were males, and 54 (43.2%) were females, with ages ranging from 41 to 96 years. The majority presented with Mild Cognitive Impairment (MCI) 36 patients (28.8%) and Vascular Dementia (VaD) (18 patients - 14.4%). Some clinical features and imaging findings overlapped, resulting in some cases being a combination of different types of dementia. MRI, MRS, and Medial Temporal Atrophy (MTA) played a crucial role in allowing clinicians to perform a differential diagnosis. Conclusion: The use of MR volumetry and spectroscopy aids in classifying the type of dementia, which, in turn, gives treating clinicians a better perspective for further treatment and its outcomes.

The computer aided diagnosis of lung cancer is majorly focused on detection and segmentation with very less work reported on volume estimation and grading of cancerous nodule. Further, lung cancer segmentation systems are semi automatic in nature requiring radiologists to demarcate cancerous portions on every slice. This leads to subjectivity and delayed diagnosis. Further, these techniques are based on standard convolution leading to inaccurate segmentation in terms of actual boundary retention of the cancerous nodule. Also, there is a need of automatic system that not only grades the lung cancer based on actual parameters but also enables early warning for flagging of anomalies in periodic screening. This research work reports the design of a fully automated end-to-end screening system that consists of 5 major models with an improved performance on cancer detection, segmentation, volume estimation, grading, and an early warning system. The traditional convolutional technique is modified to allow for retention of actual shape of cancerous nodule. The simultaneous segmentation of cancer, lymph nodes and trachea is also achieved through a focus module and a modified loss function to remove redundancy and achieve an accuracy of 92.09%. The volume estimation model is developed using GPR interpolation to give an improved accuracy of 94.18%. A grading model based on the TNM classification standard is developed to grade the detected cancerous nodule to one of the six grades with an accuracy of 96.4%. The grading model is further extended to develop an early warning system for changes in the CT scans of lung cancer patients under treatment. The research is undertaken in collaboration with Nanavati Hospital, Mumbai, and all the models are validated on a real dataset obtained from the hospital.

Abstract Background The tumor microenvironment of solid tumors governs the differentiation of otherwise non‐immunosuppressive macrophages and gamma delta (γδ) T cells into strong immunosuppressors while promoting suppressive abilities of known immunosuppressors such as myeloid‐derived suppressor cells (MDSCs) upon infiltration into the tumor beds. Recent findings In epithelial malignancies, tumor‐associated macrophages (TAMs), precursor monocytic MDSCs (M‐MDSCs), and gamma delta (γδ) T cells often acquire strong immunosuppressive abilities that dampen spontaneous immune responses by tumor‐infiltrating T cells and B lymphocytes against cancer. Both M‐MDSCs and γδ T cells have been associated with worse prognosis for multiple epithelial cancers. Conclusion Here we discuss recent discoveries on how tumor‐associated macrophages and precursor M‐MDSCs as well as tumor associated‐γδ T cells acquire immunosuppressive abilities in the tumor beds, promote cancer metastasis, and perspectives on how possible novel interventions could restore the effective adaptive immune responses in epithelial cancers.

Abstract Circulating tumor plasma cells (CTPCs) provide a noninvasive alternative for measuring tumor burden in newly diagnosed multiple myeloma (NDMM). Moreover, measurable residual disease (MRD) assessment in peripheral blood (PBMRD) can provide an ideal alternative to bone marrow MRD, which is limited by its painful nature and technical challenges. However, the clinical significance of PBMRD in NDMM still remains uncertain. Additionally, data on CTPC in NDMM patients not treated with transplant are scarce. We prospectively studied CTPC and PBMRD in 141 NDMM patients using highly sensitive multicolor flow cytometry (HS‐MFC). PBMRD was monitored at the end of three cycles (PBMRD1) and six cycles (PBMRD2) of chemotherapy in patients with detectable baseline CTPC. Patients received bortezomib‐based triplet therapy and were not planned for an upfront transplant. Among baseline risk factors, CTPC ≥ 0.01% was independently associated with poor progression‐free survival (PFS) (hazard ratio [HR] = 2.77; p = 0.0047) and overall survival (OS) (HR = 2.9; p = 0.023) on multivariate analysis. In patients with detectable baseline CTPC, undetectable PBMRD at both subsequent time points was associated with longer PFS (HR = 0.46; p = 0.0037), whereas detectable PBMRD at any time point was associated with short OS (HR = 3.25; p = 0.004). Undetectable combined PBMRD (PBMRD1 and PBMRD2) outperformed the serum‐immunofixation‐based response. On multivariate analysis, detectable PBMRD at any time point was independently associated with poor PFS (HR = 2.0; p = 0.025) and OS (HR = 3.97; p = 0.013). Thus, our findings showed that CTPC and PBMRD assessment using HS‐MFC provides a robust, noninvasive biomarker for NDMM patients not planned for an upfront transplant. Sequential PBMRD monitoring has great potential to improve the impact of the existing risk stratification and response assessment models.

Urologists commonly make use of ureteral double J stents in endourology. If a DJ stent is forgotten to be removed, then complications happen in the form of encrustations, infection, migration, renal dysfunction and hydronephrosis. Ectopic pelvic Kidney is a relatively rare congenital anomaly caused by lack of ascent of the kidney. We report a very rare case of forgotten DJ stent in an ectopic kidney in a 55 years old patient with diabetes mellitus with history of left sided open pyelolithotomy done 21 months back. Redo open surgery was done to remove DJ stent along with stone removal.

The incidence of Lower urinary tract foreign body insertions is low. The motives for such insertion of a variety of objects are difficult to comprehend. We report a case of a 20-year-old male with multiple safety pins and broken incense sticks embedded inside his urethra which were successfully removed cystoscopically.

Background: Prostatic abscess is uncommon in adults and is infrequently noted in the paediatric population. Surgical drainage with adequate antibiotics is the current recommended management for prostatic abscess larger than 1 cm. However, it is still a topic debate that what should be the appropriate management of a prostatic abscess. Case presentation: Herein, we present the case of a 16-year-old young adolescent patient with a large prostate abscess without any systemic disease who was successfully managed with antibiotics only and surgical drainage was not required for this patient. Conclusion: Thus, we conclude that in a young adolescent patient with acute prostatic abscess, medical management with intravenous antibiotics deferring surgical drainage can be used an effective treatment option for management of this condition.