Best Overall Response-associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE.

PURPOSE: This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase-3 ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers. EXPERIMENTAL DESIGN: RNA sequencing was performed on pretreatment tumor samples (n=273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was utilized for refinement and validation. RESULTS: A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2 P=2.0e-7) and grade (P=0.002). There were no associations between the BOR signature and gender, age, ethnicity or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma. CONCLUSIONS: The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.

Incidental detection of rare vascular variation during pyeloplasty and its clinical implication - A case report.

ABSTRACT: Crossing vessels is one of the important causes of pelviureteric junction obstruction (PUJO). Accessory lower polar vessels are commonly seen with congenital PUJO, but they are not always the cause of obstruction. We incidentally encountered a variation in the lower polar crossing vessel while doing laparoscopic pyeloplasty in a patient with congenital PUJO. We encountered a right accessory lower polar artery and vein along with a right gonadal artery arising from the accessory right renal artery and right gonadal vein draining into the right lower polar crossing accessory renal vein. Knowledge of variations in genitourinary vasculature is important in the current era to prevent inadvertent complications.

World Health Organization MPOWER for tobacco control in India: a 6-year retrospective analysis.

Background: Prevalence and practices of tobacco usage in India are diverse and incongruent and Government of India has enacted various laws to overcome this burden. To make tobacco control measures effective and powerful, WHO introduced MPOWER in 2004 and India was one of the first countries that implemented the MPOWER. Objective: This study is aimed to quantify the implementation of MPOWER tobacco control policies in India. Material and Methods: In this retrospective analysis, data was gathered from the WHO MPOWER of India from 2015 to 2021. This analysis was based on the checklist which was designed previously by Iranian and international tobacco control specialists in their study on tobacco control. Results: In the present comparative analysis, India was categorized by scores and these were acquired from each indicator for each activity and 2021 year got the highest scores as compared to the previous year scores i.e. 27 in 2015. In context to individual indicators, noticeable increase in scores has been seen in both health warning on cigarette packages and adult daily smoking prevalence, whereas no progress was observed in smoking related policies. Conclusion: Although MPOWER programmes are widely accepted by the Indian government, but still substantial improvement in fewer sections is required.

18F-fluoro-2-deoxy-2-d-glucose PET-CT (FDG PET-CT) in staging of high-risk renal and urothelial bladder cancers (COPPER-T) trial protocol.

Background and Study Design: Role of 18F-fluoro-2-deoxy-2-d-glucose positron emission tomography-computed tomography (FDG PET-CT) in evaluation of renal cell cancers (RCC) and urinary bladder cancers is not standardized, and the COPPER-T trial, which is a single centre prospective randomized study, was designed to compare it with conventional imaging for staging of clinically localized high risk RCC and urinary bladder carcinoma (Stage T2 and above). Patients and Methods: There will be two subgroups of patients: RCC and urinary bladder carcinoma. In each of these, the patients will be randomized to either Arm A or Arm B. In each of the arms, each patient will be subjected to diagnostic imaging by FDG PET-CT. The CT scan will be a contrast-enhanced scan like that in conventional staging. A radiologist and nuclear medicine specialist will report the scan independently. The radiologist will not have access to the PET scan sequences and will only review the contrast-enhanced computed tomography (CECT) images. In Arm A, the report of the conventional imaging modality, that is, CECT and bone scan if done, will be reviewed first by the clinician, and based on this report, a management plan will be made. Then, the PET-CT report will be reviewed, and change in the management plan will be noted. New findings or equivocal findings if any in the PET-CT report would be noted. In Arm B, the report of the PET-CT report will be reviewed first by the clinicians, and a management plan will be made. Then, the CECT and/or bone scan reports will be reviewed, and any change in the management plan will be noted. Outcome and Significance: Final analysis of the data after completion of the trial will help in clarifying the role of FDG PET-CT in high risk RCC and transitional cell carcinoma (TCC) of the bladder, its diagnostic accuracy compared with conventional imaging and the impact of using it on patient management.

Post-operative chyle leak following nephrectomy: Inference from tertiary care center and review of literature.

OBJECTIVES: Lymphatic channels (LC) are not as prominent as blood vessels, so they tend to get damaged during surgical procedures. It can present with chyle leak in the postoperative period. We aimed to study the occurrence of chyle leak in patients undergoing nephrectomy and its management. METHODS: During the period of January 2021 and January 2023, 158 adult patients underwent nephrectomy for various reasons like non-functioning kidney, donor nephrectomy, and malignancy. We retrospectively analyzed data of patients who had chyle leak after nephrectomies. RESULTS: Eight patients out of the 158 patients (5.06%) undergoing nephrectomy developed chyle leak. One out of these eight patients underwent nephrectomy by open approach while seven underwent laparoscopic approach. All eight patients who had chyle leak undergone left sided nephrectomy. Six patients of chyle leak could be managed with dietary modification while two patients needed octreotide therapy for treatment. Higher Body Mass Index (BMI; p-value = 0.012), left sides nephrectomy (p-value = 0.013), h/o pyelonephritis (p-value = 0.005) were associated with higher incidence of chyle leak on univariate analysis. While on multivariate analysis no factor was found to be independently associated with chyle leak. Hospital stay was significantly prolonged in patients with chyle leak (p-value = 0.007). CONCLUSION: Chyle leak is not a very rare complication after nephrectomy. Patients with higher BMI, who undergo left sided nephrectomies and patients who had history of pyelonephritis or infectious complications had higher incidence of chyle leak. Most cases can be managed with conservative management (CM). Chyle leak is associated with a prolonged hospital stay.

Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma.

PURPOSE: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. EXPERIMENTAL DESIGN: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. RESULTS: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. CONCLUSIONS: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.

Diffusion Weighted Imaging in Spine Tumors.

Diffusion weighted imaging (DWI) has developed into a powerful tool for the evaluation of spine tumors, particularly for the assessment of vertebral marrow lesions and intramedullary tumors. Advances in magnetic resonance techniques have improved the quality of spine DWI and diffusion tensor imaging (DTI) in recent years, with increased reproducibility and utilization. DTI, with quantitative parameters such as fractional anisotropy and qualitative visual assessment of nerve fiber tracts, can play a valuable role in the evaluation and surgical planning of spinal cord tumors. These widely available techniques can be used to enhance the diagnostic evaluation of spinal tumors.

Clinical and Genomic Characteristics of Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors.

PURPOSE: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options. EXPERIMENTAL DESIGN: Patients in the United States with HR+, HER2- MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described. RESULTS: The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005). CONCLUSIONS: Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified.

Quadrifecta outcomes and their predictors following robotic radical prostatectomy: a study of newly established robotic center in India.

Active surveillance (AS), radical prostatectomy (RP), and radical radiotherapy (RT) are the three options for localized prostate cancer. Only a few studies have been conducted in developing countries or in centers in their initial learning curve that predict the outcomes of RARP. Therefore, this study aimed to present data from a novice center; how we started and progressed, and to compare our results with the rest of the world. This is a retrospective analysis to study the outcomes following robot-assisted radical prostatectomy and to identify the predictors of quadrifecta outcomes, i.e., the patients who were continent, did not have complications, were biochemical recurrence free with at least 1 year of follow-up and had negative surgical margins. In our data, we excluded the erectile function as one of the parameters as the majority of our patients were not sexually active or did not want to discuss this parameter. Seventy-two patients were included in this study, and 50 (69.4%) of these achieved the quadrifecta outcomes. Of all the factors, studied, seven factors were statistically significantly different between Group I (quadrifecta achieved) and Group II (quadrifecta not achieved), namely, BMI, co-morbidities like CAD, COPD, ASA grade, pre-op D'Amico risk stratification groups, clinical staging, positive lymph-node status, and hospital stay. With this study, we reported outcomes of RARP in a newly established robotic center and the results were fairly comparable with the well-developed center in India and abroad, emphasizing the short learning curve, and so, the requirement of establishing more robotic surgery centers in developing as well as developed countries.

To Study the Clinical Profile and Management of Cellulitis of Lower Limb in Northern India.

Cellulitis is a bacterial infection of the dermis and subcutaneous tissues occupying a large proportion of hospital beds. This study was conducted for analysis of patients with cellulitis according to their demographics and clinical presentation and to examine their comorbidities, complications, and its management. This observational cross-sectional study was conducted in the Department of Surgery at Santosh Medical College and Hospitals involving a total of 60 cases having cellulitis and other soft tissue infections of lower limb. Analysis of their demographic profile, management, and complications was done. Cellulitis is seen commonly in males, 46 (76.6%). The mean age of patients affected by cellulitis in the study was 36.4 ± 1.23 years. The most common site affected is leg involving more people in field jobs. The most common risk factor was trauma in 46.6%, and other factors were diabetes mellitus and smoking, while abscess formation was the most common complication observed in 36.6% of cases. A total of 56.6% cases were managed conservatively, while 43.3% cases required surgical intervention. Mean hospital stay in this study was 5.02 ± 0.23 days. It was concluded that cellulitis is subcutaneous, spreading bacterial infection is more common in males, and its incidence is highest in working age group population. Lower limb is commonly involved. Trauma, smoking, and diabetes are significant risk factors for development of cellulitis. Abscess is the most common complication. About 50% patients with cellulitis can be managed conservatively and the rest require surgical intervention.

Spotlight on 4-substituted quinolines as potential anti-infective agents: Journey beyond chloroquine.

Continued emerging resistance of pathogens against the clinically approved candidates and their associated limitations continuously demand newer agents having better potency with a more suited safety profile. Quinoline nuclei containing scaffolds of natural and synthetic origin have been documented for diverse types of pharmacological activities, and a number of drugs are clinically approved. In the present review, we unprecedentedly covered the biological potential of 4-substituted quinoline and elaborated a rationale for its special privilege to afford the significant number of approved clinical drugs, particularly against infectious pathogens. Compounds with 4-substituted quinoline are well documented for antimalarial activity, but in the last two decades, they have been extensively explored for activity against cancer, tuberculosis, and several other pathogens including viruses, bacteria, fungi, and other infectious pathogens. In the present study, the anti-infective spectrum of this scaffold is discussed against viruses, mycobacteria, malarial parasites, and fungal and bacterial strains, along with recent updates in this area, with special emphasis on the structure-activity relationship.

Renal vein injury during percutaneous nephrolithotomy: A surgical catastrophe - Management and lessons learned.

Percutaneous nephrolithotomy (PCNL) is the treatment of choice for large and complex renal calculi. We encountered a patient who was planned for PCNL in a peripheral hospital, without a preoperative computed tomography scan but was abandoned during tract dilatation due to intractable bleeding and was referred to our institute with nephrostomy in situ in a clamped state. After evaluation, the tip of the nephrostomy tube was found to be in the left renal vein causing secondary thrombosis. Due to the nonfunctional status of the kidney in the dynamic scan, the patient underwent laparoscopic left simple nephrectomy with thrombectomy without any major intraoperative complication and was discharged in stable condition.

Dental professionals' attitude and willingness to respond during disaster events: a cross-sectional study.

INTRODUCTION: In the present times, natural and man-made threats have questioned our existence on this planet. Health care professionals need to be aware of all the procedures to follow during such an event that threatens to paralyze the entire community and should be able to respond effectively. OBJECTIVE: The present study was conducted to assess the willingness and attitude of dental professionals to render help during any disaster or catastrophic event. MATERIAL AND METHODS: The present cross-sectional study among 480 subjects who were residing in Tricity (Chandigarh, Mohali and Panchkula). Informed consent was taken from all the subjects. Systematic random sampling methodology was employed for selection for study sample. The study utilized a self-designed close-ended questionnaire written in English and verified by experts. The questionnaire was divided into two parts to collect the required information. The data was analyzed using SPSS software version 21; chi-square test and multiple regression analysis were used to arrive at the results. RESULTS: More than 85% of subjects had awareness regarding natural and manmade disasters. A positive response was given by 79.2% of subjects regarding willingness to help during disaster. Educational qualification of subjects was significantly associated with attitude towards some aspects of disaster response (p<0.05). Postgraduate subjects and subjects who were academicians were more willing to render help (OR: 2.18 & 3.65 respectively). CONCLUSIONS: The study emphasizes the need for educational and training programs for dentists' regarding disaster management. A short course on emergency and disaster management can be included in undergraduate and postgraduate dental curriculum.

Multimodal Pain Management in Orthopedic Surgery.

BACKGROUND: Orthopedic surgery typically results in moderate to severe pain in a majority of patients. Opioids were traditionally the primary medication to target mechanisms of pain transmission. Multimodal analgesia has become a preferred method of pain management in orthopedic practice. Utilizing more than one mode to address post-surgical pain by recruiting multiple receptors through different medications accelerates the recovery process and decreases the need for opioids. By implementing effective analgesic techniques and interventions, this practice, in turn, decreases the usage of perioperative opioids, and in the long term, prevents addiction to pain medications and risk of opioid overdose. In orthopedic surgeries, previous studies have found that multimodal analgesia has reduced early opioid usage in the postoperative course. Pain is the result of direct injury to the nervous system, with a wide variety of chemicals directly stimulating or sensitizing the peripheral nociceptors. The pathophysiology behind the mechanism of post-surgical pain, along with the importance of preoperative, perioperative, and postoperative pain regimens are emphasized. A brief overview of pain medications and their properties is provided. These medications are further categorized, with information on special considerations and typical dosage requirements. Pain management should address both neuropathic and subjective types of pain. Effective pain control requires constant reassessment with individualized strategies. CONCLUSION: By focusing on multimodal analgesia, anesthesiologists can now utilize newer techniques for postoperative pain relief from orthopedic surgery, with better short-term and long-term outcomes for the patient.

Calcifying pseudoneoplasms of the neuraxis (CAPNON): The great tumor mimicker.

Calcifying pseudoneoplasms of the neuraxis (CAPNON) are very rare intracranial lesions with less than 50 cases reported in literature. These are non-neoplastic in etiology and despite having unique imaging characteristics, are often misdiagnosed as a neoplastic condition like meningioma, chordoma and gliomas. These do not have any predilection for any age, gender or intracranial location and can be seen in a wide range of age groups. Despite having an imaging overlap with neoplastic conditions, CAPNONs have classic histopathologic findings including chondromyxoid matrix, palisading spindle cells and calcific or ossific metaplasia. As more cases are being described in literature the imaging features are also being better defined. We discuss the clinical, imaging and histopathological findings of 2 cases of CAPNON mimicking posterior fossa meningioma and glial neoplasm.

Omicron sub-variants: is the world going to witness another wave?

Omicron, the new 'Variant of Concern' of SARS-CoV-2, is rapidly evolving into new sub-variants or sub-lineages (BA.1, BA.2 etc.). These sub-variants have higher transmissibility, decreased vaccine effectiveness and increased risk of reinfection. As a result, many nations across the globe are reporting surge in infections which is a matter of concern. Understanding Omicron and its sub-variants is vital for development of public health policy and preventing disease transmission. The present paper throws a spotlight on the newly detected sub-variants of Omicron as reported in ongoing researches which are available only in pre-print form and also the importance of a booster dose of the vaccine. Information regarding recent research on a new nasal vaccine formulation, which may be effective against the new variants, is also highlighted in the paper.