Integrating network pharmacology and in silico analysis deciphers Withaferin-A's anti-breast cancer potential via hedgehog pathway and target network interplay.

This study examines the remarkable effectiveness of Withaferin-A (WA), a withanolide obtained from Withania somnifera (Ashwagandha), in encountering the mortiferous breast malignancy, a global peril. The predominant objective is to investigate WA's intrinsic target proteins and hedgehog (Hh) pathway proteins in breast cancer targeting through the application of in silico computational techniques and network pharmacology predictions. The databases and webtools like Swiss target prediction, GeneCards, DisGeNet and Online Mendelian Inheritance in Man were exploited to identify the common target proteins. The culmination of the WA network and protein-protein interaction network were devised using Stitch and String web tools, through which the drug-target network of 30 common proteins was constructed employing Cytoscape-version 3.9. Enrichment analysis was performed by incorporating Gprofiler, Metascape and Cytoscape plugins. David compounded the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, and enrichment was computed through bioinformatics tools. The 20 pivotal proteins were docked harnessing Glide, Schrodinger Suite 2023-2. The investigation was governed by docking scores and affinity. The shared target proteins underscored the precise Hh and WA network roles with the affirmation enrichment P-value of <0.025. The implications for hedgehog and cancer pathways were profound with enrichment (P < 0.01). Further, the ADMET and drug-likeness assessments assisted the claim. Robust interactions were noticed with docking studies, authenticated through molecular dynamics, molecular mechanics generalized born surface area scores and bonds. The computational investigation emphasized WA's credible anti-breast activity, specifically with Hh proteins, implying stem-cell-level checkpoint restraints. Rigorous testament is imperative through in vitro and in vivo studies.

Accuracy of contrast-enhanced CT in liver neoplasms in children under 2 years age.

BACKGROUND: Multiple differentials exist for pediatric liver tumors under 2 years. Accurate imaging diagnosis may obviate the need for tissue sampling in most cases. OBJECTIVE: To evaluate the imaging features and diagnostic accuracy of computed tomography (CT) in liver tumors in children under 2 years. METHODS: Eighty-eight children under 2 years with treatment naive liver neoplasms and baseline contrast-enhanced CT were included in this institutional review board approved retrospective study. Two blinded onco-radiologists assessed these tumors in consensus. Findings assessed included enhancement pattern, lobulated appearance, cystic change, calcifications, central scar-like appearance, and metastases. The radiologists classified the lesion as hepatoblastoma, infantile hemangioma, mesenchymal hamartoma, rhabdoid tumor, or indeterminate, first based purely on imaging and then after alpha-fetoprotein (AFP) correlation. Multivariate analysis and methods of comparing means and frequencies were used for statistical analysis wherever applicable. Diagnostic accuracy, sensitivity, and positive predictive values were analyzed. RESULTS: The mean age of the sample was 11.4 months (95% CI, 10.9-11.8) with 50/88 (57%) boys. The study included 72 hepatoblastomas, 6 hemangiomas, 4 mesenchymal hamartomas, and 6 rhabdoid tumors. Presence of calcifications, multilobular pattern of arterial enhancement, lobulated morphology, and central scar-like appearance was significantly associated with hepatoblastomas (P-value < 0.05). Fourteen out of eighty-eight lesions were called indeterminate based on imaging alone; six lesions remained indeterminate after AFP correlation. Pure radiology-based diagnostic accuracy was 81.8% (95% CI, 72.2-89.2%), which increased to 92.1% (95% CI, 84.3-96.7%) (P-value > 0.05) after AFP correlation, with one hepatoblastoma misdiagnosed as a rhabdoid tumor. If indeterminate lesions were excluded for biopsy, the accuracy would be 98.8% (95% CI, 93.4-99.9%). CONCLUSION: CT had high accuracy for diagnosing liver neoplasms in the under 2-year age population after AFP correlation. Certain imaging features were significantly associated with the diagnosis of hepatoblastoma. A policy of biopsying only indeterminate lesions after CT and AFP correlation would avoid sampling in the majority of patients.

Treatment outcomes and prognostic factors in children with hepatoblastoma using a risk-stratified approach.

BACKGROUND: Not all the significant progress made in the management of children with hepatoblastoma (HB) has translated into improved outcomes in limited-resource settings. There are limited data on outcomes in children with HB from India. METHODS: All patients diagnosed with HB between July 2013 and December 2020 were risk-stratified and treated as per International Liver Tumor Strategy Group (SIOPEL). Patients with standard-risk HB received cisplatin monotherapy and those with high-risk HB received alternating cycles of cisplatin and the combination of carboplatin plus doxorubicin. Data regarding demographic details, chemotherapy, surgery, liver transplantation, outcomes, prognostic factors, and toxicity were collected. RESULTS: Of 157 patients with HB, 117 (74%) were high risk, 31 (20%) were standard risk, and nine (6%) unknown. Patients with standard-risk disease had excellent outcomes, with 3-year event-free survival (EFS) and overall survival (OS) of 96% and 100%, respectively. Among high-risk HB, six underwent orthotopic liver transplantation of which four were alive at last follow-up. The 3-year EFS and OS of patients with high-risk disease was 56% and 66%, respectively. Outcomes of patients with PRETEXT IV (3-year EFS: 42%, 3-year OS: 50%) and metastatic disease (3-year EFS: 30%, 3-year OS: 50%) were dismal. Patients with serum alpha-fetoprotein (AFP) reduction greater than 90% following two courses of chemotherapy had favorable outcomes; 3-year EFS: 80% versus 58% (p = .013) and 3-year OS: 95% vs. 68% (p < .01). Only two (6%) of 31 patients with relapse/refractory HB were alive at a median follow-up of 36 months, and both had received salvage chemotherapy and surgery. CONCLUSIONS: While children with standard-risk HB had excellent outcomes, those with high-risk disease continue to do poorly. Serial monitoring of serum AFP values is a cost-effective and reliable predictor of outcomes. Orthotopic liver transplantation remains a viable option for inoperable disease in resource-limited settings as well.

Comparison of the Performance of APACHE II, SOFA, and mNUTRIC Scoring Systems in Critically Ill Patients: A 2-year Cross-sectional Study.

AIMS AND OBJECTIVES: Different severity scores are being used to assess outcomes in intensive care unit, but variable data had been reported so far per their performance. Main objective of this study is to compare performance of acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and modified nutrition risk in critically ill (mNUTRIC) scoring systems regarding the outcomes in the form of morbidity and mortality in medical intensive care unit (MICU) at rural tertiary-care health center. MATERIALS AND METHODS: In this cross-sectional study, 1,990 patients older than 18 years admitted in the ICU were enrolled. Age, gender, diagnosis, intubation, comorbidities, APACHE II, SOFA scores, m NUTRIC score, MICU stays in days, and need of mechanical ventilation were noted. RESULTS: When we compared different score with mortality, APACHE-II was having sensitivity of 89.9% and specificity of 97.6%; SOFA had 90.1% sensitivity and 96.6% specificity; while mNUTRIC score had 97.2% sensitivity and 74.0% specificity. APACHE-II score had sensitivity of 93.4%, SOFA had 90.5%, and mNUTRIC score 92.3% with low specificity of 76.5% in predicting requirement of mechanical ventilation. mNUTRIC score and ICU length of stay showed moderate positive correlation (p value = <0.001). CONCLUSION: All the three scores were comparable in sensitivity and specificity in predicting outcomes in the form of mortality, need of mechanical ventilation, and length of ICU stays. mNUTRIC score was more sensitive than others, and as it was based on nutritional status, hence more weightage should be given on this score. HOW TO CITE THIS ARTICLE: Kumar S, Gattani SC, Baheti AH, Dubey A. Comparison of the Performance of APACHE II, SOFA, and mNUTRIC Scoring Systems in Critically Ill Patients: A 2-year Cross-sectional Study. Indian J Crit Care Med 2020;24(11):1057-1061.

Pediatric NUT Carcinoma Is a Rare and Challenging Tumor: Single Center Experience of Five Children.

BACKGROUND: Nuclear protein of the testis (NUT) carcinoma is a rare and aggressive malignancy associated with rearrangements of the nuclear protein of the testis (NUT) gene on chromosome 15q14. Because of its rarity, this tumor is often underdiagnosed and underreported, and there is limited literature regarding its biology and optimal management. METHODS AND RESULTS: We report our experience of five patients with pediatric NUT carcinoma, all of whom presented with midline head and neck mass. In spite of aggressive multimodality treatment, only one patient survives. CONCLUSION: NUT carcinoma has a dismal prognosis in spite of aggressive multimodality management (surgery and adjuvant chemotherapy and/or radiation). Novel strategies are required to improve outcomes of patients with this tumor.

Customized approach for upfront or delayed resection using radiological criteria in unilateral, nonmetastatic pediatric renal tumors: A prospective study.

BACKGROUND: The availability of robust, equivalent data regarding outcomes for upfront or delayed surgery for renal tumors in children leads to a dilemma in selecting the initial treatment. Imaging criteria associated with the probability of rupture or incomplete resection may provide a more objective assessment for customization for the timing of surgery. PROCEDURE: Eighty-three children with unilateral, nonmetastatic renal tumors were enrolled between January 2012 and April 2018. Upfront nephrectomy was performed in the absence or delayed surgery (after a biopsy and chemotherapy) in the presence of one or more imaging-based high-risk features, including perinephric spread or adjacent organ infiltration, tumors crossing the midline, intravascular thrombus, and extensive adenopathy. Post hoc analysis for interobserver concordance for high-risk imaging features was also performed. RESULTS: The upfront surgery group (19) had predominantly stage I or II diseases (89%) and the histological types were Wilms (13), non-Wilms (5) renal tumor, and an inflammatory lesion. The delayed surgery group had 60% with stage I or II diseases and the histological types were Wilms (60) and non-Wilms (4) tumor. In addition, high-risk pathology was identified in nine patients. Overall, 27 patients with Wilms tumors required radiotherapy and anthracycline because of stage III disease, including one in the immediate surgery group. The event-free and overall survival (OS) at a median follow-up of 39 months for Wilms tumor are 88% (95% confidence interval [CI]: 78.5-94.9%) and 89% (95% CI: 81.4-96.6%), 85.1% (95% CI: 73.8-93.4%) and 86.5% (95% CI: 77.4-95.8%) for the delayed, and 100% event-free survival as well as OS (P = .1) in the upfront surgery group. CONCLUSION: A customized approach pivoted on image-based high-risk features facilitates identification of patients with early-stage renal tumor when the timing of surgery is tailored. Moreover, non-Wilms tumor and high-risk pathology are also identified.

Prophylactic hydration to protect renal function from intravascular iodinated contrast material.

Nijssen EC, Rennenberg RJ, Nelemans PJ, Essers BA, Janssen MM, Vermeeren MA, van Ommen V, Wildberger JE. (Departments of Radiology and Nuclear Medicine, Internal Medicine, Epidemiology, Clinical Epidemiology and Medical Technology Assessment, and Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands.) Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): A prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 2017;389:1312-22.

Soft-Tissue Sarcomas: An Update for Radiologists Based on the Revised 2013 World Health Organization Classification.

OBJECTIVE: Soft-tissue sarcomas are a diverse group of malignancies, and our rapidly improving understanding of their molecular pathogenesis and treatment is leading to better clinical outcomes. The revised 2013 World Health Organization (WHO) classification of soft-tissue sarcomas introduced several important changes. We provide a comprehensive overview of the relevant changes for radiologists. CONCLUSION: Rapid advances in the understanding of the pathogenesis and molecular biology of soft-tissue sarcomas led to major revisions in the 2013 WHO classification. To provide optimal multidisciplinary patient care, radiologists must remain up-to-date with the latest developments in the field of soft-tissue sarcomas to best correlate the histologic and imaging features of the various types of tumors and understand the unique patterns of treatment response and disease recurrence.

Basal cell carcinoma: a comprehensive review for the radiologist.

OBJECTIVE. Basal cell carcinoma (BCC) is the most common malignancy in the United States. The purpose of this article is to provide a comprehensive description of the clinicopathologic features, diagnostic workup, staging, treatment, and follow-up of BCC. CONCLUSION. Radiology plays an important role in the evaluation and staging of locally advanced and metastatic BCC. MRI is the modality of choice for assessing perineural disease and is equivalent or superior to CT for evaluating bony involvement. CT and PET/CT are used to evaluate metastatic disease.

Myxoid soft-tissue neoplasms: comprehensive update of the taxonomy and MRI features.

OBJECTIVE. The purpose of this article is to review the classification, clinical presentation, and histopathologic and MRI features of myxoid soft-tissue neoplasms. CONCLUSION. MRI is the modality of choice for characterization of myxoid soft-tissue tumors. A combination of imaging features (including certain characteristic signs), clinical features, and patient demographics can help the radiologist in coming to a specific diagnosis or in narrowing down the differential diagnoses.

Anti-VEGF molecular targeted therapies in common solid malignancies: comprehensive update for radiologists.

Angiogenesis is an essential component of the growth and dissemination of solid malignancies and is mediated by several proangiogenic factors. The most widely studied proangiogenic factor is vascular endothelial growth factor (VEGF). A major class of molecular targeted therapies (MTTs) inhibit the VEGF axis and are referred to as antiangiogenic MTTs. There are two main types of anti-VEGF MTTs: drugs targeting circulating VEGF and drugs interfering with the activity of the VEGF receptors. The cancers against which antiangiogenic MTTs have had the greatest effect are gliomas, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, and gastrointestinal stromal tumor. These cancers respond to antiangiogenic MTTs in a different way than they respond to conventional chemotherapy. Instead of the traditional Response Evaluation Criteria in Solid Tumors (RECIST), each of these cancers therefore requires its own individualized treatment response criteria (TRC). Examples of individualized TRC include the Response Assessment in Neuro-oncology (RANO) criteria for gliomas, modified RECIST for hepatocellular carcinoma, and Morphology, Attenuation, Size, and Structure (MASS) criteria for renal cell carcinoma. Furthermore, antiangiogenic MTTs have a unique spectrum of class-specific and drug-specific toxic effects, some of which can be detected at imaging. Increasing use of antiangiogenic MTTs in clinical practice necessitates that radiologists be aware of these drugs, their response patterns, and TRC as well as their toxic effect profiles.

MDCT of extranodal mantle cell lymphoma: a single institute experience.

OBJECTIVE: To study the pattern of extranodal and particularly gastrointestinal (GI) involvement of mantle cell lymphoma (MCL) on MDCT MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, MDCT features of 78 patients (62 males and 16 females, mean age 57 years) with MCL including 28 patients at presentation were reviewed. Clinical and histopathological (blastoid vs. non-blastoid) data were noted from medical records. RESULTS: Extranodal involvement was present in overall 51/78 patients on CT (65%), 18/28 (64%) patients at presentation. Spleen (21/78-27%) and bowel (19/78-24%) were the most common sites of extranodal involvement by MCL on imaging, followed by lungs (10/78-13%) and skin/subcutaneous tissue (9/78-12%). Bowel involvement was either in the form of endophytic polypoidal lesions (n = 11, mean size 3.1 cm), as focal mild bowel wall thickening (n = 5, mean thickness 1.4 cm), or as combination of the two (n = 3). Blastoid histology was present in 14/78 (24%) patients and was statistically associated with skin/subcutaneous involvement (p < 0.05; Fisher's exact t test). Median follow-up was 72 months during which 21 patients died with median survival of 48 months (26 months for blastoid histology vs. 47 months for non-blastoid histology). There was no statistical correlation between sites of involvement and survival. CONCLUSIONS: MCL has a predilection for extranodal disease, predominantly involving the spleen, bowel, lungs, and subcutaneous tissue. GI involvement on CT is in the form of endoluminal polypoidal lesions and mild bowel wall thickening. Skin/subcutaneous involvement was statistically more common with blastoid histology in our study.

Diagnosis and management of duodenal adenocarcinomas: a comprehensive review for the radiologist.

Duodenal adenocarcinomas are the most common duodenal tumors, and represent 15-25% of small bowel carcinomas. Their management differs from other small bowel tumors, with imaging playing a very important role. In this article, we provide a comprehensive review of the diagnosis and management of duodenal adenocarcinomas, emphasizing the role of the radiologist in the same.

Multimodality imaging of penile cancer: what radiologists need to know.

The purpose of this article is to provide a comprehensive update on the role of imaging in the diagnosis and management of penile cancer. Imaging plays a major role in the initial assessment, treatment planning, and follow-up of patients with penile carcinoma. MRI helps in assessing the T staging of the primary and in detecting local recurrence. PET/CT and CT are useful for detecting regional nodal and distant metastases.

Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients.

OBJECTIVE: To study the CT appearance and histopathology of mass-forming intrahepatic cholangiocarcinoma (IHCC) at presentation and correlate these features with metastatic disease and patient survival. MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, we reviewed pathology database of 459 patients with cholangiocarcinoma seen from 2004 through 2013 to identify 92 patients with IHCC (48 women, 44 men, mean age 61 years) who had CT scans of primary tumor available for review. All baseline and follow-up CT's were reviewed by two radiologists in consensus to record imaging characteristics and metastatic patterns. Clinical and histopathology data were obtained from electronic medical records. Imaging patterns and histopathology were analyzed for associations with metastatic spread and survival. RESULTS: Three distinct CT patterns of IHCC at presentation were identified: solitary dominant mass (type I IHCC, n = 34), dominant mass with satellite nodules in same segment (type II IHCC, n = 19), and multiple scattered hepatic lesions (type III IHCC, n = 39). Distant metastases developed in 49/92 patients (53%); 39 (42%) of which were present at diagnosis. Lungs (22/92; 24%), peritoneum (17/92; 18%), and bones (13/92; 14%) were most common metastatic sites. Type I IHCC had smaller size, lowest incidence of metastases at presentation, and best overall survival, while type III IHCC had shortest survival (p < 0.017). Poorly differentiated IHCC had higher proportion of osseous metastases (p = 0.042) and worse survival (p = 0.027). CONCLUSION: IHCC has three distinct CT patterns at presentation with different prognoses. Knowledge of these patterns can help radiologists to detect the extrahepatic disease and predict prognosis.

Eleven years of disease free survival in a case of Invasive Ductal Carcinoma (IDC) Rt Breast grade 3, stage 3, treated with add on Ayurveda treatment: A case report.

Breast cancer shows high mortality, especially in women worldwide. This report discusses a case of female patient with a history of Invasive Ductal Carcinoma (IDC) Rt Breast, ER, PR negative, Grade 3 (Gr3) Stage 3 (St3) seen in our OPD treated with supporting herbo-mineral-metallic combination of Ayurveda medicines. Generally, breast cancers of such subtype and that too in Lower Outer Quadrant (LOQ) are always of a concern and can be more troublesome to the patient. When the patient came for the first time, her chief complaint was palpable lump in her right breast for previous three months. We advised her to undergo relevant investigations and, it was found to be malignant. She underwent surgery, Modified Radical Mastectomy,(MRM), followed by chemotherapy. During chemotherapy, which was Adriamycin + Cyclophosphamide (AC) protocol 4 cycles, followed by Docetaxel 4 cycles, every 21 days. After 2 cycles, she started complaints of pain in both calf regions, numbness in fingers of hand and foot, severe generalized skin rash with itching, hyperacidity and constipation. She visited our clinic again for the same, and Ayurveda treatment was started to her at this point. So, at the time of commencement of treatment, the diagnosis was "IDC Rt Breast, LOQ, Gr3 St3, ER, PR negative HER2Neu positive, post op, on chemo". After appropriate analysis based on Ayurvedic and modern parameters, she was diagnosed to have vitiation of Rakta and Pitta (Dushti avastha), due to cyto-toxic nature of (Visha exposure) chemotherapy and medication was planned accordingly, along with chemotherapy protocol. The Ayurveda treatment showed significant relief in the chemotoxicity symptoms, within one month and she could tolerate further chemotherapy cycles very conveniently. On completion of chemotherapy, she was diagnosed to have need of good immunity (Vyadhi-Kshamatva). Based on this diagnosis, Ayurveda treatment protocol was changed and this new regimen continued for almost 6 years afterwards. Laboratory and imaging investigations performed periodically showed marked improvement, and even currently not showing any abnormality. Till date, there is no recurrence and patient is living completely normally for last 11 years. As all the symptoms and investigations showed near complete improvement; it may be concluded that probably add on Ayurveda treatment (Integrative approach) proved effective in this patient of IDC. We have observed 11 years of disease-free survival and excellent quality of life in this patient and still ongoing.

Non-operative management in low-lying rectal cancers undergoing chemoradiation.

PURPOSE: To evaluate the outcomes of post-neoadjuvant chemoradiation (NACTRT) wait-and-watch Strategy (WWS) in distal rectal cancers. MATERIALS AND METHODS: All consecutive patients from December 2012 to 2019 diagnosed with distal rectal tumors (T2-T4 N0-N+) having a complete or near-complete response (cCR or nCR, respectively) post-NACTRT and wishing for the non-surgical treatment option of WWS were included in this study. Patients were observed with 3 monthly magnetic resonance imaging (MRIs), sigmoidoscopies, and digital rectal examination for 2 years and 6 monthly thereafter. Organ preservation rate (OPR), local regrowth rate (LRR), non-regrowth recurrence-free survival (NR-RFS) and overall survival (OAS) were estimated using the Kaplan-Meier method, and factors associated with LRR were identified on univariate and multivariate analysis using the log-rank test (P < 0.05 significant). RESULTS: Sixty-one consecutive patients post-NACTRT achieving cCR[44 (72%)] and nCR[17 (28%)], respectively, were identified. All patients received pelvic radiotherapy at a dose of 45-50Gy conventional fractionation and concurrent capecitabine. An additional boost dose with either an external beam or brachytherapy was given to 39 patients. At a median follow-up of 39 months, 11 (18%) patients had local regrowth, of which seven were salvaged with surgery and the rest are alive with the disease, as they refused surgery. The overall OPR, NR-RFS, and OS were 83%, 95%, and 98%, respectively. Seven (11%) patients developed distant metastasis, of which six underwent metastatectomy and are alive and well. LRR was higher in patients with nCR versus cCR (P = 0.05). CONCLUSION: The WWS is a safe non-operative alternative management for selected patients attaining cCR/nCR after NACTRT with excellent outcomes.

Evaluation of an Objective MRI-Based Tumor Regression Grade (mrTRG) Score and a Subjective Likert Score for Assessing Treatment Response in Locally Advanced Rectal Cancers-A Retrospective Study.

Purpose: Magnetic resonance imaging (MRI) with the help of MRI-based tumor regression grade (mrTRG) score has been used as a tool to predict pathological tumor regression grade (pTRG) in patients of rectal cancer post-neoadjuvant chemoradiation. Our study aims to evaluate the ability of MRI in assessing treatment response comparing an objective mrTRG score and a subjective Likert score, with a focus on the ability to predict pathologic complete response (pCR). Methods: Post-treatment MRI studies were retrospectively reviewed for 170 consecutive cases of histopathologically proven rectal cancer after receiving neoadjuvant chemoradiation and prior to surgery by two oncoradiologists blinded to the eventual postoperative histopathology findings. An objective (mrTRG) and a subjective Likert score were assigned to all the cases. Receiver operating characteristic curves were constructed to determine the ability of Likert scale and mrTRG to predict pCR, with postoperative histopathology being the gold standard. The optimal cutoff points on the scale of 1 to 5 were obtained for mrTRG and Likert scale with the greatest sum of sensitivity and specificity using the Youden Index. Results: The most accurate cutoff point for the mrTRG to predict complete response was 2.5 (using Youden index), with a sensitivity of 69.2%, specificity of 69.6%, positive predictive value (PPV) of 85.6%, negative predictive value (NPV) of 46.4%, and accuracy of 69.3%. The most accurate cutoff for the Likert scale to predict complete response was 3.5, with a sensitivity of 47.5%, specificity of 89.1%, PPV of 91.9%, NPV of 39.4%, and accuracy of 59%. mrTRG had a lower cutoff and was more accurate in predicting pCR compared to Likert score. Conclusion: An objective mrTRG was more accurate than a subjective Likert scale to predict complete response in our study.