Anticancer potential and structure activity studies of purine and pyrimidine derivatives: an updated review.

Cancer is the world's leading cause of death impacting millions of lives globally. The increasing research over the past several decades has focused on the development of new anticancer drugs, but still cancer continues to be a global health challenge. Thus, several new alternative therapeutic strategies have been tried for the drug design and discovery. Purine and pyrimidine heterocyclic compounds have received attention recently due to their potential in targeting various cancers. It is evident from the recently published data over the last decade that incorporation of the purine and pyrimidine rings in the synthesized derivatives resulted in the development of potent anticancer molecules. This review presents synthetic strategies encompassing several examples of recently developed purine and pyrimidine-containing compounds as anticancer agents. In addition, their structure-activity relationships are represented in the schemes indicating the fragment or groups that are essential for the enhanced anticancer activities. Purine and pyrimidines combined with other heterocyclic compounds have resulted in many novel anticancer molecules that address the challenges of drug resistance. The purine and pyrimidine derivatives showed significantly enhanced anticancer activities against targeted receptor proteins with numerous compounds with an IC50 value in the nanomolar range. The review will support medicinal chemists and contribute in progression and development of synthesis of more potent chemotherapeutic drug candidates to mitigate the burden of this dreadful disease.

Anticancer potential of the S-heterocyclic ring containing drugs and its bioactivation to reactive metabolites.

Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i.e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.

Treatment outcomes in patients with Ewing sarcoma of the spine in a resource-challenged setting: 17-year experience from a single center in India.

Ewing sarcoma (ES) of the spine is a rare childhood cancer with sparse literature on treatment outcomes. We aimed to describe survival outcomes and prognostic factors in patients with spinal ES treated at a single institute in a resource-challenged setting. We conducted a retrospective analysis of patients with spinal ES registered at a tertiary care oncology center between 2003-2019. Clinical patient data was retrieved from hospital records. Cox regression analysis was used to identify the association of baseline clinical parameters with event free survival (EFS) and overall survival (OS). A cohort of 85 patients was analyzed including 38 (45%) patients with metastatic disease. The median age was 15 years with 73% being male. Local therapy was administered in 62 (72.9%) patients with surgery alone in 8 (9.4%), radiotherapy alone in 36 (42.4%) and both in 18 (21.2%) patients. A higher proportion of males received local therapy than females (80.3% versus 59.1%; p = 0.049). The median EFS and OS were 20.1 and 28.6 months, respectively. On univariable analysis, age ≤ 15 years, female sex, serum albumin ≤3.5 g/dL and hemoglobin ≤11 g/dL were associated with inferior EFS while younger age, female sex, hypoalbuminemia and metastatic disease were associated with inferior OS. On multivariable analysis, only hypoalbuminemia was predictive for inferior EFS (HR:2.41; p = 0.005) while hypoalbuminemia (HR:2.06;p = 0.033) and female sex (HR:1.83; p = 0.046) were associated with inferior OS. We concluded that hypoalbuminemia confers poor prognosis in ES spine. Survival outcomes are poorer in females treated in our setting, possibly due to prevailing sex-based biases.

Sex Bias in Treatment Abandonment of Childhood Cancer in India.

OBJECTIVES: To explore the magnitude of sex bias and determinants of treatment abandonment (TA) in childhood cancer in India. METHODS: Individual data of children (0-19 y) registered between January 1, 2017 and July 31, 2022, was compiled. TA was defined as defaulting curative intent treatment ≥4 wk. Defaulting treatment irrespective of intent ≥4 wk was defined as Treatment Default (TD). The primary outcome was the proportion of male-to-female children with TA. Secondary outcomes included the proportion of male-to-female children with upfront TA, TA at relapse, TD, TD-p (TD only in the palliative setting). The impact of clinico-demographic factors on TA was analysed using multivariable regression and propensity score matching (PSM). RESULTS: Three thousand two hundred eighty four patients were analysed. The overall male-to-female ratio (MFR) was 2.08 (95% CI 1.94-2.24). Of 2906 patients treated with curative intent, 415 (14·3%) abandoned treatment. TA was higher in females than males (16·4% vs. 13·3%; p = 0·022) with adjusted MFR of 0·81 (0·66-0·98). The adjusted MFR of TA for treatment-naïve and relapsed patients and TD were 0·73 (0·59-0·91), 1·13 (0·65-1·96) and 0·84 (0·71-1·00) respectively. Sex independently predicted TA on multivariable analysis. However, on PSM analysis including socio-economic variables, lower maternal education predicted higher TA in children with cancer (10·1% vs. 6%, p = 0·015). CONCLUSIONS: Child sex predicted TA in childhood cancer in India with more females abandoning treatment. Maternal education is a more crucial factor predicting TA over child sex, when socio-economic factors were considered. Hence, policies promoting female education and gender equality may mitigate sex-based gaps in childhood cancer care.

Expanding the therapeutic arsenal against cancer: a computational investigation of hybrid xanthone derivatives as selective Topoisomerase 2α ATPase inhibitors.

The DNA topoisomerase II (topo II) enzyme plays an important role in the replication, recombination, and repair of DNA. Despite their widespread applications in cancer therapy, new, selective, and potent topo II inhibitors with better pharmaceutical profiles are needed to handle drug resistance and severe adverse effects. In this respect, an array of 36 new anticancer compounds was designed based on a Xanthone core tethered to multifunctional Pyridine-amines and Imidazole scaffold via alkyl chain linkers. An integrated in silico approach was used to understand the structural basis and mechanism of inhibition of the hybrid xanthone derivatives. In this study, we established an initial virtual screening workflow based on pharmacophore mapping, docking, and cancer target association to validate the target selection process. Next, a simulation-based docking was conducted along with pharmacokinetic analysis to filter out the five best compounds (7, 10, 25, 27, and 30) having binding energies within the range of -60.45 to -40.97 kcal/mol. The screened compounds were further subjected to molecular dynamics simulation for 200 ns followed by MM-GBSA and ligand properties analysis to assess the stability and binding affinity to hTOP2α. The top-ranking hits 3,7-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 7) and 3,8-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 25) were found to have no toxicity, optimum pharmacokinetic and, DFT properties and stable intermolecular interactions with the active site of hTopo IIα protein. In conclusion, further in vitro and in vivo experimental validation of the identified lead molecules is warranted for the discovery of new human Topoisomerase 2 alpha inhibitors.Communicated by Ramaswamy H. Sarma.

Development of a Novel Red Clay-Based Drug Delivery Carrier to Improve the Therapeutic Efficacy of Acyclovir in the Treatment of Skin Cancer.

Acyclovir (ACV) is a promising candidate for drug repurposing because of its potential to provide an effective treatment for viral infections and non-viral diseases, such as cancer, for which limited treatment options exist. However, its poor physicochemical properties limit its application. This study aimed to formulate and evaluate an ACV-loaded red clay nanodrug delivery system exhibiting an effective cytotoxicity. The study focused on the preparation of a complex between ACV and red clay (RC) using sucrose stearate (SS) (nanocomplex F1) as an immediate-release drug-delivery system for melanoma treatment. The synthesized nanocomplex, which had nanosized dimensions, a negative zeta potential and the drug release of approximately 85% after 3 h, was found to be promising. Characterization techniques, including FT-IR, XRD and DSC-TGA, confirmed the effective encapsulation of ACV within the nanocomplex and its stability due to intercalation. Cytotoxicity experiments conducted on melanoma cancer cell lines SK-MEL-3 revealed that the ACV release from the nanocomplex formulation F1 effectively inhibited the growth of melanoma cancer cells, with an IC50 of 25 ± 0.09 µg/mL. Additionally, ACV demonstrated a significant cytotoxicity at approximately 20 µg/mL in the melanoma cancer cell line, indicating its potential repurposing for skin cancer treatment. Based on these findings, it can be suggested that the RC-SS complex could be an effective drug delivery carrier for localized cancer therapy. Furthermore, the results of an in silico study suggested the addition of chitosan to the formulation for a more effective drug delivery. Energy and interaction analyses using various modules in a material studio demonstrated the high stability of the composite comprising red clay, sucrose stearate, chitosan and ACV. Thus, it could be concluded that the utilization of the red clay-based drug delivery system is a promising strategy to improve the effectiveness of targeted cancer therapy.

Formulation and validation of a baseline prognostic score for osteosarcoma treated uniformly with a non-high dose methotrexate-based protocol from a low middle income healthcare setting: a single centre analysis of 594 patients.

Introduction: The outcomes of osteosarcoma in low middle income countries (LMICs) are different due to patients presenting in advanced stages, resource constraints and the use of non-high-dose-methotrexate (HDMTX)-based regimens. This study derived and validated a prognostic score for osteosarcoma that integrates biologic and social factors and is tailored for patients from an LMIC setting using a non-HDMTX-based protocol. Materials and methods: A retrospective study including osteosarcoma patients enrolled for treatment at a single tertiary care centre in India between 2003-19 was conducted. Baseline biologic and social characteristics were extracted from medical records and survival outcomes were noted. The cohort was randomised into a derivation and validation cohort. Multivariable Cox regression was used to identify baseline characteristics that were independently prognostic for survival outcomes in the derivation cohort. A score was derived from the prognostic factors identified in the derivation cohort and further validated in the validation cohort with estimation of its predictive ability. Results: 594 patients with osteosarcoma were eligible for inclusion in the study. Around one-third of the cohort had metastatic disease with 59% of the patients residing in rural areas. The presence of metastases at baseline (HR 3.39; p<0.001; score=3), elevated serum alkaline phosphatase (SAP) >450 IU/L (HR 1.57; p=0.001; score=1) and baseline tumour size > 10 cm (HR 1.68; p<0.001; score=1) were identified to be independent factors predicting inferior event free survival (EFS) and were included in development of the prognostic score. Patients were categorized as low risk (score 0), intermediate risk (score 1-3) and high risk (4-5). Harrell's c-indices for the score were 0.682, 0.608 and 0.657 respectively for EFS in the derivation, validation and whole cohort respectively. The timed AUC of ROC was 0.67 for predicting 18-month EFS in the derivation, validation and whole cohorts while that for 36-month EFS were 0.68, 0.66 and 0.68 respectively. Conclusions: The study describes the outcomes among osteosarcoma patients from an LMIC treated uniformly with a non-HDMTX-based protocol. Tumor size, baseline metastases and SAP were prognostic factors used to derive a score with good predictive value for survival outcomes. Social factors did not emerge as determinants of survival.

Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression.

BACKGROUND: Osteosarcoma is a type of bone cancer that predominantly affects young individuals, including children and adolescents. The disease progresses through heterogeneous genetic alterations, and patients often develop pulmonary metastases even after the primary tumors have been surgically removed. Ubiquitin-specific peptidases (USPs) regulate several critical cellular processes, such as cell cycle progression, transcriptional activation, and signal transduction. Various studies have revealed the significance of USP37 in the regulation of replication stress and oncogenesis. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was analyzed to investigate USP37 expression. RNA sequencing was utilized to assess the impact of USP37 overexpression and depletion on gene expression in osteosarcoma cells. Various molecular assays, including colony formation, immunofluorescence, immunoprecipitation, and DNA replication restart, were employed to examine the physical interaction between USP37 and PCNA, as well as its physiological effects in osteosarcoma cells. Additionally, molecular docking studies were conducted to gain insight into the nature of the interaction between USP37 and PCNA. Furthermore, immunohistochemistry was performed on archived tissue blocks from osteosarcoma patients to establish a correlation between USP37 and PCNA expression. RESULTS: Analysis of the TCGA database revealed that increased expression of USP37 was linked to decreased progression-free survival (PFS) in osteosarcoma patients. Next-generation sequencing analysis of osteosarcoma cells demonstrated that overexpression or knockdown of USP37 led to the expression of different sets of genes. USP37 overexpression provided a survival advantage, while its depletion heightened sensitivity to replication stress in osteosarcoma cells. USP37 was found to physically interact with PCNA, and molecular docking studies indicated that the interaction occurs through unique residues. In response to genotoxic stress, cells that overexpressed USP37 resolved DNA damage foci more quickly than control cells or cells in which USP37 was depleted. The expression of USP37 varied in archived osteosarcoma tissues, with intermediate expression seen in 52% of cases in the cohort examined. CONCLUSION: The results of this investigation propose that USP37 plays a vital role in promoting replication stress tolerance in osteosarcoma cells. The interaction between USP37 and PCNA is involved in the regulation of replication stress, and disrupting it could potentially trigger synthetic lethality in osteosarcoma. This study has expanded our knowledge of the mechanism through which USP37 regulates replication stress, and its potential as a therapeutic target in osteosarcoma merits additional exploration.

Factors affecting the incorporation of extracorporeally irradiated autograft for the treatment of bone tumours-a retrospective analysis from a tertiary referral centre.

PURPOSE: Re-implantation of the tumor bearing autograft following extracorporeal radiation therapy (ECRT) has been established as an oncologically safe biological reconstruction technique following resection of bone sarcomas. However, factors affecting the ECRT graft-host bone incorporation have not been fully investigated. An insight into the factors that influence graft incorporation can circumvent the complications and increase graft survival. METHODS: A total of 96 osteotomies in 48 patients with intercalary resections of primary extremity bone sarcomas (mean age 15.8 years, mean follow-up 42.1 months) were analyzed retrospectively for factors ECRT autograft-host bone union. RESULTS: On univariate analysis, age < 20 years, metaphyseal osteotomy site, V-shaped diaphyseal osteotomy, and use of additional plate at diaphyseal osteotomy had a significantly faster time to union, while gender, tumour type, bone involved, resection length, chemotherapy, type of fixation, and use of intra-medullary fibula did not influence union time. In multivariate analysis, V-shaped diaphyseal osteotomy and use of additional plate at diaphyseal ostetomy were the independent factors with favourable time to union. None of the analyzed factors was found to have a significant effect on the union rate. The major complications were non-union in 11.4% patients, graft failure in 2.1%, infection in 12.5%, and soft tissue local recurrences in 14.5% patients. CONCLUSION: Modified diaphyseal osteotomy and augmentation of the stability of the reconstruction using additional small plates enhance the incorporation of ECRT autograft.

Prepubic inflammatory liposarcoma presenting as urosepsis.

Inflammatory well-differentiated liposarcoma is a rare soft-tissue tumor which is predominantly retroperitoneal in origin. We report a 72-year-old male without co-morbidities with suspected urosepsis and an obstructing ureteric calculus. Despite adequate diversion and broad-spectrum antimicrobials, the leukocytosis persisted. Further imaging revealed a locally infiltrating prepubic mass which was suspicious of a lymphoid malignancy and was found to be a high-grade liposarcoma on biopsy. He underwent open wide local resection of the tumor and the histopathology revealed an inflammatory well-differentiated liposarcoma with areas of neutrophilic abscess and necrosis. A dramatic response to the surgical resection was seen and the leukocytosis resolved within a few days.

Recent Advances on Natural and Non-Natural Xanthones as Potential Anticancer Agents: A Review.

BACKGROUND: Xanthones, natural or synthetic, due to their wide range of biological activities, have become an interesting subject of investigation for many researchers. Xanthonic scaffold has proven to have a vital role in anticancer drug development since many of its derivatives have shown anticancer activities on various cell lines. In addition, targeting epigenetic markers in cancer has yielded promising results. There have also been reports on the impact of xanthone and related polyphenolic compounds on epigenetics markers in cancer prevention and therapy. OBJECTIVE: The objective of this review is to comprehensively highlight the main natural and nonnatural sources of xanthones having potential anti-cancer effects along with their key structural elements, structure-activity relationships (SARs), mechanisms of action, and epigenetic profile of xanthone- based anti-cancer compounds. The challenges and future directions of xanthone-based therapies are also discussed briefly. METHOD: The methods involved in the preparation of the present review included the collection of all recent information up to November 2021 from various scientific databases, indexed periodicals, and search engines such as Medline Scopus, Google Scholar, PubMed, PubMed Central, Web of Science, and Science Direct. RESULTS: Exploration of the diversity of the xanthone scaffold led to the identification of several derivatives having prominent anti-cancer activity. Their unique structural diversity and synthetic modifications showed the ongoing endeavour of enriching the chemical diversity of the xanthone molecular framework to discover pharmacologically interesting compounds. However, studies regarding their modes of action, pharmacokinetic properties, clinical data, epigenetics, and safety are limited. CONCLUSION: Elucidation of the exact biological mechanisms and the associated targets of xanthones will yield better opportunities for these compounds to be developed as potential anticancer drugs. Further clinical studies with conclusive results are required to implement xanthones as treatment modalities in cancer.

Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders.

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized.

Determinants and impact of diagnostic interval in bone sarcomas: A retrospective cohort study.

BACKGROUND: Diagnostic delays in cancers are frequent in developing countries due to poor health infrastructure. Existing literature from developed countries suggests that diagnostic interval in bone sarcomas is primarily dictated by tumour biology with no impact on survival. This study evaluates the social and biological determinants of the diagnostic interval in bone sarcomas in a resource-challenged setting and assesses its impact on treatment outcomes. METHODS: A retrospective single-institutional study was conducted on patients with high-grade bone sarcomas recorded in the sarcoma clinic database between 2003 and 2018. Baseline clinical characteristics and treatment outcomes were recorded. Logistic regression was performed to assess the impact of baseline clinical and social characteristics (distance from treating centre and rural vs. urban residence) on the diagnostic interval. Further, the impact of diagnostic interval on histologic response to neoadjuvant chemotherapy, amputation requirement in extremity sarcomas and survival was evaluated. RESULTS: A total of 1227 patients were included for analysis. The median diagnostic interval was 4 months (3-7 months). Age above 18 years, Ewing sarcoma (ES) diagnosis, absence of fever at presentation and tumour size above 7.5 cm were predictors of a longer diagnostic interval (>4 months). The length of the diagnostic interval did not impact amputation requirement or survival outcomes. However, the proportion of patients with good necrosis post-neoadjuvant chemotherapy was lower among patients with longer diagnostic intervals (25% vs. 34·16%; p-value = .04). CONCLUSION: Tumour characteristics rather than social factors determined the diagnostic interval. Diagnostic interval did not impact survival outcomes even in a resource-constrained setting.

An insight into the neuroprotective effects and molecular targets of pomegranate (Punica granatum) against Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that still has no permanent cure. The drugs prescribed in the present days are only for symptomatic relief for the patients. Many studies correlating the reduction in the incidence of AD with the diet consumed have been published. These studies showed that a diet rich in polyphenols is associated with a decrease in the incidence of AD. The present review is focused on the ability of pomegranate and its bioactive components to ameliorate the progression of AD and their ability to exert a neuroprotective effect. Various studies showing the ability of pomegranate in inhibiting enzymes, reducing reactive oxygen species, inhibition of microglial activation, inhibition of tau protein hyperphosphorylation, maintenance of synaptic plasticity, anti-inflammatory activity and its ability to inhibit Beta secretase-1 (BACE-1) has been reviewed in this article. In spite of the lack of studies on humans, there are compelling evidence indicating that pomegranate can reduce various risk factors involved in the causation of AD and thus can be used as a persistent nutraceutical to slow ageing and for providing neuroprotection for the treatment of AD.Highlights An overview of traditional and pharmacological uses of pomegranate (POM).Potential of POM in the treatment of neurodegenerative diseases especially in AD.Insight into the molecular mechanisms of neuroprotective effects of POM in AD.Clinical evaluation studies involving POM and its bioactive components.

Non-invasive intravoxel incoherent motion MRI in prediction of histopathological response to neoadjuvant chemotherapy and survival outcome in osteosarcoma at the time of diagnosis.

BACKGROUND: Early prediction of response to neoadjuvant chemotherapy (NACT) is important to aid personalized treatment in osteosarcoma. Diffusion-weighted Intravoxel Incoherent Motion (IVIM) MRI was used to evaluate the predictive value for response to NACT and survival outcome in osteosarcoma. METHODS: Total fifty-five patients with biopsy-proven osteosarcoma were recruited prospectively, among them 35 patients were further analysed. Patients underwent 3 cycles of NACT (Cisplatin + Doxorubicin) followed by surgery and response adapted adjuvant chemotherapy. Treatment outcomes were histopathological response to NACT (good-response ≥ 50% necrosis and poor-response < 50% necrosis) and survival outcome (event-free survival (EFS) and overall survival (OS)). IVIM MRI was acquired at 1.5T at baseline (t0), after 1-cycle (t1) and after 3-cycles (t2) of NACT. Quantitative IVIM parameters (D, D*, f & D*.f) were estimated using advanced state-of-the-art spatial penalty based IVIM analysis method bi-exponential model with total-variation penalty function (BETV) at 3 time-points and histogram analysis was performed. RESULTS: Good-responders: Poor-responders ratio was 13 (37%):22 (63%). EFS and OS were 31% and 69% with 16.27 and 25.9 months of median duration respectively. For predicting poor-response to NACT, IVIM parameters showed AUC = 0.87, Sensitivity = 86%, Specificity = 77% at t0, and AUC = 0.96, Sensitivity = 86%, Specificity = 100% at t1. Multivariate Cox regression analysis showed smaller tumour volume (HR = 1.002, p = 0.001) higher ADC-25th-percentile (HR = 0.047, p = 0.005) & D-Mean (HR = 0.1, p = 0.023) and lower D*-Mean (HR = 1.052, p = 0.039) were independent predictors of longer EFS (log-rank p-values: 0.054, 0.0034, 0.0017, 0.0019 respectively) and non-metastatic disease (HR = 4.33, p < 10-3), smaller tumour-volume (HR = 1.001, p = 0.042), lower D*-Mean (HR = 1.045, p = 0.056) and higher D*.f-skewness (HR = 0.544, p = 0.048) were independent predictors of longer OS (log-rank p-values: < 10-3, 0.07, < 10-3, 0.019 respectively). CONCLUSION: IVIM parameters obtained with a 1.5T scanner along with novel BETV method and their histogram analysis indicating tumour heterogeneity were informative in characterizing NACT response and survival outcome in osteosarcoma.

Functional Outcomes of Centralization of the Ulna as a Method of Reconstruction Following Resection of Campanacci Grade 3 Giant Cell Tumor of the Distal Radius.

PURPOSE: Wrist reconstruction after distal radial tumor resection poses a challenge to the orthopedic oncologist. We evaluated the functional outcomes of centralization of the ulna with ulnocarpal arthrodesis as a method of reconstruction following resection of distal radius tumors, using impairment measures and patient-reported outcomes. METHODS: Evaluation of functional outcome was performed using the Musculoskeletal Tumor Society 93 scoring system and Disabilities of the Arm, Shoulder, and Hand questionnaire. We also determined hand grip strength on the affected side, time to radiologic union at the ulnocarpal junction and reduction in wrist circumference. Local complications and oncologic outcomes were recorded. RESULTS: The study included 26 patients with Campanacci grade 3 giant cell tumor of the distal radius. Mean follow-up period in the study was 32.8 ± 12 months. Mean resection length was 10.3 ± 2.5 cm. Radiologic union at the ulnocarpal junction was achieved in 38.5%, 77% and 96% of the patients by 4, 5, and 6 months respectively. Mean hand grip strength was 74 ± 3.9% of the contralateral side whereas mean reduction in wrist circumference was 16.9 ± 6.4%. A good functional outcome with a mean the Musculoskeletal Tumor Society 93 score of 26 ± 1.4 and mean Disabilities of the Arm, Shoulder, and Hand score of 10.5 ± 6.3 was observed. Fracture of the ulna, hardware loosening, and reflex sympathetic dystrophy were each noted in 1 patient, with an overall complication rate of 10.7% (3/28). No patient had nonunion, infection, or local recurrence. CONCLUSIONS: This is a simple and effective modality of reconstruction after resection of distal radial tumors. It provides good functional outcome and preservation of good hand grip strength, with low complication rates. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Development and validation of a prognostic score at baseline diagnosis for Ewing sarcoma family of tumors: a retrospective single institution analysis of 860 patients.

INTRODUCTION: Prognostic scores in Ewing sarcoma including baseline clinical and laboratory characteristics are necessary for pre-treatment risk stratification. In this study, we formulated and validated a prognostic model for baseline risk categorization in Ewing sarcoma. MATERIALS AND METHODS: A retrospective single-institutional study was conducted on Ewing sarcoma patients treated uniformly between January 2003 and December 2018. Baseline clinical/pathological characteristics and survival outcomes were noted from medical records. The cohort was randomised into a derivation and validation cohort. A prognostic score was formulated by including independent prognostic factors from the derivation cohort by multivariable analysis. The prognostic model was validated in the validation cohort along with estimation of its predictive ability. RESULTS: A total of 860 patients were included with 40.3% having baseline metastases. Tumor diameter >5 cm (HR 2.04; P<0.001; score 2), baseline metastases (HR 2.33; P<0.001, score 2), and total leucocyte count >11000/mm3 (HR 1.44; P=0.015; score 1) were independent predictors of overall survival in derivation cohort and included for prognostic score calculation. Patients were categorized into low (score 0), intermediate (score 1-3) and high-risk (score 4-5) groups. Harrell's c-indexes of the model were 0.625, 0.622 and 0.624 in the derivation, validation and whole cohort respectively. The timed AUC of ROC of the prognostic score-group for 5-year survival was 0.72, 0.71 and 0.73 in the derivation, validation and whole cohort respectively. CONCLUSIONS: We have formulated and validated a prognostic score for Ewing sarcoma incorporating baseline clinical and laboratory parameters, with fair predictive ability for risk stratification and facilitating risk-adapted personalized therapy.

Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized Clinical Trial.

IMPORTANCE: The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited. OBJECTIVE: To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were excluded for ineligibility. INTERVENTIONS: A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen. MAIN OUTCOMES AND MEASURES: The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1 year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality. RESULTS: Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups. CONCLUSIONS AND RELEVANCE: This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01479283.

6-Shogaol Attenuates Traumatic Brain Injury-Induced Anxiety/Depression-like Behavior via Inhibition of Oxidative Stress-Influenced Expressions of Inflammatory Mediators TNF-α, IL-1ß, and BDNF: Insight into the Mechanism.

Anxiety and depression are among the major traumatic brain injury-induced psychiatric disorders in survivors. The present study was undertaken to investigate the beneficial effects of 6-Shogaol against depression-like behavior and anxiety, induced by traumatic brain injury (TBI), in mice. The mice were administered either fluoxetine, vehicle, or three different doses (10, 20 and 30 mg/kg/day, i.p.) of 6-Shogaol after 10 days of impact-accelerated TBI. The treatment was continued for 14 consecutive days. Elevated plus maze test, marble burying test, staircase test, and social interaction test were employed to investigate the effect of 6-Shogaol on anxiety-like behavior. The impact of treatment on depression-like behavior was assessed using hyper-emotionality behavior or open-field exploration test. The expressions of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and malondialdehyde (MDA) levels in brain tissue and brain water were measured to elucidate possible mechanisms involved. 6-Shogaol treatment (higher dose) was able to attenuate anxiety/depression-like behaviors in mice with TBI. 6-Shogaol treatment also altered MDA formation and expressions of TNF-α and IL-1ß that act as major inflammation-inducing cytokines in brain tissue. Additionally, brain BDNF levels were also affected by 6-Shogaol treatment. Although the lower dose of 6-Shogaol was able to rectify inflammation and BDNF expression in brain tissue, it was unable to improve anxiety/depression-like behaviors. 6-Shogaol treatment produced beneficial effects for TBI-induced anxiety/depression-like behaviors in mice, which could be attributed to the reduction of lipid peroxidation, inflammation, and enhanced BDNF expression.

Resource-appropriate selection of osteosarcoma treatment protocols in low- and middle-income countries.

Osteosarcoma is a rare malignancy; however, it is still the most common primary bone tumor in adolescents and young adults. Chemotherapy improves survival indubitably in osteosarcoma; nevertheless, the concern is the stagnant progress since the last several decades. There are a handful of active agents and unresolved issues, especially in choosing the ideal chemotherapy regimen. The oncology community is in equipoise regarding the position of high-dose methotrexate (HDMTX), mandatory or adjunct. The choice of therapy becomes widely relevant, including in low- and middle-income countries (LMIC), where HDMTX administration brings additional complexities. Research into novel non-HDMTX-based protocols adapted to the available resources is pivotal in improving disease outcomes, especially in LMIC. The current review focuses on real-world challenges in decision-making and provides a comprehensive overview of the evolution of treatment protocols in LMIC.