Equivalent dose in 2 Gy (EQD2) to pelvic lymph nodes using volume based prescription for three brachytherapy applicators — a dosimetric retrospective analysis

BACKGROUND: Pelvic lymph node (PLN) metastasis has been included in the FIGO staging, so there is a need to determine the dose contribution from brachytherapy to ascertain the total delivered dose to the pelvic lymph nodes in cervical cancer. The aim of the study was to calculate the equivalent dose in 2 Gy (EQD2) of the pelvic lymph nodes (PLNs) based on volume prescription using three applicators. Materials and methods: Forty-one patients who had undergone external beam radiotherapy followed by brachytherapy using tandem ovoids (TO), tandem ring (TR) and TO + free hand interstitial needles (TO + FH) applicators were taken for this study. 26 Gy in 4 fractions was prescribed to HRCTV. The external iliac node (ELN), internal iliac node (ILN) and obturator (OBT) were contoured and the median EQD2 of the lymph nodes was calculated. RESULTS: The median bilateral EQD2 values of ELN were 1.55 Gy (TR), 1.75 Gy (TO), 1.9 Gy (TO + FH), of ILN these were 2.57 Gy (TR), 3.27 Gy (TO), 3.04 Gy (TO + FH), and of OBT these were 3.69 Gy (TR), 4.46 Gy (TO), 4.69 Gy (TO + FH), respectively. The total median EQD2 values of TR, TO and TO + FH were 52.71 Gy, 53.03 Gy, and 53.88–62.73 Gy, respectively. CONCLUSION: Our study calculated the median EQD2 to the pelvic lymph nodes using three types of applicators in brachytherapy. This could serve as reference to decide on the EBRT boost dose while treating patients with enlarged pelvic lymph nodes

A case of endometrial carcinoma with age related hyperkyphosis treated with definitive radiotherapy

This report describes a simple brachytherapy procedure in a patient with endometrial cancer with age related hyperkyphosis.  Sixty-eight year-old postmenopausal woman with age related hyperkyphosis presented with endometrial carcinoma, and the patient was not operated on due to associated pelvic deformity. The patient received whole pelvic radiation followed by uterovaginal brachytherapy. Patient was supported with soft pillows to support her exaggerated anterior concavity during brachytherapy procedure and execution. The brachytherapy dose was 6 Gy per fraction per week for 3 weeks using image guidance. This is probably the first reported case of endometrial cancer with age related hyperkyphosis. In spite of the associated skeletal problems, a simple brachytherapy procedure is possible and provides good result.

Autophagy Interplay with Apoptosis and Cell Cycle Regulation in the Growth Inhibiting Effect of Resveratrol in Glioma Cells

Prognosis of patients with glioblastoma (GBM) remains very poor, thus making the development of new drugs urgent. Resveratrol (Rsv) is a natural compound that has several beneficial effects such as neuroprotection and cytotoxicity for several GBM cell lines. Here we evaluated the mechanism of action of Rsv on human GBM cell lines, focusing on the role of autophagy and its crosstalk with apoptosis and cell cycle control. We further evaluated the role of autophagy and the effect of Rsv on GBM Cancer Stem Cells (gCSCs), involved in GBM resistance and recurrence. Glioma cells treated with Rsv was tested for autophagy, apoptosis, necrosis, cell cycle and phosphorylation or expression levels of key players of these processes. Rsv induced the formation of autophagosomes in three human GBM cell lines, accompanied by an upregulation of autophagy proteins Atg5, beclin-1 and LC3-II. Inhibition of Rsv-induced autophagy triggered apoptosis, with an increase in Bax and cleavage of caspase-3. While inhibition of apoptosis or autophagy alone did not revert Rsv-induced toxicity, inhibition of both processes blocked this toxicity. Rsv also induced a S-G2/M phase arrest, accompanied by an increase on levels of pCdc2(Y15), cyclin A, E and B, and pRb (S807/811) and a decrease of cyclin D1. Interestingly, this arrest was dependent on the induction of autophagy, since inhibition of Rsv-induced autophagy abolishes cell cycle arrest and returns the phosphorylation of Cdc2(Y15) and Rb(S807/811), and levels of cyclin A, and B to control levels. Finally, inhibition of autophagy or treatment with Rsv decreased the sphere formation and the percentage of CD133 and OCT4-positive cells, markers of gCSCs. In conclusion, the crosstalk among autophagy, cell cycle and apoptosis, together with the biology of gCSCs, has to be considered in tailoring pharmacological interventions aimed to reduce glioma growth using compounds with multiple targets such as Rsv

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

The Oldest Case of Decapitation in the New World (Lapa do Santo, East-Central Brazil)

We present here evidence for an early Holocene case of decapitation in the New World (Burial 26), found in the rock shelter of Lapa do Santo in 2007. Lapa do Santo is an archaeological site located in the Lagoa Santa karst in east-central Brazil with evidence of human occupation dating as far back as 11.7-12.7 cal kyBP (95.4% interval). An ultra-filtered AMS age determination on a fragment of the sphenoid provided an age range of 9.1-9.4 cal kyBP (95.4% interval) for Burial 26. The interment was composed of an articulated cranium, mandible and first six cervical vertebrae. Cut marks with a v-shaped profile were observed in the mandible and sixth cervical vertebra. The right hand was amputated and laid over the left side of the face with distal phalanges pointing to the chin and the left hand was amputated and laid over the right side of the face with distal phalanges pointing to the forehead. Strontium analysis comparing Burial 26's isotopic signature to other specimens from Lapa do Santo suggests this was a local member of the group. Therefore, we suggest a ritualized decapitation instead of trophy-taking, testifying for the sophistication of mortuary rituals among hunter-gatherers in the Americas during the early Archaic period. In the apparent absence of wealth goods or elaborated architecture, Lapa do Santo's inhabitants seemed to use the human body to express their cosmological principles regarding death

Radical nephroureterectomy for pathologic T4 upper tract urothelial cancer: can oncologic outcomes be improved with multimodality therapy?

Purpose To report the outcomes of patients with pathologic T4 UTUC and investigate the potential impact of peri-operative chemotherapy combined with radical nephroureterectomy (RNU) and regional lymph node dissection (LND) on oncologic outcomes. Materials and Methods Patients with pathologic T4 UTUC were identified from the cohort of 1464 patients treated with RNU at 13 academic centers between 1987 and 2007. Oncologic outcomes were stratified according to utilization of perioperative systemic chemotherapy and regional LND as an adjunct to RNU. Results The study included 69 patients, 42 males (61%) with median age 73 (range 43-98). Median follow-up was 17 months (range: 6-88). Lymphovascular invasion was found in 47 (68%) and regional lymph node metastases were found in 31 (45%). Peri-operative chemotherapy was utilized in 29 (42%) patients. Patients treated with peri-operative chemotherapy and RNU with LND demonstrated superior oncologic outcomes compared to those not treated by chemotherapy and/or LND during RNU (3Y-DFS: 35% vs. 10%; P = 0.02 and 3Y-CSS: 28% vs. 14%; P = 0.08). In multivariate Cox regression analysis, administration of peri-operative chemotherapy and utilization of LND during RNU was associated with lower probability of recurrence (HR: 0.4, P = 0.01), and cancer specific mortality (HR: 0.5, P = 0.06). Conclusions Pathological T4 UTUC is associated with poor prognosis. Peri-operative chemotherapy combined with aggressive surgery, including lymph node dissection, may improve oncological outcomes. Our findings support the use of aggressive multimodal treatment in patients with advanced UTUC

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction &gt;0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field