Histological Risk Classification Predicts Malignancy and Recurrence in Paragangliomas

Background: Mid-term outcome information in risk stratified patient cohort is needed to inform prognosis in individual patients with paragangliomas (PGL), adjuvant therapy choice and future research. The objective is to define the outcome relevance of a novel risk stratification scheme for PGLs. Design: A classification scheme for PGLs was devised and specimen were assessed for invasion capacity (infiltrative edges with broad fibrous bands, extra-adrenal extension [recording capsular, microscopic periadrenal and gross periadrenal], capsular and peritumoral vascular invasion [recording thin- and thick-walled blood vessels]), tumorigenic expansion (expansile nodules with diffuse areas, hypercellular homogenous areas, necrosis [recording multifocal and confluent subtypes]) and mitogenic activity (MFC/10HPF, presence of atypical mitotic figures). Patients were prospectively stratified as low risk or high risk (presence of at least one feature of invasive capacity and two features of tumorigenic expansion). Patients underwent systematic treatment and follow up for their PGLs in a tertiary referral center. Results: The multilevel analysis based on 78 patients identified statistically significant differences in clinical and biochemical presentation between low risk and high risk patients for gender (p<0.05), noradrenalin (4.6±8.5 vs 11.6±16.9), dopamine (0.6±0.3 vs 1.7±2.4), size of lesion (49.8±19.5 vs 89.2±45.8) and malignancy, 0% vs 21.6% (p<0.01), treatment modalities for MIBG therapy, 0% vs 40.5% (p<.0001), MVR, 0% vs 23.3% (p<.001) and lymph node dissection, 13.5% vs 40.5% (p<0.01) and distant metastases, 0% vs 21.6% (p<0.01). Disease free survival was significantly lower in HR patients 0% vs 78.4% (p=0.004). Histological risk stratification predicts DFS with AUC of 0.8 (95% CI: 0.69-0.90; p<0.01). 7/37 patients with HR had a synchronous diagnosis of malignancy based on other criteria and 4 patients suffered local recurrence. Conclusions: Stratification as low risk excluded a synchronous diagnosis of malignancy and disease recurrence of a follow-up interval of 1-75 months (median 12 months). A high-risk status is associated with high risk of malignancy and disease recurrence.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

EUGENOL AMELIORATES RHABDOMYOLYSIS-INDUCED ACUTE KIDNEY INJURY IN MICE

ABSTRACT   Background: Acute kidney injury (AKI) is a common and dangerous consequence of rhabdomyolysis which occurs in 50% of the cases with 5-10% mortality. In recent studies, eugenol has been reported as anti-fungal, antihyperglycemic, analgesic, anti-bacterial, anti-pyretic, anti-inflammatory and anti-oxidant agent. This study aimed to investigate the protective activity of eugenol on rhabdomyolysis-induced acute kidney injury (AKI) in mice.   Methods: Male, 24 BALB/c mice were divided into 4 groups (controls, AKI, eugenol and ascorbic acid as positive control). Controls and AKI were given normal saline, Eugenol (100 mg/kg bw) and ascorbic acid (200mg/kg) were given orally eugenol and ascorbic acid respectively for four days. After water deprivation for 24 hours, all animals, except controls, were injected with glycerol (50% - 10 ml/kg body weight intra-muscularly). After another 24 hours, blood samples were collected and kidneys were dissected out for biochemical investigations (serum urea and creatinine) and histopathological examination.    Results: Serum urea and creatinine levels compared to controls were significantly elevated in AKI group (p < 0.001) and significantly decreased, in eugenol and ascorbic acid groups (p < 0.001) compared to AKI group.  Histopathological examination revealed about 44% damage in the AKI group compared to the normal group (p < 0.001). Eugenol and ascorbic acid decreased the damage to 13% and 8% respectively compared to AKI group (p < 0.001). The tested compounds were found to reduce tubular cast formation. Conclusion: Eugenol has protective effects on rhabdomyolysis-induced AKI in mice. Further studies are required for evaluation of protective role of this compound in AKI

Lesion-based indicators predict long-term outcomes of pheochromocytoma and paraganglioma– SIZEPASS

AimWe seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL).MethodsThis single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy.Results76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p&lt;0.0001). Across PPGL, SIZEPASS &gt;1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P&lt;0.001). It retained an accuracy &gt;90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status.ConclusionsThe SIZEPASS&gt;1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status

Locus for severity implicates CNS resilience in progression of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults(1,2). Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility(3), these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

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

Summary 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 middleincome 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 lowincome 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 lowincome, 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

Margin Free Resection Achieves Excellent Long Term Outcomes in Parathyroid Cancer

Long-term outcomes of parathyroid cancer remain poorly documented and unsatisfactory. This cohort includes 25 consecutive parathyroid cancer patients with median follow-up of 10.7 years (range 4.1–26.5 years). Pre-operative work-up in the center identified a suspicion of parathyroid cancer in 17 patients. En bloc resection, including the recurrent laryngeal nerve in 4/17 (23.5%), achieved cancer-free resection margins (R0) in 82.4% and lasting loco-regional disease control in 94.1%. Including patients referred after initial surgery elsewhere, R0 resection was achieved in merely 17/25 (68.0%) of patients. Cancer-positive margins (R1) in 8 patients led to local recurrence in 50%. On multivariate analysis, only margin status prevailed as independent predictor of recurrence free survival (χ2 19.5, p 95: 1.1–11.3; p = 0.03), and a 6.4-fold higher risk of locoregional recurrence (CI95: 0.8–52.1; p = 0.08). R1-status was associated with an 18.0-fold higher risk of recurrence and redo surgery (CI95: 1.1–299.0; p = 0.04), and a 22.0-fold higher probability of radiation (CI95: 1.4–355.5; p = 0.03). In patients at risk, adjuvant radiation reduced the actuarial risk of locoregional recurrence (p = 0.05). When pre-operative scrutiny resulted in upfront oncological surgery achieving cancer free margins, it afforded 100% recurrence free survival at 5- and 10-year follow-up, whilst failure to achieve clear margins caused significant burden by outpatient admissions (176 vs. 4 days; χ2 980, p 2 11.3, p = 0.003). Although limited by cohort size, our study emphasizes the paradigm of getting it right the first time as key to improve survivorship in a cancer with excellent long-term prognosis

Mediastinal Parathyroid Cancer

Parathyroid cancer (PC) is rare, but its pre-operative recognition is important to choose appropriate access strategies and achieve oncological clearance. This study characterizes features of mediastinal parathyroid cancer (MPC) and explores criteria aiding in the pre-operative recognition of malignancy. We assembled data from 502 patients with mediastinal parathyroid neoplasms (MPNs) from a systematic review of the literature 1968–2020 (n = 467) and our own patient cohort (n = 35). Thirty-two of the 502 MPNs (6.4%) exhibited malignancy. Only 23% of MPC patients underwent oncological surgery. Local persistence and early recurrence at a median delay of 24 months were frequent (45.8%), and associated with a 21.7-fold (95%CI 1.3–351.4; p = 0.03) higher risk of death due to disease. MPCs (n = 30) were significantly larger than cervical PC (n = 330), at 54 ± 36 mm vs. 35 ± 18 mm (χ2 = 20; p n = 226) at 22 ± 15 mm (χ2 = 33; p p p p p < 0.05). The composite 3 + 3 criterion recognized 74% of all MPC with an accuracy of 83%. Inversely, no MPN presenting with a calcium < 3.0 mM and size < 3.0 cm was malignant. When faced with pHPT in mediastinal location, consideration of the 3 + 3 rule may trigger an oncological team approach based on simple, available criteria