Assessing Bladder Radiotherapy Response With Quantitative Diffusion-Weighted Magnetic Resonance Imaging Analysis.

AIMS: Radiotherapy with radiosensitisation offers opportunity for cure with organ preservation in muscle-invasive bladder cancer (MIBC). Treatment response assessment and follow-up are reliant on regular endoscopic evaluation of the retained bladder. In this study we aim to determine the role of diffusion-weighted magnetic resonance imaging (DWI) and apparent diffusion coefficient (ADC) analysis to assess bladder radiotherapy response. MATERIALS AND METHODS: Patients with T2-T4aN0-3M0 MIBC suitable for radical radiotherapy were recruited prospectively to an ethics approved protocol. Following transurethral resection of the bladder tumour and prior to any treatment, magnetic resonance imaging including DWI was performed on a 1.5T system using b values of 0, 100, 150, 250, 500, 750 s/mm2. DWI was repeated 3 months after completing radiotherapy. Cystoscopy and tumour site biopsy were undertaken following this. The response was dichotomised into response (0.9, P < 0.01). ΔADCall mean of 0.16 × 10-3 mm2/s and ΔADCb100 mean 0.12 × 10-3 mm2/s predicted radiotherapy response with sensitivity/specificity/positive predictive value/negative predictive value of 92.9%/100.0%/100.0%/75.0% and 89.3%/100.0%/100.0%/66.7%, respectively. CONCLUSIONS: Quantitative DWI analysis can successfully provide non-invasive assessment of bladder radiotherapy response. Multicentre validation is required before prospective testing to inform MIBC radiotherapy follow-up schedules and decision making.

Slow gait speed is associated with worse postoperative outcomes in cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Frailty is associated with poorer outcomes in cardiac surgery, but the heterogeneity in frailty assessment tools makes it difficult to ascertain its true impact in cardiac surgery. Slow gait speed is a simple, validated, and reliable marker of frailty. We performed a systematic review and meta-analysis to examine the effect of slow gait speed on postoperative cardiac surgical patients. METHODS: PubMED, MEDLINE, and EMBASE databases were searched from January 2000 to August 2021 for studies comparing slow gait speed and "normal" gait speed. Primary outcome was in-hospital mortality. Secondary outcomes were composite mortality and major morbidity, AKI, stroke, deep sternal wound infection, prolonged ventilation, discharge to a healthcare facility, and ICU length of stay. RESULTS: There were seven eligible studies with 36,697 patients. Slow gait speed was associated with increased likelihood of in-hospital mortality (risk ratio [RR]: 2.32; 95% confidence interval [CI]: 1.87-2.87). Additionally, they were more likely to suffer from composite mortality and major morbidity (RR: 1.52; 95% CI: 1.38-1.66), AKI (RR: 2.81; 95% CI: 1.44-5.49), deep sternal wound infection (RR: 1.77; 95% CI: 1.59-1.98), prolonged ventilation >24 h (RR: 1.97; 95% CI: 1.48-2.63), reoperation (RR: 1.38; 95% CI: 1.05-1.82), institutional discharge (RR: 2.08; 95% CI: 1.61-2.69), and longer ICU length of stay (MD: 21.69; 95% CI: 17.32-26.05). CONCLUSION: Slow gait speed is associated with poorer outcomes in cardiac surgery. Frail patients are twofold more likely to die during hospital admission than nonfrail counterparts and are at an increased risk of developing various perioperative complications.

Imaging features of the evolving patterns of metastatic prostate cancer.

The pattern of metastases in prostate cancer (PC) is evolving. Increased use of imaging, newer imaging techniques with higher sensitivity for disease detection and patients receiving multiple lines of novel therapies with increased life expectancy are likely to be contributory. Awareness of metastatic disease patterns improves early diagnosis, accurate staging, and initiation of appropriate therapy, and can inform prognostic information and anticipate potential disease complications. The aim of this review is to document the spectrum of metastases in PC including emerging and unusual patterns, and to highlight the role of novel imaging including prostate-specific membrane antigen (PSMA)-positron-emission tomography (PET) and whole-body magnetic resonance imaging (WB-MRI) to improve diagnostic and response assessment accuracy.

Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance.

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH to mpARH circuit and inhibition of ERαvlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERαvlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Impact of Concomitant Urologic Intervention on Clinical Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: The impact of concomitant urologic procedures (UPs) on perioperative and long-term outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is uncertain. METHODS: In total, 935 consecutive CRS/HIPEC procedures were performed between 1996 and 2016 in Sydney, Australia. Among these, 73 (7.8%) involved concomitant UP. The association of concomitant UP with 21 perioperative outcomes and overall survival was assessed using univariate and multivariate analyses. RESULTS: In-hospital mortality was 1.8%. Patients requiring UP were more likely to require transfusion of ≥5 units of red blood cells (P=0.031) and have a complete cytoreduction (79% vs. 60%, P<0.001). On multivariate analysis, UP was not associated with in-hospital mortality (2.7% vs. 1.7%, P=0.407) or grade III/IV morbidity (52% vs. 41%, P=0.376). The incidence of ureteric fistula (4% vs. 1%, P=0.004), return to theater (26% vs. 14%, P=0.005) and digestive fistula (22% vs. 11%, P=0.005) was higher in the UP group. The addition of a UP did not significantly impact overall survival for appendiceal cancer (P=0.162), colorectal cancer (P=0.315), or pseudomyxoma peritonei (P=0.120). CONCLUSIONS: Addition of a UP was not associated with an increased risk of grade III/IV morbidity or poorer long-term survival after CRS/HIPEC.

Heart Valve Surgery Performed by Trainee Surgeons: Meta-Analysis of Clinical Outcomes.

BACKGROUND: Cardiac surgical units must balance trainee education with the duty to provide optimal patient care. This is particularly challenging with valvular surgery, given the lower volume and increased complexity of these procedures. The present meta-analysis was conducted to assess the impact of trainee operator status on clinical outcomes following valvular surgery. METHODS: Medline, Embase and CENTRAL databases were systematically searched for studies reporting clinical outcomes according to the training status of the primary operator (consultant or trainee). Data were extracted and meta-analysed according to pre-defined endpoints. RESULTS: Eleven observational studies met the inclusion criteria, reporting on five patient cohorts undergoing mitral valve surgery (n=3975), six undergoing aortic valve replacement (AVR) (n=6236) and three undergoing combined AVR and coronary artery bypass grafting (CABG) (n=3495). Perioperative mortality was not significantly different between trainee and consultant cases for mitral valve surgery (odds ratio [OR] 0.92; 95% confidence interval [CI], 0.62-1.37), AVR (OR 0.67; 95% CI, 0.37-1.24), or combined AVR and CABG (OR 1.07; 95% CI, 0.40-2.85). The incidences of perioperative stroke, myocardial infarction, arrhythmias, acute renal failure, reoperation or wound infection were not significantly different between trainee and consultant cases. There was a paucity of mid-term survival data. CONCLUSIONS: Valvular surgery cases performed primarily by trainees were not associated with adverse perioperative outcomes. These findings suggest the rigorous design of cardiac surgical trainee programs can sufficiently mitigate trainee deficiencies. However, studies with longer follow-up duration and echocardiographic data are required to assess long-term durability and safety.

Mitral valve surgery and coronary artery bypass grafting for moderate-to-severe ischemic mitral regurgitation: Meta-analysis of clinical and echocardiographic outcomes.

OBJECTIVE: This meta-analysis was conducted to compare clinical and echocardiographic outcomes following isolated coronary artery bypass grafting (CABG) versus CABG and mitral valve (MV) surgery in patients with moderate-to-severe ischemic mitral regurgitation (IMR). METHODS: Seven databases were systematically searched to identify relevant studies. For eligibility, studies were required to report on the primary endpoint of perioperative or late mortality. Data were analyzed according to predefined clinical endpoints. RESULTS: Four randomized controlled trials (RCTs) (n = 505) and 15 observational studies (OS) (n = 3785) met the criteria for inclusion. Compared with isolated CABG, concomitant CABG and MV surgery was not associated with increased perioperative mortality (RCTs: relative risk [RR] 0.89, 95% confidence interval [CI], 0.26-3.02; OS: RR 1.40, 95% CI, 0.88-2.23). CABG and MV surgery was associated with significantly lower incidence of moderate-to-severe MR at follow-up (RCTs: RR 0.16, 95% CI, 0.04-0.75; OS: RR 0.20, 95% CI, 0.09-0.48). Late mortality was similar between the surgical approaches in RCTs (hazard ratio [HR] 1.20, 95% CI, 0.57-2.53) and OS (HR 0.99, 95% CI, 0.81-1.21). There were no significant differences in echocardiographic outcomes. These results remained consistent in subgroup analyses restricted to patients with strictly moderate IMR. CONCLUSIONS: In patients with moderate-to-severe IMR, the addition of MV surgery to CABG was not associated with increased perioperative mortality. Although concomitant MV surgery reduced recurrence of moderate-to-severe MR at follow-up, this was not associated with a reduction in late mortality. Larger trials with longer follow-up duration are required to further assess long-term survival and freedom from reintervention.

Systematic review and meta-analysis on the impact of preoperative atrial fibrillation on short- and long-term outcomes after aortic valve replacement.

INTRODUCTION: This systematic review and meta-analysis was performed to evaluate the impact of preoperative atrial fibrillation (preAF) on early and late outcomes after aortic valve replacement (AVR). EVIDENCE ACQUISITION: Medline, EMBASE, and CENTRAL were systematically searched for studies that reported AVR outcomes according to the presence or absence of preAF. Data were independently extracted by two investigators; a meta-analysis was conducted according to predefined clinical endpoints. Studies including patients undergoing concomitant atrial fibrillation surgery were excluded. EVIDENCE SYNTHESIS: Six observational studies with 8 distinct AVR cohorts (AVR± concomitant surgery) met criteria for inclusion, including a total of 6693 patients. Of these, 1014 (15%) presented with preAF. Overall, perioperative mortality was increased in patients with preAF (odds ratio [OR] 2.33; 95% CI: 1.48-3.67; P<0.001). Subgroup analysis of patients undergoing isolated AVR also demonstrated preAF as a risk factor for perioperative mortality (OR 2.49; 95% CI: 1.57-3.95; P<0.001). PreAF was also associated with acute renal failure (OR 1.42; 95% CI: 1.07-1.89; P=0.02) but not stroke (OR 1.11; 95% CI: 0.59-2.12; P=0.74). Late mortality was significantly higher in patients with preAF (hazard ratio [HR] 1.75; 95% CI: 1.33-2.30; P<0.001). This relationship remained true when only patients who underwent isolated AVR were analyzed (HR 1.97; 95% CI: 1.11-3.51; P=0.02). CONCLUSIONS: PreAF is associated with an increased risk of early- and late-mortality after AVR. These data support the more widespread utilization of concomitant AF ablation.

Technical Challenges in the Clinical Application of Radiomics.

Radiomics is a quantitative approach to medical image analysis targeted at deciphering the morphologic and functional features of a lesion. Radiomic methods can be applied across various malignant conditions to identify tumor phenotype characteristics in the images that correlate with their likelihood of survival, as well as their association with the underlying biology. Identifying this set of characteristic features, called tumor signature, holds tremendous value in predicting the behavior and progression of cancer, which in turn has the potential to predict its response to various therapeutic options. We discuss the technical challenges encountered in the application of radiomics, in terms of methodology, workflow integration, and user experience, that need to be addressed to harness its true potential.

p16 expression independent of human papillomavirus is associated with lower stage and longer disease-free survival in oral cavity squamous cell carcinoma.

There is limited information regarding the incidence of p16 expression, its association with human papillomavirus (HPV) and prognosis in oral cavity squamous cell carcinoma (OSCC). The role of p16 in OSCC is evaluated in 215 cases using tissue microarrays (TMAs). p16 immunohistochemistry and HPV in situ hybridisation were performed on TMAs following histopathology review of 215 patients with OSCC in the Sydney Head and Neck Cancer Institute database. Thirty-seven (17.2%) cases showed p16 expression without association with HPV. p16 expression significantly decreased with increasing pT category (p=0.002). p16 expression was associated with longer disease-specific survival on univariable analysis (p=0.044) but not on multivariable analysis adjusting for depth of invasion. Amongst patients receiving adjuvant radiotherapy, patients with p16 expression had significantly longer disease-free and overall survival. p16 expression was seen in early stage OSCCs and was associated with better survival following surgery and radiotherapy. While not an independent predictor of survival, p16 may mediate its effects by contributing to reduced proliferative capacity, leading to smaller tumour size and lower invasive potential.

Estrogen Receptor-α in the Medial Amygdala Prevents Stress-Induced Elevations in Blood Pressure in Females.

Psychological stress contributes to the development of hypertension in humans. The ovarian hormone, estrogen, has been shown to prevent stress-induced pressor responses in females by unknown mechanisms. Here, we showed that the antihypertensive effects of estrogen during stress were blunted in female mice lacking estrogen receptor-α in the brain medial amygdala. Deletion of estrogen receptor-α in medial amygdala neurons also resulted in increased excitability of these neurons, associated with elevated ionotropic glutamate receptor expression. We further demonstrated that selective activation of medial amygdala neurons mimicked effects of stress to increase blood pressure in mice. Together, our results support a model where estrogen acts on estrogen receptor-α expressed by medial amygdala neurons to prevent stress-induced activation of these neurons, and therefore prevents pressor responses to stress.

Margin to tumor thickness ratio - A predictor of local recurrence and survival in oral squamous cell carcinoma.

OBJECTIVES: To assess whether small oral squamous cell carcinomas (OSCC) require the same margin clearance as large tumors. We evaluated the association between the ratio of the closest margin to tumor size (MSR) and tumor thickness (MTR) with local control and survival. METHODS AND METHODS: The clinicopathologic and follow up data were obtained for 501 OSCC patients who had surgical resection with curative intent at our institution. MTR and MSR were computed and their associations with local control and survival were assessed using multivariable Cox-regression model. Survival curves were generated using the Kaplan-Meier method. RESULTS: MTR was a better predictor of disease control than MSR. MTR was a predictor of local failure (p=0.033) and disease specific death (p=0.038) after adjusting for perineural invasion, lymphovascular involvement, nodal status, and radiotherapy. A threshold MTR value of 0.3 was identified, above which the risk of local recurrence was low. CONCLUSION: The ratio of margin to tumor thickness was an independent predictor for local recurrence and disease specific death in this cohort. A MTR>0.3 can serve as a useful tool for adjuvant therapy planning as it combines tumor thickness and margin clearance, two well established prognostic factors. The minimum safe margin can be calculated by multiplying the tumor thickness by 0.3. Further prospective studies in other institutions are warranted to confirm the prognostic utility of MTR and assess the generalizability of our threshold values.

Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein.

To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10 pM, 1 nM, 100 nM, and 10 µM) and time points (8, 24, and 48 h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evaluated (10 µM). The GES' estrogenic activity was identified by comparing the Ishikawa cells' response to GES versus 17 α-ethynyl estradiol (EE, at equipotent doses, ie, 10 µM vs 1 µM, respectively) and was defined by changes in the expression of 284 unique genes elicited by GES and EE in the same direction, although the magnitude of the change for some genes was different. Further, comparing the response of the Ishikawa cells exposed to high doses of GES and EE versus the response of the juvenile rat uterus exposed to EE, we identified 66 unique genes which were up- or down regulated in a similar manner in vivo as well as in vitro Genistein elicits changes in multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response and offer an in vitro model to assess this mode of action.

Equivalent outcomes after coronary artery bypass graft surgery performed by consultant versus trainee surgeons: A systematic review and meta-analysis.

OBJECTIVE: In recent years, concerns have been raised about the learning opportunities available to cardiac surgical trainees. This meta-analysis was conducted to assess the impact of trainee operator status on clinical outcomes after coronary artery bypass graft (CABG) surgery. METHODS: Medline, EMBASE, and the Cochrane Library were systematically searched for studies that reported CABG outcomes according to the training status of the primary operator (consultant vs trainee). Data were independently extracted by 2 investigators; a meta-analysis was conducted according to predefined clinical endpoints. RESULTS: Sixteen observational studies (n = 52,966) met criteria for inclusion, with 8 studies (n = 36,479) reporting propensity-adjusted analyses. Trainee cases were associated with increased aortic crossclamp duration (mean difference: 4.80; 95% confidence interval [CI], 0.76-8.83) and cardiopulmonary bypass duration (mean difference: 4.24; 95% CI, 0.00-8.47). Perioperative mortality was similar for CABG performed primarily by trainees versus consultants (odds ratio 0.98; 95% CI, 0.81-1.18). No significant difference was found in the incidence of perioperative stroke, myocardial infarction, acute renal failure, reoperation for bleeding, or wound infection. Trainee operator status was not associated with increased midterm mortality (hazard ratio 1.00; 95% CI, 0.90-1.11). In subgroup analysis that included 5 studies and 8025 patients, off-pump CABG trainee cases were not associated with increased perioperative mortality or morbidity. CONCLUSIONS: With appropriate supervision, conventional CABG can be performed by trainee surgeons without an adverse impact on perioperative outcomes or midterm survival. Data regarding off-pump CABG are limited, and further research is warranted to ascertain the impact of trainee operator status on long-term outcomes after off-pump CABG.

A meta-analysis of mitral valve repair versus replacement for ischemic mitral regurgitation.

BACKGROUND: The development of ischemic mitral regurgitation (IMR) portends a poor prognosis and is associated with adverse long-term outcomes. Although both mitral valve repair (MVr) and mitral valve replacement (MVR) have been performed in the surgical management of IMR, there remains uncertainty regarding the optimal approach. The aim of the present study was to meta-analyze these two procedures, with mortality as the primary endpoint. METHODS: Seven databases were systematically searched for studies reporting peri-operative or late mortality following MVr and MVR for IMR. Data were independently extracted by two reviewers and meta-analyzed according to pre-defined study selection criteria and clinical endpoints. RESULTS: Overall, 22 observational studies (n=3,815 patients) and one randomized controlled trial (n=251) were included. Meta-analysis demonstrated significantly reduced peri-operative mortality [relative risk (RR) 0.61; 95% confidence intervals (CI), 0.47-0.77; I(2)=0%; P<0.001] and late mortality (RR, 0.78; 95% CI, 0.67-0.92; I(2)=0%; P=0.002) following MVr. This finding was more pronounced in studies with longer follow-up beyond 3 years. At latest follow-up, recurrence of at least moderate mitral regurgitation (MR) was higher following MVr (RR, 5.21; 95% CI, 2.66-10.22; I(2)=46%; P<0.001) but the incidence of mitral valve re-operations were similar. CONCLUSIONS: In the present meta-analysis, MVr was associated with reduced peri-operative and late mortality compared to MVR, despite an increased recurrence of at least moderate MR at follow-up. However, these findings must be considered within the context of the differing patient characteristics that may affect allocation to MVr or MVR. Larger prospective studies are warranted to further compare long-term survival and freedom from re-intervention.

The ERα-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice.

Estrogens act upon estrogen receptor (ER)α to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERα specifically in proopiomelanocortin (POMC) progenitor neurons. These mutant mice also develop insulin resistance and are insensitive to the glucose-regulatory effects of estrogens. Moreover, we showed that propyl pyrazole triol (an ERα agonist) stimulates the phosphatidyl inositol 3-kinase (PI3K) pathway specifically in POMC progenitor neurons, and that blockade of PI3K attenuates propyl pyrazole triol-induced activation of POMC neurons. Finally, we show that effects of estrogens to inhibit food intake and to improve insulin sensitivity are significantly attenuated in female mice with PI3K genetically inhibited in POMC progenitor neurons. Together, our results indicate that an ERα-PI3K cascade in POMC progenitor neurons mediates estrogenic actions to suppress food intake and improve insulin sensitivity.