Obesity does not increase the risk of lymph node metastases in patients with clinically localized prostate cancer undergoing radical prostatectomy and extended pelvic lymph node dissection

Objectives: Several studies have shown that obesity is associated with more aggressive prostate cancer (PCa) variants. We hypothesized that obesity, quantified as body mass index (BMI), is associated with a higher risk of lymph node invasion (LNI) in patients undergoing extended pelvic lymph node dissection (ePLND). Methods: Clinical and pathological data were available for 994 consecutive men with PCa treated with radical prostatectomy (RP) and ePLND at a single European tertiary academic centre. Univariable and multivariable logistic regression analyses addressed the rate of LNI. Covariates consisted of pre‐treatment prostate specific antigen (PSA), biopsy Gleason sum, clinical stage history of diabetes mellitus as well as BMI coded as either continuous or categorized (<25, 25.0–29.9, 30 kg/m² or more) variable. Predictive accuracy was assessed with area under curve estimates. Results: Overall LNI was diagnosed in 105 patients (10.6%). Mean number of removed lymph nodes was 18.3 (range 7–60). Of all 994 patients, 372 (37.4%) were normal weight, 518 (52.1%) overweight, and 104 (10.5%) were clinically obese. Prevalence of LNI did not significantly differ across different BMI categories (<25, 25.0–29.9 and 30 kg/m² or more; 9.9, 10.6 and 12.5%, respectively; P = 0.75). In logistic regression models, neither continuously coded nor categorized BMI was a significant predictor of LNI at univariable or multivariable analyses (all P‐values ≥0.1). Moreover, inclusion of BMI with PSA, clinical stage, biopsy Gleason sum and presence of DM did not increase the ability of these variables to predict LNI (82.2% without BMI vs 82.5% and 82.9% with BMI coded as continuous and categorized variable, respectively; all P ≥ 0.4). Conclusions: In men undergoing RP and ePLND, increased BMI was not associated with increased risk of lymph node metastases. Therefore, routinely considering patient BMI in risk stratification schemes or prognostic LNI models may not be warranted.     

The patterns of spontaneous Ca2+ signals generated by ventral spinal neurons in vitro show time-dependent refinement

Embryonic spinal neurons maintained in organotypic slice culture are known to mimic certain maturation-dependent signalling changes. With such a model we investigated, in embryonic mouse spinal segments, the age-dependent spatio-temporal control of intracellular Ca²⁺ signalling generated by neuronal populations in ventral circuits and its relation with electrical activity. We used Ca²⁺ imaging to monitor areas located within the ventral spinal horn at 1 and 2 weeks of in vitro growth. Primitive patterns of spontaneous neuronal Ca²⁺ transients (detected at 1 week) were typically synchronous. Remarkably, such transients originated from widespread propagating waves that became organized into large-scale rhythmic bursts. These activities were associated with the generation of synaptically mediated inward currents under whole-cell patch-clamp. Such patterns disappeared during longer culture of spinal segments: at 2 weeks in culture, only a subset of ventral neurons displayed spontaneous, asynchronous and repetitive Ca²⁺ oscillations dissociated from background synaptic activity. We observed that the emergence of oscillations was a restricted phenomenon arising together with the transformation of ventral network electrophysiological bursting into asynchronous synaptic discharges. This change was accompanied by the appearance of discrete calbindin immunoreactivity against an unchanged background of calretinin-positive cells. It is attractive to assume that periodic oscillations of Ca²⁺ confer a summative ability to these cells to shape the plasticity of local circuits through different changes (phasic or tonic) in intracellular Ca²⁺.     

The probability of Gleason score upgrading between biopsy and radical prostatectomy can be accurately predicted

The objective of this study was to test the external validity of a previously developed nomogram for the prediction of Gleason score upgrading (GSU) between biopsy and radical prostatectomy (RP). The study population consisted of 973 assessable patients treated with RP at a tertiary care institution. The accuracy of the nomogram was quantified with the receiver operating characteristics curve-derived area under the curve. The performance characteristics (predicted vs observed rate of GSU) were tested within a calibration plot. Overall, GSU was recorded in 39.8% ( n  = 387) of patients at RP. Of patients with GSU, 70 (18.1%), 23 (5.9%) and 32 (8.3%), respectively, had extracapsular extension, seminal vesicle invasion and lymph node invasion. The accuracy of the nomogram was 74.9% (confidence interval 72.1–77.6%). The model tended to underestimate the observed rate of GSU and the discordance between the predicted and observed rate of GSU ranged from −7 to +10%. The current tool represents the most accurate method of predicting GSU between biopsy and RP. Nonetheless it is not perfect and its performance characteristics should be known prior to its use in clinical decision-making.     

Ventricular Septal Crypts: Remnants of Spontaneous Interventricular Defect Closure?

Background: Ventricular crypts are quite a common finding during cardiac imaging, but their etiology is unclear. A possible final result of a spontaneous ventricular septal defect closure has been supposed but never investigated in earlier studies. Method: From January 1997 to December 2020, all newborns diagnosed to have a ventricular septal defect were prospectively entered in our database and those with an isolated defect were included in the study. Ventricular septal defects were classified into four types: perimembranous, trabecular muscular, inlet and outlet. A long-term follow up was performed in order to visualize the possible residual formation of a septal myocardial crypt. Results: A total of 376 isolated ventricular septal defects (314 muscular and 54 perimembranous, 4 inlet, 4 outlet) were detected. Follow up ranged from 1 to 23 years and showed that, among muscular type, a spontaneous closure occurred in 284 (91%), 26 did not close (8,28%), 2 required surgical intervention (0,63%), 3 were lost at follow up (0,95%). During this period, after spontaneous defect closure closure, 20 crypts were found (6,4%). Conclusion: This study shows that a muscular ventricular septal defect may evolve in the 6.4% of cases in a residual septal crypt. Although septal crypts occur more frequently in patients affected by hypertrophic and hypertensive cardiomyopathy, they may also represent the evolution of a spontaneous closure of a muscular interventricular defect.     

Practical insights into chronic management of hepatic Wilson’s disease

Wilson’s disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson’s disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.     

Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

To date, metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile. Indeed, metformin is the most widely used oral insulinsensitizing agent, being prescribed to more than 100 million people worldwide, including patients with prediabetes, insulin resistance, and polycystic ovary syndrome. However, over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. Of note, evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status. Vitamin B12(also referred to as cobalamin) is a water-soluble vitamin that is mainly obtained from animal-sourced foods. At the cellular level, vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection. Thus, vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities(e.g., megaloblastic anemia and formation of hypersegmented neutrophils), progressive axonal demyelination and peripheral neuropathy. Nevertheless, no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy, and vitamin B12 deficiency remains frequently unrecognized in such individuals. Therefore, in this "field of vision" article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition. Moreover, we discuss additional relevant topics related to this field, including:(1) The lack of consensus about the exact definition of vitamin B12 deficiency;(2) The definition of reliable biomarkers of vitamin B12 status;(3) Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis; and(4) Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency. Finally, we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency, particularly when this condition is induced by metformin.     

Venous outflow reconstructions with the piggyback technique in liver transplantation: a single-center experience of 431 cases

The ideal method of venous outflow reconstruction with the piggyback technique (PB) in orthotopic liver transplantation (OLT) is not well-established. The complications related to PB in 431 primary OLTs were analyzed comparing the orifices used for the anastomosis (cuff of the recipient left and middle hepatic veins [LM], LM with a >1 cm cavoplasty [LM+], or also including the right hepatic vein [LMR]). Treatment strategies and outcome were also evaluated. Twenty patients (4.6%) experienced complications: 13 of 120 (10.8%) with LM, four of 225 (1.8%) with LM+, and three of 86 (3.5%) with LMR (LM versus LM+: P < 0.0001; LM versus LMR: P = NS; LM+ versus LMR = NS). Balloon dilation was successful in 10 of 13 cases in which it was attempted (77%). Eight patients required retransplantation (40%). Three patients (0.7%) died from causes linked to stenosis. Five-year survival of patients with and without complications was 75% and 79%, respectively (P =NS); 5-year graft survival was 50% and 76%, respectively (P = 0.001). The stump formed by the recipient left and middle hepatic veins with a transversal incision >1 cm of the caval wall constantly provides an adequate width for the caval anastomosis with the PB.