The secret life of the mitral valve

In secondary mitral regurgitation, the concept that the mitral valve (MV) is an innocent bystander, has been challenged by many studies in the last decades. The MV is a living structure with intrinsic plasticity that reacts to changes in stretch or in mechanical stress activating biohumoral mechanisms that have, as purpose, the adaptation of the valve to the new environment. If the adaptation is balanced, the leaflets increase both surface and length and the chordae tendineae lengthen: the result is a valve with different characteristics, but able to avoid or to limit the regurgitation. However, if the adaptation is unbalanced, the leaflets and the chords do not change their size, but become stiffer and rigid, with moderate or severe regurgitation. These changes are mediated mainly by a cytokine, the transforming growth factor‐β (TGF‐β), which is able to promote the changes that the MV needs to adapt to a new hemodynamic environment. In general, mild TGF‐β activation facilitates leaflet growth, excessive TGF‐β activation, as after myocardial infarction, results in profibrotic changes in the leaflets, with increased thickness and stiffness. The MV is then a plastic organism, that reacts to the external stimuli, trying to maintain its physiologic integrity. This review has the goal to unveil the secret life of the MV, to understand which stimuli can trigger its plasticity, and to explain why the equation “large heart = moderate/severe mitral regurgitation” and “small heart = no/mild mitral regurgitation” does not work into the clinical practice.     

Human liver stem cell-derived extracellular vesicles reduce injury in a model of normothermic machine perfusion of rat livers previously exposed to a prolonged warm ischemia

Livers from donors after circulatory death (DCD) are a promising option to increase the donor pool, but their use is associated with higher complication rate and inferior graft survival. Normothermic machine perfusion (NMP) keeps the graft at 37°C, providing nutrients and oxygen supply. Human liver stem cell-derived extracellular vesicles (HLSC-EVs) are able to reduce liver injury and promote regeneration. We investigated the efficacy of a reconditioning strategy with HLSC-EVs in an experimental model of NMP. Following total hepatectomy, rat livers were divided into 4 groups: (i) healthy livers, (ii) warm ischemic livers (60 min of warm ischemia), (iii) warm ischemic livers treated with 5 × 10⁸ HLSC-EVs/g-liver, and (iv) warm ischemic livers treated with a 25 × 10⁸ HLSC-EVs/g-liver. NMP lasted 6 h and HLSC-EVs (Unicyte AG, Germany) were administered within the first 15 min. Compared to controls, HLSC-EV treatment significantly reduced transaminases release. Moreover, HLSC-EVs enhanced liver metabolism by promoting phosphate utilization and pH self-regulation. As compared to controls, the higher dose of HLSC-EV was associated with significantly higher bile production and lower intrahepatic resistance. Histologically, this group showed reduced necrosis and enhanced proliferation. In conclusion, HLSC-EV treatment during NMP was feasible and effective in reducing injury in a DCD model with prolonged warm ischemia.     

The Use of Oral Amino-Bisphosphonates and Coronavirus Disease 2019 (COVID-19) Outcomes

The determinants of the susceptibility to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and severe coronavirus disease 2019 (COVID-19) manifestations are yet not fully understood. Amino-bisphosphonates (N-BPs) have anti-inflammatory properties and have been shown to reduce the incidence of lower respiratory infections, cardiovascular events, and cancer. We conducted a population-based retrospective observational cohort study with the primary objective of determining if oral N-BPs treatment can play a role in the susceptibility to development of severe COVID-19. Administrative International Classification of Diseases, Ninth Revision, Clinical ModificationI (ICD-9-CM) and anatomical-therapeutic chemical (ATC) code data, representative of Italian population (9% sample of the overall population), were analyzed. Oral N-BPs (mainly alendronate and risedronate) were included in the analysis, zoledronic acid was excluded because of the low number of patients at risk. Incidence of COVID-19 hospitalization was 12.32 (95% confidence interval [CI], 9.61–15.04) and 11.55 (95% CI, 8.91–14.20), of intensive care unit (ICU) utilization because of COVID-19 was 1.25 (95% CI, 0.38–2.11) and 1.42 (95% CI, 0.49–2.36), and of all-cause death was 4.06 (95% CI, 2.50–5.61) and 3.96 (95% CI, 2.41–5.51) for oral N-BPs users and nonusers, respectively. Sensitivity analyses that excluded patients with prevalent vertebral or hip fragility fractures and without concomitant glucocorticoid treatment yielded similar results. In conclusion, we found that the incidence of COVID-19 hospitalization, intensive care unit (ICU) utilization, and COVID-19 potentially related mortality were similar in N-BPs–treated and nontreated subjects. Similar results were found in N-BPs versus other anti-osteoporotic drugs. We provide real-life data on the safety of oral N-BPs in terms of severe COVID-19 risk on a population-based cohort. Our results do not support the hypothesis that oral N-BPs can prevent COVID-19 infection and/or severe COVID-19; however, they do not seem to increase the risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Postoperative hyperamylasemia (POH) and acute pancreatitis after pancreatoduodenectomy (POAP): State of the art and systematic review

BackgroundPostoperative hyperamylasemia is a frequent finding after pancreatoduodenectomy, but its incidence and clinical implications have not yet been analyzed systematically. The aim of this review is to reappraise the concept of postoperative hyperamylasemia with postoperative acute pancreatitis, including its definition, interpretation, and correlation.MethodsOnline databases were used to search all available relevant literature published through June 2019. The following search terms were used: “pancreaticoduodenectomy,” “amylase,” and “pancreatitis.” Surgical series reporting data on postoperative hyperamylasemia or postoperative acute pancreatitis were selected and screened.ResultsAmong 379 screened studies, 39 papers were included and comprised data from a total of 9,220 patients. Postoperative hyperamylasemia was rarely defined in most of these series, and serum amylase values were measured at different cutoff levels and reported on different postoperative days. The actual levels of serum amylase activity and the representative cutoff levels required to reach a diagnosis of postoperative acute pancreatitis were markedly greater on the first postoperative days and tended to decrease over time. Most studies analyzing postoperative hyperamylasemia focused on its correlation with postoperative pancreatic fistula and other postoperative morbidities. The incidence of postoperative acute pancreatitis varied markedly between studies, with its definition completely lacking in 40% of the analyzed papers. A soft pancreatic parenchyma, a small pancreatic duct, and pathology differing from cancer or chronic pancreatitis were all predisposing factors to the development of postoperative hyperamylasemia.ConclusionPostoperative hyperamylasemia has been proposed as the biochemical expression of pancreatic parenchymal injury related to localized ischemia and inflammation of the pancreatic stump. Such phenomena, analogous to those associated with acute pancreatitis, could perhaps be renamed as postoperative acute pancreatitis from a clinical standpoint. Patients with postoperative acute pancreatitis experienced an increased rate of all postoperative complications, particularly postoperative pancreatic fistula. Taken together, the discrepancies among previous studies of postoperative hyperamylasemia and postoperative acute pancreatitis outlined in the present review may provide a basis for stronger evidence necessary for the development of universally accepted definitions for postoperative hyperamylasemia and postoperative acute pancreatitis.     

ASO Visual Abstract: Optimal Treatment of cT2N0 Esophageal Carcinoma—Is Upfront Surgery Really the Way?

Annals of Surgical Oncology -     

BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: A systematic review

Objective: Intravesical Bacillus Calmette-Guèrin (BCG) is an effective treatment in non––muscle-invasive bladder cancer, however, extravesical BCG infection may occur in remote organs as a potentially serious complication. Researchers aimed to assess whether a different timing of BCG infection after intravesical administration of BCG could be identified and estimated for each single involved organ. Methods: We performed a systematic literature review over systemic and genitourinary BCG infection case reports, including 271 published case reports for a total of 307 patients. Demographic data, clinical features, and timing of BCG infection development were collected and analyzed for each patient. Results: BCG infection developed with a different timing from last instillation, depending on the involved organ. Among the genitourinary complications, penile lesions occurred as early as 1 (1;3) weeks, while orchiepididymitis occurred as late as 56 (6.25;156) weeks. At the same time, granulomatous hepatitis and lungs involvement such as miliary pulmonary BCG infection occurred earlier, with a median time of 1 (1;4) and 1 (1;6) weeks respectively, whereas vascular, osteoarticular, and muscular complications developed with a median timing from last instillation of 52 (20;104), 68 (14;156), and 93 (29;156) weeks, respectively. The analysis detected a cluster between lungs, liver, and bone marrow complications on one side and muscular and osteoarticular or vascular complications on the other side was also observed. Conclusions: BCG infection after intravesical BCG for bladder cancer may develop even several months or years after the last instillation, depending on the involved organs. When BCG infection interests one or more organ, 2 main associative patterns are common: one involving lungs, liver, and bone marrow, with earlier occurrence but lower rates of microbiological diagnosis achievement, and one involving muscular and osteoarticular or vascular districts, with later occurrence but higher rates of microbiological evidence.     

Comparison between small renal masses 0-2 cm vs. 2.1-4 cm in size: A population-based study

BackgroundThe NCCN guidelines recommend active surveillance (AS) as an option for the initial management of cT1a 0-2 cm renal lesions. However, data about comparison between renal cell carcinoma (RCC) 0-2 cm vs. 2.1-4 cm are scarce.MethodsWithin the Surveillance, Epidemiology, and End Results database (2002–2016), 46,630 T1a N_anyM_any stage patients treated with nephrectomy were identified. Data were tabulated according to histological subtype, tumor grade (low [LG] vs. high [HG]), as well as age category and gender. Additionally, rates of synchronous metastases were quantified.ResultsOverall, 69.3 vs. 74.1% clear cell, 21.4 vs. 17.6% papillary, 6.9 vs. 6.8% chromophobe, 2.0 vs. 1.1% sarcomatoid dedifferentiation, 0.2 vs. 0.2% collecting duct histological subtype were identified for respectively 0-2 cm and 2.1-4 cm RCCs. In both groups, advanced age was associated with higher rate of HG clear cell and HG papillary histological subtype. In 0-2 cm vs. 2.1-4 cm RCCs, 13.8% vs. 20.2% individuals operated on harbored HG tumors and were more prevalent in males. Lower synchronous metastases rates were recorded in 0-2 cm RCC and ranged from 0 in respectively multilocular cystic to 0.9% in HG papillary histological subtype. The highest synchronous metastases rates were recorded in sarcomatoid dedifferentiation histological subtype (13.8% and 9.7%) in both groups.ConclusionsRelative to 2.1-4 cm RCCs, 0-2 cm RCCs harbored lower rates of HG tumors, lower rates of aggressive variant histology and lower rates of synchronous metastases. The indications and demographics of patients selected for AS may be expanded in the future to include younger and healthier patients.