SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses

Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a ‘superfuel’ in the cardiac and renal tissue (the ‘thrifty substrate’ hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na⁺–H⁺ exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.     

Surgical ethics and the challenge of surgical innovation

Surgical ethics as a specific discipline is relatively new to many. Surgical ethics focuses on the ethical issues that are particularly important to the care of surgical patients. Informed consent for surgical procedures, the level of responsibility that surgeons feel for their patients' outcomes, and the management of surgical innovation are specific issues that are important in surgical ethics and are different from other areas of medicine. The future of surgical progress is dependent on surgical innovation, yet the nature of surgical innovation raises specific concerns that challenge the professionalism of surgeons. These concerns will be considered in the following pages.     

alphaB-crystallin is a marker of aggressive breast cancer behavior but does not independently predict for patient outcome: a combined analysis of two randomized studies

Background

alphaB-crystallin is a small heat shock protein that has recently been characterized as an oncoprotein correlating with the basal core phenotype and with negative prognostic factors in breast carcinomas. The purpose of this study was to evaluate alphaB-crystallin with respect to clinicopathological parameters and the outcome of patients with operable high-risk breast cancer.

Methods

A total of 940 tumors were examined, derived from an equal number of patients who had participated in two randomized clinical trials (paclitaxel-containing regimen in 793 cases). Immunohistochemistry for ER, PgR, HER2, Ki67, CK5, CK14, CK17, EGFR, alphaB-crystallin, BRCA1 and p53 was performed. BRCA1 mutation data were available in 89 cases.

Results

alphaβ-crystallin was expressed in 170 cases (18.1%) and more frequently in triple-negative breast carcinomas (TNBC) (45% vs. 14.5% non-TNBC, p <?0.001). alphaB-crystallin protein expression was significantly associated with high Ki67 (Pearson chi-square test, p <?0.001), p53 (p =?0.002) and basal cytokeratin protein expression (p <?0.001), BRCA1 mutations (p =?0.045) and negative ER (p <?0.001) and PgR (p <?0.001). Its overexpression, defined as >30% positive neoplastic cells, was associated with adverse overall survival (Wald’s p =?0.046). However, alphaB-crystallin was not an independent prognostic factor upon multivariate analysis. No interaction between taxane-based therapy and aβ-crystallin expression was observed.

Conclusions

In operable high-risk breast cancer, alphaB-crystallin protein expression is associated with poor prognostic features indicating aggressive tumor behavior, but it does not seem to have an independent impact on patient survival or to interfere with taxane-based therapy.

Trial registrations

ACTRN12611000506998 (HE10/97 trial) andACTRN12609001036202 (HE10/00 trial).

     

Concurrent pleural infiltration by chronic lymphocytic leukemia and adenocarcinoma of unknown primary site diagnosed by effusion cytology

Synchronous malignancies in a pleural effusion are rare. A case of concurrent pleural infiltration by adenocarcinoma of unknown primary site and chronic lymphocytic leukemia (CLL) is presented in this case study, which was diagnosed by effusion cytology. Pleural effusion is not an uncommon complication in patients with B‐CLL. Even in a pleural effusion rich in monoclonal lymphocytes, the presence of a second cancer must be excluded because this can be the main cause of mortality. The role of cytology in such cases is of paramount importance. Diagn. Cytopathol. 2014;42:151–155. © 2012 Wiley Periodicals, Inc.     

Palliative thyroidectomy for malignant lymphoma of the thyroid

Background Current treatment of malignant lymphoma of the thyroid consists of chemotherapy and external beam radiation. The diagnosis can routinely be made by fine-needle aspiration, obviating the need for surgery. However, a significant number of patients present with symptoms of obstruction, necessitating thyroidectomy for palliation. Methods To determine the outcomes of patients with malignant thyroid lymphoma after palliative thyroidectomy, we reviewed our experience. Between 1980 and 2001, 27 patients with thyroid lymphoma and symptoms or signs of airway and/or esophageal obstruction were evaluated at 1 of 3 academic institutions. Results The mean age of the patients was 66±3 years, and the majority was female. Patients presented with symptoms of dyspnea/stridor (30%), dysphagia/pain (30%), or impending airway obstruction (40%). All underwent palliative surgery. In addition to surgery, 10 patients had combined chemo- and radiotherapy, 10 had radiotherapy alone, and 4 had only chemotherapy. Symptom-free survival after palliative surgery was determined by Kaplan-Meier analysis. The mean actuarial symptom-free survival of patients with symptomatic, malignant thyroid lymphoma was 10 years (95% confidence interval, 7.67 to 12.33 years). Conclusions Patients with malignant lymphoma of the thyroid can present with obstructive symptoms requiring palliative intervention. In this group of patients, thyroidectomy can be associated with good long-term palliation and low morbidity.     

Aortobipopliteal Bypass Grafting for In Situ Replacement of Infected Aortobifemoral Prosthesis

Conventional treatment of an infected aortobifemoral graft includes total graft excision and ex situ bypass grafting, but has been associated with significant perioperative morbidity and mortality. Additionally, the presence of infection in the groin makes limb revascularization problematic. There is increasing evidence that in situ replacement of an infected graft can achieve promising results in selected patients. We present a case of an aortobifemoral graft infection, affecting both the groin as well as the entire pelvis. The patient underwent successful in situ graft replacement with a new aortobipopliteal prosthesis via an alternative extraperitoneal route.