Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation.

Obesity induces low-grade chronic inflammation, manifested by proinflammatory polarization of adipose tissue innate and adaptive resident and recruited immune cells that contribute to insulin resistance (IR). The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that mediates postprandial insulin secretion and has anabolic effects on the adipose tissue. Importantly, recent evidence suggested that GIP is a potential suppressor of inflammation in several metabolic models. In this study, we aimed to investigate the immunoregulatory role of GIP in a murine model of diet-induced obesity (DIO) using the long-acting GIP analog [d-Ala(2)]GIP. Administration of [d-Ala(2)]GIP resulted in adipocytes of increased size, increased levels of adipose tissue lipid droplet proteins, indicating better lipid storage capacity, and reduced adipose tissue inflammation. Flow cytometry analysis revealed reduced numbers of inflammatory Ly6C(hi) monocytes and F4/80(hi)CD11c(+) macrophages, associated with IR. In addition, [d-Ala(2)]GIP reduced adipose tissue infiltration of IFN-γ-producing CD8(+) and CD4(+) T cells. Furthermore, [d-Ala(2)]GIP treatment induced a favorable adipose tissue adipokine profile, manifested by a prominent reduction in key inflammatory cytokines (TNF-α, IL-1ß, IFN-γ) and chemokines (CCL2, CCL8, and CCL5) and an increase in adiponectin. Notably, [d-Ala(2)]GIP also reduced the numbers of circulating neutrophils and proinflammatory Ly6C(hi) monocytes in mice fed regular chow or a high-fat diet. Finally, the beneficial immune-associated effects were accompanied by amelioration of IR and improved insulin signaling in liver and adipose tissue. Collectively, our results describe key beneficial immunoregulatory properties for GIP in DIO and reveal that its augmentation ameliorates adipose tissue inflammation and improves IR.

Pushing the envelope in breast conserving surgery - is multiple-wire localization (3 or more wires) associated with increased risk of compromised margins and long-term recurrence?

INTRODUCTION: In the last two decades there has been a paradigm shift with breast conserving surgery (BCS) being applied to larger and more extensive breast malignancies. The aim of this study is to examine the success of BCS being performed in patients with extensive breast malignancies requiring at least 3 wires for localization, and to assess possible risk factors for failure. MATERIALS AND METHODS: We performed a retrospective single center review of 232 patients who underwent BCS between 2010 and 2020 requiring at least 3 wires for localization, thus comprising the multi-wire group (MWG). The cohort included a control group of 232 single-wire BCS patients (SWG) chronologically matched with the MWG. Patients with either invasive malignancy or ductal carcinoma in situ (DCIS) were included in the study. Clinical, radiological, and pathological data was collected. Proportions of positive surgical margins, re-lumpectomies and conversion to mastectomy were calculated. Survival analysis for locoregional and distant recurrence was performed. RESULTS: Women in the MWG were younger (mean age 57 vs. 63.1, P < 0.001), had larger tumor size (mean size 5.1 cm vs. 1.3 cm, p < 0.001), a higher prevalence of calcifications on mammograms (72 % vs. 17 %, P < 0.001), a higher proportion of positive lymph nodes (75 % vs. 45 %, P = 0.019), and an elevated incidence of a ductal carcinoma in situ (DCIS) component (72 % vs. 38 %, P < 0.001). Positive surgical margins were higher in the MWG (13 % vs 7 %, P = 0.03), which lead to higher proportions of re-lumpectomies or conversion to mastectomies (7 % vs 4 %, P = 0.17). On multivariate analysis of the entire cohort, patients with positive margins were more likely to have a DCIS component (77 % vs 53 %, P = 0.001), an infiltrating lobular carcinoma (ILC) component (15 % vs 9 %, P = 0.013), and positive ER hormonal status (94 % vs 85 %, p = 0.05). The number of wires was not an independent predictor of positive margins. On long-term analysis, the locoregional disease-free survival was similar between the SWG and MWG (P = 0.1). However, the MWG showed higher rates of distant metastasis (12 % vs 4 %, P = 0.006). CONCLUSIONS: BCS requiring 3 or more wires is associated with a slightly higher proportion of positive margins. The increased risk of positive margins appears to be related to the type of tumor (DCIS component, ILC component and ER status) rather than to the number of wires. The number of wires does not significantly impact locoregional disease-free survival.

The Benefit of Routine Axillary Sonographic Assessment in cN0 Breast Cancer Patients.

Objective: Axillary ultrasound (US) is often part of the routine assessment of the clinically negative axilla in primary breast cancer, which determines the extent of axillary surgery to be performed. This study aims to ascertain the burden of disease in the axilla of patients with a normal clinical examination (cN0) but with US detected metastatic axillary lymph nodes. Materials and Methods: We retrospectively identified 345 female patients who underwent axillary lymph node dissection, following a positive lymph node biopsy, between January 2015 and August 2019.Eighty-nine of those had a positive biopsy prior to surgery. They were divided into two groups: Those with clinically palpable axillary disease preoperatively, cN1 (n = 41), and those with a normal clinical axillary examination, cN0 (n = 48). We assessed the number of positive axillary lymph nodes dissected in the two groups. Results: In the cN0 group the mean value of excised disease-positive axillary lymph nodes was 3.6, while in the cN1 group it was 8.0 (p<0.01). However, further analysis showed that 25 patients of the cN0 who had T1/T2 tumors had ≥3 positive lymph nodes. Conclusion: Our study suggests that the presence of clinically palpable axillary lymph nodes appears to be correlated to a higher number of positive lymph nodes. However, in cases of non-palpable sonographically positive lymph nodes there might still be significant axillary disease, even in T1 and T2 tumors. Therefore we still support the routine use of preoperative sonographic assessment of the axilla for early breast cancer.

One-Anastomosis Gastric Bypass: First 407 Patients in 1 year.

BACKGROUND: One-anastomosis gastric bypass (OAGB) is a promising laparoscopic procedure with various benefits including shorter operating times and less operative complications. That said, it is yet to gain widespread acceptance. Here, we describe our first-year experience with OAGB in our department, in particular the safety and efficacy of this procedure. METHODS: This study is a retrospective analysis of all patients who underwent OAGB between March 2015 and March 2016 by our bariatric surgery unit. Patient demographics, comorbidities, operative and postoperative data were collected and analyzed as well as outcomes during the first year. RESULTS: Four hundred and seven patients underwent OAGB (254 females, average age 41.8 ± 12.05, BMI = 41.7 ± 5.77 kg/m2). Ninety-eight patients (24%) had prior bariatric surgery. Ninety-four patients (23%) had diabetes, 93 patients (22.8%) had hypertension, 123 (28.8%) had hyperlipidemia, and 35 patients (8.6%) suffered from obstructive sleep apnea. Eight patients (1.96%) had early minor complications (Clavien-Dindo 1-3a), and 10 patients (2.45%) suffered early major complications (Clavien-Dindo ≥3b). The average length of hospital stay was 2.2 ± 0.84 days (range 2-10 days). Twenty patients (4.8%) were readmitted, and 10 patients underwent reoperation. Patients who had had previous bariatric surgery had higher rates of complications, a prolonged hospital admission, higher rates of readmission, and early reoperations. The average excess weight loss (%EWL) 1 year following surgery was 88.9 ± 27.3 and 72.8 ± 43.5% in patients that underwent primary and revision OAGB, respectively. CONCLUSIONS: OAGB is both safe and effective as a primary as well as a revision bariatric surgery.

Discriminatory metabolic and inflammatory parameters in serum and omental adipose tissue of obese patients with different insulin sensitivity.

OBJECTIVE: Metabolically healthy obese phenotype is defined by high insulin sensitivity and lack of metabolic syndrome, parameters regulated by omental adipose tissue inflammation, ectopic fat deposition and adipose tissue dysfunction. Our study aimed to identify novel metabolic and inflammatory markers in serum and omental adipose tissue which characterize the "unhealthy" obese patients and distinguish them from obese patients with better metabolic profile. DESIGN: Cross-sectional study. PATIENTS: Subjects included 75 obese patients undergoing bariatric surgery at the Tel-Aviv Medical Center (mean age 43.9 ± 13.9, mean BMI 41 ± 8.4). The HOMA median value was used as a cut-off to differentiate between patients with better or worse insulin resistance. MEASUREMENTS: Demographic data, fasting serum insulin, glucose, bile acids, serum metabolic and inflammatory markers were obtained. During the bariatric surgery, omental adipose tissue was harvested and analyzed for metabolic and inflammatory markers using qRT-PCR. Logistic regressions were used to calculate odds ratio and 95% confidence interval for the prediction of the metabolic profile. RESULTS: Serum markers that were significantly higher among the obese with HOMA >6 were total bile acids. In the omental adipose tissue the inflammatory markers TNFα and ADAM17 were significantly higher among obese patients with HOMA >6. In multivariate analysis, the strongest predictor for insulin resistance was ADAM17 (OR = 1.82, 1.06-3.14, P = 0.031). CONCLUSIONS: The study highlighted the predictive value of serum bile acids in identifying obese patients at high risk. Secondly, omental adipose tissue ADAM17 was revealed as a novel and strongest independent predictor for higher insulin resistance in morbidly obese patients.