Citations

Introduction Visceral obesity is associated with GERD and, traditionally, it has been assumed that visceral fat predisposes to GERD primarily by increasing intra‐abdominal pressure. However, transmission electron microscopy (TEM) of esophageal biopsies from obese individuals without GERD exhibit dilated intercellular spaces (DIS) and, in earlier studies, we found that substances secreted by mature adipocytes in visceral fat from obese patients impair esophageal epithelial barrier function, induce DIS and reduce transepithelial resistance (TER). There is a fat pad at the gastroesophageal junction (GEJ) that is in intimate contact with the distal esophagus. We now explore whether whole GEJ fat tissue of obese individuals secretes substances that impair esophageal barrier function. Methods We obtained GEJ fat from 3 obese (BMI 46, 60, 74) and 3 non‐obese (BMI 24, 26, 27) patients having foregut surgery. Human esophageal squamous cells were seeded into transwells and grown to confluence for 3 days. On day 4, cells were raised to an air‐liquid interface (ALI) to allow for differentiation, stratification, and esophageal barrier formation. ALI cultures were exposed to conditioned media (CM) from GEJ fat or to control medium beginning at day 4. TER was measured on days 4, 6, and 8 using the EVOM2 Epithelial Volt/Ohm Meter. On day 8, ALI cultures were stained with H&E and Ki‐67 and imaged; barrier permeability was assessed by a biotinylation reagent applied to the ALI surface. TEM of ALIs and of esophageal biopsies from 2 non‐obese and 2 obese patients without GERD were assessed. Results CM from all 3 obese patients significantly reduced TER on days 6 and 8; CM from 2 non‐obese patients did not reduce TER whereas CM from 1 non‐obese patient induced a slight reduction in TER at day 8 (Table 1). Marked DIS were found only in ALI cultures grown with CM from obese patients. In ALIs grown with CM from non‐obese patients, the biotinylation reagent stopped at the superficial layers of esophageal cells. In contrast, the biotinylation reagent diffused through all cell layers in ALIs grown with obese patient CM. Increases in basaloid cells and in Ki‐67 were found in ALIs grown with obese patient CM. TEMs of ALIs grown with non‐obese patient CM demonstrated well‐oriented cell‐cell junctions similar to TEMs of non‐obese patient esophageal biopsies. In contrast, ALIs grown with obese patient CM demonstrated cell‐cell junctional structures that were disorganized, aggregated, and floating within the DIS, similar in appearance to TEMs of the obese patients’ esophageal biopsies. Conclusion Substances produced by GEJ fat of obese patients impair esophageal epithelial barrier integrity, cause basal cell hyperplasia and DIS, and disrupt intercellular connections. These findings in ALI cultures recapitulate abnormalities seen by TEM in esophageal biopsies of obese patients.

Recent studies indicated that activated transcription of serum‐inducible genes in humans requires topoisomerase IIβ (TOP2B)‐mediated DNA strand break (DSB) and DNA damage response (DDR) signaling. However, the mechanisms by which TOP2B is regulated in this process are unknown. Here, we identified a novel role of BRCA1‐BARD1 complex in transcription of these genes by regulating TOP2B binding to the transcription start site (TSS). Our genomic and in vitro biochemical analyses demonstrated that BRCA1‐BARD1 complex and TOP2B colocalize in a large number of genes and physically interact for TOP2B ubiquitination. Upon transcriptional activation, BRCA1 is phosphorylated at S1524 by ataxia telangiectasia‐mutated (ATM) and ataxia telangiectasia and Rad3‐related protein (ATR). Intriguingly, unphosphorylatable BRCA1 (S1524A)‐BARD1 complex ubiquitinates TOP2B, but not WT or S1524D BRCA1. Using the TSS of a representative serum‐inducible gene, EGR1 , we found that ubiquitinated TOP2B binds to the DNA with much more stability than deubiquitinated one does. Together, our findings suggest that BRCA1‐BARD1 complex stabilizes TOP2B association with serum‐inducible genes through its E3 ligase function in transcription. Transcriptional activation induces TOP2B‐mediated DSB and DDR signaling to activate ATM/ATR that phosphorylates BRCA1 S1524. Phosphorylated BRCA1 is ineffective in ubiquitinating TOP2B, which loosens it from the DNA. We propose that this loosening may contribute to either mobility or removal of TOP2B.

3575 Background: Pts with mCRC frequently receive ≥1 sequential treatment TL. Approximately 50%-60% of pts receive second-line (L2) and 20%-30% third-line (L3) regimens in routine practice. We investigated the pts clinical/tumor characteristics and their prognostic impact across TL. Methods: Data from 37,560 pts enrolled in 48 randomized trials (34 in first (L1), 9 in L2, and 5 in L3) were analyzed. Candidate variables (VAR) measured at enrollment were sex, age, body mass index, performance status (PS), bilirubin, hemoglobin (Hb), platelets (Pl), derived white blood cells-to-absolute neutrophil counts ratio (WBC/ANC), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), primary tumor location, and number and location of metastatic sites (MS). Missing data were imputed. VAR with significant value at all TL were selected to construct a prognostic score of overall survival (OS) in training set (TS, n=30,050; 80%). For each TL, the score was calculated as the sum on the estimations of the VAR’ coefficients from the common multivariate model; Cox’s model was used to define risk groups. The discrimination capability was assessed using the Harrell’s C-index. External validation was done in the validation set (VS, n=7,510; 20%). Results: A total of 26,974 pts in L1, 7,693 pts in L2 and 2,893 pts in L3 were analyzed. The following characteristics increased continuously over TL: ≥2 MS (57%, 72%, 82%), lung metastases (50%, 74%, 91%), lymph nodes metastases (51%, 61%, 80%), KRAS mutation (37%, 47%, 51%) and elevated ALP (46%, 52%, 61%). BRAF mutation decreased (9%, 7%, 5%). In L1 vs L3 trials, 70% vs 89% of patients had primary tumor resection, 10% vs 80% had at least one metastasectomy and 31% vs 78% had a late metachronous (>12 months) metastasis. 7 independent VAR were retained in the prognostic score (PS, Hb, Pl, WBC/ANC, LDH, ALP, and the number of MS); four pt groups with significantly different prognoses were defined (table). This score remained valid when excluding pts with PS 2. Third-line oral drugs (vs placebo) and subsequent line (L2/L1 or L3/L2) were effective in all prognostic groups. Conclusions: Clinical/tumor pt characteristics significantly varied over subsequent TL in patients included in randomized trials. The same prognostic model using practical clinical and biological variables can be used in all TL.[Table: see text]

Purpose To describe double radial tears of the lateral meniscus (LM), report early clinical treatment outcomes, and determine reoperation and failure rates. Methods Twenty‐one (N = 21) consecutive cases of arthroscopic‐treated lateral meniscus double radial tears treated between 2012 and 2018 were reviewed, including 15 males (71.4%) and 6 females (28.6%). Meniscus repairs were all performed at the time of anterior cruciate ligament (ACL) reconstruction. Patients with associated fractures or prior surgeries were excluded. Concomitant injuries were reported, as were preinjury and postoperative Tegner scores, preoperative and postoperative visual analogue pain scale (VAS) scores, and postoperative International Knee Documentation Committee (IKDC) subjective scores. Reoperation and failure rates were documented. Results Twenty‐one (N = 21) tears were located in the posterior horn of the meniscus near the root attachment; 15 (71.4%) underwent all‐inside repair, 4 (19.0%) underwent transtibial pull‐through repair, 1 (4.8%) was partially debrided, and 1 (4.8%) was left untreated. Twenty‐one tears (N = 21) were in the body of the meniscus; 7 (33.3%) were repaired, 7 (33.3%) were partially debrided, and 7 (33.3%) were left untreated. Thirteen patients (62%) had associated medial collateral ligament (MCL) injuries. Mean follow‐up was 2.6 years. VAS at rest and with activity improved by 2.1 points ( P < .001) and 3.1 points ( P = .017) after surgery. The mean postoperative Tegner activity score was 6.4, and the mean IKDC score was 83.2 at final follow‐up. Reoperation was required in 5 patients (23.8%), and the surgical treatment failed in 1 patient (4.7%). Conclusions Double radial tears of the LM are uncommon injuries that occur in the setting of ACL tears, usually combined with MCL injury. The variety of surgical treatment techniques have a low failure rate at short‐term follow‐up. Patients tend to have good clinical outcomes with improvement in pain and overall function after surgically treating these injuries with simultaneous ACL reconstruction. Level of Evidence Level IV, therapeutic study, case series

PURPOSEThe purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery.MATERIALS AND METHODSPatients were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m2for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics.RESULTSOf 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard ( P = .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37; P = .05). There was no significant difference in median overall survival (52.5 v 59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67; P = .31). These analyses were exploratory.CONCLUSIONHIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.

Background: Ten-year all-cause death according to incomplete (IR) versus complete revascularization (CR) has not been fully investigated in patients with 3-vessel disease and left main coronary artery disease undergoing percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). Methods: The SYNTAX Extended Survival study (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]) evaluated vital status up to 10 years in patients who were originally enrolled in the SYNTAX trial. In the present substudy, outcomes of the CABG CR group were compared with the CABG IR, PCI CR, and PCI IR groups. In addition, in the PCI cohort, the residual SYNTAX score (rSS) was used to quantify the extent of IR and to assess its association with fatal late outcome. The rSS of 0 suggests CR, whereas a rSS>0 identifies the degree of IR. Results: IR was more frequently observed in patients with PCI versus CABG (56.6% versus 36.8%) and more common in those with 3-vessel disease than left main coronary artery disease in both the PCI arm (58.5% versus 53.8%) and the CABG arm (42.8% versus 27.5%). Patients undergoing PCI with CR had no significant difference in 10-year all-cause death compared with those undergoing CABG (22.2% for PCI with CR versus 24.3% for CABG with IR versus 23.8% for CABG with CR). In contrast, those with PCI and IR had a significantly higher risk of all-cause death at 10 years compared with CABG and CR (33.5% versus 23.7%; adjusted hazard ratio, 1.48 [95% CI, 1.15–1.91]). When patients with PCI were stratified according to the rSS, those with a rSS≤8 had no significant difference in all-cause death at 10 years as the other terciles (22.2% for rSS=0 versus 23.9% for rSS>0–4 versus 28.9% for rSS>4–8), whereas a rSS>8 had a significantly higher risk of 10-year all-cause death than those undergoing PCI with CR (50.1% versus 22.2%; adjusted hazard ratio, 3.40 [95% CI, 2.13–5.43]). Conclusions: IR is common after PCI, and the degree of incompleteness was associated with 10-year mortality. If it is unlikely that complete (or nearly complete; rSS<8) revascularization can be achieved with PCI in patients with 3-vessel disease, CABG should be considered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00114972. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03417050.

Background: There are no specific treatments for patients with HFpEF and pulmonary hypertension (PH-HFpEF). Increased central and pulmonary venous pressures (CVP, PCWP) are believed to contribute importantly to symptoms at rest and during exercise. Levosimendan (LEVO), a calcium sensitizer/KATP channel activator, is known to reduce CVP and PCWP in patients with reduced LVEF. We hypothesized that LEVO would have similar effects in PH-HFpEF. Methods: 44 PH-HFpEF patients with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II or III symptoms underwent hemodynamic measurements at rest, during passive leg raise (PLR) and during supine bicycle exercise for 3 minutes at 25 Watts (EX) at baseline and following a continuous 24-hour infusion of LEVO (0.1 μg/kg/min) as part of a multicenter clinical trial. Measurements included CVP, mPAP, PCWP, mean arterial pressure (MAP) and cardiac index (CI); pulmonary and systemic vascular resistances (PVR, SVR) were calculated. Hemodynamic tracings were analyzed in a core lab blinded to condition and timepoint. The primary endpoint was the change of PCWP at 25 Watts. Results: Patients averaged 69±9.1 years old, 61.4% were female and had a mPAP of 41.0±9.3 mmHg at rest. LEVO decreased mPAP at rest, CVP and PCWP at rest and EX, and increased CI with EX; there were no significant changes in mPAP, PVR or SVR. Resting and EX hemodynamic data are summarized in the Table. 37 of the 44 patients (84%) were considered hemodynamic “responders” based on a pre-specified ≥4 mmHg decrease of EX PCWP. Conclusions: In patients with PH-HFpEF, a 24 hour levosimendan infusion at 0.1 μg/kg/min decreased CVP and PCWP and increased CI at rest and EX, despite no significant effect on SVR or PVR. A majority of patients exhibited acute hemodynamic response. While the underlying mechanism(s) remain to be clarified, LEVO’s effects on CVP and PCWP warrant further study of this drug as a treatment for PH-HFpEF.

Objective: To compare the validity indices of the King-Devick (KD) test in hockey players using any increase in test time over baseline to a 6-second increase as a positive concussion test. We hypothesized the KD test using the 6-second change would yield greater validity indices. Design: Prospective observational cohort study. Setting: Sports complex. Participants: Sixty-five male hockey players aged 13 to 20 years. Independent Variable: Concussion diagnosis. Main Outcome Measures: Time to complete the KD test. Sensitivity (SN), specificity (SP), and the positive likelihood ratios (LRs+) were calculated using 2 thresholds for a positive test: (1) any increase in time and (2) an increase of 6 seconds or greater. Results: Eighteen players (27.7%) were diagnosed with a concussion. Using any increase in time as a positive test yielded the following: SN 72.2%, SP 78.7%, LR+ 3.4, and LR− 0.4. Using the 6-second threshold yielded the following: SN 44.4%, SP 93.6%, LR+ 7.0, and LR− 0.6. A receiver operator curve analysis confirmed 6.40 seconds or greater maximized the LR+. Conclusions: A 6-second or greater increase in the KD test performance provides greater validity in diagnosing concussion as compared with any increase in performance time.

AbstractObjectivesWe investigated the impact of total stent length (TSL) and average nominal stent diameter (ASD) on 10‐year mortality after percutaneous coronary intervention (PCI) in the SYNTAXES trial.BackgroundTSL and ASD in patients treated with PCI are associated with major adverse cardiovascular events. However, the treatment effect of PCI with extensive and/or small stenting as compared with coronary artery bypass grafting (CABG) for complex coronary artery disease has not been fully evaluated.MethodsImpacts on mortality of extensive stenting defined as TSL >100 mm and small stenting as ASD <3 mm were analyzed in 893 PCI patients and were compared to 865 CABG patients.ResultsTSL as a continuous variable was significantly associated with 10‐year mortality (adjusted hazard ratio [HR], 1.05 [1.01–1.09] per 10 mm increase). PCI patients with extensive stenting had a higher 10 year mortality than CABG patients (adjusted HR, 1.97 [1.41–2.74]) or not‐ extensive stenting PCI (adjusted HR, 1.94 [1.36–2.77]). Although ASD did not have a significant association with 10 year mortality (adjusted HR, 0.97 [0.85–1.11] per 0.25 mm increase), PCI with small stents was associated with a higher 10 year mortality, compared to CABG (adjusted HR, 1.66 [1.23–2.26]) and PCI performed with large stents (adjusted HR, 1.74 [1.19–2.53]). Patients treated with not‐extensive and large stents had similar mortality rates (24.0 versus 23.8%) as those treated with CABG.ConclusionsExtensive and small stenting were associated with higher 10 year mortality, compared with CABG. When patients have to be treated with extensive or small stenting, revascularization with CABG should be preferred.