Harmsen, William S.

AbstractBackground/AimsHypothyroidism has been associated with hepatocellular carcinoma (HCC) incidence; however, the relationship between hypothyroidism and HCC patient outcomes is unclear. We investigated the impact of hypothyroidism on outcomes after liver transplantation for HCC.Materials and MethodsWe retrospectively studied HCC patients transplanted between January 2000 and December 2015. Hypothyroidism was defined as a thyroid‐stimulating hormone (TSH) level continuously greater than 5 mIU/L, a documented history of hypothyroidism, or treatment with thyroid hormone replacement therapy. Multivariate Cox regression was used to assess the impact of hypothyroidism on overall survival (OS) and recurrence‐free survival (RFS) adjusting for potential confounders. Subgroup analyses and interaction tests were conducted to compare the impact of hypothyroidism in different subgroups and assess for possible synergistic effects. Sensitivity analyses were performed among different cohorts to verify the stability of the results.ResultsA total of 343 HCC patients who underwent liver transplantation were included in the analysis. The primary analysis was conducted among 288 patients diagnosed with HCC prior to transplantation. Hypothyroidism was independently associated with worse OS and RFS, as was elevated TSH. The adjusted hazard ratio (AHR) of hypothyroidism was 2.45 (95% confidence interval [CI], 1.44‐4.18) for OS and 5.54 (2.36, 13.01) for RFS. The AHR of TSH for OS was 1.05 (1.02, 1.09) and 1.08 (1.03, 1.13) for RFS. No interaction was found among different subgroups categorized by etiology and comorbidity. The results were stable to sensitivity analyses.ConclusionHypothyroidism is associated with poorer overall and recurrence‐free survival of HCC patients receiving liver transplantation. These results require validation.

Background: Increasing body mass index (BMI) has been shown to correlate with increased rates of complications after total knee arthroplasty. To our knowledge, body surface area, body mass, and height have not been investigated in this manner. BMI and body surface area are affected differently by changes in height, and they are affected similarly by changes in weight. The purpose of this study was to quantify revision for any reason, mechanical failure, aseptic loosening, polyethylene wear, reoperation, and any infection after total knee arthroplasty using BMI, body surface area, body mass, and height as continuous variables. Methods: Prospectively collected data from a single institution’s total joint registry were used to analyze 22,243 consecutive knees, in 16,106 patients, treated with a primary total knee arthroplasty from 1985 to 2012. The Kaplan-Meier survival method was used to evaluate revision and other common complications, with outcomes assessed using Cox regression analysis. Smoothing spline parameterization was used on physical parameters in these models. Results: Increasing BMI, body surface area, body mass, and height were associated with an increased risk of any revision surgical procedure, mechanical failure, and aseptic loosening after total knee arthroplasty. The risk of a revision surgical procedure was directly associated with each 1 standard deviation increase in BMI (hazard ratio [HR], 1.19; p < 0.01), body surface area (HR, 1.37; p < 0.01), body mass (HR, 1.30; p < 0.01), and height (HR, 1.22; p < 0.01). This association was especially demonstrated with revision for mechanical failure (BMI: HR, 1.15; p < 0.01; body surface area: HR, 1.35; p < 0.01; body mass: HR, 1.27; p < 0.01; and height: HR, 1.23; p < 0.01). The risk of failure in the subgroups of mechanical failure including a revision surgical procedure for aseptic loosening or polyethylene wear was also associated with increasing body surface area, body mass, and height. Increasing BMI (HR, 1.22; p < 0.01), body surface area (HR, 2.56; p < 0.01), and body mass (HR, 2.54; p < 0.01) were also associated with increased risk of any infection. Conclusions: Increasing BMI, body surface area, body mass, and height were strongly associated with the rates of revision, aseptic loosening, and other common complications following total knee arthroplasty. Body surface area and body mass appear to correlate more strongly with mechanical failure outcomes than BMI or height. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Background Aortic syndromes (ASs), including aortic dissection, intramural hematoma, and penetrating aortic ulcer, carry significant acute and long-term morbidity and mortality. However, the contemporary incidence and outcomes of AS are unknown. Methods and Results We used the Rochester Epidemiology Project record linkage system to identify all Olmsted County, MN, residents with AS (1995–2015). Diagnostic imaging, medical records, and death certificates were reviewed to confirm the diagnosis and AS subtype. Age- and sex-adjusted incidence rates were estimated using annual county-level census data. Survival for patients with AS was compared with age- and sex-matched controls using Cox regression to adjust for comorbid conditions. We identified 133 patients with AS (77, aortic dissection; 21, intramural hematoma; and 35, penetrating aortic ulcer). Average age was 71.8 years (SD=14.1), and 57% were men. The age- and sex-adjusted incidence was 7.7 per 100 000 person-years, was higher for men than women (10.2 versus 5.7 per 100 000 person-years), and increased with age. Among subtypes, the incidence of aortic dissection was highest (4.4 per 100 000 person-years), whereas the incidence of penetrating aortic ulcer and intramural hematoma was lower (2.1 and 1.2 per 100 000 person-years). Overall, the incidence of AS was stable over time ( P trend=0.33), although the incidence of penetrating aortic ulcer seemed to increase from 0.6 to 2.6 per 100 000 person-years ( P =0.008) with variability over the study interval. Patients with AS had more than twice the mortality rate at 5, 10, and 20 years when compared with population-based controls (5-, 10-, and 20-year mortality 39%, 57%, and 91% versus 18%, 41%, and 66%; overall adjusted mortality hazards ratio=2.1; P <0.001). Survival was lower than expected up to 90 days after AS diagnosis and did not differ significantly by subtype or by 5-year strata of diagnosis. Conclusions Overall, the incidence of aortic dissection and intramural hematoma has remained stable since 1995, despite the decline noted for other cardiovascular disease. AS confers increased early and long-term mortality that has not changed. These data highlight the need to improve long-term care to impact the prognosis of this patient group.

Abstract Triple-negative breast cancer (TNBC) is characterized by elevated locoregional recurrence risk despite aggressive local therapies. New tumor-specific radiosensitizers are needed. We hypothesized that the ATR inhibitor, VX-970 (now known as M6620), would preferentially radiosensitize TNBC. Noncancerous breast epithelial and TNBC cell lines were investigated in clonogenic survival, cell cycle, and DNA damage signaling and repair assays. In addition, patient-derived xenograft (PDX) models generated prospectively as part of a neoadjuvant chemotherapy study from either baseline tumor biopsies or surgical specimens with chemoresistant residual disease were assessed for sensitivity to fractionated radiotherapy, VX-970, or the combination. To explore potential response biomarkers, exome sequencing was assessed for germline and/or somatic alterations in homologous recombination (HR) genes and other alterations associated with ATR inhibitor sensitivity. VX-970 preferentially inhibited ATR-Chk1-CDC25a signaling, abrogated the radiotherapy-induced G2–M checkpoint, delayed resolution of DNA double-strand breaks, and reduced colony formation after radiotherapy in TNBC cells relative to normal-like breast epithelial cells. In vivo, VX-970 did not exhibit significant single-agent activity at the dose administered even in the context of genomic alterations predictive of ATR inhibitor responsiveness, but significantly sensitized TNBC PDXs to radiotherapy. Exome sequencing and functional testing demonstrated that combination therapy was effective in both HR-proficient and -deficient models. PDXs established from patients with chemoresistant TNBC were also highly radiosensitized. In conclusion, VX-970 is a tumor-specific radiosensitizer for TNBC. Patients with residual TNBC after neoadjuvant chemotherapy, a subset at particularly high risk of relapse, may be ideally suited for this treatment intensification strategy. Mol Cancer Ther; 17(11); 2462–72. ©2018 AACR.

Background and ObjectivesTo describe the patterns of failure in patients with in‐transit (IT) melanoma undergoing surgical excision.MethodsA retrospective review of patients who underwent their first IT lesion(s) resection between May 2005 and September 2014. Cumulative incidence of local failure (new lesion within 2 cm of IT resection) was estimated. Associations between clinicopathologic characteristics, local failure, and any recurrence were analyzed.ResultsOne hundred and thirty patients presented to our institution with IT disease over the study period and met the inclusion criteria. The 2‐year cumulative incidence of local failure was 19.5%. Twenty‐four patients developed disease within 2 cm of the resected IT disease; however, only eight were isolated local events. Cumulative incidence of local failure and of any disease differed with respect to less than 1 year disease‐free interval (DFI) from primary melanoma to first IT event, and having greater than 1 IT lesion at presentation. Incidence of local failure was not found to differ with respect to gross margin greater than 5 mm, after adjusting for DFI and greater than 1 IT lesions.ConclusionsPatients with greater than 1 IT lesion and a DFI less than 1 year are at a higher risk of failure after surgical excision of a first IT event. Very few failures were isolated local disease within 2 cm of the IT resection scar, regardless of IT excision margin.

Objective: Determine the safety of overlapping surgery in a tertiary care colorectal surgery practice. Summary: Although overlapping surgery is common in academic centers, reports on outcomes of this practice are limited. The primary aim of this study was to investigate the safety of overlapping surgery in a dedicated tertiary care academic colorectal practice by comparing groups of patients who did or did not have their surgery performed in an overlapping fashion. Methods: Retrospective review of 1270 colorectal patients undergoing inpatient colorectal surgery at our institution. Eligible participants were all patients undergoing elective inpatient colorectal surgery by one of the colorectal surgeons at the Mayo Clinic Rochester between January 1, 2012 and December 31, 2015. Patients under the age of 18 or who underwent an emergent procedure were excluded. Data were abstracted using the American College of Surgeons National Quality Improvement Program (ACS-NSQIP) database. Additionally, each subject's chart was reviewed and further abstracted. The safety of overlapping surgery on outcomes was assessed using multiple multivariable models. Results: One thousand two hundred seventy patients were included in the study cohort of whom 50.7% were female and the average age was 55.4 years. Overlapping surgery occurred in 576 patients (45%). There were no significant differences in demographic, surgical indications, procedures, or operative complexity between patients undergoing overlapping surgery and those who did not. Overall adverse events were significantly less likely in patients undergoing overlapping surgery compared with those who did not (18.4% vs 23.6%, P = 0.02). We found that overlapping surgery was associated with significantly less adverse events compared with patients not undergoing overlapping surgery using a model that controlled for the effect of the individual surgeon (OR 0.7, 95% CI 0.6 – 0.96; P = .02) and a multivariable propensity score (OR 0.7, 95% CI 0.5– 0.9; P = 01). Conclusions: Overlapping surgery in a tertiary care colorectal practice is safe and not associated with adverse patient outcomes.

Background: Deficient soft tissue following total knee arthroplasty (TKA) can jeopardize outcome. The gastrocnemius flap is an important means of providing coverage of a knee with deficient soft tissue. There is a paucity of long-term studies on the use of the gastrocnemius flap in the setting of TKA. The purpose of this study was to review the outcomes after the use of pedicled gastrocnemius flaps for coverage of a soft-tissue defect at the time of TKA. Methods: Eighty-three patients in whom a gastrocnemius flap had been used to cover the site of a primary (n = 18) or revision (n = 65) TKA over a 25-year period were identified. There were 48 women (58%) and 35 men (42%) with a mean age and body mass index (BMI) of 65 years and 32.6 kg/m 2 . The mean wound size was 49 cm 2 , and the wound was most commonly located over the anterior aspect of the knee/patellar tendon (n = 33). Patients were followed to the time of implant or flap revision, amputation, or death or for a minimum of 2 years (mean, 8 years). Clinical outcomes were assessed using the Knee Society Score (KSS) for pain and the KSS for function. The Kaplan-Meier method was used to assess revision and amputation-free survival. Risk factors for amputation and revision were identified with Cox regression. Results: The 10-year revision and amputation-free survival rates following gastrocnemius flap coverage were 68% and 79%, respectively. The risk of implant failure was increased by morbid obesity (BMI of ≥40 kg/m 2 ) (hazard ratio [HR] = 2.82, 95% confidence interval [CI] = 1.09 to 7.32, p = 0.03) and ≥5 prior surgical procedures on the knee (HR = 2.68, 95% CI = 1.04 to 6.88, p = 0.04). The risk of amputation was increased in patients with ≥5 prior surgical procedures (HR = 10.76, 95% CI = 2.38 to 48.58, p = 0.002), an age of ≥65 years (HR = 4.94, 95% CI = 1.10 to 22.09, p = 0.03), and a wound size of ≥50 cm 2 (HR = 3.29, 95% CI = 1.14 to 9.53, p = 0.02). Preoperatively the mean KSSs for pain and function were 46 and 28, and these scores significantly (p < 0.05) improved to 78 and 43, respectively, at the time of follow-up. Conclusions: The gastrocnemius flap reliably provides coverage of components used in complex knee reconstruction. A history of multiple surgical procedures on the knee and larger soft-tissue defects increase the risk of revision TKA and of amputation. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.