Citations

AbstractBackgroundSkin cancer prevalence is well‐characterized for white solid organ transplant recipients. Although the prevalence of skin cancer in non‐white (Black, Asian, Hispanic) kidney transplant recipients (KTRs) has been assessed, no study has reported the prevalence of skin cancer in Native American (NA) KTRs. The aim of this study is to determine if the prevalence of skin cancer in NAKTRs is the same as in white KTRs.MethodsWe conducted a case‐controlled retrospective review from a single transplant center. One hundred thirteen NAKTRs who received a transplant between 2001 and 2011 were age‐ and transplant‐year matched with 113 white controls.ResultsThe 226 KTRs consisted of 141 (62.4%) men and 85 (37.6%) women, with a mean age of 50.2 ± 10.8 years. There was no skin cancer found in NAKTRs prior to or post transplantation, while seven (6.2%) white KTRs had eight skin cancers prior to transplantation, and 28 (24.8%) white KTRs developed 66 skin cancers post transplantation. Twenty‐two (19.5%) NAKTRs did not follow‐up with dermatology at this institution. The median follow‐up in NAKTRs was 3.3 years compared to 3.0 years in white KTRs.ConclusionNAKTRs have a decreased prevalence of skin cancer compared to their white counterparts.

AbstractBackgroundPatients at low risk for acute coronary syndrome are frequently admitted for observation and cardiac testing, resulting in substantial burden and cost to the patient and the health care system.ObjectivesThe purpose of this investigation was to measure the effect of the Chest Pain Choice (CPC) decision aid on overall health care utilization as well as utilization of specific services both during the index emergency department (ED) visit and in the subsequent 45 days.MethodsThis was a planned secondary analysis of data from a pragmatic multicenter randomized trial of shared decision making in adults presenting to the ED with chest pain who were being considered for observation unit admission for cardiac stress testing or coronary computed tomography angiography. The trial compared an intervention group engaged in shared decision making facilitated by the CPC decision aid to a control group receiving usual care. Hospital‐level billing data were used to measure utilization for the index ED visit and during the following 45 days. Patients in both groups also were asked to keep a diary recording health care utilization over the same 45‐day period. Outcomes assessed included length of time in the ED and observation, ED visits, office visits, hospitalizations, testing, imaging, and procedures.ResultsOf the 898 patients included in the original trial, we were able to contact 834 (92.9%) patients for 45‐day health care diary review. There was no difference in patient‐reported health care utilization between the study arms. Hospital‐level billing data were obtained for all 898 (100%) patients. During the initial ED visit the length of stay (LOS) was similar, and there was no difference in the frequency of observation unit admission between study arms. However, the mean observation unit LOS was 95 minutes (95% confidence interval [CI] = 40.8–149.8) shorter in the CPC arm and the mean number of tests was lower in the CPC arm (decrease in 19.4 imaging studies per 100 patients, 95% CI = 15.5–23.3). When evaluating the entire encounter and follow‐up period, the intervention arm underwent fewer tests (decrease in 125.6 tests per 100 patients, 95% CI = 29.3–221.6). More specifically, there were fewer advanced cardiac imaging tests completed (25.8 fewer per 100 patients, 95% CI = 3.74–47.9) in the intervention arm.ConclusionsShared decision making in low‐risk chest pain can lead to decreased diagnostic testing without worsening outcomes measured over 45 days.

Objective. To investigate the role of whole blood viscosity in digital ulcer (DU) development in patients with diffuse and limited Systemic sclerosis.Methods. A convenience sample of patients with Systemic sclerosis (SSc) was selected from the adult Rheumatology clinic at the University of Chicago. The study group consisted of patients with SSc (with ulcers present, a history of ulcers, and no ulcers); the control group consisted of matched healthy Rheumatology clinic staff. WBV was measured using a scanning capillary viscometer at different shear rates (1–1000 1/s).Results. Whole blood viscosity as measured by a scanning capillary viscometer was increased in patients with SSc compared to healthy controls (p<0.0001). Additionally, patients with present DU had significantly higher whole blood viscosity when compared to patients with a history of DU and patients with no history of DU (p<0.0001). These findings were most pronounced at lower shear rates between 1 and 10 1/s.Conclusion. Whole blood viscosity might be a contributing factor in DU development in patients with SSc. Further studies with larger patient cohorts are required to fully evaluate how increased WBV contributes to the development of DU and whether the currently available treatment options improve the microcirculation by influencing WBV.

ABSTRACTX‐chromosome inactivation (XCI) epigenetically silences transcription of an X chromosome in females; patterns of XCI are thought to be aberrant in women's cancers, but are understudied due to statistical challenges. We develop a two‐stage statistical framework to assess skewed XCI and evaluate gene‐level patterns of XCI for an individual sample by integration of RNA sequence, copy number alteration, and genotype data. Our method relies on allele‐specific expression (ASE) to directly measure XCI and does not rely on male samples or paired normal tissue for comparison. We model ASE using a two‐component mixture of beta distributions, allowing estimation for a given sample of the degree of skewness (based on a composite likelihood ratio test) and the posterior probability that a given gene escapes XCI (using a Bayesian beta‐binomial mixture model). To illustrate the utility of our approach, we applied these methods to data from tumors of ovarian cancer patients. Among 99 patients, 45 tumors were informative for analysis and showed evidence of XCI skewed toward a particular parental chromosome. For 397 X‐linked genes, we observed tumor XCI patterns largely consistent with previously identified consensus states based on multiple normal tissue types. However, 37 genes differed in XCI state between ovarian tumors and the consensus state; 17 genes aberrantly escaped XCI in ovarian tumors (including many oncogenes), whereas 20 genes were unexpectedly inactivated in ovarian tumors (including many tumor suppressor genes). These results provide evidence of the importance of XCI in ovarian cancer and demonstrate the utility of our two‐stage analysis.

SummaryObjectiveThe multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia.MethodsPatients aged 2 months to 2 years were enrolled prospectively with new‐onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation.ResultsEighty‐two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first‐line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4–4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR3.2, 95%CI1.9–5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR1.09 per month, 95%CI1.03–1.15) and absence of preexisting epilepsy (OR1.7, 95%CI1.06–2.81) had a small impact on the likelihood of responding to the first‐line treatment. However, receiving standard first‐line treatment increased the likelihood of responding dramatically: vigabatrin (OR5.2 ,95%CI2–13.7), prednisolone (OR8, 95%CI3.1–20.6), and adrenocorticotropic hormone (ACTH;OR10.2, 95%CI4.1–25.8) .SignificanceFirst‐line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.

Abstract Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 &gt;10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor–positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.

BackgroundImproving the quality of healthcare is a complex and resource intensive process. To optimize the allocation of scarce resources, quality improvement (QI) should focus on high‐value diseases that will produce the largest improvement in health system performance. Given the breadth and multidisciplinary nature of sinonasal disease management, the purpose of this study was to transparently develop a prioritized list of sinonasal diseases for QI from the perspective of the specialty of rhinology and the American Rhinologic Society (ARS).MethodsThe RAND modified Delphi methodology was used to rank the priority of nine sinonasal disease categories from 1 (lowest priority) to 9 (highest priority). Two rounds of ranking along with a teleconference meeting was performed by a panel of 9 experts from the ARS Quality Improvement Committee.ResultsThe final QI‐prioritized list of sinonasal diseases are as follows: chronic rhinosinusitis (CRS) (mean score = 8.9), recurrent acute rhinosinusitis (RARS) (mean score = 7.9), sinonasal neoplasms (mean score = 7.0), anatomic nasal obstruction (mean score = 5.9), refractory epistaxis (mean score = 5.2), complicated acute rhinosinusitis (mean score = 5.2), chronic nonallergic rhinitis (mean score = 4.4), orbital disease (mean score = 4.3), uncomplicated acute rhinosinusitis (mean score = 4.1), and allergy/allergic rhinitis (mean score = 3.7).ConclusionThe three most important disease categories for QI from the perspective of the specialty of rhinology were CRS, RARS, and sinonasal neoplasms. Future studies need to define and validate quality metrics for each of these important disease categories in order to facilitate appropriate measurement and improvement initiatives.