Citations

Although HER2‐positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2‐positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2‐targeted therapies that penetrate the blood‐brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative‐intent surgery during a time period (1980–1997) when no patient received HER2‐targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow‐up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2‐positive (vs ‐negative) primary tumors showed a higher 5‐year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non‐breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2‐positive EACs have a predilection for CNS metastases.

Abstract Gene expression profiling has identified molecular subtypes that classify invasive breast cancers into distinct categories that vary in their clinical behavior and response to treatment. These subtypes highlight the many possible biologically and clinically distinct types of breast cancer. Immunohistochemical (IHC) staining of tumor sections using antibody panels has been used as a surrogate for the molecular subtypes identified through gene expression profiling, resulting in a set of intrinsic molecular subtypes. Given the heterogeneity within breast cancer, one might expect that different risk factors influence specific subtypes of breast cancer through various etiologic pathways. We evaluated whether percent mammographic density (MD), the proportion of fibroglandular or white tissue on a mammogram and one of the strongest and most consistent risk factors for breast cancer, is associated equally with all intrinsic molecular subtypes. Data were pooled from six cohort or case-control studies including 3389 women with invasive breast cancer and 9860 without, who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms (for cases, at a median 4 years prior to diagnosis) using a computer-assisted threshold technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+. Receptor status was abstracted from clinical pathology records and supplemented by IHC staining of tumor sections or microarrays. With estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) information, we classified tumors into the intrinsic molecular subtypes: Luminal A ( ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (ER-/PR-/HER2-). For cancers found to be triple negative (TN), we also stained for epidermal growth factor receptor (EGFR) and cytokeratins (CK) 5/6 to differentiate basal-like tumors (positive for EGFR and/or CK 5/6) from the unclassifieds (negative on both EGFR and CK 5/6). We used polytomous logistic regression to calculate the odds (OR) of each of the intrinsic subtypes of breast cancer by categories of percent MD, adjusting for age, BMI and study. Contrasts were constructed and tested within the polytomous model framework to investigate differences in the strength of association of percent MD across subtypes. On average, cases were slightly older (56.4 years [SD=11.3]) than controls (55.8 [10.9]). Of the 3389 invasive breast cancer cases, 2146 (63%) were classified as Luminal A, 709 (21%) as Luminal B, 169 (5%) as HER-2 expressing, and 365(11%) as triple negative (TN). Of the TN tumors, 203 had tumor tissue available and were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) as unclassified. Percent (%) MD was associated with breast cancer risk across all intrinsic subtypes. For Luminal A, compared to women with 11-25% MD (reference), women with 0-10% MD had a reduced risk of breast cancer (OR=0.64 [95% confidence interval (CI): 0.55, 0.74]) while women with 26-50% MD had an OR=1.5 (1.3,1.7) and women with 51%+ MD had the highest risk, OR=2.4 (2.0, 2.8). Similar associations were seen for Luminal B, HER2 expressing, and TN across percent MD categories. The small differences among the percent MD-breast cancer associations observed for the different subtypes were not statistically significant, either when comparing the four (Luminal A, Luminal B, HER-2 expressing and TN; p=0.61) or five categories of subtypes (Luminal A, Luminal B, HER-2 expressing, basal-like, unclassified; p=0.66). Our results suggest percent MD is a risk factor for all intrinsic molecular subtypes. Additional study is needed to examine whether these results hold for younger and older aged women. Understanding the importance of mammographic density measures for subtypes of breast cancer has significance for development of subtype-specific risk models. Citation Format: Celine Vachon, Rulla Tamimi, Yunn-Yi Chen, Christopher Scott, Kimberly Bertrand, Matthew Jensen, Daniel Visscher, Aaron Norman, Fergus Couch, John Shepherd, Bo Fan, Fang-Fang Wu, Lin Ma, Andrew Beck, Steve Cummings, V. Shane Pankratz, Karla Kerlikowske. Mammographic density: A risk factor for all breast cancers or only specific subtypes? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA22.

Purpose To examine medical student attitudes toward cost-conscious care and whether regional health care intensity is associated with reported exposure to physician role-modeling behaviors related to cost-conscious care. Method Students at 10 U.S. medical schools were surveyed in 2015. Thirty-five items assessed attitudes toward, perceived barriers to and consequences of, and observed physician role-modeling behaviors related to cost-conscious care (using scales for cost-conscious and potentially wasteful behaviors; Cronbach alphas of 0.82 and 0.81, respectively). Regional health care intensity was measured using Dartmouth Atlas End-of-Life Chronic Illness Care data: ratio of physician visits per decedent compared with the U.S. average, ratio of specialty to primary care physician visits per decedent, and hospital care intensity index. Results Of 5,992 students invited, 3,395 (57%) responded. Ninety percent (2,640/2,932) agreed physicians have a responsibility to contain costs. However, 48% (1,1416/2,960) thought ordering a test is easier than explaining why it is unnecessary, and 58% (1,685/2,928) agreed ordering fewer tests will increase the risk of malpractice litigation. In adjusted linear regression analyses, students in higher-health-care-intensity regions reported observing significantly fewer cost-conscious role-modeling behaviors: For each one-unit increase in the three health care intensity measures, scores on the 21-point cost-conscious role-modeling scale decreased by 4.4 (SE 0.7), 3.2 (0.6), and 3.9 (0.6) points, respectively (all P < .001). Conclusions Medical students endorse barriers to cost-conscious care and encounter conflicting role-modeling behaviors, which are related to regional health care intensity. Enhancing role modeling in the learning environment may help prepare future physicians to address health care costs.

ABSTRACT Injury to the joint provokes a number of local pathophysiological changes, including synthesis of inflammatory cytokines, death of chondrocytes, breakdown of the extra‐cellular matrix of cartilage, and reduced synthesis of matrix macromolecules. These processes combine to engender the subsequent development of post‐traumatic osteoarthritis (PTOA). To prevent this from happening, it is necessary to inhibit these disparate responses to injury; given their heterogeneity, this is challenging. However, dexamethasone has the necessary pleiotropic properties required of a drug for this purpose. Using in vitro models, we have shown that low doses of dexamethasone sustain the synthesis of cartilage proteoglycans while inhibiting their breakdown after injurious compression in the presence or absence of inflammatory cytokines. Under these conditions, dexamethasone is non‐toxic and maintains the viability of chondrocytes exposed chronically to such cytokines as interleukin (IL) ‐1, IL‐6, and tumor necrosis factor‐α. Moreover, the anti‐inflammatory properties of dexamethasone have been appreciated for decades. In view of this information, we have initiated a pilot clinical study to determine whether a single, intra‐articular injection of dexamethasone into the wrist shows promise in preventing PTOA after intra‐articular fracture of the distal radius. CLINICAL SIGNIFICANCE: Suppressing the various etiopathophysiological responses to injury in the joint is an attractive strategy for lowering the clinical burden of PTOA. The intra‐articular administration of dexamethasone soon after injury offers a simple and inexpensive means of accomplishing this. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:406–411, 2017.

Objective. To examine the efficacy of interdisciplinary rehabilitation for improving function in people with chronic pain. Design. Retrospective Chart Review. Setting. The Pain Rehabilitation Center (PRC) at a medical center. Participants. Individuals admitted to the PRC. Interventions. The PRC operates a 3-week outpatient program that utilizes an interdisciplinary approach to treat people with chronic pain. The main treatment elements include physical therapy, occupational therapy, cognitive behavioral therapy (CBT), and medication management. Physical therapy groups focus on moderate exercise despite symptoms. Occupational therapists teach moderation, time management, and activity modification. CBT groups, led by a pain psychologist, address the psychosocial comorbidities of chronic pain. Medical staff oversee the tapering of opiate analgesics and other symptom targeted treatments. This integrated approach is indicated when conventional treatments have been ineffective. Outcome Measures. The objective outcome was the 6-minute walk test (6 mWT) distance. The subjective outcomes were performance (COPM-PER) and satisfaction (COPM-SAT) as measured by the Canadian Occupational Performance Measure (COPM). Results. Average 6 mWT distances improved by 39% from 375 m to 523 m. Average COPM-PER scores increased from 3.4 to 7.5. Average COPM-SAT scores increased from 2.4 to 7.5. Conclusions. Comprehensive interdisciplinary outpatient rehabilitation can significantly improve function in people with chronic pain.

The US Centers for Disease Control and Prevention (CDC) recommend human immunodeficiency virus (HIV) screening for all persons aged 13 to 64 years who present to a health care provider. We sought to improve adherence to the CDC guidelines on the Internal Medicine Resident Hospital Service. We surveyed residents about the CDC guidelines, sent email reminders, provided education, and engaged them in friendly competition. Credit for guideline adherence was awarded if an offer of HIV screening was documented at admission, if a screening test was performed, or if a notation in the resident sign out sheet indicated why screening was not performed. We examined HIV screening of a postintervention group of patients admitted between August 8, 2012, and June 30, 2013, and compared them to a preintervention group admitted between August 1, 2011, and June 30, 2012. Postintervention offers of HIV screening increased significantly (7.9% [44/559] vs 55.5% [300/541]; P<.001), as did documentation of residents' contemplation of screening (8.9% [50/559] vs 67.5% [365/541]; P<.001). A significantly higher proportion of HIV screening tests was ordered postintervention (7.7% [43/559] vs 44.4% [240/541]; P<.001). Monthly HIV screening documentation ranged from 0% (0/53) to 17% (9/53) preintervention, whereas it ranged from 30.6% (11/36) to 100% (62/62) postintervention. HIV screening adherence can be improved through resident education, friendly competition, and system reminders. Barriers to achieving sustained adherence to the CDC guidelines include a heterogeneous patient population and provider discomfort with the subject.

Simple interventions resolve the problem of missed lab appointments. It is essential that patients complete ordered laboratory studies. This maintains clinical quality and, potentially, keeps patients safe from harm. In our academic family medicine practice, baseline data demonstrated patients completed 94.7% of labs as ordered (26850/28348 patients per year) while 1498 (5.3%) did not. Our baseline patient reminder process, a mail or portal based generic letter, resulted in only 449 (30%) of patients ultimately completing them (1049 [70%] did not). Our baseline system was 96.3 % reliable. This process did not allow for provider review or input, and was not personalized for patients. We designed a quality improvement project involving three PDSA (Plan, Do, Study, and Act) cycles of about two months each. Desk staff created weekly reports of unresolved lab orders. A message in the electronic medical record (EMR) solicited provider input. Providers could elect to cancel studies (if already completed, reordered, or no longer clinically indicated) or have the patient receive a personalized reminder, including provider name and associated diagnoses. This reminder was sent by patient portal secure messaging (if an account existed) or with a mailed letter. These interventions resulted in 98.8 % process reliability. The frequency of unresolved lab orders decreased from 70% at baseline to 25%. In the second PDSA cycle, we contacted patients by the portal only if there was evidence of an active account. Otherwise, they were contacted by telephone. Patients without a portal account continued to receive a letter by mail. These modified processes resulted in an overall reliability rate of 99.2%. The frequency of unresolved lab orders decreased to 17%. A final PDSA cycle utilized only telephone contact with patients with unresolved lab orders. Schedulers offered patients a choice of appointment dates if they spoke personally. Otherwise, they were left messages with a future lab appointment date two weeks later.Overall process reliability now increased to 100%. The frequency of unresolved lab orders decreased to 0%. Our interventions resulted in increased system reliability.Provider input was not perceived as burdensome. Desk staff work effort was not increased.Telephone patient contact resulted in more frequent lab order completion than other methods.

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34 + stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI ( N = 167), patients treated with autologous CD34 + stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 10 5 CD34/kg body weight), and high dose (5 × 10 5 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA ® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III–IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency ( p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time ( p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34 + cells had significant reduction in angina frequency ( p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose ( p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively ( p = 0.08). Autologous CD34 + cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.