Sutter Medical Center

Abstract BACKGROUND. Tumor markers are becoming increasingly important in breast cancer research because of their impact on prognosis, treatment, and survival, and because of their relation to breast cancer subtypes. The triple‐negative phenotype is important because of its relation to the basal‐like subtype of breast cancer. METHODS. Using the population‐based California Cancer Registry data, we identified women diagnosed with triple‐negative breast cancer between 1999 and 2003. We examined differences between triple‐negative breast cancers compared with other breast cancers in relation to age, race/ethnicity, socioeconomic status (SES), stage at diagnosis, tumor grade, and relative survival. RESULTS. A total of 6370 women were identified as having triple‐negative breast cancer and were compared with the 44,704 women with other breast cancers. Women with triple‐negative breast cancers were significantly more likely to be under age 40 (odds ratio [OR], 1.53), and non‐Hispanic black (OR, 1.77) or Hispanic (OR, 1.23). Regardless of stage at diagnosis, women with triple‐negative breast cancers had poorer survival than those with other breast cancers, and non‐Hispanic black women with late‐stage triple‐negative cancer had the poorest survival, with a 5‐year relative survival of only 14%. CONCLUSIONS. Triple‐negative breast cancers affect younger, non‐Hispanic black and Hispanic women in areas of low SES. The tumors were diagnosed at later stage and were more aggressive, and these women had poorer survival regardless of stage. In addition, non‐Hispanic black women with late‐stage triple‐negative breast cancer had the poorest survival of any comparable group. Cancer 2007. © 2007 American Cancer Society.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term follow-up results. MATERIALS AND METHODS: Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF). RESULTS: Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. CONCLUSION: The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.

As the novel coronavirus disease (COVID-19) pandemic spreads throughout the United States, evidence is mounting that racial and ethnic minorities and socioeconomically disadvantaged groups are bearing a disproportionate burden of illness and death. We conducted a retrospective cohort analysis of COVID-19 patients at Sutter Health, a large integrated health system in northern California, to measure potential disparities. We used Sutter's integrated electronic health record to identify adults with suspected and confirmed COVID-19, and we used multivariable logistic regression to assess risk of hospitalization, adjusting for known risk factors, such as race/ethnicity, sex, age, health, and socioeconomic variables. We analyzed 1,052 confirmed cases of COVID-19 from the period January 1-April 8, 2020. Among our findings, we observed that compared with non-Hispanic white patients, non-Hispanic African American patients had 2.7 times the odds of hospitalization, after adjustment for age, sex, comorbidities, and income. We explore possible explanations for this, including societal factors that either result in barriers to timely access to care or create circumstances in which patients view delaying care as the most sensible option. Our study provides real-world evidence of racial and ethnic disparities in the presentation of COVID-19.

PURPOSE: Patients with centrally located early-stage non-small-cell lung cancer (NSCLC) are at a higher risk of toxicity from high-dose ablative radiotherapy. NRG Oncology/RTOG 0813 was a phase I/II study designed to determine the maximum tolerated dose (MTD), efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for centrally located NSCLC. MATERIALS AND METHODS: Medically inoperable patients with biopsy-proven, positron emission tomography-staged T1 to 2 (≤ 5 cm) N0M0 centrally located NSCLC were accrued into a dose-escalating, five-fraction SBRT schedule that ranged from 10 to 12 Gy/fraction (fx) delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any treatment-related grade 3 or worse predefined toxicity that occurred within the first year. MTD was defined as the SBRT dose at which the probability of DLT was closest to 20% without exceeding it. RESULTS: One hundred twenty patients were accrued between February 2009 and September 2013. Patients were elderly, there were slightly more females, and the majority had a performance status of 0 to 1. Most cancers were T1 (65%) and squamous cell (45%). Organs closest to planning target volume/most at risk were the main bronchus and large vessels. Median follow-up was 37.9 months. Five patients experienced DLTs; MTD was 12.0 Gy/fx, which had a probability of a DLT of 7.2% (95% CI, 2.8% to 14.5%). Two-year rates for the 71 evaluable patients in the 11.5 and 12.0 Gy/fx cohorts were local control, 89.4% (90% CI, 81.6% to 97.4%) and 87.9% (90% CI, 78.8% to 97.0%); overall survival, 67.9% (95% CI, 50.4% to 80.3%) and 72.7% (95% CI, 54.1% to 84.8%); and progression-free survival, 52.2% (95% CI, 35.3% to 66.6%) and 54.5% (95% CI, 36.3% to 69.6%), respectively. CONCLUSION: The MTD for this study was 12.0 Gy/fx; it was associated with 7.2% DLTs and high rates of tumor control. Outcomes in this medically inoperable group of mostly elderly patients with comorbidities were comparable with that of patients with peripheral early-stage tumors.

BACKGROUND: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS: Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS: Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

An estimated 30 million passengers are transported on 272 cruise ships worldwide each year* (1). Cruise ships bring diverse populations into proximity for many days, facilitating transmission of respiratory illness (2). SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) was first identified in Wuhan, China, in December 2019 and has since spread worldwide to at least 187 countries and territories. Widespread COVID-19 transmission on cruise ships has been reported as well (3). Passengers on certain cruise ship voyages might be aged ≥65 years, which places them at greater risk for severe consequences of SARS-CoV-2 infection (4). During February-March 2020, COVID-19 outbreaks associated with three cruise ship voyages have caused more than 800 laboratory-confirmed cases among passengers and crew, including 10 deaths. Transmission occurred across multiple voyages of several ships. This report describes public health responses to COVID-19 outbreaks on these ships. COVID-19 on cruise ships poses a risk for rapid spread of disease, causing outbreaks in a vulnerable population, and aggressive efforts are required to contain spread. All persons should defer all cruise travel worldwide during the COVID-19 pandemic.

Hypertriglyceridemia (HTG) is reported to cause 1-4% of acute pancreatitis (AP) episodes. HTG is also implicated in more than half of gestational pancreatitis cases. Disorders of lipoprotein metabolism are conventionally divided into primary (genetic) and secondary causes, including diabetes, hypothyroidism, and obesity. Serum triglyceride (TG) levels above 1,000 mg/dl are usually considered necessary to ascribe causation for AP. The mechanism for hypertriglyceridemic pancreatitis (HTGP) is postulated to involve hydrolysis of TG by pancreatic lipase and release of free fatty acids that induce free radical damage. Multiple small studies on HTGP management have evaluated the use of insulin, heparin, or both. Many series have also reported use of apheresis to reduce TG levels. Subsequent control of HTG with dietary restrictions, antihyperlipidemic agents, and even regular apheresis has been shown anecdotally in case series to prevent future episodes of AP. However, large multicenter studies are needed to optimize future management guidelines for patients with HTGP.

Prospective data was recorded on 217 percutaneous transluminal angioplasty (PTA) procedures performed in the superficial femoral and popliteal arteries over an 8-year period. After the initial procedure, patients were followed with serial noninvasive studies and, in 71 patients, repeat angiography. The mean follow-up period was 7 years (range, 2-11 years). Standard life-table survival analysis was used to assess the factors potentially affecting long-term outcome. Excluding an initial technical failure rate of 10%, overall patencies at 1, 3, and 5 years were 81%, 61%, and 58%, respectively. After the first year, the prognosis (i.e., failure rate) appears to be linear over the long term (i.e., up to 10 years). Factors negatively influencing long-term patency include the presence of diabetes mellitus, diffuse atherosclerotic cardiovascular disease, or threatened limb loss. Technical factors correlated with failure include lesion length, moderate eccentricity, and a poor post-PTA appearance.

BACKGROUND: Neutropenia is a common side effect of chemotherapy, often requiring hospitalization for treatment of severe cases. Neutropenia hospitalization (NH) rates have been reported in individual studies, but national estimates are needed. METHODS: Chemotherapy-induced NHs were identified in the 1999 hospital discharge data bases from 7 states. Cancer and chemotherapy prevalence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program and the National Cancer Data Base were used to calculate national NH rates for 13 cancer types. NH cost was estimated by multiplying charges by institution-specific, cost-to-charge ratios from the 1999 Centers for Medicare and Medicaid Services Hospital Cost Report. NH incidence was projected to national levels using population data from the United States Census and the Centers for Disease Control and Prevention. RESULTS: There were 20,780 discharges with documentation of cancer, chemotherapy, and neutropenia identified. Projecting to national levels, NH incidence was estimated at 60,294 cases (7.83 cases per 1000 cancer patients). The mean NH cost was 13,372 dollars. The mortality rate among patients with NH was estimated at 6.8% or 1 death for every 14 hospitalized patients. Among 13 selected cancer types, the NH rate was 34.20 cases per 1000 patients receiving chemotherapy (1 in 29 patients). NH was particularly common in patients with hematologic tumors, with an incidence of 43.3 cases per 1000 patients with such tumors (1 in 23 patients). The average NH cost for hematologic malignancies was 20,400 dollars, more than double the cost of NH for solid tumors. CONCLUSIONS: According to the current study, NH affects > 60,000 patients with cancer each year in the United States, with an average cost of 13,372 dollars per hospitalization and an associated inpatient mortality rate of 6.8%.

BACKGROUND: Chronic illnesses are significant to individuals and costly to society. When systematically implemented, the well-established and tested Chronic Care Model (CCM) is shown to improve health outcomes for people with chronic conditions. Since the development of the original CCM, tremendous information management, communication, and technology advancements have been established. An opportunity exists to improve the time-honored CCM with clinically efficacious eHealth tools. OBJECTIVE: The first goal of this paper was to review research on eHealth tools that support self-management of chronic disease using the CCM. The second goal was to present a revised model, the eHealth Enhanced Chronic Care Model (eCCM), to show how eHealth tools can be used to increase efficiency of how patients manage their own chronic illnesses. METHODS: Using Theory Derivation processes, we identified a "parent theory", the Chronic Care Model, and conducted a thorough review of the literature using CINAHL, Medline, OVID, EMBASE PsychINFO, Science Direct, as well as government reports, industry reports, legislation using search terms "CCM or Chronic Care Model" AND "eHealth" or the specific identified components of eHealth. Additionally, "Chronic Illness Self-management support" AND "Technology" AND several identified eHealth tools were also used as search terms. We then used a review of the literature and specific components of the CCM to create the eCCM. RESULTS: We identified 260 papers at the intersection of technology, chronic disease self-management support, the CCM, and eHealth and organized a high-quality subset (n=95) using the components of CCM, self-management support, delivery system design, clinical decision support, and clinical information systems. In general, results showed that eHealth tools make important contributions to chronic care and the CCM but that the model requires modification in several key areas. Specifically, (1) eHealth education is critical for self-care, (2) eHealth support needs to be placed within the context of community and enhanced with the benefits of the eCommunity or virtual communities, and (3) a complete feedback loop is needed to assure productive technology-based interactions between the patient and provider. CONCLUSIONS: The revised model, eCCM, offers insight into the role of eHealth tools in self-management support for people with chronic conditions. Additional research and testing of the eCCM are the logical next steps.

PREFACE: The leadership of Women in Neurosurgery (WINS) has been asked by the Board of Directors of the American Association of Neurological Surgeons (AANS) to compose a white paper on the recruitment and retention of female neurosurgical residents and practitioners. INTRODUCTION: Neurosurgery must attract the best and the brightest. Women now constitute a larger percentage of medical school classes than men, representing approximately 60% of each graduating medical school class. Neurosurgery is facing a potential crisis in the US workforce pipeline, with the number of neurosurgeons in the US (per capita) decreasing. WOMEN IN THE NEUROSURGERY WORKFORCE: The number of women entering neurosurgery training programs and the number of board-certified female neurosurgeons is not increasing. Personal anecdotes demonstrating gender inequity abound among female neurosurgeons at every level of training and career development. Gender inequity exists in neurosurgery training programs, in the neurosurgery workplace, and within organized neurosurgery. OBSTACLES: The consistently low numbers of women in neurosurgery training programs and in the workplace results in a dearth of female role models for the mentoring of residents and junior faculty/practitioners. This lack of guidance contributes to perpetuation of barriers to women considering careers in neurosurgery, and to the lack of professional advancement experienced by women already in the field. There is ample evidence that mentors and role models play a critical role in the training and retention of women faculty within academic medicine. The absence of a critical mass of female neurosurgeons in academic medicine may serve as a deterrent to female medical students deciding whether or not to pursue careers in neurosurgery. There is limited exposure to neurosurgery during medical school. Medical students have concerns regarding gender inequities (acceptance into residency, salaries, promotion, and achieving leadership positions). Gender inequity in academic medicine is not unique to neurosurgery; nonetheless, promotion to full professor, to neurosurgery department chair, or to a national leadership position is exceedingly rare within neurosurgery. Bright, competent, committed female neurosurgeons exist in the workforce, yet they are not being promoted in numbers comparable to their male counterparts. No female neurosurgeon has ever been president of the AANS, Congress of Neurological Surgeons, or Society of Neurological Surgeons (SNS), or chair of the American Board of Neurological Surgery (ABNS). No female neurosurgeon has even been on the ABNS or the Neurological Surgery Residency Review Committee and, until this year, no more than 2 women have simultaneously been members of the SNS. Gender inequity serves as a barrier to the advancement of women within both academic and community-based neurosurgery. STRATEGIC APPROACH TO ADDRESS ISSUES IDENTIFIED: To overcome the issues identified above, the authors recommend that the AANS join WINS in implementing a strategic plan, as follows: 1) Characterize the barriers. 2) Identify and eliminate discriminatory practices in the recruitment of medical students, in the training of residents, and in the hiring and advancement of neurosurgeons. 3) Promote women into leadership positions within organized neurosurgery. 4) Foster the development of female neurosurgeon role models by the training and promotion of competent, enthusiastic, female trainees and surgeons.

Caspase-8 is a member of the cysteine proteases, which are implicated in apoptosis and cytokine processing. Like all caspases, caspase-8 is synthesized as an inactive single polypeptide chain zymogen procaspase and is activated by proteolytic cleavage, through either autoactivation after recruitment into a multimeric complex or trans-cleavage by other caspases. Thus, ligand binding-induced trimerization of death receptors results in recruitment of the receptor-specific adapter protein Fas-associated death domain (FADD), which then recruits caspase-8. Activated caspase-8 is known to propagate the apoptotic signal either by directly cleaving and activating downstream caspases or by cleaving the BH3 Bcl2-interacting protein, which leads to the release of cytochrome c from mitochondria, triggering activation of caspase-9 in a complex with dATP and Apaf-1. Activated caspase-9 then activates further "downstream caspases," including caspase-8. Knockout data indicate that caspase-8 is required for killing induced by the death receptors Fas, tumor necrosis factor receptor 1, and death receptor 3. Moreover, caspase-8-/- mice die in utero as a result of defective development of heart muscle and display fewer hematopoietic progenitor cells, suggesting that the FADD/caspase-8 pathway is absolutely required for growth and development of specific cell types.

BACKGROUND: Breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) (triple negative [TN]) have been associated with high-grade histology, aggressive clinical behavior, and poor survival. It has been determined that breast cancers that are negative for ER and PR but positive for HER2 (double negative [DN]) share features with TN breast cancers. In this report, the authors quantified the contribution of HER2 as well as demographic and tumor characteristics to the survival of women with TN tumors, DN tumors, and other breast cancers (OBC). METHODS: In total, 61,309 women who were diagnosed with invasive breast cancer between 1999-2004 were identified in the California Cancer Registry. Demographic and tumor characteristics of women with TN tumors were compared with those from women with DN tumors and women with OBC. A compound proportional hazards regression analysis (PHPH) (a generalization of the Cox proportional hazards model) was used to model these characteristics. RESULTS: Women with TN tumors were younger, African American, Hispanic, and of lower socioeconomic status (SES), whereas women with DN tumors were slightly older; African American, and Asian/Pacific Islander. Women with TN and DN tumors presented with larger, higher grade, and higher stage than women with OBC. Survival among women with TN tumors was poorer compared with that among women with OBC but was nearly the same as that of women with DN tumors. Results of the regression analysis indicated that disease stage, tumor grade, SES, and race/ethnicity were significant risk factors for survival. Negative ER and PR status was associated with an increased risk of death. There was a small but significant difference in both long-term and short-term survival patients who had TN tumors compared with patients who had DN tumors. CONCLUSIONS: Patients with TN tumors shared many clinical, demographic, and tumor features and had survival that was very similar survival to that of patients with DN tumors, and survival for both groups contrasted greatly with survival for patients with OBC. Disease stage, tumor grade, SES, race/ethnicity, negative ER and PR status, rather than negative HER2 status, were risk factors for survival.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with comorbidities that contribute to poor health, impaired life quality, and mortality risk. OBJECTIVE: To provide evidence-based screening recommendations for comorbidities linked to HS. METHODS: Systematic reviews were performed to summarize evidence on the prevalence and incidence of 30 comorbidities in patients with HS relative to the general population. The screening recommendation for each comorbidity was informed by the consistency and quality of existing studies, disease prevalence, and magnitude of association, as well as benefits, harms, and feasibility of screening. The level of evidence and strength of corresponding screening recommendation were graded by using the Strength of Recommendation Taxonomy (SORT) criteria. RESULTS: Screening is recommended for the following comorbidities: acne, dissecting cellulitis of the scalp, pilonidal disease, pyoderma gangrenosum, depression, generalized anxiety disorder, suicide, smoking, substance use disorder, polycystic ovary syndrome, obesity, dyslipidemia, diabetes mellitus, metabolic syndrome, hypertension, cardiovascular disease, inflammatory bowel disease, spondyloarthritis, and sexual dysfunction. It is also recommended to screen patients with Down syndrome for HS. The decision to screen for specific comorbidities may vary with patient risk factors. The role of the dermatologist in screening varies according to comorbidity. LIMITATIONS: Screening recommendations represent one component of a comprehensive care strategy. CONCLUSIONS: Dermatologists should support screening efforts to identify comorbid conditions in HS.

BACKGROUND: Pivotal study data examining carotid stenting with embolic protection as a less invasive alternative to endarterectomy for high surgical risk patients have been acquired under controlled conditions with highly selected physicians and hospitals. This report examines outcomes of carotid stenting post-approval after diffusion of this technology to a broader cross-section of physicians and hospitals. METHODS: The Carotid Acculink/Accunet Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE) is a prospective, multi-center registry to assess two important aspects of the post-IDE experience: the safety of carotid stenting by physicians with varying levels of experience as a measure of the adequacy of physician training, and the identification of rare/unexpected device-related complications. The primary endpoint was a composite of death, any stroke, or myocardial infarction within 30 days post-procedure. RESULTS: 3,500 patients were enrolled by 353 physicians at 144 sites. The 30-day primary endpoint event rate was 6.3% (95% CI: 5.5-7.1%) and did not differ among the three operator experience levels (5.3%, 6.0%, and 7.4%; P = 0.31) from most to least experienced, respectively. There were no differences in outcomes among physician specialties when adjusted for case mix. There were no unanticipated device related adverse events. CONCLUSIONS: The results of the CAPTURE study compare favorably to those achieved in the predicate pivotal investigations, and suggest that the post-approval transfer of this new therapy to the community practice setting via carotid stent training programs is effective in preparing physicians with varying experience levels and specialty training backgrounds.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

Several types of glioneuronal tumors are known to induce intractable partial seizures in children and adults. The most frequent are dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas. We report here a new clinicopathological entity within the spectrum of glioneuronal tumors observed in 10 children who underwent surgery for refractory epilepsy. These tumors demonstrate a unique, pathognomonic histological pattern and a specific appearance at magnetic resonance imaging (MRI). The most striking neuropathological feature is an angiocentric polarity of the tumor with gliofibrillary acidic protein (GFAP) positive fusiform and bipolar astrocytic cells arranged around blood vessels (perivascular cuffing with tumoral astrocytes). Characteristic MRI findings include involvement of cortical gray and white matter, intrinsically high signal on T1-weighted images, as well as a stalk like extension to the ventricle. Immunohistochemical neuronal markers (neurofilament protein, synaptophysin and chromogranin) confirm the presence of a neuronal cell component. Therefore, the term angiocentric neuroepithelial tumor (ANET) is proposed.

Background: Patent foramen ovale (PFO) is a vestigial congenital cardiovascular structure present in around 25% of adults. In most cases, PFO is entirely benign and requires no treatment. However, it may cause serious complications under certain circumstances. Objective: These evidence-based guidelines from the Society for Cardiovascular Angiography and Interventions (SCAI) aim to support patients, clinicians, and other stakeholders in decisions about management of PFO. Methods: SCAI convened a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The Evidence Foundation, a registered 501(c)(3) nonprofit organization, provided methodological support for the guideline-development process. Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the guideline panel formulated and prioritized clinical questions in population, intervention, comparison, outcome (PICO) format. A separate technical review team of clinical and methodological experts conducted systematic reviews of the evidence, synthesized data, and graded the certainty of the evidence across outcomes. The guideline panel then reconvened to formulate recommendations and supporting remarks informed by the results of the technical review and additional contextual factors described in the GRADE evidence-to-decision framework. Results: The panel agreed on 13 recommendations to address variations on 5 clinical scenarios. Conclusions: Key recommendations address patient selection for PFO closure in the prevention of recurrent PFO-associated stroke, including populations not commonly included in randomized studies, and scenarios where the PFO closure might serve a role in the prevention of other outcomes such as migraine headaches and decompression illness. The panel has also identified future research priorities to advance the field.

OBJECTIVE: To compare stage distribution, tumor characteristics, and survival outcome in pregnancy-associated and non-pregnancy-associated breast cancer, and to evaluate pregnancy as a risk factor for mortality in breast cancer. METHODS: The California Cancer Registry (1991-1999) was linked with the California Patient Discharge Data Set to identify women with breast cancer occurring within 9 months before or 1 year after an obstetric delivery. Age-matched, non-pregnancy-associated breast cancer controls were also identified. Demographics, cancer stage, tumor size, histology, hormone receptor status, type of treatment, and survival were reviewed and compared. Predictive factors for death from breast cancer were identified using proportional hazards modeling. RESULTS: Seven hundred ninety-seven pregnancy-associated breast cancer cases were compared with 4,177 non-pregnancy-associated breast cancer controls. Pregnancy-associated breast cancer cases were significantly more likely to have more advanced stage, larger primary tumor, hormone receptor negative tumor, and mastectomy as a component of their treatment. In survival analysis, pregnancy-associated breast cancer had a higher death rate than non-pregnancy-associated breast cancer (39.2% compared with 33.4%, P=.002). In a multivariable analysis, advancing stage (2.22-10.76 times the risk of death for stages II-IV), race (African Americans had 68% increased risk of death over non-Hispanic whites), hormone receptor-negative tumors (20% increased risk of death over receptor-positive tumors), and pregnancy (14% increased risk of death over nonpregnant women) all were significant predictors of death. CONCLUSION: Pregnancy-associated breast cancer presented with more advanced disease, larger tumors, and increased percentage of hormone receptor-negative tumors. When controlled for stage, race, and hormone receptor status, pregnancy-associated breast cancer cases had a slightly higher risk of death, even when only localized-stage disease was considered. LEVEL OF EVIDENCE: II.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.