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Balanced fusion and fission are key for the proper function and physiology of mitochondria1,2. Remodelling of the mitochondrial inner membrane is mediated by the dynamin-like protein mitochondrial genome maintenance 1 (Mgm1) in fungi or the related protein optic atrophy 1 (OPA1) in animals3–5. Mgm1 is required for the preservation of mitochondrial DNA in yeast6, whereas mutations in the OPA1 gene in humans are a common cause of autosomal dominant optic atrophy—a genetic disorder that affects the optic nerve7,8. Mgm1 and OPA1 are present in mitochondria as a membrane-integral long form and a short form that is soluble in the intermembrane space. Yeast strains that express temperature-sensitive mutants of Mgm19,10 or mammalian cells that lack OPA1 display fragmented mitochondria11,12, which suggests that Mgm1 and OPA1 have an important role in inner-membrane fusion. Consistently, only the mitochondrial outer membrane—not the inner membrane—fuses in the absence of functional Mgm113. Mgm1 and OPA1 have also been shown to maintain proper cristae architecture10,14; for example, OPA1 prevents the release of pro-apoptotic factors by tightening crista junctions15. Finally, the short form of OPA1 localizes to mitochondrial constriction sites, where it presumably promotes mitochondrial fission16. How Mgm1 and OPA1 perform their diverse functions in membrane fusion, scission and cristae organization is at present unknown. Here we present crystal and electron cryo-tomography structures of Mgm1 from Chaetomium thermophilum. Mgm1 consists of a GTPase (G) domain, a bundle signalling element domain, a stalk, and a paddle domain that contains a membrane-binding site. Biochemical and cell-based experiments demonstrate that the Mgm1 stalk mediates the assembly of bent tetramers into helical filaments. Electron cryo-tomography studies of Mgm1-decorated lipid tubes and fluorescence microscopy experiments on reconstituted membrane tubes indicate how the tetramers assemble on positively or negatively curved membranes. Our findings convey how Mgm1 and OPA1 filaments dynamically remodel the mitochondrial inner membrane. Crystal and electron cryo-tomography structures of Mgm1 from Chaetomium thermophilum reveal that Mgm1 forms bent tetramers, which further assemble into helical filaments on both positively and negatively curved membranes.

BACKGROUND: The current neuroblastoma (NBL) staging system employs image-defined risk factors (IDRFs) to assess numerous anatomic features, but the impact of IDRFs on surgical and oncologic outcomes is unclear. METHODS: The Vanderbilt Cancer Registry identified children treated for NBL from 2002 to 2017. Tumor volume (TV) and IDRFs were measured radiographically at diagnosis and before resection. Perioperative and oncologic outcomes were evaluated. RESULTS: At diagnosis of 106 NBL, 61% were IDRF positive. MYCN-amplified and undifferentiated NBL had more IDRFs than nonamplified and more differentiated tumors (p = 0.001 and p = 0.01). Of 86 NBLs resected, 43% were IDRF positive, which associated with higher stage, risk, and TV (each p < 0.001). The presence of IDRF at resection was also associated with increased blood loss (p < 0.001), longer operating times (p < 0.001), greater incidence of intraoperative complications (p = 0.03), more frequent ICU admissions postoperatively (p < 0.001), and longer hospital stays (p < 0.001). IDRF negative and positive tumors did not have significantly different rates of gross total resection (p = 0.2). Five-year relapse-free and overall survival was similar for IDRF negative and positive NBL (p = 0.9 and p = 0.8). CONCLUSIONS: IDRFs at diagnosis were associated with larger, less differentiated, advanced stage, and higher risk NBL and at resection with increased operative difficulty and perioperative morbidity. However, the frequency of gross total resection and patient survival after resection were not associated with the presence of IDRFs. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level III.

BACKGROUND: Circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA may represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples. METHODS: A CRISPR-augmented RT-PCR assay that sensitively detects SARS-CoV-2 RNA was employed to analyze viral RNA kinetics in longitudinal plasma samples from nonhuman primates (NHPs) after virus exposure; to evaluate the utility of blood SARS-CoV-2 RNA detection for coronavirus disease 2019 (COVID-19) diagnosis in adults cases confirmed by nasal/nasopharyngeal swab RT-PCR results; and to identify suspected COVID-19 cases in pediatric and at-risk adult populations with negative nasal swab RT-qPCR results. All blood samples were analyzed by RT-qPCR to allow direct comparisons. RESULTS: CRISPR-augmented RT-PCR consistently detected SARS-CoV-2 RNA in the plasma of experimentally infected NHPs from 1 to 28 days after infection, and these increases preceded and correlated with rectal swab viral RNA increases. In a patient cohort (n = 159), this blood-based assay demonstrated 91.2% diagnostic sensitivity and 99.2% diagnostic specificity versus a comparator RT-qPCR nasal/nasopharyngeal test, whereas RT-qPCR exhibited 44.1% diagnostic sensitivity and 100% specificity for the same blood samples. This CRISPR-augmented RT-PCR assay also accurately identified patients with COVID-19 using one or more negative nasal swab RT-qPCR results. CONCLUSION: Results of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04358211. FUNDING: Department of Defense, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the National Center for Research Resources.

Background: Despite the paucity of evidence supporting chemotherapy in the treatment of node-negative, HER2-positive breast cancer measuring

1. Monika L. Dietrich, MD* 2. Russell W. Steele, MD†,‡ 1. *Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 2. †Department of Pediatrics, Ochsner Health Center for Children, New Orleans, LA 3. ‡University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA * Abbreviations: ANF: : acute necrotizing fasciitis ARF: : acute rheumatic fever GAS: : group A Streptococcus IVIG: : intravenous immunoglobulin MRSA: : methicillin-resistant Staphylococcus aureus MSSA: : methicillin-susceptible S aureus PANDAS: : pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections PSGN: : poststreptococcal glomerulonephritis STSS: : streptococcal toxic shock syndrome 1. Clinical prediction rules for group A Streptococcus pharyngitis are unreliable in children, and unless viral etiology is strongly suspected, throat swab with a rapid antigen detection test should be performed. 2. Avoid “proof of cure” cultures when treating pharyngitis. 3. Clindamycin is important in invasive group A Streptococcus infection for toxin mediation but should not be used alone secondary to possible resistance. After completing this article, readers should be able to: 1. Understand the epidemiology, transmission, and major virulence factors of group A Streptococcus (GAS) infections. 2. Plan the appropriate diagnostic evaluation of suspected GAS infection. 3. Recognize the clinical features of, and major complications associated with, invasive and noninvasive GAS infections. 4. Plan appropriate management for a patient with a GAS infection. In 1933, Rebecca Lancefield changed our understanding of β-hemolytic streptococci by developing a system of serologic classification based on the carbohydrate composition of cell wall antigens. Of these organisms, the most significant in human pathogenicity is group A Streptococcus (GAS), otherwise known as Streptococcus pyogenes . (1) GAS is responsible for an impressively wide variety of clinical manifestations, from noninvasive infections, such as pharyngitis, scarlet fever, erysipelas, and cellulitis, to invasive disease, including sepsis, streptococcal toxic shock syndrome (STSS), and necrotizing fasciitis (Table 1). It has also been linked to multiple nonsuppurative complications including acute rheumatic fever (ARF), poststreptococcal glomerulonephritis (PSGN), and the controversial pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Globally, an estimated 18 million people are suffering from a serious GAS-related illness, with about 1.78 million new cases annually. Hundreds of millions of people develop less serious GAS infection every year, placing a massive burden on healthcare systems. The …

Objectives To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. Study design The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5 years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. Results Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200 cells/μL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. Conclusions Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

Background: Congenital cytomegalovirus (cCMV) is the leading cause of nongenetic congenital hearing loss in much of the world and a leading cause of neurodevelopmental disabilities. Infected babies can be born to women who are seropositive and seronegative prior to pregnancy, and the incidence is approximately 0.6%-0.7% in the United States. Symptoms vary from mild to severe, and hearing loss can be delayed in onset and progressive. Methods: We reviewed the literature to summarize the epidemiology, clinical manifestations, diagnosis, treatment, and future directions of cCMV. Results: The best way to diagnose the infection is with polymerase chain reaction of urine or saliva within 3 weeks after birth, followed by a repeat confirmatory test if positive. Moderately to severely symptomatic neonates should be treated for 6 months with valganciclovir, and some practitioners also choose to treat infants who have isolated hearing loss only. Treatment is not recommended for asymptomatic infants. All infected infants should be screened for hearing loss and neurodevelopmental sequelae. Universal and targeted screening may be cost effective. Currently, no vaccine is commercially available, although multiple candidates are under study. Conclusion: Congenitally acquired cytomegalovirus is found in all communities around the world with a disease burden that is greater than many other well-known diseases. Advances are being made in prevention and treatment; however, improved awareness of the disease among clinicians and patients is needed.

Recent observational studies are concerning because they document rising mastectomy rates coinciding with more than a dozen reports that lumpectomy has better overall survival (OS) than mastectomy. Our aim was to determine if there were differences in OS of matched breast cancer patients undergoing lumpectomy versus mastectomy in the National Cancer Database (NCDB).A retrospective cohort of patients with stage I-III breast cancer in the NCDB (2004-2013) was identified. Propensity score matching (PSM), Kaplan-Meier, and multivariate Cox proportional hazards models were used to examine OS by type of surgery.Of 845,136 patients, 464,052 (54.9%) underwent lumpectomy and 381,084 (45.1%) underwent mastectomy. After PSM, the hazard ratio (HR) and confidence interval (CI) for OS in all patients comparing lumpectomy with mastectomy was 1.02 (CI, 1.00-1.04; P = .002). In patients with stage I, II, and III, they were HR 1.27 (CI, 1.23-1.36; P .001), HR 0.98 (CI, 0.95-1.01; P = .21), and HR 0.83 (CI, 0.80-0.86; P .001), respectively. In subgroup analyses of all patients by estrogen receptor (ER) status, they were HR 1.05 (CI, 1.03-1.07; P .001) and HR 1.00 (CI, 0.96-1.03; P = .65) in ER+ and ER- patients.In our primary model of all stage I-III matched patients, using the most recent NCDB data and the largest observational sample size to date, the OS after mastectomy was not inferior to lumpectomy. This finding can be reassuring to patients and providers. In subgroup analyses, the association between type of surgery and OS differed by cancer stage and hormone receptor status.

The purpose of this study was to determine if receipt of chemotherapy was associated with utilization of the 21-gene recurrence score assay (RS assay) or with recurrence score (RS) in eligible patients. Using the National Cancer Data Base (NCDB), we identified female patients eligible for RS assay based on National Comprehensive Cancer Network (NCCN) guidelines: age 18–70, ER-positive and HER2-negative early-stage breast cancer diagnosed during 2010–2013. We excluded patients not meeting testing guidelines. Inclusion required result of RS in patients who underwent RS assay and status for receipt of chemotherapy. Multivariable logistic regression models and propensity matched analysis were used to determine associations between RS assay and RS with receipt of chemotherapy. Among 129,765 patients who were eligible, 74,778 underwent RS assay and had results available. Of these, 59.5 % (44,505) had low-risk, 32.0 % (23,920) had intermediate-risk, and 8.5 % (6353) had high-risk RS. Patients with intermediate- and high-risk RS were more likely to receive chemotherapy [OR 12.9 (CI 12.2–13.6), p

Background Estrogen receptor beta (ERβ) is expressed by 50% to 80% of triple-negative breast cancers (TNBC). Agonism of ERβ has antiproliferative effects in TNBC cells expressing ERβ. This phase 2 study evaluated single-agent high-dose estradiol in patients with advanced TNBC. Patients and Methods Adult women with measurable advanced TNBC were treated with estradiol 10 mg oral 3 times daily provided continuously for 28-day cycles. A Simon optimal 2-stage design was used. The primary end point was objective response (OR). Secondary end points included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB, and PFS by ERβ status were also examined. Results Seventeen evaluable women were enrolled. Median age was 58 years (range, 34-90 years); the median number of prior systemic therapies was 2 (range, 0-6). One patient had a confirmed partial response (OR rate, 5.9%) and remained on the study for > 24 weeks. Three patients had stable disease, with one lasting more than 16 weeks. ERβ expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ERβ-positive patients and 0% (0 of 4) in ERβ-negative patients ( P = 1). PFS was poor (median, 1.9 months) and not statistically significantly different between ERβ-positive versus -negative patients. No new adverse events from estradiol were identified. The study closed after the first stage as a result of limited responses in these unselected patients. Conclusion In unselected TNBC, high-dose estradiol has limited efficacy. However, further evaluation of ERβ selective agonists in TNBC selected by ERβ expression may be warranted.

Purpose: This study assesses the effectiveness of a single institution’s breast cancer survivorship program on patient perceptions, quality of life (QOL), and compliance with National Comprehensive Cancer Network (NCCN) guidelines for follow-up. Methods: Sampled patients completed all their breast cancer treatment at a single tertiary center. Surveys designed to evaluate QOL were obtained, and retrospective medical record review was conducted to assess NCCN compliance. Survivorship clinic (SC) attendees and nonattendees were matched for age and disease stage for comparison of the outcomes (QOL, NCCN compliance, and overall effectiveness). Results: SC patients (n = 63) tended to perceive their concerns in various categories to be addressed more adequately than did nonattendees (n = 54), with significant differences in the areas of practical concerns (P = .03) and late-term adverse effects (P = .03). There was a significant difference in compliance with three NCCN guidelines (history and physical every 3 to 6 months, annual mammography, and a pelvic examination if on tamoxifen) between survivorship attendees and nonattendees (P < .001, P = .02, and P < .001, respectively). Women who attended an SC used other survivorship support resources more often. Conclusion: Survivorship programs can be time and resource consuming, but our study is one of the first to show that a survivorship program effectively changes patient behavior in important ways. Patients who attended an SC were more likely to be compliant with NCCN-recommended follow-up and to use other survivorship resources and felt their concerns were better addressed. These measures can be used to help us improve our survivorship services and by other institutions to measure the quality and effectiveness of their programs.

Adjuvant therapy for breast cancer can be improved by increasing dose density. We tested the feasibility of delivering dose-dense docetaxel-cyclophosphamide (TC) in a single-arm phase II trial of 42 patients via the Wisconsin Oncology Network. Treatment was safe, tolerable, and most patients completed therapy as plan- ned. Thus, this commonly used regimen can be delivered in 8 weeks. Introduction: Dose-dense therapies have had a major effect on reducing toxicity and improving outcomes in breast cancer. A combination of TC every 3 weeks has emerged as a common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast cancer. We tested whether it is feasible to deliver TC on a dose- dense schedule, with therapy completed within 10 weeks. Patients and Methods: We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC through a regional oncology network. All women completed primary surgery before accrual, and subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m 2 plus cyclophosphamide 600 mg/m 2 every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24 to 48 hours after the administration of each chemotherapy cycle. Results: Of 42 women enrolled, 41 were evaluable using prespecified criteria. Of these, 37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose modification. Rates of neuropathy were similar to that reported previously. The rate of neutropenic fever was low (2.5%). Rash and plantar-palmar erythrodythesia were common and reached grade 3 in 4 subjects (9.8%). Conclusion: Dose-dense TC is feasible with tolerability profiles similar to standard TC and a low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant chemotherapy regimen.

Background: Dose-dense therapies have had a major impact on reducing toxicity and improving outcomes in breast cancer. A combination of docetaxel plus cyclophosphamide (TC) every 3 weeks has emerged as a common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast cancer. We tested whether it is feasible to deliver TC on a dose-dense schedule. Patients and Methods: We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC (ddTC) through a regional oncology network (WON). All women completed primary surgery; subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24-48 hours after the administration of each chemotherapy cycle. The primary endpoint was feasibility of administering therapy within 10 weeks. A Simon Optimal 2-Stage design was employed for the study design. Results: Of 42 women enrolled, 41 were evaluable by prespecified criteria. Median age was 54 (28-73). Most subjects had node negative (73%) or hormone receptor positive (71%) tumors. Of the 41 subjects, 37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose modification. Rates of grade 2 neuropathy were similar to that reported previously (15%) and there were no cases of grade 3 or higher neuropathy. The rate of neutropenic fever was low (2.5%). Rash and plantar/palmar erythrodythesia were common and reached grade 3 in four subjects (9.8%). Conclusion: Dose-dense TC is feasible with tolerability profiles similar to standard TC and a low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant chemotherapy regimen. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-10.

Background: Sialophorin is a transmembrane sialoglycoprotein. Normally, the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signalling, apoptosis, migration and proliferation. Methods: Normal breast tissue and primary breast tumours were analysed by immunohistochemistry for sialophorin expression. The sialophorin-positive breast cancer cell line MCF7 was engineered to stably express either non-targeted or sialophorin-targeted small interfering RNA (siRNA). Assays were then performed in vitro to assess apoptosis, intracellular adhesion, transendothelial migration and cytotoxicity. An orthotopic mouse model assayed ability to produce tumours in vivo. Results: Normal breast epithelial cells exhibit expression of the N-terminal domain of sialophorin in the cytoplasm but not the nucleus. The majority of these normal cells are also negative for expression of the C-terminal domain. In contrast, malignant breast epithelial cells exhibit N-terminal expression both in the cytoplasm and nucleus and the majority express the C-terminus in the nucleus. Using differential patterns of intracellular expression of the N and C termini of sialophorin, we define six subtypes of breast cancer that are independent of histological and receptor status classification. Targeting sialophorin with siRNA resulted in the MCF7 breast cancer cell line exhibiting increased homotypic adhesion, decreased transendothelial migration, increased susceptibility to apoptosis, increased vulnerability to lysis by natural killer cells and decreased ability to produce tumours in mice. Conclusion: Our results indicate that intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and that sialophorin represents a novel therapeutic target.

Background The prevalence of congenital cytomegalovirus infection (cCMV) at birth is 0.5%–1% in the United States. Most cCMV newborns are asymptomatic at birth with 10%–15% subsequently developing sequelae, such as hearing loss. Higher cCMV prevalence (2.5%–11.4%) is reported in infants born to HIV-infected women, associated with maternal immune suppression and lack of antiretroviral therapy (ART), with few studies addressing neurodevelopmental (ND) outcomes in their offspring. We report birth prevalence of cCMV in a cohort of HIV-exposed, uninfected infants (HEU) born to women on combination ART with well-controlled HIV and describe ND outcomes through age 5 years. Methods The Surveillance Monitoring for ART Toxicities (SMARTT) study is an ongoing NICHD-funded observational multi-centered cohort study (United States and Puerto Rico) of growth and development of HEU children that commenced in 2007. As of August 1, 2017, participants with stored blood pellets collected ≤3 weeks after birth and at least 1 ND assessment ≥1 year of age had pellets tested by DNA PCR to establish cCMV. Comparisons of ND outcomes (defined in figure) at ages 1, 2, and 5 by cCMV status were made using Wilcoxon and Fisher’s Exact tests. Results Of 895 children meeting study criteria (55% black; 32% white; 40% Latino), 8 had cCMV, yielding a birth prevalence of 0.89% (95% CI 0.39–1.75%). All were asymptomatic and similar to CMV-uninfected infants in gestational age and anthropometric measurements at birth. The last HIV viral load prior to delivery was undetectable in 88% of women. The last available CD4% was Conclusion Birth prevalence of cCMV in HEU children born within the last decade approaches national US prevalence. Preschool HEU children with asymptomatic cCMV at birth did not show poorer language, hearing, and developmental outcomes compared with CMV-uninfected HEU children. Disclosures All authors: No reported disclosures.

Measurement of quality indicators and peer comparison has been demonstrated to improve quality of care. The goal of this study was to determine whether a community breast center, in collaboration with the National Consortium of Breast Centers (NCBC), could voluntarily audit the quality of breast cancer care, confidentially transmit quality information to the NCBC, and receive peer performance comparisons. Quality indicator metrics from consecutive breast cancer patients undergoing care at a community interdisciplinary breast center were entered into a prospective database of quality measures that were defined by the NCBC. Retrospective review of patients from 2004 to 2006 was performed and subsequent quality indicator data was submitted electronically to the NCBC National Quality Measures for Breast Centers (NQMBC(TM) ) program. The percentage of new cancer diagnoses made by needle biopsy techniques was 94%, 95% and 96% from 2004 to 2006. Sentinel lymph node utilization in eligible patients was 93%, 96% and 91% from 2004 to 2006 and the immediate intraoperative pathologic frozen section false negative rate of the sentinel lymph node was 6.5%, 4.7% and 4%. Chart documentation of "patient participation in shared decision making for breast conserving therapy versus mastectomy" improved from 74% to 99% (p

49 Background: The 2005 Institute of Medicine report recommended providing a cancer TSCP, but barriers including time needed to complete these documents led to limited implementation. In 2014, in order to facilitate delivery, ASCO released a streamlined version of a TSCP. The current prospective, randomized study compares a Breast Cancer ASCO 2014 derived template (concise TSCP) with a facility derived Breast Cancer TSCP template based on the “old” ASCO version and NCCN guideline recommended elements (detailed TSCP). Methods: Female breast cancer survivors who completed therapy at Gundersen Health System were randomized between a concise TSCP and a detailed TSCP. Subjects received a survey prior to their survivorship visit assessing their baseline knowledge of their breast cancer diagnosis and treatment (pre visit knowledge). After the visit, participants completed the same survey (post visit knowledge) and a satisfaction survey. Pre and post visit knowledge survey scores, patient satisfaction scores and time needed to complete the TSCP were compared between the two study groups. Results: Both TSCP groups showed significant improvement in patient-specific disease and treatment knowledge scores (% of applicable knowledge questions answered correctly) after their survivorship visit. There was no significant difference between the concise and detailed groups’ pre-visit knowledge score (mean 78% vs. 79%, p=0.88). Calculated difference between the groups’ post knowledge scores met the pre-determined threshold for non-inferiority (p=0.013). Conclusions: Our study demonstrates the value of a cancer TSCP and Survivorship visit in improving breast cancer survivors’ knowledge of their disease characteristics and treatment. The concise version was found to be non-inferior to the detailed TSCP in terms of patient knowledge and satisfaction and required less time to complete. These results assist us and other institutions in choosing a more streamlined version of TSCP without compromising patient knowledge or satisfaction. [Table: see text]

PURPOSE Symptoms of gastroesophageal reflux disease (GERD) occur in 2% to 7% of children. The manifestations of GERD can be limited to symptoms (eg, heartburn, regurgitation) or can be more complicated, such as erosive esophagitis, esophageal strictures, or Barrett esophagus. The prevalence of such GERD complications in children is unknown. The purpose of this study was to determine the prevalence of endoscopic findings of erosive esophagitis in children. PATIENTS AND METHODS All children ages 0 to 17 years, 11 months who underwent upper endoscopy that was recorded in the Pediatric Endoscopic Database System-Clinical Outcomes Research Initiative between 1999 and 2002 were included. Endoscopic reports that were incomplete or that did not include demographic features, indications for endoscopy, or endoscopic findings were excluded. Erosive esophagitis was defined either descriptively or by the Los Angeles classification. Esophageal biopsy was not evaluated. RESULTS A total of 7188 children who underwent upper endoscopy fulfilled the inclusion and exclusion criteria. Of those, 888 (12.4%) had erosive esophagitis. The median age of children with erosive esophagitis was 12.7 +/- 4.9 years versus 10.0 +/- 5.1 years in those without erosive esophagitis (P

Background Variations exist in compliance with NCCN Guidelines. Prior reports of adherence to NCCN Guidelines contain limitations because of lack of contemporary review and incomplete listing of reasons for noncompliance. Purpose To assess institutional compliance and assist national quality improvement strategies through identifying valid reasons for noncompliance. Methods Compliance with NCCN Guidelines was recorded prospectively using electronic synoptic templates for patients with newly diagnosed breast cancer treated at a single institution between January 2010 and December 2011. Compliance with NCCN Guidelines was recorded. The accuracy of real-time synoptic auditing methods compared with retrospective chart review and reasons for noncompliance was assessed. SAS 9.3 software was used for data analysis. Results Compliance with NCCN Guidelines among 395 patients was 94% for initial staging evaluation, 97% for surgery, 91% for chemotherapy, 89% for hormone therapy, 91% for radiation therapy, 85% for follow-up, and 100% for determination of estrogen receptor/progesterone receptor and HER2 status. Age, comorbidities, and stage influenced guideline compliance. The most common reasons for noncompliance were patient refusal, patient choice after shared decision-making, and overuse of testing. Synoptic templated reporting was accurate in 97% patients. Conclusions High compliance with NCCN Guidelines was demonstrated. Reasons for noncompliance were identifiable. Compliance and nonadherence can be evaluated quickly with electronic synoptic reporting. This allows real-time action plans to address quality concerns and aids national risk adjustment for comparison and benchmarking.

Background & aims: Surgical fundoplication has been recommended for children with persistent GERD. The purpose of this study was to determine the frequency of postoperative symptoms requiring medical evaluation and/or treatment after fundoplication in children with or without associated medical disorders. Methods: In a retrospective cohort study, we reviewed the medical records of all children who underwent fundoplication during 1996–1999. Data were collected to analyze the following: (1) postoperative complications, (2) postoperative symptoms, (3) procedures performed to evaluate postoperative symptoms, (4) medical treatment, and (5) repeat surgery. Results: A total of 198 children underwent fundoplication, and 176 (89%) came for follow-up evaluation within 2 months after surgery. The median age at the time of surgery was 2.1 y (range, 6 mo–18 y) and the median duration of follow-up was 2.0 y (range, 1.2–4.8 y). A total of 130 (74%) children had one or more associated medical disorders including neurodevelopmental delay (70%), cystic fibrosis (8%), tracheoesophageal anomalies (8%), bronchopulmonary dysplasia (8%), and reactive airway disease (35%). Postoperatively, children with associated medical disorders had a higher frequency of lung infections (52% vs. 22%, P = .03) and dumping syndrome (2% vs. 0%, P = .05). Most children (63%) received evaluation and treatment for symptoms suggestive of recurrent reflux despite fundoplication. Conclusions: Nearly two thirds of children who received fundoplication and were followed-up within 2 months after surgery either have symptoms or receive medical therapy for reflux. Fundoplication for the control of GERD in children needs further evaluation.

Summary. Objective: The main objective of this study was to examine factors associated with utilization and costs for persons with haemophilia. Study design: Utilization data and patient characteristics were collected through medical record review of 336 patients receiving treatment for at least 90% of their haemophilia care at one of five comprehensive haemophilia treatment centres in California. Principal findings: The range of factor VIII deficiency in our sample was similar to the distribution among haemophilic patients in the Western United States; 215 (64%) had severe FVIII deficiency. The mean age in our sample was 21.4 (SD ¼ 16.2) years old and 114 (34%) were HIV-positive. In the multivariate model predicting the total cost of health care during 1995 (adjusted R 2 ¼ 0.40), total annual costs were significantly (P < 0.05) associated with being HIV-seropositive, infusing FVIII concentrate through a port vs. i.v. infusion, the number of comorbidities, moderate arthropathy (compared with no arthropathy), mild arthropathy, history of inhibitor to FVIII, and current prophylactic FVIII concentrate infusion. Conclusion: As expected, total health-care costs were correlated with comorbid medical conditions, such as HIV and sequelae of haemophilia such as arthropathy. Health policy should consider risk adjustment for the presence of complications such as arthropathy and HIV infection in the financing of haemophilia treatment to promote more equitable delivery of these services.

The purpose of this study was to assess the relationship between health care and utilization of that health care, and to provide a base measurement of health status in patients with haemophilia. Provider interview and retrospective chart review of 336 patients with haemophilia treated during 1995 at one of five comprehensive haemophilia treatment centres was conducted to measure patient health status characteristics and utilization of health care. Two health status scales were included. The first, the Self-Care Measure, was a four-point single item scale measuring the patient's ability for basic self-care, which was scored by a chart review and an interview with the health-care provider. The second, the Haemophilia Utilization Group Study (HUGS) Functional Status Measure, is a four-item, 10-point scale developed specifically for patients with haemophilia. Our sample represents 27% of actively treated patients in region IX. The mean score on the HUGS Functional Status Measure was 8.7 (SD=2.4). The HUGS scale exhibited a ceiling effect across all four scales: attitude (n=269, 80.1%), overall wellbeing (n=263, 78.3%), working (n=254, 75.6%) and orthopaedic status (n=195, 58.0%). Both higher total health-care costs and factor VIII annual costs were significantly associated with lower scores on the HUGS Functional Status Measure. Health status is a critical component in the assessment of the utilization and outcomes of care. In the absence of the availability of a patient interview, the HUGS Functional Status Measure can be used as one characteristic that explains the variation in the utilization of health care by patients with haemophilia.

57 Background: Patients treated for cancer are surviving their disease in increasing numbers. The 2005 Institute of Medicine (IOM) report From Cancer Patient to Cancer Survivor - Lost in Transition resulted in a call to develop survivorship programs. The Commission on Cancer (CoC) standard 3.3 became effective in 1/2015 requiring the delivery of a survivorship care plan (SCP) at the completion of treatment. Many cancer patients use social media (SM) as a way to obtain support and information. We sought to determine if SM savvy patients have received a SCP. Methods: An IRB-approved survey was conducted via the online tool SurveyMonkey between 3/21/2016 and 4/2/2016. Patients were invited to participate via SM outlets reaching cancer-related communities including Twitter chats, Facebook groups, blogs, and targeted emails. Cochran-Armitage Trend test, exact version, was performed by year for % of survivors receiving a SCP. Results: A total of 312 patients responded. 63% had completed their treatment (excluding endocrine therapy). Of a total of 194 individuals only 11.8% (23) were given a SCP at the end of treatment. A breakdown by treatment completion year is given below. Of those who did not receive a care plan 65% (112/172) answered that it would still be helpful to receive one. Most SCPs (86%) were supplied in paper form. However, patient-reported preferences for SCP delivery were paper (50%), online patient portal (41%), and email (9%). Conclusions: Despite the IOM report and CoC standard 3.3, the majority of SM savvy cancer survivors (88.2%) do not receive SCPs. In the respondents to this survey, there was no significant increase from 2015 onwards, p = 0.11, confirming an Advisory Board survey that just over 1/3 of programs felt confident that they could implement 3.3 by 2015. The CoC has updated its standard such that 25% of eligible patients should receive a plan by 12/31/2016. According to these data, that goal of 25% may not be achieved. [Table: see text]

An association between auto-immune disorders and interferon (IFN) has been reported. High levels of natural IFNalpha are present in the blood of patients with auto-immune disease and correlate with disease activity. In addition, IFNalpha treatment of humans has resulted in multiple reports of associated auto-immune phenomena. We describe a patient who underwent resection of regionally metastatic melanoma, was given adjuvant high-dose IFNalpha2b, and subsequently developed dermatomyositis. To the authors' knowledge this is the first report of dermatomyositis in association with IFNalpha treatment. We review the literature reporting associations between IFNalpha and auto-immune disease and discuss possible mechanisms by which IFNalpha may contribute to the development of auto-immune disease. High dose IFNalpha2b is more commonly prescribed since it was approved as an adjuvant treatment for patients with surgically resected high-risk melanoma. The potential for cases of IFN-associated auto-immune disease is therefore a clinical concern. Standard side effects of high-dose IFN therapy resemble symptoms of auto-immune diseases, which may make prompt diagnosis difficult. Therefore, it is important that auto-immune diseases such as dermatomyositis are recognized as potential side effects of treatment with high-dose IFNalpha.

Background National Comprehensive Cancer Network (NCCN) guideline compliance for breast cancer was determined in a breast center. Methods A retrospective study of 200 new breast cancer patients seen in 2004 was performed. Results NCCN guideline compliance rates for preoperative evaluation, breast surgery, lymph node surgery, radiation treatment, and systemic adjuvant therapy were 87%, 97%, 97%, 77%, and 63%, respectively. The most common reasons for noncompliance were partial breast radiation, no radiation, limited life expectancy, and patient choice to defer systemic treatment. Conclusions The investigation of quality of breast cancer care requires measurement of compliance and reasons for noncompliance with established guidelines. A review that focuses only on percentage compliance has the potential to penalize institutions that (1) practice informed consent detailing absolute risks of survival with and without systemic therapy, (2) practice evidence-based medicine before the standardized guideline is changed to reflect it, and (3) serve populations with limited life expectancy.

CERVICAL epidural steroid injections (CESIs) are generally used for the treatment of radiculopathy and pain. Other reasons cited for using CESIs include postlaminectomy syndrome, bulging cervical disc, and brachial plexitis. 1 Side effects of CESIs include stiff neck, flushing, wet tap, failed block, vomiting, upper extremity motor weakness, and transient paresthesia. 1-2 Rare but potentially catastrophic complications of CESI can occur, such as arachnoiditis, hematoma, meningitis, and quadraplegia. 3,4 We present a case of cervical epidural granuloma and intracranial hypotension after administration of epidural triamcinolone acetonide (Kenalog; Bristol-Myers Squibb, Princeton, NJ).

Age differences among risk groups may account for rate differences in progression of human immunodeficiency virus type 1 (HIV-1) infection to AIDS. Institutions in 6 US cities used a common protocol to study infected homosexual blood donors, recipients of blood components, and factor VIII-treated hemophiliacs. Follow-up was every 6 months. Actuarial risk for AIDS 8 years after infection was 51% among blood recipients, 36% among homosexual donors, and 24% among hemophiliacs. Significant risk group differences were explained by age differences among cohorts (medians of 61, 29, and 22 years, respectively). When age was adjusted for and both CD4 cell value and zidovudine treatment were used as time-dependent covariates, homosexual donors had more rapid progression than the other groups. Omitting Kaposi's sarcoma as an AIDS-defining condition removed any significant differences among risk groups except CD4 cell count and age. Thus, major factors in AIDS progression are age-related.

Einleitung: Midkine (MK) ist ein heparin-bindender Wachstumsfaktor und ist erstmalig entdeckt worden als Genprodukt, das im, durch Retinolsäure induzierten Differenzierungsprozess embryonaler Tumorzellen, exprimiert wird. MK spielt in der Tumorgenese verschiedener Tumorerkrankungen eine Rolle und[for full text, please go to the a.m. URL], 127. Kongress der Deutschen Gesellschaft für Chirurgie

e11511 Background: Oncotype DX, a 21 gene recurrence score (RS) is used to predict the likelihood of benefit from systemic chemotherapy in women with node-negative, estrogen receptor (ER) positive ...

New therapies are needed to improve the prognosis of patients with metastatic melanoma. This study evaluates the safety and efficacy of weekly paclitaxel in patients with metastatic melanoma. Patients received paclitaxel at 80 mg/m over 1 h, weekly for 3 weeks, followed by a 1-week rest period. Disease status was assessed every other cycle. Treatment was continued until patients experienced either disease progression or unacceptable toxicity. Twenty-seven patients were enrolled in this phase II clinical trial. Of these patients, two were subsequently determined to be ineligible. All patients, however, were considered to be evaluable for toxicity and all patients were included for response assessment in an intention-to-treat analysis. Patients received paclitaxel for a median of two cycles (range

123 Background: After the IOM report “From Cancer Patient to Cancer Survivor - Lost in Transition” was issued, there was a widespread call to develop Survivorship programs. Few studies have evaluated the effectiveness of these programs. Prior studies have focused on perceptions of, or preferences for, certain models of survivorship care. Therefore, our goal was to retrospectively evaluate our effectiveness based on patient perception, quality of life (QOL) and compliance with NCCN guidelines for follow-up. Methods: Eligible patients completed all of their breast cancer treatment at GHS. Surveys were sent out to evaluate patient knowledge and QOL. Chart review was conducted to assess NCCN compliance. Survivorship clinic attendees and non-attendees were matched for age and disease stage for comparison purposes of the outcomes (QOL, NCCN compliance, overall effectiveness) using descriptive statistics analysis. Chi-squares and t-tests/ANOVA statistical tests were used for categorical and continuous data significance respectively. Results: We found survivorship clinic patients (n=65) tended to perceive their concerns, in various categories, to be more adequately addressed than non-attendees (n=52), with significant differences in the areas of practical concerns and questions regarding late-term side effects. Categories in which there were no significant differences tended to be highly rated in both groups. There was also a significant difference in compliance with two NCCN guidelines for those attending survivorship. Additionally, women attending the survivorship appointment utilized supportive resources more than those who did not attend. Conclusions: Survivorship clinic attendees felt certain concerns were better addressed, were more compliant with NCCN recommended follow-up, and used supportive services more often than non-attendees. Statistically significant differences in other categories may be found in a larger sample size. These measures can be used to help us improve our survivorship services and for other institutions to measure quality and effectiveness of their programs.

DELAYED diagnosis of traumatic diaphragmatic injuries may result in gastric or intestinal herniation and intestinal obstruction. 1,2 If the hernia becomes strangulated, ischemia, necrosis, and sepsis may develop. Pulmonary and cardiac complications occur because of compression of the lung and heart by the herniated organs or herniation of organs into the pericardial sac. 3-5 Rarely, perforation of herniated organs may lead to pneumothorax and pneumomediastinum. 6

197 Background: There is a wide variation of compliance with National Comprehensive Cancer Network (NCCN) guidelines for diagnosis and treatment. Overutilization of preoperative testing and underutilization of adjuvant treatments have been documented. The former is associated with higher costs of care; the latter with poor patient outcomes. Prior reports of adherence to NCCN Guidelines contain methodological limitations due to lack of contemporary review and incomplete listing of reasons for non-compliance. This limits the “real time” analysis of breast cancer quality and delays action plans to address quality and cost issues of care. Methods: NCCN Guideline compliance was recorded prospectively by use of electronic synoptic templates for all newly diagnosed breast cancer patients treated at a single institution between January 2010 and December 2011. A retrospective review of the synoptic templates was then conducted. Accuracy of the synoptic auditing method was assessed as well as NCCN compliance and reasons for non-compliance. Results: A total of 312 new breast cancer patients who underwent surgery as initial treatment were identified. Compliance with NCCN Guidelines for preoperative testing, breast surgery and lymph node surgery was 98% (306/312), 99.7% (311/312) and 93% (290/312) respectively. Reasons for non-compliance include patient refusal, comorbidities, advanced age and overutilization of systemic imaging. There was 100% compliance to College of American Pathologist (CAP) molecular profile documentation for all breast cancer cases. There were two discrepancies noted between the prospective template reporting and medical record review. The average time needed to populate data into synoptic templates was less than 2 minutes per patient. Conclusions: Prospective auditing of adherence to NCCN Guidelines with electronic synoptic templates is accurate and time efficient. High compliance rates with NCCN Guidelines were demonstrated. Electronic synoptic NCCN templates potentially facilitate early recognition of quality gaps in compliance and provide a framework for peer performance comparison.

One in eight of the female population of the United States will be diagnosed with breast cancer in their lifetime. This statistic defines breast cancer as the most common cancer affecting American women. Advances in breast cancer treatment will be facilitated by the identification and targeting of the causative molecular defects. We have found that breast cancer is characterized by expression of CD43. This sialoglycoprotein is normally only produced by leukocytes. Strikingly, an N-terminal domain of CD43 that is extracellular in leukocytes is expressed predominantly in the cytoplasm of breast cancers. The C-terminal domain that is expressed in the nucleus of leukocytes only upon activation exhibits constitutive nuclear localization in breast cancer. Segregation of the N and C terminal domains of CD43 between different subcelluar compartments suggests that in breast cancer it is subjected to specific proteolytic cleavage events. The normal function of CD43 is to regulate leukocyte adhesion, apoptosis and migration. We reasoned that if these normal functions are extrapolated to breast cancer, then CD43 could contribute to disease progression and, therefore, represent a novel therapeutic target. We tested this hypothesis by using small-interfering RNA to target CD43 expressed by the breast cancer cell line MCF7. This targeting resulted in cancer cells exhibiting increased susceptibility to apoptosis and increased vulnerability to lysis by natural killer cells. In addition, targeting demonstrated that CD43 likely facilitates metastasis by inhibiting homotypic adhesion and driving transendothelial migration. Using an othrotopic mouse model, we demonstrate that CD43-targeting reduces the size of primary tumors by 76%. Taken together, our results indicate that expression of CD43 is a robust breast cancer biomarker and its targeting has the potential to be developed into a new breast cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1844. doi:1538-7445.AM2012-1844

e19509 Background: Female Hodgkin Lymphoma (HL) survivors treated with mantle radiation have 3-10 times the risk of the general population for developing breast cancer. Forty percent are unaware of...

6545 Background: Compliance with National Initiative for Cancer Care Quality (NICCQ) quality indicators and National Comprehensive Cancer Network (NCCN) guidelines for breast cancer care are proposed measures of quality breast cancer care. Previously, we had determined NCCN guideline compliance rates for breast cancer care by physician review of electronic medical record (EMR). In the present study, we sought to compare NCCN guideline compliance and NICCQ adherence at our institution in regard to percent compliance, time taken to complete review, and comparison of physician reviewer (PR) versus non-physician reviewer (NPR). Methods: Review of the EMR was conducted for all 200 female patients who were newly diagnosed with breast cancer and treated at our multi-specialty institution in 2004. A PR and a NPR reviewed compliance with NICCQ quality indicators and NCCN guidelines for breast cancer care and time spent reviewing charts was recorded. Results: Adherence rate was less than 85% in only 7 of 36 NICCQ breast cancer quality measures for PR and only 6 of 36 for NPR. Patients overall received 91.5 % of NICCQ recommended care according to PR and 89.8% according to NPR. NICCQ measures were divided into categories to correspond with NCCN guideline categories and results are compared and summarized in the table below. Differences in observed compliance rates between PR and NPR were not significant for NCCN (except in pre-op workup where NPR was more accurate) or overall NICCQ audit, however differences were seen in individual NICCQ items with small numbers of patients. Average time for review of charts for NCCN guideline compliance vs. NICCQ adherence was not significantly different (6.8 vs. 6.3 minutes for PR and 8.3 vs. 8.9 minutes for the NPR). Conclusions: Our adherence rates for NICCQ and NCCN measures compare favorably with published values. Despite both being proposed quality measures, comparison of adherence rates for the two systems varied. PR is slightly faster than NPR but offset by PR's time value. A NPR performs as well, if not better, than a PR. No significant financial relationships to disclose. [Table: see text]

6585 Background: We compared two existing sets of QIs for colorectal cancer care to evaluate our performance as compared to published data. We also explored reasons for non-adherence to these QIs to determine how we could increase our compliance. Methods: Chart review of all patients who were newly diagnosed with colorectal cancer at our institution in 2004 and 2005 for compliance with QIs for colorectal cancer care as presented by National Initiative for Cancer Care Quality (NICCQ) and Moffitt Network Initiative on Practice Quality (MNIPQ). When 85% compliance was not observed, charts were reviewed as to why care differed from QI. Results: Adherence rate was less than 85% in 5 of 25 NICCQ colon cancer measures and patients overall received 83% of recommended care. Reasons for No significant financial relationships to disclose.

The Prevalence of Erosive Esophagitis in Children: A Populationbased Study Mark A. Gilger, Hashem B. El-Serag, Craig L. Dietrich Symptoms of gastroesophageal reflux disease (GERD) occur in 2-7% of children. The manifestations of GERD can be limited to symptoms (e.g. heartburn, regurgitation) or can be more complicated, such as erosive esophagitis (EE), esophageal strictures or Barrett’s esophagus. The prevalence of such GERD complications in children is unknown. PURPOSE: To determine the prevalence of endoscopic findings of EE in children.METHODS: All children aged 0 to 18 years who underwent EGD that was recorded in the Pediatric Endoscopic Database System Clinical Outcomes Research Initiative (PEDS-CORI) between 1999 and 2002 were included. Endoscopic reports that were incomplete, missing demographic features, indications for endoscopy or endoscopic findings were excluded. EE was defined either descriptively (erythema, erosion, ulcer) or by Los Angeles classification. Esophageal biopsy was not evaluated. RESULTS: 8038 children who underwent EGD fulfilled the inclusion and exclusion criteria. Of those, 1070 (13.3%) had EE. The mean age of children with children with EE was 12.6 (+/ 5.6) yrs vs. 10.0 (+/ 6.0) yrs in those without EE (p=

SUMMARY Haemophilia is a congenital, life-long disorder that may cause major disabilities. The goal of comprehensive care is to prevent problems when possible, to treat early in order to minimize morbidity, and to restore function to disabled patients. The co-ordinated efforts of many experts are needed for success.

This prospective investigation was undertaken to compare the value of routine versus selective diabetes screening in a group of predominantly middle-class, healthy, Caucasian pregnant women. Two thousand consecutively chosen persons were divided into two groups: those to undergo routine screening between 24 and 24 weeks' gestation and those to be tested selectively in the presence of standard risk factors. The two groups of patients were otherwise similar. The method of screening involved a 50 gm oral glucose challenge, followed by a 3-hour glucose test if necessary. The incidence of gestational onset diabetes in the selectively screened group (19/453, 4.2%) was twice that in the routinely screened group (21/1000, 2.1%). Evidence of glucose intolerance without a risk factor was found in only one case (1 /1000, 0.1%) in the routinely screened group. This assessment of our clinical practice has allowed us to safely eliminate the need for diabetes screening in more than half of our private patients, which will reduce office time, patient inconvenience, and expense.

Background Reoperations occur frequently after initial lumpectomy for breast cancer. The authors hypothesized that the receipt of neoadjuvant chemotherapy (NAC) is associated with fewer reoperations. Methods The association between timing of chemotherapy and reoperation rates (ROR) after lumpectomy was investigated for patients with stages 1–3 breast cancer in the National Cancer Database (NCDB) from 2010 to 2013 by multivariable logistic regression modeling. Then propensity score-matching was performed. Results The unadjusted ROR for 71,627 stages 1–3 patients was 11.4% for those who had NAC compared with 20.3% for those who had postoperative chemotherapy (p < 0.001) (odds ratio [OR] 0.53; 95% confidence interval [CI] 0.49–0.57; p < 0.001). The ORs for the reoperations performed for patients with stages 1, 2, and 3 cancers who received NAC were respectively 0.65 (95% CI 0.56–0.75), 0.50 (95% CI 0.45–0.56), and 0.27 (95% CI 0.19–0.38) The p values for all were lower than 0.001. Conclusion For a population of patients receiving chemotherapy, the receipt of chemotherapy before instead of after surgery was associated with fewer reoperations after initial lumpectomy for breast cancer.

To understand the mechanisms that initiate the increase in ammonia formation during acute acidosis in kidney [amino-15N]- and [amino-15N]glutamine were used as substrates in isolated perfused rat kidney experiments. Perfused kidneys from methionine sulfoximine-treated rats take up glutamine nitrogen at the rate of 1.50 +/- 0.08 mumol.g kidney-1.min-1 while forming ammonia at a rate of 0.65 +/- 0.09 mumol.g.kidney-1.min-1. Mass spectrometer analysis of the perfusate and urine reveals that ammonia is formed from the amide nitrogen of glutamine at the rate of 0.32 +/- 0.06 mumol.g kidney-1.min-1 and ammonia is formed from glutamate derived from glutamine at the rate of 0.21 +/- 0.04 mumol.g kidney-1.min-1. The balance of the ammonia formed is from unidentified endogenous sources. Addition of HCl to the perfusate to lower perfusate pH increases ammonia formation to 1.09 +/- 0.10 mumol.g kidney-1.min-1. The results exclude a role for the purine nucleotide cycle during acute acidosis and confirm that ammonia formation from glutamate derived from glutamine is via glutamate dehydrogenase. Lowering perfusate pH increases the rate of glutamine deamidation significantly by 0.33 +/- 0.06 mumol.g kidney-1.min-1 and increases the rate of ammonia formation via glutamate dehydrogenase insignificantly by only 0.08 +/- 0.04 mumol.g kidney-1.min-1, whereas ammonia formation from endogenous sources remains unchanged. The results demonstrate that regulation of glutamine deamidation is an important controlling step in ammonia formation during acute metabolic acidosis in kidney.

Induction of immune tolerance in patients with severe hemophilia A and inhibitors to factor VIII was attempted by daily infusion of 50 U of factor VIII per kilogram of body weight without adjunctive immunosuppressive drugs. Modest initial anamnestic elevation of inhibitor levels occurred in six patients within the first month of therapy; inhibitor levels then fell sharply. The other six patients had no increase in inhibitor levels while on the study protocol. Inhibitors became undetectable within one to ten months in nine of the patients; they now receive smaller and less frequent infusions of factor VIII to maintain suppression. Inhibitors were not eradicated in three patients, who had the highest baseline and historic inhibitor levels. Ten patients gave consent for human immunodeficiency virus (HIV) testing; three had no antibody to HIV at the outset. Two of these patients seroconverted while on the protocol, one of whom had received only donor-screened, heat-treated factor VIII. Thus, the benefits of inhibitor suppression must be weighed against the risks of HIV seroconversion or transient elevation of inhibitor levels, as well as against the cost of the factor concentrate used. (JAMA1988;259:65-68)

From mid-1967 to mid-1983, three hundred fifty surgical operations were performed on 163 patients with hemophilia A, without factor VIII inhibitor. One death occurred, in a patient with a serious head injury. Postoperative hemorrhages occurred after 23% of operations, but the incidence after surgery on the knee, 40%, was decidedly higher than the 15% incidence after operations at other sites. Concurrent plasma factor VIII levels were over 0.40 units/mL in 72% of instances and under 0.30 units/mL in only 15% of instances. The incidence of postoperative hemorrhage did not change over the study period despite a threefold increase in typical dosage of factor VIII (from 600 to 2,000 units/kg per operation) and doubling of typical trough factor VIII levels (from 0.37 units/mL to 0.70 units/mL). Circulating factor VIII levels apparently are not the sole determinants of postoperative bleeding in hemophilia A. ( JAMA 1985;253:1279-1283)