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Objective To characterize and identify risk factors for 30-day surgical site infections (SSIs) in patients with head and neck cancer who underwent microvascular reconstruction. Study Design Cross-sectional study with nested case-control design. Setting Nine American tertiary care centers. Subjects and Methods Hospitalized patients were included if they underwent head and neck cancer microvascular reconstruction from January 2003 to March 2016. Cases were defined as patients who developed 30-day SSI; controls were patients without SSI at 30 days. Postoperative antibiotic prophylaxis (POABP) regimens were categorized by Gram-negative (GN) spectrum: no GN coverage, enteric GN coverage, and enteric with antipseudomonal GN coverage. All POABP regimens retained activity against anaerobes and Gram-positive bacteria. Thirty-day prevalence of and risk factors for SSI were evaluated. Results A total of 1307 patients were included. Thirty-day SSI occurred in 189 (15%) patients; median time to SSI was 11.5 days (interquartile range, 7-17). Organisms were isolated in 59% of SSI; methicillin-resistant Staphylococcus aureus (6%) and Pseudomonas aeruginosa (9%) were uncommon. A total of 1003 (77%) patients had POABP data: no GN (17%), enteric GN (52%), and antipseudomonal GN (31%). Variables independently associated with 30-day SSI were as follows: female sex (adjusted odds ratio [aOR], 1.6; 95% CI, 1.1-2.2), no GN POABP (aOR, 2.2; 95% CI, 1.5-3.3), and surgical duration ≥11.8 hours (aOR, 1.9; 95% CI, 1.3-2.7). Longer POABP durations (≥6 days) or antipseudomonal POABP had no association with SSI. Conclusions POABP without GN coverage was significantly associated with SSI and should be avoided. Antipseudomonal POABP or longer prophylaxis durations (≥6 days) were not protective against SSI. Antimicrobial stewardship interventions should be made to limit unnecessary antibiotic exposures, prevent the emergence of resistant organisms, and improve patient outcomes.

Patient: Male, 57-year-old Final Diagnosis: Hepatitis • herpes Symptoms: Fever Medication: — Clinical Procedure: — Specialty: General and Internal Medicine Objective: Challenging differential diagnosis Background: Herpes simplex virus-2 (HSV-2) affects nearly 1 in 5 adults in the United States. Complications such as viral hepatitis and dissemination are rare in immunocompetent hosts. In this report, we describe a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent patient with recurrent fevers and elevated aminotransferases. Case Report: A 57-year-old man with a history of type 2 diabetes and hypertension was admitted with a right index finger lesion concerning for an abscess. He underwent successful incision and drainage and was started on ampicillin-sulbactam. On Day 2 of hospitalization, he developed recurrent fevers and elevated aminotransferases and inflammatory markers. An extensive infectious, rheumatologic, and malignancy workup were pursued without immediate findings. Imaging demonstrated cirrhotic morphology of the liver and splenomegaly, but lab markers were intact for liver synthetic function. On Day 7 of hospitalization, fever frequency decreased, and HSV-2 titers resulted, with positive IgM and negative IgG. He subsequently developed erythematous, raised lesions in multiple dermatomes. Nucleic acid amplification testing of biopsied lesions was positive for HSV-2, confirming viral hepatitis secondary to disseminated HSV-2. He was started on intravenous acyclovir and discharged on valacyclovir following improvement in symptoms. Conclusions: We report a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent host. Up to 25% of cases occur in immunocompetent hosts and many patients do not develop characteristic skin lesions. Early diagnosis and treatment of viral hepatitis secondary to disseminated HSV remains vital to minimize morbidity and mortality.

Purpose In response to the increasing cancer burden in Kenya, this study identified barriers to patients seeking access to cancer testing and treatment and to clinicians in delivering these services. Policy recommendations based on findings are presented. Methods This qualitative study used semistructured key informant interviews. Purposive sampling was used to recruit 14 participants: seven oncology clinicians and seven support and advocacy leaders for patients with cancer. Qualitative analysis was used to identify themes. Results Seven barriers to cancer testing and treatment were identified: high cost of testing and treatment, low level of knowledge about cancer among population and clinicians, poor health-seeking behaviors among population, long distances to access diagnostic and treatment services, lack of decentralized diagnostic and treatment facilities, poor communication, and lack of better cancer policy development and implementation. Conclusion Kenyans seeking cancer services face significant barriers that result in late presentation, misdiagnosis, interrupted treatment, stigma, and fear. Four policy recommendations to improve access for patients with cancer are (1) improve health insurance for patients with cancer; (2) establish testing and treatment facilities in all counties; (3) acquire diagnosis and treatment equipment and train health personnel to screen, diagnose, and treat cancer; and (4) increase public health awareness and education about cancer to improve diagnoses and treatment. Effective cancer testing and treatment options can be developed to address cancer in a resource-constrained environment like Kenya. An in-depth look at effective interventions and policies being implemented in countries facing similar challenges would provide valuable lessons to Kenya’s health sector and policymakers.

Approximately 15% of men with newly diagnosed prostate cancer have high risk features which increase the risk of recurrence and metastasis. Better predictive biomarkers could allow for earlier detection of biochemical recurrence and change surveillance and adjuvant treatment paradigms. Circulating tumor cells are thought to represent the earliest form of metastases. However, their role as biomarkers in men with high risk, localized prostate cancer is not well defined.Two to 5 months after prostatectomy we obtained blood samples from 37 patients with high risk, localized prostate cancer, defined as stage T3a or higher, Gleason score 8 or greater, or prostate specific antigen 20 ng/ml or greater. Circulating tumor cells were enumerated using a commercial platform. Matched tumor and single circulating tumor cell sequencing was performed.Circulating tumor cells were detected in 30 of 37 samples (81.1%) with a median of 2.4 circulating tumor cells per ml (range 0 to 22.9). Patients with detectable circulating tumor cells showed a trend toward shorter recurrence time (p=0.12). All patients with biochemical recurrence had detectable circulating tumor cells. Androgen receptor over expression was detected in 7 of 37 patients (18.9%). Patients with biochemical recurrence had more circulating tumor cell copy number aberrations (p=0.027). Matched tumor tissue and single circulating tumor cell sequencing revealed heterogeneity.We noted a high incidence of circulating tumor cell detection after radical prostatectomy and shorter time to biochemical recurrence in men with a higher circulating tumor cell burden and more circulating tumor cell copy number aberrations. Genomic alterations consistent with established copy number aberrations in prostate cancer were detectable in circulating tumor cells but often discordant with cells analyzed in bulk from primary lesions. With further testing in appropriately powered cohorts early circulating tumor cell detection could be an informative biomarker to assist with adjuvant treatment decisions.

Violence reduction efforts should be modeled on noncontagious diseases, which have as their root cause environmental determinants, not contagious diseases.

Objective. To elucidate the incidence of cisplatin induced ototoxicity in adult patients, with a focus on an adult population. Study Design. IRB approved retrospective study. Methods. The charts of patients who underwent cisplatin therapy from 1995 to present were reviewed. Inclusion criteria were (1) cisplatin as the primary chemotherapeutic agent and (2) hearing evaluation performed prior to and after treatment. Audiometric thresholds were measured by presenting pure-tone stimuli at 0.25 to 10.0 kHz. Criteria for hearing loss were based on the Chang criteria. Cochlear radiation doses were also calculated in patients with primary tumors in their head and neck or brain. Results. There were 1565 patients that had undergone therapy with cisplatin from 1995 to 2014, which 30 met inclusion criteria. Eight were patients treated for head and neck or brain cancer. Evaluation with ANOVA testing identified statistically significant decline in audiometric scores for WRS and pure tone frequencies 500, 2000, 4000, 6000, and 8000 Hz in the right ear. Overall, hearing loss was noted with 63% incidence and in patients who received radiation to their cochlea and cisplatin. Conclusion. The incidence of cisplatin induced ototoxicity was significant and even more prevalent in those patients receiving both cisplatin and radiation to their cochlea.

Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of known EMT regulators, miR-200 family of microRNAs in controlling the epithelial state, stem-like properties and therapeutic response in an in vivo primary, syngeneic p53(null) claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. miR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion and motility. Accordingly, induced miR200c expression significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53(null) claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity and metastatic potential in vivo.

The heterogeneity of an individual patient's tumor has been linked to treatment resistance, but quantitative biomarkers to rapidly and reproducibly evaluate heterogeneity in a clinical setting are currently lacking. Using established tools available in a College of American Pathologists–accredited and Clinical Laboratory Improvement Amendments–certified clinical laboratory, we quantified digital pathology features on 9,225 individual circulating tumor cells (CTC) from 179 unique metastatic castration-resistant prostate cancer (mCRPC) patients to define phenotypically distinct cell types. Heterogeneity was quantified on the basis of the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival (OS) in the 145 specimens collected prior to initiation of the second or later lines of therapy. Low CTC phenotypic heterogeneity was associated with better OS in patients treated with androgen receptor signaling inhibitors (ARSI), whereas high heterogeneity was associated with better OS in patients treated with taxane chemotherapy. Overall, the results show that quantifying CTC phenotypic heterogeneity can help inform the choice between ARSI and taxanes in mCRPC patients. Cancer Res; 77(20); 5687–98. ©2017 AACR.

The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility.

Despite evidence-based guidelines, oral anticoagulation therapy (OAT) initiation is low among incident atrial fibrillation (AF) patients. Patient-centered medical homes (PCMHs) may increase access, quality, and value through coordinating care. As such, PCMHs hold potential for improving OAT initiation among AF patients. We estimated the effect of receiving care in accredited PCMHs on OAT initiation for incident AF patients compared with those not receiving care in accredited PCMHs. Our study, a retrospective cohort new user design, included privately insured patients in North Carolina during years 2006 to 2010. We developed propensity scores for PCMH exposure, performed inverse probability of treatment weighting, and estimated effects with generalized estimating equations. We found a positive association between PCMH exposure and OAT initiation in unadjusted (6.78%; p < .001) and adjusted (6.25%; p < .001) models. Greater implementation and optimization of PCMH model principles may enhance this association, reducing AF-related stroke morbidity and mortality.

Importance A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane. Objective To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes. Design, Setting, and Participants For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years. Main Outcomes and Measures Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS). Results Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7–positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7–positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7–positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7–positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7–positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative to ARS inhibitors when AR-V7–positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035). Conclusions and Relevance The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.

Background High-risk HPV DNA testing has been proposed as a primary tool for cervical cancer screening (HPV-CCS) as an alternative to the Papanicolaou cytology- method. This study describes factors associated with women’s intentions to attend cervical cancer screening if high-risk HPV DNA testing (HPV-CCS) was implemented as a primary screening tool, and if screening were conducted every 4 years starting after age 25. Methods This online survey was designed using the Theory of Planned Behaviour to assess factors that impact women’s intentions to attend HPV-CCS among women aged 25–69 upon exit of the HPV FOCAL trial. Univariate and regression analyses were performed to compare the demographic, sexual history, and smoking characteristics between women willing and unwilling to screen, and scales for intention to attend HPV-CCS. A qualitative analysis was performed by compiling and coding the comments section of the survey. Results Of the 981 women who completed the survey in full, only 51.4 % responded that they intended to attend HPV-CCS with a delayed start age and extended screening interval. Women who intended to screen were more likely to have higher education (AOR 0.59, 95 % CI [0.37, 0.93]), while both positive attitudes (AOR 1.26, 95 % CI [1.23, 1.30]) and perceived behavior control (AOR 1.06, 95 % CI [1.02, 1.10]) were significant predictors of intention to screen. Among women who provided comments in the survey, a large number of women expressed fears about not being checked more than every 4 years, but 12 % stated that these fears may be alleviated by having more information. Conclusions Acceptability of increased screening intervals and starting age could be improved through enhanced education of benefits. Program planners should consider measures to assess and improve women’s knowledge, attitudes and beliefs prior to the implementation of new screening programs to avoid unintended consequences.

Heart rate variability biofeedback (HRVB) therapy may be useful in treating the prominent anxiety features of perinatal depression. We investigated the use of this non-pharmacologic therapy among women hospitalized with severe perinatal depression. Three questionnaires, the State Trait Anxiety Inventory (STAI), Warwick–Edinburgh Mental Well-Being Scale, and Linear Analog Self Assessment, were administered to 15 women in a specialized inpatient perinatal psychiatry unit. Participants were also contacted by telephone after discharge to assess continued use of HRVB techniques. The use of HRVB was associated with an improvement in all three scales. The greatest improvement (−13.867, p

Background: Medication errors are highly prevalent in long-term care facilities and are responsible for preventable injury. Repeat medication errors, or identical events occurring multiple times in the same patient, may be particularly preventable. Objectives: This study assessed the factors that contribute to repeat medication errors and the association between repeat medication errors and patient harm. Methods: In this cross-sectional analysis, medication error reports submitted by licensed nursing homes to North Carolina's Medication Error Quality Initiative-Individual Error Web-based incident reporting system were analyzed for fiscal years 2006–2008. When reporting errors, the sites were asked whether the event was identically repeated within the same patient. Repeat medication errors were defined as identical events in terms of patient characteristics, drug involved, error type, potential cause, phase of the medication care process, and personnel involved. Repeat errors were compared with nonrepeat errors. Multivariate logistic regression was used to explore whether certain patient or error characteristics were related to a higher likelihood of repeat errors, and a similar analysis was used to explore whether repeat errors were related to patient harm. Results: Of the total 15,037 errors reported by 294 unique nursing homes, 5615 (37.3%) were repeated one or more times. Among the repeat errors, the associated event within each error was repeated a mean (SD) of 10.7 (14.3) times. Wrong dosage (65.1% [3654/5615]) and wrong administration (10.2% [571/5615]) were the most frequent repeated events. In multivariate analysis, repeat errors occurred less frequently among younger residents (aged

Recent studies have demonstrated that miR-205 has a role in both normal development and cancer, however conflicting reports on its function illustrate the complexity of its regulation and targets. Additionally, miR-205 was found to be highly expressed in stem cell-enriched populations from the mouse mammary gland, and thus may play a function in normal mammary stem cell maintenance. The role that miR-205 plays in tumor formation and metastasis is likely context-dependent as reports have indicated that it may function as either a tumor suppressor or an oncogene. The role that miR-205 plays in directing stem cell fate is still unknown.

Background The introduction of limited explorations (LE) for parathyroidectomy broadened the management possibilities for hyperparathyroidism. We sought to document this evolution of change in parathyroid surgery. Study Design Members of the American Association of Endocrine Surgeons and the American College of Surgeons were sent a 49-question survey, and 256 surgeons, accounting for 46% of parathyroid operations nationwide, responded. Associations derived from questionnaire data were tested for significance using chi-square and Kruskal-Wallis methods. Results Currently, 10% of surgeons practice bilateral neck exploration, 68% practice LE, and 22% have a mixed practice. Five years ago, these percentages were, respectively, 26%, 43%, and 31%; and 10 years ago they were 74%, 11%, and 15%. Shift to LE was greatest among endocrine surgeons, high-volume surgeons, and surgeons trained by mentors who practiced LE. A focal, single-gland examination under general anesthesia and 23-hour observation are preferred by most surgeons. Half of all general surgeons, in contrast to fewer than 10% of endocrine surgeons, never monitor parathyroid hormone intraoperatively, even with LE. Dramatic differences were apparent among subsets of surgeons in operative volumes, indications for bilateral neck exploration, followup care, expertise with ultrasound and sestamibi, and perceptions of cure and complication rates. Evidence-based literature and guidance from surgical societies had the greatest influence on the decision to practice LE. Conclusions This survey formally documents the evolution of practice patterns in parathyroid surgery over the last decade. Although LE has achieved wide acceptance, surgical management of hyperparathyroidism has become increasingly disparate. This trend may highlight a need to define best-practice guidelines.

The aim of this study was to determine the success of limited neck exploration (LE) for primary hyperparathyroidism (1 degrees HPT).Between 1999 and 2007, 1407 patients with hyperparathyroidism underwent bilateral neck exploration (BE). Of these, 1158 patients with first-time sporadic 1 degrees HPT were analyzed prospectively. Based on surgeon-performed ultrasound (US) and sestamibi scan (MIBI), LE was initially performed. Regardless of results, BE followed to identify the presence of additional parathyroid pathology.Of 1158 patients, 242 (21%) were found to require concomitant thyroid surgery thus excluding LE. Of the remaining 916 patients, a single abnormal gland was identified on MIBI in 682 (74%), US in 731 (80%), and concordance of both in 588 (64%). Unsuspected multiglandular disease (MGD) was identified at BE in 22%, 22%, and 20% of patients, respectively. Adding intraoperative parathyroid hormone sampling (IOPTH) further reduced the rate of unsuspected MGD to 16%, 17%, and 16%. Overall, IOPTH correctly predicted MGD in only 22%. Neither concomitant nonsurgical thyroid disease nor more stringent selection criteria (preop Ca11 mg/dL and PTH120 pg/dL) altered success rates. In patients with MGD, a subsequent gland identified was larger than the index gland in 23%. Ninety-eight percent of BE patients were cured of 1 degrees HPT.This is the largest study to evaluate the prevalence of additional parathyroid pathology in patients who are candidates for LE. Limitations in localizing studies and IOPTH fail to identify MGD in at least 16% of patients, risking future recurrence.

We sought to explore optimism/pessimism, knowledge of HIV, and attitudes toward HIV screening and treatment among Ghanaian pregnant women.Pregnant women in Accra, Ghana, completed a self-administered questionnaire including the Life Orientation Test-Revised (LOT-R, an optimism/pessimism measure), an HIV knowledge and screening attitudes questionnaire, the Short Form 12 (SF-12, a measure of health-related quality of life [HRQOL]), and a demographic questionnaire. Data were analyzed using t-tests, ANOVA, correlations, and the chi2 test.There were 101 participants; 28% were nulliparous. Mean age was 29.7 years, and mean week of gestation was 31.8. All women had heard of AIDS, 27.7% had been tested for HIV before this pregnancy, 46.5% had been tested during this pregnancy, and 59.4% of the sample had ever been tested for HIV. Of those not tested during this pregnancy, 64.2% were willing to be tested. Of all respondents, 89% said they would get tested if antiretroviral drugs (ARVs) were readily available and might prevent maternal-to-child transmission. Neither optimism/pessimism nor HRQOL was associated with attitudes toward HIV screening. Optimism was negatively correlated with HIV knowledge (p = .001) and was positively correlated with having never been tested before this pregnancy (p = .007).The relationship between optimism/pessimism and HIV knowledge and screening behavior is worthy of further study using larger samples and objective measures of testing beyond self-report.

Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression. To that end, we developed a single cell Copy Number Variation (CNV) Assay to evaluate genomic instability and CNVs in patient CTCs. For proof of concept, prostate cancer cell lines, LNCaP, PC3 and VCaP, were spiked into healthy donor blood to create mock patient-like samples for downstream single cell genomic analysis. In addition, samples from seven metastatic castration resistant prostate cancer (mCRPC) patients were included to evaluate clinical feasibility. CTCs were enumerated and characterized using the Epic Sciences CTC Platform. Identified single CTCs were recovered, whole genome amplified, and sequenced using an Illumina NextSeq 500. CTCs were then analyzed for genome-wide copy number variations, followed by genomic instability analyses. Large-scale state transitions (LSTs) were measured as surrogates of genomic instability. Genomic instability scores were determined reproducibly for LNCaP, PC3, and VCaP, and were higher than white blood cell (WBC) controls from healthy donors. A wide range of LST scores were observed within and among the seven mCRPC patient samples. On the gene level, loss of the PTEN tumor suppressor was observed in PC3 and 5/7 (71%) patients. Amplification of the androgen receptor (AR) gene was observed in VCaP cells and 5/7 (71%) mCRPC patients. Using an in silico down-sampling approach, we determined that DNA copy number and genomic instability can be detected with as few as 350K sequencing reads. The data shown here demonstrate the feasibility of detecting genomic instabilities at the single cell level using the Epic Sciences CTC Platform. Understanding CTC heterogeneity has great potential for patient stratification prior to treatment with targeted therapies and for monitoring disease evolution during treatment.

Objective: To describe the implementation and evaluation of a web-based medication error reporting system. Design: Evaluation study. Setting: Long-term care. Participants: 25 nursing homes in the US state of North Carolina. Intervention: Detailed information about all medication errors occurring in a facility during a 1 year period was entered into a web-based reporting system. An evaluation survey was conducted to assess usability and the potential for the system to prevent errors. Main outcome measures: Number and specific characteristics of medication errors reported. A survey evaluating ease of use of the system and whether the participants thought it would help improve medication safety. Results: 23 (92%) sites entered 631 error reports for 2731 discrete error instances when weighted by the number of times the errors were repeated. 51 (8%) errors were classified as having a serious patient impact requiring monitoring/intervention or worse. The most common errors were dose omission (203, 32%), overdose (91, 14%), underdose (43, 7%), wrong patient (38, 6%), wrong product (38, 6%), and wrong strength (38, 6%). Errors most commonly occurred during medication administration (296, 47%) and were attributed to basic human error (402, 48%). Seven drugs were implicated in a third (175, 28%) of all errors: lorazepam, oxycodone, warfarin, furosemide, hydrocodone, insulin and fentanyl. 20 sites (86% of respondents) completed the evaluation survey and participants found the system easy to use and thought it would increase accuracy of reporting and improve patient safety. Conclusions: The web-based medication error reporting system was easy to use, with strong indications that it would be a valuable tool for preventing future errors.

Purpose Androgen receptor (AR) is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+) breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs) can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer. Methods Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK), and biomarkers of interest (AR, estrogen receptor [ER], and HER2) on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM) using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms. Results Of 68 patients, 51 (75%) had at least 1 CTC, and 49 of these 51 (96%) had hormone-receptor-positive (HR+)/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells. Conclusions CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.

Background: Epithelial Plasticity (EP) is a proposed mechanism of immune escape, resistance to programmed cell death, resistance to specific drugs, and promotion of metastasis. EP has been extensively explored in mathematical, cell biological, and animal models, which predict the presence of these tumor cells in circulation. Most studies on CTCs in human subjects are based on enrichment of cells expressing EpCAM prior to enumeration or molecular interrogation, which precludes analysis of cells that might be EP. The non-enrichment Epic Sciences platform was utilized to identify CTCs in metastatic castration-resistant prostate cancer patient samples phenotypically consistent with EP: CTCs that do not express cytokeratins (CK), but do express malignant or EP biomarkers: Androgen Receptor (AR), AR splice variant 7 isoform (AR-V7) or N-cadherin. Phenotypic and genotypic analyses of individual CTCs were performed to assess the malignant origin of CK- CTCs and their prevalence associated with overall patient survival. Methods: 221 pre-therapy mCRPC blood samples were collected at Memorial Sloan-Kettering Cancer Center and shipped to Epic Sciences. Patients represent a diverse number of previous therapies and tumor burdens. All nucleated cells were plated to glass slides and subjected to DAPI and immunofluorescent (IF) staining of cytokeratin (CK), CD45 and another tumor marker (AR, AR-V7, or N-cadherin), followed by CTC identification by fluorescent scanners and malignant morphology. All samples were stained for AR, with a subset of samples stained for AR-V7 or N-Cadherin as well. Additionally, 83 AR(+)/CK(-) and 9 AR-V7(+)/CK(-) CTCs were analyzed for copy number variation (CNV) by low pass whole genome single CTC sequencing. Abnormal genomes were identified by amplifications and deletions of known oncogenes and tumor suppressors. Results: 3931 AR(+) CTCs were detected, of which 2996 (76%) expressed CK and 935 (24%) did not. The AR(+)/CK(-) CTCs had a lower median AR signal, less nucleoli, and more nuclear speckles by digital pathology vs. CK(+) CTCs. AR(+)/CK(-) and AR-V7(+)/CK(-) CTCs had gross genomic alterations consistent with malignant prostate origin (AR gain, PTEN loss, RB1 loss, 8q gain, 8p loss, etc), often sharing the same genomic alterations with CK(+) CTCs in the same patients, with some having unique CNV profiles Presence of AR(+)/CK(-) CTCs was associated with worse overall survival (median 13.7 mo vs. 33.9 mo, p < 0.0001) and remained additive and independent to treatment Line, pre-therapy PSA, and therapy type in multivariate models. Conclusions: Similar to CTCs expressing epithelial markers, CK(-) CTCs have gross genomic aberrations consistent with metastatic prostate cancer and are a negative prognostic factor associated with worse overall survival in both iterative threshold and multivariable analyses. Citation Format: Ryon P. Graf, Yipeng Wang, Nicole Schreiber, Brigit McLaughlin, Stephanie Greene, Angel Rodriguez, Adam Jendrisak, Jerry Lee, Mark Landers, Ryan Dittamore, Howard I. Scher. Phenotypic, genomic, and clinical associations of Circulating Tumor Cells (CTCs) lacking epithelial biomarkers in metastatic Castration Resistant Prostate Cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1740. doi:10.1158/1538-7445.AM2017-1740

110 Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, many of these patients will recur despite definitive therapy. Better predictive biomarkers could allow for earlier detection of recurrence and change surveillance paradigms. The role of circulating tumor cells (CTCs) as biomarkers in this context is not well defined. Here, we evaluate the ability to detect CTCs from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples from 31 patients with high risk, localized PCa were obtained 2-4 months post RP and sent to Epic Sciences on an IRB approved protocol. Nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N-terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. Cytokeratin expressing (CK+) CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transitions (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were detected in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in this population using a novel platform. We observed a trend toward shorter PFS in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa.

139 Background: Genomic profiling of metastatic tumors can identify mCRPC pts w/ “actionable” targets. However, responses from this approach are infrequent and not durable, broadly attributed to intra-tumor and intrer-cellular het. We sought to understand relationships between single CTC phenotypic and genomic patterns present when starting ARSi or taxane therapy (Tx) to develop more effective biomarker-directed treatment approaches. Methods: 9225 CTCs from 319 blood samples from 179 mCRPC pts were detected and digital phenotypically profiled using the Epic Sciences platform. Unsupervised clustering revealed 15 phenotypic CTC subtypes based on digital pathology features (Type ‘A’-‘O’). Phenotypic diversity was determined by a Shannon index of these subtypes in pt samples. Next, 856 CTCs representing each subtype were individually whole genome sequenced for copy number variation and genomic instability, to define phenogenomic single cell profile and taxonomy. Tx outcomes were associated with CTC profiles. Results: Pre-therapy identification of certain CTC phenotypic subtypes was associated with poor overall survival (OS) following ARSi and/or taxanes. 5/15 subtypes existed primarily in pts w/ high CTC het (84-94%, Bonferroni adjusted p < 0.05, permutation test), and linked to amp of AR and cMYC, and loss of TP53 and PTEN. Clusters of genomic events were linked to phenotypic features (i.e. small cell CTC w/AuroraK & nMYC amp) and provide single cell phenogenomic associations with pathways such as AR/PTEN feedback and DNA repair machinery. Conclusions: Presence ofspecific CTC subtypes was associated w/ poor survival on ARSi and/or taxanes and may inform Tx selection. Identifying CTC subtypes present in high het samples can provide insight into individual pt disease evolution and potential approaches to maximize benefit. Longitudinal monitoring of CTC phenogenomics is being studied in novel Tx trials.[Table: see text]

The period of recovery following a lung-cancer surgery presents unique challenges and psychological demands. The study utilized ecological momentary assessments (EMA) to repeatedly sample mindfulness states in a sample of mindfulness-untrained individuals following hospital discharge. Intra- and inter- individual variability was assessed to examine cancer patients' natural capacity to exhibit mindfulness states during two weeks of recovery. Fifty nine stage I lung cancer patients (61% women, mean age = 66.1, SD = 7.9) completed EMA twice a day for two weeks. Mean level of mindfulness in the sample was low and equaled .49 (SD = .51) on the 5 point scale, with older participants being less likely to endorse mindful states. Net variability in mindfulness, defined as the person-based standard deviation in momentary scores, equaled .42 (SD = .26), ranging for 0 to 1.3 and indicating very modest variability for most participants. Results of the multi-level variance partitioning model revealed 41.4% of variance in mindfulness scores at the inter-individual, 2.4% on the temporal (i.e., .2% weekly and 2.2% daily), and 56.2% on the momentary levels. Findings indicate that, for cancer patients recovering from surgery, the innate ability to exhibit mindfulness is limited. From the methodological standpoint, consideration of intra-individual variability has implications for conceptualization and design of EMA studies.

Objectives:Elucidate the incidence of cisplatin-induced ototoxicity in patients treated for head and neck cancer.Methods:This was an institutional review board approved retrospective study of patients treated with cisplatin for cancer at a tertiary referral hospital. The charts of patients of any age that had undergone cisplatin therapy from 1995 to the present were reviewed. We then narrowed this group down to those who had a diagnosis of cancer of the head and neck (hypopharyngeal, laryngeal, nasopharyngeal, oropharyngeal, scalp/face skin cancer, temporal, thyroid) and had pre- and posttreatment audiologic testing.Results:There were 1565 patients that had undergone therapy with cisplatin from 1995 to 2014. Of those, 203 patients had pre- and posttreament audiologic testing. Twenty patients had diagnosis of cancer involving the head and neck. The cochlear radiation doses were also collected from these patients. Preliminary results demonstrate that patients with head and neck cancer that were treated with...

Two young children (three hips) with Down syndrome and dislocation of the hip were successfully treated by nonoperative methods by using the principle of prolonged immobilization or bracing. A 5-year, 6-month-old patient with bilateral habitual dislocation used an ambulatory abduction orthosis full-time for 6 months and then part-time for 4 months. Complete dislocation of the right hip in a 4-year, 6-month-old patient was managed by closed reduction, spica cast immobilization for 4 months, and then an ambulatory abduction orthosis for 8 months. Both patients developed stable, well-contained hips. Nonoperative management of hip dislocation in Down syndrome can be successful and avoids the complications associated with operations previously recommended for these patients.

The decision analysis for managing femoral shaft fractures in children should included such factors as the possibility of child abuse, overgrowth, and the potential for remodeling. Direct and indirect costs must be understood. Factors to consider in determining treatment include the age of the child, the extent of the soft tissue injury, and associated injuries. Non-operative methods, universally used in the past to treat these injuries, still are indicated, but operative modalities should be considered for a greater number of pediatric femoral fractures. Early enthusiasm for external fixation and rigid intramedullary rodding has been tempered by a greater awareness of their particular complications. The role of flexible intramedullary rodding, however, is expanding.

Liesegang rings are laminated ring-like structures occasionally found in benign cysts and abscesses. They have been confused with parasites (especially eggs), algae, calcifications, and psammoma bodies. We examined Liesegang rings from fine-needle aspiration (FNA) biopsies of a benign cyst of the breast and a complex renal cyst. Liesegang rings were best observed with Papanicolaou, hematoxylin-eosin, Masson's trichrome, acid-fast (AFB), and Gram stains, which accentuate the concentrically laminated morphology. An amorphous electron-dense core and fibrillary lucent concentric rings were seen with transmission electron microscopy with no significant energy peaks by electron probe microanalysis or distinct diffraction patterns by X-ray diffraction. This investigation indicates that Liesegang rings are composed of organic substances most likely formed by periodic precipitation from a supersaturated solution within cystic fluid. Awareness of the Liesegang phenomenon within cystic lesions will decrease the possibility of erroneous misdiagnosis as another type of pathologic process. Diagn. Cytopathol. 1998;19:116–119. © 1998 Wiley-Liss, Inc.

In the 1960s, effective techniques were developed for shunting hydrocephalus and for early closure of neural tube defects. As a result, orthopaedic surgeons were presented with the challenge of managing an emerging population of children who had myelomeningocele. Initially, the musculoskeletal problems in these children were treated with the modalities and expectations that had been learned from the treatment of poliomyelitis. However, it soon became apparent that the management of children who have myelomeningocele was not so simple. Additional factors include a decrease or loss of sensation affecting some or all parts of the lower extremities, associated congenital anomalies of the spine and lower extremities, and muscle imbalance that affects skeletal development over the entire period of growth. Furthermore, some patients who have myelomeningocele have a static encephalopathy that impairs coordination and results in the loss of strength of the lower and upper extremities29,30,45. Also, progressive neurological deterioration may occur because of tethered cord syndrome or syringomyelia2. As a result, the evaluation and treatment of musculoskeletal problems in these patients can be quite difficult. The purpose of this Instructional Course Lecture is to review the natural history of myelomeningocele as well as the types of deformity that are associated with it, the treatment options that are available, and the expected results of treatment of hip and knee problems related to myelomeningocele. Although other factors must be considered, the neurological level is the key to understanding the hip and knee deformities seen in these patients. Unless otherwise specified, a modification of the classification system described by Asher and Olson3 will be used to define the neurological level (Table I). This classification is based on muscle strength, is simple to use, and, in my experience, has been helpful in predicting gross motor function …

Background Galactoceles are benign cystic lesions that generally occur during pregnancy and postpartum lactation. Fine needle aspiration (FNA) yields milky fluid that is often both diagnostic and therapeutic. Cytologically, aspirates are generally noted to contain occasional foam cells and benign epithelium displaying lactational change with an abundant background of lipid micelles and proteinaceous material. Case A 23-year-old, black female presented with a 1.0-cm, discrete, nontender nodule involving the upper middle area of the left breast. FNA showed crystals of varying size and shape, best viewed with Diff-Quik and demonstrating metachromasia, polarization and birefringence. They were also positive with periodic acid-Schiff stain and both alizarin red S and von Kossa stain for calcium. Scanning electron microscopy revealed angulated, well-defined geometric crystals often with scalloped edges and smooth surfaces. The internal structure of the crystals consisted of electron-lucent material without periodicity or lattice formation, as observed by transmission electron microscopy and x-ray diffraction. Electron probe microanalysis identified small quantities of calcium, chlorine, potassium and sulphur within the crystals. Conclusion We think that in this case the crystals represented precipitation of inspissated lactational secretions. There are several possible mechanisms of precipitation. The differential diagnosis includes other breast lesions with acellular amorphous components that may be confused with crystallizing galactocele in FNA biopsy specimens.

I prevention activities are a defining characteristic of the modern trauma center. Violent injuryVwith a 5-year reinjury rate as high as 45%Vrepresents a priority area for preventive intervention. Advances in trauma care increase the likelihood that a patient will survive violent injury but do nothing to reduce the chances that they will be reinjured after leaving the hospital. The recurrent nature of violent injury strains trauma systems financially, and the absence of preventive intervention is inconsistent with trauma centers’ commitment to providing optimal care. Hospital-based violence intervention programs (HVIPs) offer a strategy to address these issues. HVIPs combine brief in-hospital intervention with intensive community-based case management and provide targeted services to high-risk populations to reduce risk factors for reinjury and retaliation while cultivating protective factors. Rigorous evaluations of HVIPs have demonstrated promising results in preventing violent reinjury, violent crime, and substance misuse. Violent injury, as a focus of HVIPs, is generally defined as any injury intentionally inflicted by another person by any mechanism, excluding family, intimate partner, and sexual violence. The latter are excluded because they generally involve different dynamics and intervention strategies.

We explored the potential impact of human papillomavirus (HPV) testing on women's intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 years from an ongoing trial were sent a questionnaire to assess women's intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioral control, and direct and indirect subjective norms. Demographic data and scales that were significantly different (p < 0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2,016 invitations emailed, 1,538 were received, and 981 completed surveys for a response rate of 63% (981/1,538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age of 25. Predictors of intentions to undergo screening were attitudes (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.15, 1.30), indirect subjective norms (OR: 1.02; 95% CI: 1.01, 1.03) and perceived behavioral control (OR: 1.16; 95% CI: 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age of 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.

The etiology and treatment of Kienbock disease, or osteonecrosis of the lunate, remain controversial. The condition is frequently associated with repetitive trauma, and the typical patient is twenty to forty years old and has noted an insidious onset of pain and stiffness in the wrist. Kienbock disease is uncommon in children. In four large series, only five (1 per cent) of 404 patients were less than sixteen years old at the time of diagnosis7,9,36,44. Furthermore, the children in those reports were involved either in sports activities that had caused repetitive trauma to the wrist, such as gymnastics, or they had sustained an acute injury. A ten-year-old child who had diplegic cerebral palsy and Kienbock disease is described in the present report. A ten-year and ten-month-old white girl who had moderately severe diplegic cerebral palsy was seen two weeks after the onset of pain and decreased motion of the left wrist. The pain in the wrist was mild, but it had compromised her ability to grasp a walker. The patient reported no recent episodes of trauma to the wrist and had not needed to use analgesics. The patient was highly motivated and intelligent and had been able to walk independently about the house since the age of seven years. She needed a reverse rolling walker as an aid for walking and, before the onset of pain in the wrist, she had used a wheelchair only for long distances, such as when she went to a shopping mall. Previous operations included iliopsoas recession and adductor myotomy bilaterally when she was three years old and lengthening of the gastrocnemius aponeurosis bilaterally when she was six years old. Physical examination revealed no obvious swelling and only slight tenderness to palpation over the mid-part of the dorsum …

Background: A critical decision in the management of patients (pts) with mCRPC is when to administer an androgen receptor signaling (ARS) directed or a taxane therapy. The detection of AR-V7 mRNA in CTCs has been shown to predict for resistance to ARS,but not to taxane chemotherapy. We evaluated the relationship between AR-V7 protein expression and localization on CTCs to treatment outcomes in a separate, larger cohort as a predictive biomarker for clinical decision making. Methods: 193 prospectively collected blood samples from 161 unique pts with progressive mCRPC about to start an ARS or taxane therapy were evaluated with an Epic Sciences CTC immunoflorescent assay that assesses CTC AR-V7 protein expression and localization in individual cells. Associations between the presence AR-V7(+) CTCs pre-therapy and anti-tumor effects post-therapy included prostate-specific antigen (PSA) changes, radiographic progression free survival (rPFS), time on therapy, and overall survival (OS). Results: 130 pre-ARS inhibitor and 63 pre-taxane samples were assessed of which 191 (99%) were evaluable. AR-V7(+) CTCs were found in 34 (18%) samples including 3% of the 1st, 18% of the 2nd and 31% of the 3rd+ line baseline pre-therapy samples. Patients with AR-V7 positive CTCs in a pre-ARS sample showed no PSA response and had shorter rPFS, time on therapy, and OS than those without AR-V7(+) CTCs. PSA resistance to ARS was also seen in 65 of 112 (58%) of the AR-V7(-) samples. There was no association between PSA response, rPFS, and time on therapy between AR-V7(+) and AR-V7(-) pts treated with taxane therapy. In a multivariate model adjusting for age, type of therapy, line of therapy, and pre-therapy LDH, Hgb, and presence of visceral metastasis, AR-V7(+) pts had a superior OS on taxane therapy relative to ARS (HR: 0.242, CI: 0.103 to 0.569, p = 0.0350). Conclusions: The results validate the expression of the AR-V7 protein in the nucleus of CTCs in men with mCRPC as a treatment specific biomarker that predicts resistance to ARS inhibitor therapy and separately, clinical benefit with taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further determine its clinical utility. Citation Format: Howard I. Scher, David Lu, Nicole A. Schreiber, Jessica Louw, Ryon P. Graf, Ann Johnson, Adam Jendrisak, Glenn Heller, Richard Bambury, Herbert A. Vargas Alverez, Brigit McLaughlin, Justin Wahl, Stephanie Greene, Martin Fleisher, Ryan Dittamore. Nuclear localized AR-V7 protein as a predictive biomarker for treatment selection in metastatic castration resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4954.

e16027 Background: Platinum-based chemotherapy including cisplatin, 5-fluorouracil (5-FU), and the EGFR-directed monoclonal antibody cetuximab, are active in the treatment of head and neck squamous cell carcinoma (HNSCC). Patients with inoperable recurrent or metastatic HNSCC have a poor prognosis and many have difficulty tolerating cisplatin-based regimens. Oxalipatin, a third-generation platinum derivative, has demonstrated antitumor activity and lacks many of the limiting side effects of cisplatin. We conducted a phase I pilot study to investigate the dose-limitation of oxaliplatin in addition to infusional 5-FU and cetuximab in patients with untreated recurrent or metastatic HNSCC. Methods: The planned dose escalation schedule included: dose level 1: oxaliplatin 100mg/m2 day 1, 5-FU CIV 750mg/m2 over 96 hours beginning day 1, and cetuximab 400mg/m2 cycle 1, day 1 (and 250mg/m2 weekly thereafter) on a 21-day cycle. Dose level 2: oxaliplatin 130mg/m2 day 1, 5-FU CIV 1000mg/m2 over 96 hours beginning day 1 and the same dose and schedule of cetuximab. Results: A total of 10 patients were accrued, consisting of 4 females and 6 males. The first seven were enrolled onto dose level 1 and the following three onto dose level 2. Dose level 1 was tolerated well with acceptable toxicity, including grade 1-2 oral mucositis, grade 1-2 fatigue, grade 1-2 acneiform rash, grade 1 nausea, grade 1-2 anemia and grade 1 transaminitis. All responses observed, (1 MR, 1 PR, 1 CR), were short-lived. Dose level 2 was more toxic than anticipated; 2 of 3 patients experienced grade 4 toxicities (mucositis, diarrhea, acute renal failure) requiring hospitalization with a treatment-related death in one of these patients. The phase I portion of the trial was therefore closed and dose level 1 is considered the maximum tolerated dose. Conclusions: The regimen of oxaliplatin 100mg/m2 day 1, infusional 5-FU 750mg/m2 over 96 hours beginning day 1, and cetuximab 400mg/m2 cycle 1, day 1 (with 250mg/m2 weekly thereafter), given on a 21-day cycle, has manageable toxicity; these doses are recommended for phase II evaluation in the treatment of unresectable or metastatic HNSCC.

The results of five patients who had hemophilia and a history of recurrent hemarthrosis and hypertrophic synovitis and who had been managed with a synovectomy of the ankle were studied at an average age of nine years (range, four years and seven months to nineteen years). Compared with the complications encountered after synovectomy of the knee or the elbow, the rehabilitation process after synovectomy of the ankle was relatively easy, even for the three youngest children in this series. The average duration of follow-up was five years (range, one to nine years). By the latest follow-up examination, the range of motion of the ankle had increased an average of 10 degrees (range, -5 to 15 degrees). The rate of hemarthrosis episodes requiring transfusion was reduced from an average of 3.4 per month (range, 0.3 to 5.0 per month) for the six months before the synovectomy to 0.1 per month (range, zero to 0.2 per month) for the twelve months before the latest follow-up examination.

The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer that expresses low levels of tight and adherens junction genes and shows high expression of epithelial-to-mesenchymal transition (EMT) genes. These tumors are enriched in gene expression signatures derived from human tumor-initiating cells (TICs) and human mammary stem cells. Through cross-species analysis, we discovered mouse mammary tumors that have similar gene expression characteristics as human claudin-low tumors and were also enriched for the human TIC signature. Such claudin-low tumors were similarly rare but came from a number of distinct mouse models, including the p53 null transplant model. Here we present a molecular characterization of 50 p53 null mammary tumors compared with other mouse models and human breast tumor subtypes. Similar to human tumors, the murine p53 null tumors fell into multiple molecular subtypes, including two basal-like, a luminal, a claudin-low, and a subtype unique to this model. The claudin-low tumors also showed high gene expression of EMT inducers, low expression of the miR-200 family, and low to absent expression of both claudin 3 and E-cadherin. These murine subtypes also contained distinct genomic DNA copy number changes, some of which are similarly altered in their cognate human subtype counterpart. Finally, limiting dilution transplantation revealed that p53 null claudin-low tumors are highly enriched for TICs compared with the more common adenocarcinomas arising in the same model, thus providing a unique preclinical mouse model to investigate the therapeutic response of TICs.

We set out to determine experimentally whether particles of polytetrafluoroethylene migrate to the lungs and brain when relatively small volumes of Teflon paste are injected into the bladder in the manner used to correct reflux. Numerous particles of polytetrafluoroethylene were recovered from these organs within 2 weeks of injection. Those in the brain measured up to 15 microns in diameter, indicating that the pulmonary bed is an inefficient filter of particles gaining access to the venous circulation. Although clinically no adverse neurological effects have hitherto been reported, this study suggests that following the 'sting' procedure, some particles may lodge in the brain where they can block the cerebral microcirculation. We believe these findings represent a contraindication to the use of Teflon paste in children.

More than 1,000,000 persons in the United States are living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome, with 24% unaware of their HIV status. In this study, the authors explored patients' attitudes toward HIV testing in academic medical clinics and investigated the possible impact of the 2006 Centers for Disease Control and Prevention (CDC) HIV screening guidelines.Cross-sectional survey study of adult patients in 9 academic internal medicine clinics (response rate 73%). The survey consisted of 76 questions, which assessed demographics, HIV risk factors, knowledge, beliefs, attitudes and characteristics of patient-physician interactions. Patient self-reported HIV testing was the main outcome. Bivariate analyses were performed, and variables with a P-value of0.1 were included in a logistic regression model to determine characteristics most associated with HIV testing.Four hundred forty-three patients completed the survey (response rate 73%) and 61% reported being screened for HIV. Physician recommendation (P0.0001), patient's own request (P0.0001), African American race (P0.0001) better knowledge about HIV (P = 0.0002), agreement with CDC recommendations (P0.0001), being comfortable with their doctor (P0.0001) and using street drugs (P0.0001) were all strongly associated with testing. In logistic regression, the only factors that remained statistically significant predictors of patients self-reported HIV testing were a patient's request for testing (OR: 103.3) and patient's knowledge about HIV (OR: 1.3).In this study, patient request was the strongest predictor for HIV screening and majority of patients accepted the idea of HIV testing in congruence with the CDC recommendations. Therefore, simple waiting room prompts and public education campaigns may represent the most efficient interventions to increase HIV testing rate.

Purpose A significant number of survivors of hematopoietic stem-cell transplantation (HSCT) report enduring adverse effects of treatment, including illness-related post-traumatic stress disorder (PTSD) symptoms and general distress. We report results of a randomized clinical trial that tested the effects of a 10-session, telephone-administered cognitive-behavioral therapy (CBT) intervention on PTSD, depression, and distress symptoms. Methods Survivors who had undergone HSCT 1 to 3 years earlier (N = 408) were assessed for study eligibility. Those who met study eligibility criteria (n = 89) completed a baseline assessment that included a clinical interview and self-report measures of PTSD symptoms (the primary outcome) and depression and general distress (the secondary outcomes). Next, they were randomly assigned to CBT or an assessment-only condition. Survivors in the CBT group completed 10 individual telephone-based CBT sessions (T-CBT) that included strategies to reduce PTSD symptoms, depression, and general distress. Follow-up assessments occurred at 6, 9, and 12 months after the baseline assessment. Results Linear mixed-model analyses revealed that, compared with HSCT survivors in the assessment-only condition, survivors who completed T-CBT reported fewer illness-related PTSD symptoms, including less avoidance (P < .001) and fewer intrusive thoughts (P < .05) as well as less general distress and fewer depressive symptoms (P < .05) even after controlling for potential demographic and medical covariates. These results were consistent across the three follow-up assessments. Conclusion A brief, telephone-administered CBT intervention developed for HSCT survivors is an efficacious treatment for reducing illness-related PTSD symptoms and general distress.

As modulators of gene expression, microRNAs (miRNAs) are essential for normal development. Not surprisingly, aberrant expression of miRNAs is associated with many diseases, including cancer. Studies of various breast cancer subtypes have demonstrated that, like gene expression profiles and pathological differences, miRNA profiles can distinguish various tumor subtypes. Over the last few years, roles for miRNAs during many stages of breast cancer progression have been established. This includes potential breast cancer associated polymorphisms in miRNA target sites or miRNAs themselves, miRNAs that can act as tumor suppressors or oncogenes, and miRNAs that can modulate metastatic spread. Recent studies have also suggested key roles for miRNAs in regulating cancer stem cells. Thus, miRNAs have now become important therapeutic targets. This can be achieved by replacing miRNA expression where it has been lost or decreased, or conversely by inhibiting miRNA expression where it has been amplified or overexpressed in cancers. Ultimately, miRNAs should provide both important prognostic biomarkers as well as new targetable molecules for the treatment of breast cancer.

Transfer of the posterior tibialis tendon to the dorsum of the foot was compared with lengthening of this tendon in 15 patients with Duchenne's muscular dystrophy.Patients undergoing tendon transfer ( N = 9) had a longer operating time and two perioperative complications, but retained plantigrade posture of their feet even after walking ceased. By contrast, lengthening of the posterior tibialis tendon (A/ = 6) was associated with a recurrent equinovarus foot deformity that frequently interfered with shoe wear. Although transfer of the posterior tibialis is out of phase and technically more demanding, the unique prolongation of posterior tibialis strength in Duchenne's muscular dystrophy makes this operation a better option for these patients.