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Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+; R26R-CAG-LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance. Using lineage tracing and molecular profiling, Abate-Shen and colleagues identify a Ras and Myc co-activation signature that predicts metastasis and castration resistance in localized prostate cancer.

Bladder paragangliomas are rare tumors, with no prospective studies or guidelines on the management of this disease. We present a case series of 6 patients managed with bladder preservation over a median follow-up period of 124 months. We also present a review of the recent literature on bladder paragangliomas. We aim to provide a timely synthesis of the recent evidence on bladder paragangliomas as changing paradigms necessitate individualized treatment.

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is an emergent rare T cell non-Hodgkin lymphoma arising in association with a breast implant, particularly textured ones. Recent guidelines list cytopathological examination as the first essential step for diagnosis, routinely followed by CD30 immunohistochemistry (IHC) and flow cytometry (FC) for a T cell clone. The majority of BIA-ALCL literature regarding cytopathological evaluation describes morphology based on various preparation methods limited to cytospins and smears with the exception of at least one case report detailing cytomorphological and IHC findings on ThinPrep. This case report details initial diagnosis of BIA-ALCL rendered with CytoLyt prepared ThinPrep and cell block, including the specific antibodies used for IHC. The ThinPrep slide showed numerous singly dispersed large, atypical cells with abundant cytoplasm containing irregular nuclei with dispersed chromatin and prominent nucleoli in a background of macrophages, inflammatory cells and granular debris. TIA-1 and CD30 along with other T-cell markers, including specific antibodies, remains immunoreactive in tissue collected in CytoLyt solution. Cell size reduction, artifactual lymphoid cell aggregation and prominent nucleoli in benign and reactive conditions are among other ThinPrep cellular alterations pathologists should bear in mind.

Metastatic progression is the key feature of prostate cancer primarily responsible for mortality caused by this disease. RAD9 is an oncogene for prostate cancer, and the encoded protein enhances metastasis-related phenotypes. RAD9 is a transcription factor with a limited set of regulated target genes, but the complete list of downstream genes critical for prostate carcinogenesis is unknown. We used microarray gene expression profiling and chromatin immunoprecipitation in parallel to identify genes transcriptionally controlled by RAD9 that contribute to this cancer. We found expression of 44 genes altered in human prostate cancer DU145 cells when RAD9 is knocked down by siRNA, and all of them bind RAD9 at their genomic location. FOXP1 and NDRG1 were down regulated when RAD9 expression was reduced, and we evaluated them further. We demonstrate that reduced RAD9, FOXP1 or NDGR1 expression decreases cell proliferation, rapid migration, anchorage-independent growth, anoikis resistance, and aerobic glycolysis. Ectopic expression of FOXP1 or NDRG1 partially restored aerobic glycolysis to prostate cancer cells with reduced RAD9 abundance, but only FOXP1 significantly complemented the other deficiencies. We thus show, for the first time, that RAD9 regulates FOXP1 and NDRG1 expression, and they function differently as downstream effectors for RAD9-mediated prostate cancer cell activities.

Introduction The 2014 Bethesda System categorizes squamous lesions as low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). It also includes intermediate morphologic terminology, such as atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot rule out a high grade squamous intraepithelial lesion (ASC-H). Consensus is lacking if when ASC-H is present in an unequivocal LSIL (LSIL + ASC-H) versus ASC-H alone predicts a neoplasm with a different biologic behavior and which is its association with high-risk human papillomavirus (HPV). Materials and methods We reviewed the Columbia University Medical Center Pathology department patient’s database from October 2012 through December 2014 and found 2498 cytology samples of LSIL, ASC-H, HSIL, and LSIL + ASC-H with both follow-up histologic samples and HPV tests by Roche cobas. Our objective was to identify, if any, differences in biologic behavior and HPV status present in LSIL + ASC-H compared with ASC-H and other lesions. Results CIN2+ was documented in tissue examination in 102 from 311 LSIL + ASC-H (32.8%), 101 from 219 ASC-H (46.1%), 252 from 326 HSIL+ (77.3%), and 150 from 1642 LSIL (9.08%). HPV distribution shows significant differences between all diagnostic categories. Conclusions LSIL + ASC-H appears to have a distinctive HPV distribution pattern that clearly differs from ASC-H and LSIL and approaches HSIL; however, the predictive value for CIN2+ appears higher for ASC-H than LSIL + ASC-H. Our literature review identified conflicting findings, probably suggesting a lack of reproducibility in cytologic criteria and the need for consistent inclusion of ASC-H and LSIL when both are present.

Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. Significance: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance. See related commentary by Finch and Baena, p. 2132. This article is highlighted in the In This Issue feature, p. 2113

COVID‐19 has extraordinarily impacted every facet of the health care facilities’ operations. Various strategies and policies were implemented promptly to preserve resources, not only to provide medical care to the expected massive numbers of COVID‐19 patients, but also to mitigate the contagion spread at the workplace to ensure safety of healthcare workers. All routine, non‐essential medical services and procedures were ramped down and workers deemed non‐essential were directed to work remotely from home to reduce the number of people at hospital premises and preserve much needed personal protective equipment that were in short supply at the outset of the pandemic. The laboratories did not remain unscathed and were under immense pressure to maintain workplace safety while being operational and provide best patient care with limited resources. In this paper, we share our experience and challenges that we faced in a cytopathology laboratory at a major academic centre in New York, USA during the peak of infection., This study reviews the impact of COVID‐19 on cytopathology specimen numbers during the peak of pandemic in New York City. Most specimens decreased in number and proportion except for effusion cytology which almost doubled. The rate of malignant and indeterminate diagnostic categories significantly increased while the benign category decreased, and the non‐diagnostic category remained the same. Adaptations to staffing and clinical operations to provide continuous patient care and trainee education while maintaining workplace safety are described.

For patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer, multi-agent intravesical trials have been limited. In this study we investigate the safety of intravesical cabazitaxel, gemcitabine and cisplatin in the salvage setting.This was a dose escalation, drug escalation trial for patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer who declined or were ineligible for radical cystectomy. All patients underwent a 6-week induction regimen of sequentially administered cabazitaxel, gemcitabine and cisplatin. Complete response was defined as no cancer on post-induction transurethral bladder tumor resection and negative urine cytology, while partial response allowed for positive cytology. Responders continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year.A total of 18 patients were enrolled. Mean age was 71 years, median followup was 27.8 months (range 16.3 to 46.9) and mean number of previous rounds of intravesical therapies before trial enrollment was 3.7. Nine patients (50%) had received intravesical chemotherapy after bacillus Calmette-Guérin and 7 (39%) were previously treated in a phase I clinical trial setting. At enrollment 6 (33%) subjects had T1 disease and 13 (72%) had carcinoma in situ. There were no dose limiting toxicities. Initial partial and complete response rates were 94% and 89%, respectively. At 1 year recurrence-free survival was 0.83 (range 0.57 to 0.94) and at 2 years estimated recurrence-free survival was 0.64 (0.32 to 0.84).In this high risk and highly pretreated cohort of bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer cases combination intravesical cabazitaxel, gemcitabine and cisplatin was a well tolerated and potentially effective regimen.

Objective To investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance. Methods We identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy. Results Two hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence. Conclusions The prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.

Venous aneurysms are benign vascular lesions usually located in the neck, lower extremity, and abdomen, but rarely in the upper extremity. There may be a mistake or delay in diagnosis because they are uncommon. We report a case of a healthy 54-year-old man who had a cephalic venous aneurysm in his wrist that grew slowly over 20 years. The diagnosis was made on MRI and confirmed with excisional surgery. Radiologists should consider venous aneurysms in the differential when evaluating soft tissue masses as they will often be the first to make the correct diagnosis.

The Centers for Disease Control and Prevention recognizes Medicaid as a high-risk population for fatal opioid overdose. Further research is needed to identify factors that put Medicaid patients at increased risk.To determine whether patterns of opioid use are associated with risk of opioid-related mortality among opioid users.This is a retrospective cohort study.In total, 150,821 noncancer pain patients aged 18-64 years with ≥1 opioid prescription, April 2006 to December 2010, Washington Medicaid.Average daily dose (morphine equivalents), opioid schedule/duration of action, sedative-hypnotic use.Compared with patients at 1-19 mg/d, risk of opioid overdose death significantly increased at 50-89 mg/d [adjusted hazard ratio (aHR), 2.3; 95% confidence interval (CI), 1.4-4.1], 90-119 mg/d (aHR, 4.0; 95% CI, 2.2-7.3), 120-199 mg/d (aHR, 3.8; 95% CI, 2.1-6.9), and ≥200 mg/d (aHR, 4.9; 95% CI, 2.9-8.1). Patients using long-acting plus short-acting Schedule II opioids had 4.7 times the risk of opioid overdose death than non-Schedule II opioids alone (aHR, 4.7; 95% CI, 3.3-6.9). Sedative-hypnotic use compared with nonuse was associated with 6.4 times the risk of opioid overdose death (aHR, 6.4; 95% CI, 5.0-8.4). Risk was particularly high for opioids combined with benzodiazepines and skeletal muscle relaxants (aHR, 12.6; 95% CI, 8.9-17.9). Even at opioid doses 1-19 mg/d, patients using sedative-hypnotics concurrently had 5.6 times the risk than patients without sedative-hypnotics (aHR, 5.6; 95% CI, 1.6-19.3).Our findings support Federal guideline-recommended dosing thresholds in opioid prescribing. Concurrent sedative-hypnotic use even at low opioid doses poses substantially greater risk of opioid overdose.

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that non-homologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.

Indeterminate cytologic diagnoses in endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) of solid pancreatic lesions include the diagnostic categories “atypical” (ATY) and “suspicious for malignancy” (SUSP), which are used at variable rates and are associated with variable underlying risk of malignancy. The aim of this study was to determine individual cytopathologists' rates of indeterminate diagnoses in EUS-FNA of solid pancreatic lesions and their relationship to cytopathologists' experience and volume of pancreatic EUS-FNA examined, as well as the potential impact of departmental consensus review on indeterminate diagnoses. Design The diagnostic rates of ATY and SUSP and their underlying risk of malignancy were calculated for six cytopathologists who diagnosed 1,114 of 1,225 EUS-FNA of solid pancreatic lesions from 1/1/2001 to 9/15/2014, and were then compared for the periods before and after the implementation of departmental consensus review during 2009. Results The six cytopathologists diagnosed 10% of cases as indeterminate; 82 (7.4%) as “atypical” and 29 (2.6%) as “suspicious”. The individual cytopathologists' indeterminate diagnosis rates varied twofold (6.67–12.80%) and did not correlate with their experience, total or annual volume of EUS-FNAs. Of the 56/99 (56.57%) cases with follow-up, the underlying rate of malignancy was 47% (35/75; for “atypical” and 87.5% (21/24); for “suspicious”). The underlying rates of malignancy were 33–67% for “atypical” and 80–100% for “suspicious” diagnoses made by individual cytopathologists. The rate of indeterminate diagnoses decreased from 11.55 to 7.88% after the implementation of departmental consensus review. Conclusion Individual cytopathologists' rates of indeterminate diagnoses and their significance vary; however, consensus review is helpful in reducing these rates. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Marriage and family therapy educators increasingly emphasize training competencies. What we know less about is what makes family therapy education meaningful to marriage and family therapy (MFT) graduate students and what does not. In this study, through an Internet survey, we explored the most and least meaningful learning experiences of 68 MFT graduate students and recent graduates of Commission on Accreditation for Marriage and Family Therapy Education-accredited programs. We used thematic analysis to identify and illustrate resulting themes, which included the importance of experiential and personal components to learning, the professor-student alliance, tying theory to practice, and the experiences of students with their clients, among others. We discuss the implications of these findings to support family therapy education and offer tentative suggestions for formative discussions both within and across programs. Video Abstract is found in the online version of the article.

ContextThyroid carcinoma is the most common malignant tumor of endocrine organs, yet it only accounts for approximately 1% of all cancers in the United States with more than 35 000 new cases diagnosed each year and more than 450 000 people living with this disease. While most tumors can be diagnosed without much difficulty, a few tumor types, especially tumors with follicular pattern, sometimes pose a diagnostic challenge.ObjectiveTo discuss morphologic, immunohistochemical, and molecular features of thyroid tumors. We also explore the clinicopathologic features of papillary microcarcinoma and medullary microcarcinoma and how the latter is related and differentiated from C-cell hyperplasia. Finally with the ever-growing list of organ systems involved in immunoglobulin (Ig) G4–related diseases, we discuss the still not completely explored IgG-4–related thyroid disease.Data SourcesData were obtained from review of the pertinent peer-reviewed literature and institutional experience.ConclusionsHistomorphologic evaluation still remains the gold standard for diagnosis in most cases of thyroid diseases. The application of ancillary studies such as immunohistochemistry and molecular diagnosis, including next-generation sequencing, is becoming more common.

Although it is known that inflammation plays a critical role in prostate tumorigenesis, the underlying processes are not well understood. Based on analysis of genetically engineered mouse models combined with correlative analysis of expression profiling data from human prostate tumors, we demonstrate a reciprocal relationship between inflammation and the status of the NKX3.1 homeobox gene associated with prostate cancer initiation. We find that cancer initiation in aged Nkx3.1 mutant mice correlates with enrichment of specific immune populations and increased expression of immunoregulatory genes. Furthermore, expression of these immunoregulatory genes is similarly increased in human prostate tumors having low levels of NKX3.1 expression. We further show that induction of prostatitis in Nkx3.1 mutant mice accelerates prostate cancer initiation, which is coincident with aberrant cellular plasticity and differentiation. Correspondingly, human prostate tumors having low levels of NKX3.1 have de-regulated expression of genes associated with these cellular processes. We propose that loss of function of NKX3.1 accelerates inflammation-driven prostate cancer initiation potentially via aberrant cellular plasticity and impairment of cellular differentiation. This article has an associated First Person interview with the first author of the paper., Summary: Chronic inflammation collaborates with loss of function of the prostate-specific tumor-suppressor NKX3.1 to promote prostate cancer initiation, increase cellular plasticity and impair cellular differentiation.

BACKGROUND: Opioid poisonings have increased as use of prescription opioid medications have increased. To reduce these poisonings, guidelines for chronic opioid use have been implemented. However, if opioid poisonings occur in individuals who do not have high prescribed doses and who are not chronic opioid users, the current guidelines may need revision. OBJECTIVES: To examine changes in rates of methadone and other opioid poisonings after implementation of the WA State Opioid Guideline in 2007 and to examine the prescription history before poisonings. METHODS: The study sample consisted of individuals who had at least 1 paid claim for an opioid prescription in the Medicaid fee-for-service system between April 2006 and December 2010 and had an emergency department or inpatient hospital claim for an opioid poisoning. RESULTS: Methadone poisonings occurred at 10 times the rate of other prescription opioid poisonings and increased between 2006 and 2010. Rates of other prescription opioid poisonings appeared to level off after implementation of the WA opioid guideline in 2007. Among individuals with nonmethadone opioid poisonings, only 44% had chronic opioid use, 17% had prescribed doses in the week before the poisoning >120 mg/d morphine-equivalent dose (MED), 28% had doses CONCLUSIONS: It may be prudent to revise guidelines to address opioid poisonings occurring at relatively low prescribed doses and with acute and intermittent opioid use. Research is needed to establish the best strategies to prevent opioid poisonings. Language: en

Context Idiopathic bronchiolocentric interstitial pneumonia, airway-centered interstitial fibrosis, centrilobular fibrosis, and bronchiolitis interstitial pneumonia are increasingly recognized histopathologic variants of idiopathic interstitial pneumonia that are difficult to fit within existing classification schemes. Objective To review and analyze the appropriate literature that describes the spectrum of histopathologic changes in these conditions, in an effort to ascertain similarities as well as their differences. In addition, we examined associations with hypersensitivity, cigarette smoking, and survival data. Data Sources Relevant and peer-reviewed literature indexed in PubMed (National Library of Medicine) coupled with experience gained by review of personal cases with appropriate histopathology constitute the basis of this study. Conclusions As anticipated, the common link among the above-cited conditions is their bronchiolocentricity, with a predominance of either fibrosis or inflammation. Clear-cut associations with hypersensitivity or cigarette smoking are not evident in this study. The airway-centered interstitial fibrosis variant of bronchiolocentric interstitial lung disease appears to have a poor outcome.

BACKGROUND An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children. METHODS The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing. RESULTS Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAFV600E) (13 of 27 tumors; 48%), 11 measured

Background The tall cell variant of papillary thyroid carcinoma is an aggressive subtype that generally present as large tumors in advanced stage. However, little is known about the tall cell variant of microcarcinoma (tumors measuring

Background Although men on active surveillance for prostate cancer (PCa) may benefit from intervention with 5α-reductase inhibitors (5-ARIs), it has not been resolved whether 5-ARIs are effective for delaying disease progression and, if so, whether specific patients are more likely to benefit. Objective To identify molecular features predictive of patient response to 5-ARIs. Design, setting, and participants Nkx3.1 mutant mice, a model of early-stage PCa, were treated with the 5-ARI finasteride, and histopathological and molecular analyses were performed. Cross-species computational analyses were used to compare expression profiles for treated mice with those of patients who had received 5-ARIs before prostatectomy. Intervention Finasteride administered to Nkx3.1 mutant mice. 5-ARI-treated patient specimens obtained retrospectively. Outcome measurements and statistical analysis Endpoints in mice included histopathology, immunohistochemistry, and molecular profiling. GraphPad Prism software, R-studio, and Matlab were used for statistical and data analyses. Results and limitations Finasteride treatment of Nkx3.1 mutant mice resulted in a significant reduction in prostatic intraepithelial neoplasia (PIN), as evident from histopathological and expression profiling analyses. Cross-species computational analysis comparing finasteride-treated mice with two independent 5-ARI–treated patient cohorts showed that reduced NKX3.1 expression is predictive of response to 5-ARI. A limitation of the study is that these retrospective human cohorts have relatively few patients with limited clinical outcome data. Future prospective clinical trials are needed to validate whether stratifying patients on the basis of NKX3.1 expression improves the benefit of 5-ARIs during active surveillance. Conclusions This co-clinical study implicates NKX3.1 status as a predictor of response to 5-ARIs, and suggests that molecular features, including NKX3.1 expression, may help to identify PCa patients most likely to benefit from 5-ARIs during active surveillance. Patient summary The aim of precision cancer prevention is to tailor interventions on the basis of individualized patient characteristics. We propose that patients with low NKX3.1 expression are optimal candidates for intervention with 5α-reductase inhibitors as an adjunct to active surveillance.

Purpose: Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation. Experimental Design: To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, and in vitro/in vivo assays for CSC viability and tumorigenicity. Results: We identified in ACC CD133-positive CSC that expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. CD133+ ACC cells produced activated NOTCH1 (N1ICD) and generated CD133− cells that expressed JAG1 as well as neural differentiation factors NR2F1, NR2F2, and p27Kip1. Knockdowns of NOTCH1, SOX10, and their common effector FABP7 had negative effects on each other, inhibited spheroidogenesis, and induced cell death pointing at their essential roles in CSC maintenance. Downstream effects of FABP7 knockdown included suppression of a broad spectrum of genes involved in proliferation, ribosome biogenesis, and metabolism. Among proliferation-linked NOTCH1/FABP7 targets, we identified SKP2 and its substrate p27Kip1. A γ-secretase inhibitor, DAPT, selectively depleted CD133+ cells, suppressed N1ICD and SKP2, induced p27Kip1, inhibited ACC growth in vivo, and sensitized CD133+ cells to radiation. Conclusions: These results establish in the majority of ACC the presence of a previously uncharacterized population of CD133+ cells with neural stem properties, which are driven by SOX10, NOTCH1, and FABP7. Sensitivity of these cells to Notch inhibition and their dependence on SKP2 offer new opportunities for targeted ACC therapies. Clin Cancer Res; 22(8); 2083–95. ©2016 AACR.

The aim of this study was to evaluate the potential use of the UroVysion® fluorescent in situ hybridization test (U-FISH) to stratify the risk of urothelial carcinoma (UC) in patients with a diagnosis of "atypical urothelial cells" (AUC) in urinary tract cytology (UTCy).Using a histologic diagnosis of UC and respectively of high grade UC (HGUC) within 12 months of the index UTCy as a reference standard, we determined the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of U-FISH for patients with AUC diagnosed 2008 to 2014.Of the 377 patients with AUC, 62 (16.45%) were diagnosed with UC (29 low grade UC and 33 HGUC) within 12 months. U-FISH were uninformative in 45 (11.94%), positive in 63 (16.71%) and negative in 269 (71.35%). UC was diagnosed more frequently in patients with positive than in those with negative U- FISH results (31/63, 49.21% vs. 25/269, 9.29%, P 0.0001). The sensitivity, specificity, PPV, NPV and accuracy of U-FISH in the setting of AUC were 44.64%, 81.82%, 47.17%, 80.25%, and 71.91% for UC and respectively 48.39%, 78.77%. 28.3%, 89.81%, and 74.29% for HGUC. U-FISH showed a high false positive rate (28/53, 52.83%) that remained high even after extended follow-up, arguing against "anticipatory positive" results.U-FISH allows risk stratification in patients with AUC. However, its usefulness is diminished by the high false-positive rate, making it important to interpret U- FISH results in the patient's clinical context. Diagn. Cytopathol. 2017;45:481-500. © 2017 Wiley Periodicals, Inc.

Autoimmune pancreatitis (AIP) is a chronic inflammatory disease of the pancreas. Examination of pancreatic resection specimens from patients with AIP has shown that there are 2 subclasses of this disease. However, there is no widely accepted pathologic classification scheme and the clinical significance of such a classification remains to be established. In this study, we revisited the subclassification of AIP and examine whether this provides clinically and prognostically meaningful information. We evaluated 29 pancreatic resection specimens from patients with AIP. Demographic, clinical, and imaging data were recorded, as was evidence of extrapancreatic manifestations. In addition to a detailed and semiquantitative histologic evaluation, immunohistochemistry for IgG4 was performed on pancreatic and extrapancreatic tissues. We also evaluated 48 consecutive cases of chronic pancreatitis, not otherwise specified. The resected specimens could readily be subclassified into 2 subtypes: type 1 (n=11) and type 2 (n=18). In comparison with patients with type 2 disease, patients with type 1 disease were significantly more likely to be males (P=0.09), older (P=0.02), and present with jaundice (P=0.01), and less likely to be associated with abdominal pain (P=0.04). On imaging, the pancreatic tail cut-off sign was exclusively seen in patients with type 2 disease (4 of 10 cases). Hypercellular inflamed interlobular stroma was unique to type 1 pattern (91%), whereas significant ductal injury in the form of microabscesses and ductal ulceration was almost exclusively seen in type 2 pattern (78%). Eight of 10 patients with a type 1 pattern had evidence of a systemic disease. Three patients with type 2 disease had recurrent episodes of pancreatitis after their pancreatic resection. In comparison with the cohort of chronic pancreatitis, not otherwise specified, type 2 AIP cases were less likely to be associated with a history of alcohol abuse, and showed significantly more foci of periductal inflammation and neutrophilic microabscesses. Our review of pancreatic resection specimens shows 2 histologically distinct forms of AIP. Our data support the concept that type 1 AIP is a systemic disease and is the pancreatic manifestation of IgG4-related systemic disease. Type 2 disease is confined to the pancreas. The intensity of the periductal inflammatory infiltrate and the presence of ductal neutrophilic abscesses are features that assist in distinguishing type 2 AIP from chronic pancreatitis, not otherwise specified. Although imperfect, clinical and imaging features may help distinguish the 2 subtypes of AIP. On the basis of these significant differences between the 2 types of AIP, we advocate the position that all subsequent studies attempt to substratify their patients into these 2 groups.

We explore the magnitude of and current trends in HIV infection among people who inject drugs and estimate the reach of harm reduction interventions among them in seven high-burden countries of the South-East Asia Region. Our data are drawn from the published and unpublished literature, routine national HIV serological and behavioural surveillance surveys and information from key informants. Six countries (Thailand, Myanmar, Nepal, Indonesia, India, and Bangladesh) had significant epidemics of HIV among people who inject drugs. In Thailand, Indonesia, Bangladesh, Myanmar and India, there is no significant decline in the prevalence of HIV epidemics in this population. In Nepal, north-east India, and some cities in Myanmar, there is some evidence of decline in risk behaviours and a concomitant decline in HIV prevalence. This is countered by the rapid emergence of epidemics in new geographical pockets. Available programme data suggest that less than 12 000 of the estimated 800 000 (1.5%) people who inject drugs have access to opioid substitution therapy, and 20-25% were reached by needle-syringe programmes at least once during the past 12 months. A mapping of harm reduction interventions suggests a lack of congruence between the location of established and emerging epidemics and the availability of scaled-up prevention services. Harm reduction interventions in closed settings are almost nonexistent. To achieve significant impact on the HIV epidemics among this population, governments, specifically national AIDS programmes, urgently need to scale up needle-syringe programmes and opioid substitution therapy and make these widely available both in community and closed settings.

Background— Hypertension-related risk in urban areas may vary from national estimates; however, objective data on prevalence and treatment in local areas are scarce. We assessed hypertension prevalence, awareness, treatment, and control among New York City (NYC) adults. Methods and Results— The NYC Health And Nutrition Examination Survey (HANES), modeled on the national HANES, was conducted in 2004 with a representative sample of noninstitutionalized NYC residents ≥20 years of age. Hypertension outcomes were examined with interview and examination data (n=1975). Multiple logistic regression was used to assess factors associated with control among adults with hypertension. We found that 25.6% of NYC adults had hypertension. Blacks had a higher prevalence than whites (32.8% versus 21.1%, P P P Conclusions— In NYC, hypertension is common and frequently uncontrolled. Low levels of control are associated with poor access to care. Racial disparities in prevalence and control are evident among nonelderly adults.

This study assessed the prevalence, diagnosis, and treatment of major depressive disorder and generalized anxiety disorder among New York City adults.As part of the first community-specific Health and Nutrition Examination Survey in the United States, depression and anxiety were assessed in a representative sample of 1,817 noninstitutionalized adults in 2004.A total of 8% had major depressive disorder and 4% had generalized anxiety disorder. Respondents with depression were more likely to be formerly married, publicly insured, younger, and U.S. born. Only 55% of adults with depression were diagnosed, and 38% of those with depression or anxiety were in treatment; individuals with a diagnosis of depression were more likely to receive treatment than those without a diagnosis (61% versus 7%; p.001). Immigrants with depression were 60% less likely to be diagnosed than their U.S.-born counterparts; immigrants arriving in this country ten or more years ago had slightly more anxiety than immigrants arriving less than ten years ago (3% versus 2%, not significant). Among respondents with anxiety, 23% reported disability compared with 15% of those with depression. Compared with adults with neither diagnosis, adults with depression or anxiety were twice as likely to smoke tobacco (p.05), adults with depression were twice as likely to have diabetes (p.01), and those with anxiety were twice as likely to have asthma (p.01).Mental disorders are often disabling and inadequately diagnosed and treated. Foreign-born adults experience barriers to diagnosis and treatment despite having less depression; anxiety may increase with time since immigration. Increased awareness of and linkage to mental health services are needed, especially in larger, more diverse urban communities.

Background Herpes simplex virus type 2 (HSV-2) infection is associated with substantial morbidity and increased risk for human immunodeficiency virus acquisition. We describe HSV-2 seroprevalence in adult New Yorkers, and examine the relationship between select characteristics, infection, and diagnosis. Methods HSV-2 seroprevalence and risk factors were measured using the 2004 New York City Health and Nutrition Examination Survey, a population-based cross-sectional survey of adults. HSV-2 seroprevalence and corresponding 95% confidence intervals were computed for select characteristics. Associations between proposed risk factors and HSV-2 infection and diagnosis were estimated using unadjusted and adjusted odds ratios. Results Nearly 28% of adults were infected with HSV-2; 88.4% of HSV-2 positive persons were undiagnosed. Black women had the highest seroprevalence (59.7%) of any sex or race/ethnicity group. Women, non-Hispanic blacks, and Hispanics (vs. non-Hispanic whites), and men who have sex with men were at greater odds of HSV-2 infection. Among HSV-2 infected individuals, non-Hispanic blacks (vs. non-Hispanic whites), uncircumcised men, and those with no routine place of care were less likely to be diagnosed. Conclusions HSV-2 is highly prevalent and largely undiagnosed in New York City; seroprevalence varies by subgroup. Targeted HSV-2 screening, counseling and treatment may help reduce transmission of HSV-2 and human immunodeficiency virus.

Objective Retinoids are crucial in the regulation of fundamental cellular processes including terminal differentiation of both normal and malignant myeloid progenitors. The aim of this study was to identify and characterize retinoic acid (RA) target genes. Methods and Results RTP801 is a recently cloned stress response gene that acts as a negative regulator of the mTOR pathway. Here we identified RTP801 as a novel early RA target gene in myeloid cells. RTP801 mRNA levels are induced in acute myeloid leukemia (AML) cell lines during RA-dependent differentiation and are differentially expressed during maturation of normal CD34 + cells. The myeloid-specific, differentiation-related transcription factor C/EBPɛ also induces RTP801 expression. Overexpression of RTP801 in the U937 leukemic cells leads to growth inhibition and apoptosis. Conversely, silencing of endogenous RTP801 by shRNA reduces RA-induced differentiation of the U937 cells. Downregulation of RTP801 also abrogates hypoxia-induced inhibition of mTOR in those cells. Conclusion Taken together, our data suggest that RTP801 is an important RA-regulated gene involved in myeloid differentiation, which could represent a therapeutic target in leukemia.

By 2007, opioid-related mortality in Washington state (WA) was 50% higher than the national average, with Medicaid patients showing nearly 6 times the mortality of commercially-insured patients. In 2007, the WA Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain was released, which recommended caution in prescribing120 mg morphine-equivalent dose per day for patients not showing clinically meaningful improvement in pain and function. We report on opioid dosing in the WA Medicaid fee-for-service population for 273,200 adults with a paid claim for an opioid prescription between April 1, 2006 and December 31, 2010. Linear regression was used to test for trends in dosing over that time period, with quarter-year as the independent variable and median daily dose as the dependent variable. Prescription opioid use among WA Medicaid adults peaked in 2009, as evidenced by the unique number of opioid users (105,232), the total number of prescriptions (556,712), and the total person-years of prescription opioid use (29,442). Median opioid dose was unchanged from 2006 to 2010 at 37.5 mg morphine-equivalent dose, but doses at the 75th, 90th, 95th, and 99th percentiles declined significantly (P .001). These results suggest that opioid treatment guidelines with dosing guidance may be able to reduce high-dose opioid use without affecting the median dose used.Some fear that opioid dosing guidelines might restrict access to opioid therapy for patients who could benefit. However, there is evidence that high-dose opioid therapy entails significant risks without demonstrated benefit. These findings indicate that high-dose opioid therapy can be reduced without altering median opioid dose in a Medicaid population.

Summary Germline mutations in RET proto-oncogene associated with multiple endocrine neoplasia type 2 (MEN2) may affect codons for the extracellular cysteine-rich (ECR) or the intracellular tyrosine kinase (ITK) domain of the transmembrane receptor tyrosine kinase protein. We compared C-cell pathology in asymptomatic carriers of RET mutation affecting the 2 domains. Twenty-two asymptomatic carriers (median age, 9.5 years), 10 with mutations in the ECR (codons 634, 611, 618, and 620) and 12 with mutations in the ITK domain (codons 804, 790, 891, and 918), underwent total thyroidectomy. C-cell hyperplasia was identified in 16 (73%), was multifocal and/or bilateral in 11, and was associated with medullary thyroid carcinoma (MTC) in 10 thyroids. When comparing the ECR and ITK groups in 21 carriers from MEN2A/familial MTC families, C-cell hyperplasia was more frequent in the former (90% versus 55%), as was multifocality (70% versus 27%) and MTC (60% versus 27%), despite the significantly younger median age in the former group (5 versus 23 years, P = .04). One asymptomatic carrier had de novo codon 918 mutation (MEN2B) and showed bilateral microcarcinoma with lymph node metastasis at presentation and progressive disease on follow-up. In conclusion, asymptomatic carriers of high-risk RET mutations affecting the ECR were significantly younger and frequently showed C-cell neoplasia, multifocality, and MTC when compared with mutations affecting the ITK domain in the MEN2A/familial MTC families. The presence of C-cell disease, its severity, and aggressiveness correlated with the mutated codon and with increasing age.

To examine trends in opioid poisonings and adverse effects in Washington (WA) State and nationally.We calculated rates of opioid poisonings and adverse effects and examined opioid prescriptions in the WA workers' compensation system, 2004-2010. Using Health Care Cost and Utilization Project (HCUP), Nationwide Inpatient Sample (NIS) data, we also calculated national rates of opioid poisonings and adverse effects, 1993-2010.We identified 96 opioid poisonings and 312 opioid-related adverse effects in WA, 2004-2010. The rates did not change substantially over these years. Most poisonings and adverse effects occurred in cases without chronic opioid use and with prescribed doses120 mg/day morphine-equivalent dose. Nationally, the rates of opioid poisonings and adverse effects increased significantly from 1993 to 2010.Many poisonings and adverse effects occurred in patients without high dose or long-term opioid therapy, suggesting that opioid dosing and duration guidelines may not be sufficient to reduce morbidity related to prescription opioid use.

Papillary thyroid carcinomas (PTC) with BRAF (V600E) mutation are morphologically distinctive. They are typically classic or tall cell variants, show infiltrative borders, and are associated with desmoplasia/fibrosis, psammoma bodies, and well-developed nuclear features of papillary carcinoma. We hypothesize that morphologic features of PTC can help in the prediction of BRAF (V600E) mutation, and we evaluate the accuracy and the interobserver reproducibility of such prediction. Hematoxylin and eosin-stained sections from 50 PTCs comprising of 26 mutation-positive and 24 mutation-negative tumors were examined. BRAF (V600E) mutation was predicted correctly in 42/50 tumors (accuracy, 84 %) with 96 % sensitivity, 71 % specificity, and 78 % positive and 94 % negative predictive values (NPV). Subtle nuclear features of PTC (n = 10) had the highest (100 %) negative predictive value followed by well-circumscribed non-infiltrative tumor borders (17/22 mutation-negative tumors, 95 % NPV). The positive predictive value of infiltrative tumor borders (21/28 [75 %] mutation-positive), desmoplasia/fibrosis (23/31 [74 %] mutation-positive), and psammoma bodies (13/20 [65 %] mutation-positive) increased to 100 % when all three features were present (n = 8/8 mutation-positive). To assess interobserver reproducibility, two pathologists blinded to the mutational status evaluated 30 PTCs (15 mutation-positive and 15 mutation-negative) after self-training on 10 PTCs with known BRAF (V600E) mutational status (five mutation-positive and five mutation-negative). The prediction of the mutation was achieved with substantial agreement (κ value, 0.79) and accuracy (25/30, 83 %). This study demonstrates that BRAF (V600E) mutation in papillary thyroid carcinoma can be predicted on morphology with accuracy and with substantial interobserver agreement.

BACKGROUND: Fine-needle aspiration (FNA) is the most accurate and cost-effective method for evaluating thyroid nodules. However, FNA-induced secondary changes completely replacing thyroid tumors (vanishing tumors) may create a novel problem. In this study, we highlight the diagnostic and management issues associated with the unintended consequences of ultrasonography (US)-guided FNA. METHODS: Fourteen thyroid glands (11 women and 3 men, ages 33–64 years) with vanishing tumors were prospectively identified between 2009 and 2012 upon surgical resection. Cytology and histopathology slides were reviewed, and second opinions were obtained when necessary. RESULTS: The cytology of the 14 vanishing tumors was suspicious/positive for papillary thyroid carcinoma (PTC) in 5, indeterminate (atypia of unknown significance) in 5, benign in 2, follicular neoplasm in 1, and nondiagnostic in 1 nodule. Upon thyroidectomy, the vanishing tumors ranged in size from 0.4 to 3.5 cm (median 0.7 cm). Microscopically, the nodules showed cystic degeneration, organizing hemorrhage, granulation tissue, fibrosis, and microcalcifications. In seven tumors, a few residual malignant cells (PTC in five) or residual benign follicles (hemorrhagic cyst in two) at the periphery of the vanishing tumors helped with the final diagnosis. The remaining seven tumors were completely replaced by FNA-induced secondary changes, and had the cytology diagnosis of benign in one, follicular neoplasm in one, and suspicious/positive for PTC in five. Of the latter five, two showed additional separate foci of PTC, while three vanishing tumors (0.5, 1.2, and 1.6 cm) had no residual malignant cells and no additional carcinoma leading to a final diagnosis of negative for malignancy. CONCLUSIONS: US-guided FNA may lead to complete obliteration of thyroid nodules, rendering final diagnosis upon thyroidectomy difficult or impossible. In these unusual circumstances, the possibility that the surgical pathology may be nonrepresentative should be considered if the cytologic features on FNA are sufficient by themselves to support a definitive diagnosis of PTC.

The distinction of Crohn's disease from ulcerative colitis is based on clinical, endoscopic, radiological, and histological findings, a paradigm that remains unchanged despite the advent of new understanding of the immunological and genetic basis of inflammatory bowel disease. There is a strong correlation between inflammatory bowel disease, predominantly ulcerative colitis, and autoimmune pancreatitis. We hypothesized that colonic biopsies from patients with inflammatory bowel disease would demonstrate increased numbers of IgG4-positive plasma cells and that this elevation might be restricted to ulcerative colitis. We examined a cohort of 78 cases of inflammatory bowel disease: 50 ulcerative colitis and 38 Crohn's disease. We identified treatment-naive biopsies. Additionally, four cases of inflammatory bowel disease associated with autoimmune pancreatitis and 15 cases of lymphocytic/collagenous colitis were also identified. Immunohistochemical stains for IgG4 were performed. Biopsies from patients with ulcerative colitis showed significantly higher numbers of IgG4-bearing plasma cells than those with Crohn's disease (mean IgG4 counts per high-power field (hpf) 9.8 vs 2.8, P=0.001). Samples from 19 (38%) ulcerative colitis patients had IgG4 counts >10/hpf, compared with only two (5%) patients with Crohn's disease; the sensitivity and specificity of a cutoff at 10 IgG4-positive plasma cells per hpf was 38 and 95%, respectively. Among individuals

Introduction Body mass index (BMI) and indicators of central adiposity have been associated with cardiovascular disease (CVD) risk factors, but ambiguity remains about which measure optimally predicts CVD risk and is best suited for different racial/ethnic groups. We sought to characterize excess adiposity among New York City adults and assess the potential associations between multiple adiposity indicators and CVD risk factors, by race/ethnicity. Methods The New York City Health and Nutrition Examination Survey (NYC HANES) is a population-based survey of noninstitutionalized New York City adult residents aged 20 years or older. We compared the prevalence of obesity (BMI ≥30 kg/m2), elevated waist circumference (>102 cm for men, >88 cm for women), and elevated waist-to-height ratio (≥0.5) for participants in the 2004 NYC HANES (n = 1,912) and the 2003-2004 National Health and Nutrition Examination Survey (n = 4,075). Logistic regression was used to assess potential associations between each of these indicators of excess adiposity and CVD risk factors (diabetes, impaired fasting glucose, hypertension, and hypercholesterolemia), overall and by race/ethnicity. Results The prevalence of obesity among NYC HANES participants was 26% and of elevated waist circumference was 46%, both significantly lower than national estimates (31% and 52%, respectively), whereas the prevalence of elevated waist-to-height ratio was higher (82% vs 79%). Most measures of excess adiposity were significantly associated with all CVD risk factors. No single measure of excess adiposity emerged as most consistently predictive of CVD risk in the general population or by race/ethnicity. Conclusion New York City has a lower prevalence of obesity and elevated waist circumference but a higher prevalence of elevated waist-to-height ratio than found nationally. Further investigation into the optimal adiposity measure to predict CVD risk across racial/ethnic populations may be warranted.

Automated pharmacy databases are increasingly available for assessing medication use, but research on the validity of these data is incomplete. This study aimed to measure agreement on warfarin and aspirin use between medical records and automated pharmacy data among patients with newly detected atrial fibrillation (AF).Patients with newly detected AF (n = 1953) were previously identified in a cohort study at Group Health (GH) in Washington State. Medical records were reviewed for information on risk factors and medication use, as well as clinical care during the 6 months after AF onset. Medication data were also obtained from the GH pharmacy database. We determined the sensitivity, specificity, and positive predictive value (PPV) as measures of the validity of the GH pharmacy database as compared with medical records for warfarin and aspirin use during the first 6 and 3 months after AF onset. We also calculated the κ statistic.For warfarin use, in comparison with the medical record review, the sensitivity, specificity, and PPV for the GH pharmacy database were excellent, and agreement was almost perfect in the 3- and 6-month periods after AF onset (κ = 0.92 and 0.93, respectively). For aspirin use, the GH pharmacy database had low sensitivity but high specificity, and agreement was only fair for these two periods (κ = 0.28 and 0.31, respectively).The GH pharmacy database is a valuable source of data for pharmacoepidemiologic research on warfarin use among patients with AF. However, the database cannot be recommended for assessment of aspirin use. Copyright © 2010 John WileySons, Ltd.

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign, proliferative mesenchymal lesion with possible hormonal etiology. It typically affects women in the reproductive age group. Pseudoangiomatous stromal hyperplasia is frequently an incidental histologic finding in breast biopsies performed for other benign or malignant lesions. Rarely, it can present as a firm, painless breast mass, which has been referred to as nodular or tumorous PASH. Grossly, tumorous PASH is a well-circumscribed, firm, rubbery mass with solid, homogenous, gray-white cut surface. On histologic examination, it is characterized by the presence of open slitlike spaces in dense collagenous stroma. The spaces are lined by a discontinuous layer of flat, spindle-shaped myofibroblasts with bland nuclei. The spindle cells express progesterone receptors and are positive for vimentin, actin, and CD34. The most important differential diagnosis on histopathology is angiosarcoma. Pseudoangiomatous stromal hyperplasia discovered incidentally does not require any additional specific treatment. Tumorous PASH is treated by local surgical excision with clear margins and the prognosis is excellent, with minimal risk of recurrence after adequate surgical excision.

Introduction: We describe smoking prevalence and second- hand smoke (SHS) exposure among adult nonsmokers in New York City (NYC) across key demographic strata and compare exposure estimates with those found nationally. Methods: We used serum cotinine data from the 2004 NYC Health and Nutrition Examination Survey ( n = 1,767 adults aged 20 years or older) and the 2003 - 2004 National Health and Nutrition Examination Survey ( n = 4,476 adults aged 20 years or older) to assess and compare smoking prevalence and the prevalence of elevated cotinine levels ( ≥ 0.05 ng/ml) among nonsmokers. We conducted multivariate logistic regression to assess independent predictors of elevated cotinine levels in NYC. Results: Although the smoking prevalence in NYC was lower than that found nationally (23.3% vs. 29.7%, p < .05), the pro- portion of nonsmoking adults in NYC with elevated cotinine levels was greater than the national average overall (56.7% vs. 44.9%, p < .05) and was higher for most demographic sub- groups. In NYC, the highest cotinine levels among nonsmokers were among adults aged 20 - 39 years, males, and Asians. Discussion: Although NYC enacted comprehensive smoke- free workplace legislation in 2003, fi ndings suggest that expo- sure to SHS remains a signifi cant public health issue, especially among certain subgroups. The fi nding of a higher prevalence of SHS exposure in NYC despite lower smoking rates is puzzling but suggests that SHS exposure in dense, urban settings may pose a particular challenge.

Hepatitis C virus (HCV) is the leading cause of chronic liver disease in the United States. Accurate hepatitis C prevalence estimates are important to guide local public health programs but are usually unavailable to local health jurisdictions. National surveys may not reflect local variation, a particular challenge for urban settings with disproportionately large numbers of residents in high-risk population groups. In 2004, the New York City Department of Health and Mental Hygiene conducted the NYC Health and Nutrition Examination Survey, a population-based household survey of non-institutionalized NYC residents ages 20 and older. Study participants were interviewed and blood specimens were tested for antibody to HCV (anti-HCV); positive participants were re-contacted to ascertain awareness of infection and to provide service referrals. Of 1,786 participants with valid anti-HCV results, 35 were positive for anti-HCV, for a weighted prevalence of 2.2% (95% confidence interval [CI] 1.5% to 3.3%). Anti-HCV prevalence was high among participants with a lifetime history of injection drug use (64.5%, 95% CI 39.2% to 83.7%) or a lifetime history of incarceration as an adult (8.4%, 95% CI 4.3% to 15.7%). There was a strong correlation with age; among participants born between 1945 and 1954, the anti-HCV prevalence was 5.8% (95% CI 3.3% to 10.0%). Of anti-HCV positive participants contacted (51%), 28% (n = 5) first learned of their HCV status from this survey. Continued efforts to prevent new infections in known risk behavior groups are essential, along with expansion of HCV screening and activities to prevent disease progression in people with chronic HCV.

A 62-year-old woman with a pre-existing psoriasis was treated with oral imatinib (400 mg/day) for a metastatic gastrointestinal stromal tumour. Within 4 weeks of starting therapy, she developed a guttate psoriasis flare. The eruption markedly improved within 2 weeks following cessation of imatinib. However, it recurred when imatinib was recommenced. She has been able to continue on imatinib (400 mg/day) with low-dose oral methotrexate (12.5 mg/week) controlling the psoriasis.

Objectives. We sought to evaluate the contribution of the New York City Health and Nutrition Examination Survey (NYC-HANES) to local public health surveillance. Methods. Examination-diagnosed estimates of key health conditions from the 2004 NYC-HANES were compared with the National Health and Nutrition Examination Survey (NHANES) 2003–2004 national estimates. Findings were also compared with self-reported estimates from the Community Health Survey (CHS), an annually conducted local telephone survey. Results. NYC-HANES estimated that among NYC adults, 25.6% had hypertension, 25.4% had hypercholesterolemia, 12.5% had diabetes, and 25.6% were obese. Compared with US adults, NYC residents had less hypertension and obesity but more herpes simplex 2 and environmental exposures (P < .05). Obesity was higher and hypertension was lower than CHS self-report estimates (P < .05). NYC-HANES and CHS self-reported diabetes estimates were similar (9.7% vs 8.7%). Conclusions. NYC-HANES and national estimates differed for key chronic, infectious, and environmental indicators, suggesting the need for local data. Examination surveys may provide more accurate information for underreported conditions than local telephone surveys. Community-level health and nutrition examination surveys complement existing data, providing critical information for targeting local interventions.

OBJECTIVE—To determine the prevalence of diabetes and impaired fasting glucose (IFG) and to assess clinical management indicators among adults with diabetes in a representative sample of New York City adults. RESEARCH DESIGN AND METHODS—In 2004, New York City implemented the first community-level Health and Nutrition Examination Survey (NYC HANES), modeled after the National Health and Nutrition Examination Survey (NHANES). We used an interview to determine previously diagnosed diabetes and measured fasting plasma glucose to determine undiagnosed diabetes and IFG in a probability sample of 1,336 New York City adults. We assessed glycemic control and other clinical indicators using standardized NHANES protocols. RESULTS—The prevalence of diabetes among New York City adults was 12.5% (95% CI 10.3–15.1): 8.7% diagnosed and 3.8% undiagnosed. Nearly one-fourth (23.5%) of adults had IFG. Asians had the highest prevalence of impaired glucose metabolism (diabetes 16.1%, IFG 32.4%) but were significantly less likely to be obese. Among adults with diagnosed diabetes, less than one-half (45%) had A1C levels CONCLUSIONS—In New York City, diabetes and IFG are widespread. Policies and structural interventions to promote physical activity and healthy eating should be prioritized. Improved disease management systems are needed for people with diabetes.

Sertoli-Leydig cell tumor (SLCT) is a rare tumor involving the ovary. Approximately 20% of SLCT are associated with heterologous elements that are either of endodermal or mesodermal origin. The gastrointestinal-type epithelium is the most commonly described endodermal heterologous element. SLCT with benign and borderline mucinous neoplasm has been reported in the literature. However, SLCT with mucinous adenocarcinoma as heterologous element has been rarely documented. Herein, we describe a rare case of intermediately differentiated Sertoli-Leydig cell tumor with mucinous adenocarcinoma as the heterologous element in a 21-year-old woman. She presented with throbbing lower abdominal pain and was found to have a large, complex left ovarian mass on imaging studies. She underwent left salpingo-oophorectomy, appendectomy and lymph node staging. Gross examination of the surgical specimen showed a large, encapsulated, solid-cystic mass completely replacing the ovary. Microscopically, the tumor was composed of intermediately differentiated Sertoli-Leydig cell tumor and well-differentiated mucinous adenocarcinoma. Interestingly, the bulk of the tumor (more than 90%) was composed of mucinous adenocarcinoma, whereas the SLCT component comprised less than 10% of the total tumor. The mucinous adenocarcinoma expressed positivity for CK20, CEA, CDX2 and CK7, and the SLCT component was positive for inhibin expression. The histopathological features and results of immunostaining were consistent with the diagnosis of the intermediately differentiated SLCT with mucinous adenocarcinoma as the heterologous element. This case was a diagnostic challenge as more than 90% of the tumor was composed of mucinous adenocarcinoma and SLCT constituted only the minor part of the tumor. This feature was in contrast to the previously described two cases, where mucinous adenocarcinoma as heterologous element was present as microscopic foci. This case highlights the importance of identifying the SLCT component in a case of an apparently pure mucinous adenocarcinoma in a young patient.

Diffuse cavernous hemangioma of the uterus in pregnant woman is an extremely rare condition. A total of eight cases have been described in the literature till date. The antenatal diagnosis as well as management requires considerable skill. Although it is a benign condition but it can have serious consequences for the mother as well as the baby.Here we describe an interesting case of diffuse cavernous hemangioma of the uterus in a 21-year-old G3, P2-0-0 pregnant woman, who underwent hysterectomy for uncontrollable bleeding during third cesarean section. The diagnosis of diffuse cavernous hemangioma was made only on histopathological examination of the hysterectomy specimen.Diffuse hemangioma of the uterus in a pregnant woman is a serious condition, which may not be detected early during the pregnancy. This can result in uncontrolled bleeding especially during operative delivery and may require hysterectomy.

Background: Surveillance for HIV likely underestimates infection among the general population: 25% of US residents are estimated to be unaware of their HIV infection. Objective: To determine the prevalence of HIV infection and risk behaviors among New York City (NYC) adults and compare these with surveillance findings. Methods: The NYC Health and Nutrition Examination Survey (HANES) provided the first opportunity to estimate population-based HIV prevalence among NYC adults. It was conducted in 2004 among a representative sample of adults > 20 years. Previously reported HIV infection was identified from the NYC HIV/AIDS Surveillance Registry. A blinded HIV serosurvey was conducted on archived blood samples of 1626 NYC HANES participants. Data were used to estimate prevalence for HIV infection, unreported infections, high-risk activities, and self-perceived risk. Results: Overall, 18.1% engaged in one or more risky sexual/needle-use behaviors, of which 92.2% considered themselves at lowor no risk of HIV or another sexually transmitted disease. HIV occurred in 21 individuals (prevalence 1.4%; 95% confidence interval (Cl), 0.8-2.5]; one infection (5%; 95% Cl, 0.7-29.9) was not reported previously and possibly undiagnosed. HIV infection was significantly elevated in those with herpes simplex virus 2 (4%), men who have sex with men (14%), and needle-users (21 %) (P < 0.01). Conclusions: Among NYC adults, HIV prevalence was consistent with surveillance findings overall. The proportion of unreported HIV was less than estimated nationally, but findings were limited by sample size. Most adults with risky behaviors perceived themselves to be at minimal risk, highlighting the need for risk reduction and routine HIV screening.

Purpose: Epigenetic events are a critical factor contributing to cancer development. The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non–small cell lung cancer (NSCLC). Experimental Design: We used microarray analysis to screen for tumor suppressor genes. Results: We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1 levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1 in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1 expression NSCLC. Conclusions: These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.

Endocrine, neuroendocrine and exocrine cells store regulated secretory proteins in secretory granules, while constitutive and constitutive-like secretory proteins are secreted directly without storage. Sorting of secretory proteins takes place in the trans-Golgi network (sorting for entry) or immature secretory granules (sorting by retention). The relative contribution of these sorting steps and the sorting signals and mechanisms involved in each step has been the subject of intense studies and debate in recent years. New evidence now suggests that: (1) two proteins with structurally similar sorting signals can use different sorting mechanisms; (2) one protein with multiple sorting signals can be sorted differently in different cell types; and (3) one cell type can recognize different sorting signals and use different sorting mechanisms. The latter finding suggests that sorting must be a regulated event. While the current image of sorting is complex, recent findings are pointing to common features that form a mosaic of related sorting mechanisms.