The Effect of Night Float Rotation on Resident Sleep, Activity, and Well-Being.

BACKGROUND: Night float call systems are becoming increasingly common at training programs with the goal of reducing fatigue related to sleep deprivation and sleep disturbance. Previous studies have shown that trainees obtain less sleep during the night float rotation and have decreased sleep efficiency for several days after the rotation. The impact on physical and emotional well-being has not been documented. METHODS: Twenty-seven anesthesia residents were enrolled in a study using wearable sleep and activity trackers and National Institutes of Health Patient-Reported Outcome Measurement Information System (NIH PROMIS) surveys for sleep disturbance, fatigue, and positive affect to record data the week before ("baseline"), during ("night float"), and 1 week after ("recovery") their night float rotation. Each subject's data during the night float week and recovery week were compared to his or her own baseline week data using a paired, nonparametric analysis. The primary outcome variable was the change in average daily sleep hours during the night float week compared to the baseline week. Average daily rapid eye movement (REM) sleep, daily steps, and NIH PROMIS scores comparing night float and recovery weeks to baseline week were prespecified secondary outcomes. NIH PROMIS scores range from 0 to 100 with 50 as the national mean and more of the construct having a higher score. RESULTS: There was no difference in average daily sleep hours between the night float and the baseline weeks (6.7 [5.9-7.8] vs 6.7 [5.5-7.7] hours, median [interquartile range]; P = .20). Residents had less REM sleep during the night float compared to the baseline weeks (1.1 [0.7-1.5] vs 1.4 [1.1-1.9] hours, P = .002). NIH PROMIS fatigue scores were higher during the night float than the baseline week (58.8 [54.6-65.1] vs 48.6 [46.0-55.1], P = .0004) and did not return to baseline during the recovery week (51.0 [48.6-58.8], P = .029 compared to baseline). Sleep disturbance was not different among the weeks. Positive affect was reduced after night float compared to baseline (39.6 [35.0-43.5] vs 44.8 [40.1-49.6], P = .0009), but returned to baseline during the recovery week (43.6 [39.6-48.2], P = .38). CONCLUSIONS: The residents slept the same number of total hours during their night float week but had less REM sleep, were more fatigued, and had less positive affect. All of these resolved to baseline except fatigue, that was still greater than the baseline week. This methodology appears to robustly capture psychophysiological data that might be useful for quality initiatives.

Identification of the coexisting HER2 gene amplification and novel mutations in the HER2 protein-overexpressed mucinous epithelial ovarian cancer.

BACKGROUND: Although overexpression, amplification, and somatic mutation of the HER2 gene have been noted in various types of human cancers, we report here for the first time that novel mutations and amplification of the HER2 gene occurred concomitantly in mucinous epithelial ovarian cancer (EOC). METHODS: Twenty-seven tissue microarray samples from EOC patients were analyzed by immunohistochemistry (IHC) with Dako c-erb-B2 antibody and subsequently were examined by fluorescence in situ hybridization (FISH) with the Abbott PathVysion HER2 DNA Probe Kit. HER2 gene, exon 18-24, encoding a tyrosine kinase domain, was analyzed by polymerase chain reaction (PCR) and direct sequencing. RESULTS: The FISH-IHC paired results confirmed 19 concordant negative results and 3 concordant positive results. Moreover, all 4 HER2-amplified cases were of the mucinous type, whereas the remaining 23 HER2-nonamplified cases were of the nonmucinous type. The 4 mucinous EOC cases with HER2 gene amplification were selected and further analyzed for HER2 gene mutations. Data revealed that somatic mutations were present in 2 cases (R970W and E971G), but absent in the other 2 cases. CONCLUSIONS: HER2 protein overexpression correlated significantly with HER2 gene amplification in EOC (P = 0.027). It is surprising that all 4 cases of mucinous EOC showed HER2 gene amplification confirmed by FISH testing. However, we suppose that increasing the number of cases would possibly modify the results. This study also showed that both HER2 gene amplification and somatic mutations are not mutually exclusive in mucinous EOC. Further studies are warranted to investigate the potential role of anti-HER2 therapy.

Assessing the impact of polysomy-17 on HER2 status and the correlations of HER2 status with prognostic variables (ER, PR, p53, Ki-67) in epithelial ovarian cancer: a tissue microarray study using immunohistochemistry and fluorescent in situ hybridization.

Although HER2 overexpression and Her2 amplification have been noted in breast and a variety of human cancers, we report here for the first time the impact of polysomy-17 on HER2 status and the correlations between HER2 status and other prognostic factors in patients with epithelial ovarian cancers (EOC).We analyzed HER2, estrogen receptor (ER), progesterone receptor (PR), p53, and Ki-67 protein overexpressions by immunohistochemistry (IHC) and determined Her2 gene amplification by fluorescence in situ hybridization (FISH) in 27 tissue microarray samples from EOC patients.We achieved 100% positive concordance (3/3) and 100% negative concordance (19/19) between HER2 testing by IHC and FISH. Both the total Her2 gene copies and FISH scores increased significantly in a stepwise order through the negative, equivocal, and positive HER2 IHC result categories in all 27 cases (P=0.001, P=0.001), and still increased significantly in 18 nonpolysomy-17 cases (P=0.007 and 0.013) after the exclusion of 9 polysomy-17 cases. HER2 protein expression is inversely correlated with both ER (P=0.002) and PR expressions (P=0.046). Her2 gene amplification is inversely correlated with ER expression (P=0.007) but not with PR expression (P=0.106).This study showed extremely high positive and negative concordances between Her2 FISH and HER2 IHC assays. Polysomy-17 is insufficient for causing a significant impact on the relationship between HER2 testing by IHC and FISH in EOC. ER and PR expressions were inversely correlated with HER2 protein expression. In addition, ER but not PR expression is inversely correlated with Her2 gene amplification.

The HER2 gene copies per tumor cell either before or after correction for chromosome-17 correlated significantly with HER2 IHC results in epithelial ovarian cancer in a tissue microarray study.

BACKGROUND: HER2 gene amplification and HER2 protein overexpression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast cancer patients. The purpose of this study is to evaluate the correlation between HER2 protein expressions and the HER2 gene copies per tumor cell either before or after chromosome-17 correction in epithelial ovarian cancer (EOC). METHODS: Adopting 2007 ASCO/CAP guideline recommendations for HER2 testing, 27 tissue microarray (TMA) samples from EOC patients were analyzed by immunohistochemistry (IHC) using Dako, c-erb-B2 antibody and subsequently examined by fluorescence in situ hybridization (FISH) using Abbott/Vysis, PathVysion HER2 DNA Probe Kit. RESULTS: The overall concordance revealed 81.5% between HER2 IHC and HER2 FISH results. Additionally, HER2 gene copies prior to chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal, and positive IHC result categories (P = 0.026), as did the HER2 gene copies after chromosome-17 correction (P = 0.028). On the other hand, HER2 IHC results correlated significantly with both chromosome-17 uncorrected HER2 gene copy numbers (ρ = 0.430, P = 0.025) and chromosome-17 corrected HER2 gene copy numbers (ρ = 0.524, P = 0.027). CONCLUSION: We demonstrated that both chromosome-17 corrected and uncorrected HER2 gene copies correlated significantly with HER2 IHC result categories; and tests for the HER2 gene copies per tumor cell either before or after correction for chromosome-17 can be applied as a potentially valuable tool in analyzing the HER2 status in EOC.

Five commonly used markers (p53, TTF1, CK7, CK20, and CK34betaE12) are of no use in distinguishing between primary endocervical and endometrial adenocarcinomas in a tissue microarray extension study.

BACKGROUND: The choice of appropriate therapeutic plans for primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) depends on the tumor's site of origin. Some panels of antibodies help to distinguish primary ECA from EMA. However, unexpected expressions of those markers often exist, which causes this diagnostic dilemma to be still unresolved. In this study, we investigate five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34betaE12) to evaluate their potential use in distinguishing between these two gynecologic malignancies. METHODS: A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin-biotin (ABC) technique, tissue array sections were immunostained with the five aforementioned commercially available antibodies. RESULTS: Immunohistochemical (IHC) expressions of p53, TTF1, CK7, CK20, and CK34betaE12 were all nonsignificant (P>0.05) in frequency differences between the immunostaining results (positive vs. negative) in tumors from both the two primary adenocarcinomas (ECA vs. EMA). CONCLUSION: It is still uncertain which markers or panels would be the most appropriate for making diagnoses; hence, exploration of other useful markers, which make a definitive distinction between ECA and EMA merits further studies. This study, however, uncovered that the five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34betaE12) are of no beneficial value in distinguishing between primary ECA and EMA.

Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study.

BACKGROUND: Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect uterus; however, their biological behaviors are quite different. This distinction has clinical significance, because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate 3 different scoring mechanisms of p16INK4a immunohistochemical (IHC) staining in distinguishing between primary ECAs and EMAs. METHODS: A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 24 EMAs. Tissue array sections were immunostained with a commercially available antibody of p16INK4a. Avidin-biotin complex (ABC) method was used for antigens visualization. The staining intensity and area extent of the IHC reactions was evaluated using the semi-quantitative scoring system. The 3 scoring methods were defined on the bases of the following: (1) independent cytoplasmic staining alone (Method C), (2) independent nucleic staining alone (Method N), and (3) mean of the sum of cytoplasmic score plus nucleic score (Method Mean of C plus N). RESULTS: Of the 3 scoring mechanisms for p16INK4a expression, Method N and Method Mean of C plus N showed significant (p-values < 0.05), but Method C showed non-significant (p = 0.245) frequency differences between ECAs and EMAs. In addition, Method Mean of C plus N had the highest overall accuracy rate (81.6%) for diagnostic distinction among these 3 scoring methods. CONCLUSION: According to the data characteristics and test effectiveness in this study, Method N and Method Mean of C plus N can significantly signal to distinguish between ECAs and EMAs; while Method C cannot do. Method Mean of C plus N is the most promising and favorable means among the three scoring mechanisms.

Adding the p16(INK4a) marker to the traditional 3-marker (ER/Vim/CEA) panel engenders no supplemental benefit in distinguishing between primary endocervical and endometrial adenocarcinomas in a tissue microarray study.

Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect the uterus; however, their biologic behaviors are quite different. This distinction has clinical significance, because the appropriate therapy may depend on the site of tumor origin. In this study, we not only compare the individual expression status of 4 immunomarkers [estrogen receptor (ER), vimentin (Vim), carcinoembryonic antigen (CEA), and p16], but also evaluate whether p16 adds value to the ER/Vim/CEA panel characteristics and performance in distinguishing between primary ECA and EMA. A tissue microarray (TMA) was constructed using paraffin-embedded, formalin-fixed tissues from 38 hysterectomy specimens, including 14 ECAs and 24 EMAs. Tissue microarray sections were immunostained with 4 antibodies, by the avidin-biotin complex method for antigen visualization. The staining intensity and area extent of the immunohistochemical reactions were evaluated using the semiquantitative scoring system. The 3 markers (ER, Vim, CEA) and their respective panel expressions showed statistically significant (P<0.05) frequency differences in ECA and EMA tumors. The p16 marker also revealed a significant frequency difference (P<0.05) between ECA and EMA, but did not demonstrate any supplementary benefit to the traditional 3-marker panel. In conclusion, when histomorphologic and clinical doubt exist as to the primary site of origin, we suggest that the conventional 3-marker (ER/Vim/CEA) panel is appropriate. Ancillary p16-marker testing does not add value to the 3-marker panel in distinguishing between primary ECA and EMA.

Brief Report: Macrophage Activation in HIV-Infected Adolescent Males Contributes to Differential Bone Loss by Sex: Adolescent Trials Network Study 021.

Accumulating evidence suggests that rates of low bone mass are greater in HIV-infected males than females. Of 11 biomarkers assessed by sex and HIV-status, HIV-infected males had increased levels of soluble CD14 which inversely correlated with bone mineral content and bone mineral density measures, suggesting macrophage activation as a possible mechanism of differential bone loss.

Multipoint Kras oncogene mutations potentially indicate mucinous carcinoma on the entire spectrum of mucinous ovarian neoplasms.

Kras mutation is a common phenomenon in many human neoplasms. We aimed to assess the Kras mutational status along the histological continuum from normal ovaries to the development of benign, borderline and malignant ovarian mucinous neoplasms. We analyzed 41 cases of malignant, 10 cases of borderline, 7 cases of benign mucinous ovarian tumors and 7 cases of normal ovarian tissue. The prevalence of Kras mutations in the normal ovary was 0.00% (n=0/7), while the prevalence in benign, borderline and malignant mucinous neoplasms was 57.14% (n=4/7), 90.00% (n=9/10) and 75.61% (n=31/41), respectively. Multiple Kras mutations were detected in 6 cases of mucinous carcinoma, including 5 double mutations with G13D/V14I (n=1), G12V/G13S (n=1), G12D/G13S (n=3) and one triple mutation with A11V/G13N/V14I (n=1). We identified six cases with 3 novel Kras mutations not previously described in the COSMIC database, which included A11V (n=3) and V14I (n=2) in mucinous carcinomas, and A11T (n=1) in a mucinous borderline tumor. In conclusion, Kras mutation appears to be one of the imperative events in the ovarian mucinous adenoma-borderline tumor-carcinoma sequence, as increased numbers of Kras mutations have been shown to be the strongest predictor of unequivocal malignancy in ovarian mucinous neoplasms.

A promising hypothesis of c-KIT methylation/ expression paradox in c-KIT (+) squamous cell carcinoma of uterine cervix ----- CTCF transcriptional repressor regulates c-KIT proto-oncogene expression.

We recently reported one interesting case showing mutation-free c-KIT proto-oncogene overexpression and paradoxical hypermethylation in 54 cases of primary squamous cell carcinoma of uterine cervix (SCC). However, its molecular mechanisms still remain unknown. We propose the hypothesis that increased methylation at the CpG islands on the promoter near the first exon region might interfere with the binding of CTCF repressor with c-KIT promoter that regulates c-KIT proto-oncogene expression in such case. Further studies focusing on the status of epigenetic modifications of mutation-free c-KIT (+) tumors are encouraged.

Assessment of HER2 Status Using Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) Techniques in Mucinous Epithelial Ovarian Cancer: A Comprehensive Comparison between ToGA Biopsy Method and ToGA Surgical Specimen Method.

We aimed to compare the assay performance characteristics of HER2 status in mucinous epithelial ovarian cancer (EOC) by ToGA (Trastuzumab for Gastric Cancer) biopsy versus ToGA surgical specimen methods. Forty-nine tissue microarray (TMA) samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using ToGA trial HER2 scoring methods. The overall concordance between IHC and FISH by the ToGA surgical specimen method is 97.56% and by the ToGA biopsy specimen method is 97.14%. The agreements of HER2 IHC results under both biopsy and surgical specimen methods were nearly perfect (weighted kappa = 0.845). Additionally, the percentage of Her2 FISH amplification showed increasing trend with increasing HER2 IHC ordinals (negative, equivocal, positive) by both TOGA biopsy (P<0.001) and surgical specimen method (P<0.001). After excluding equivocal cases, the sensitivity (100%), PPV (88.89%) and NPV (100%) of HER2 IHC were unchanged under either surgical specimen method or biopsy method. However, the specificity (96.97%) and accuracy (97.56%) of HER2 IHC was slightly higher under the surgical specimen method than those (specificity 96.30%, accuracy 97.14%) under the biopsy method. Of the total 49 cases, the number (n = 14) of HER2 IHC equivocal results under the ToGA biopsy method was 1.75-fold higher than those (n = 8) under the ToGA surgical specimen method (28.57% vs. 16.32%). Therefore, compared to ToGA surgery specimen method, the ToGA biopsy method caused more equivocal IHC cases to be referred to FISH testing and did not increase the detection rates of Her2 FISH amplification.