tbuckley/cabot-search huggingface dataset:
Psychopathology in 7‐year‐old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder – The Danish High Risk and Resilience Study ‐ VIA 7, a population‐based cohort study
Authors: Ditte Ellersgaard, Kerstin Jessica Plessen, Jens Richardt Jepsen, Katrine Soeborg Spang, Nicoline Hemager, Birgitte Klee Burton, Camilla Jerlang Christiani, Maja Gregersen, Anne Søndergaard, Md Jamal Uddin, Gry Poulsen, Aja Greve, Ditte Gantriis, Ole Mors, Merete Nordentoft, Anne Amalie Elgaard Thorup
Journal: World Psychiatry (2018)

This study aimed to compare the psychopathological profiles of children at familial high risk of schizophrenia spectrum psychosis (FHR-SZ) or bipolar disorder (FHR-BP) with population-based controls. We used Danish nationwide registers to retrieve a cohort of 522 seven-year-old children of parents with schizophrenia spectrum psychosis (N=202), bipolar disorder (N=120) or none of these disorders (N=200). Psychopathology was assessed by reports from multiple informants, including children, parents and teachers. Lifetime DSM-IV diagnoses were ascertained by blinded raters through the Schedule for Affective Disorders and Schizophrenia for School-Age Children. The dimensional assessment of psychopathology was performed by the Child Behavior Checklist, the Teacher's Report Form, a modified version of the ADHD-Rating Scale, the Test Observation Form, and the State-Trait Anxiety Inventory for Children. Current level of functioning was evaluated using the Children's Global Assessment Scale (CGAS). The prevalence of lifetime psychiatric diagnoses was significantly higher in both FHR-SZ children (38.7%, odds ratio, OR=3.5, 95% confidence interval, CI: 2.2-5.7, p < 0.001) and FHR-BP children (35.6%, OR=3.1, 95% CI: 1.8-5.3, p < 0.001) compared with controls (15.2%). FHR-SZ children displayed significantly more dimensional psychopathology on all scales and subscales compared with controls except for the Anxious subscale of the Test Observation Form. FHR-BP children showed higher levels of dimensional psychopathology on several scales and subscales compared with controls, but lower levels compared with FHR-SZ children. Level of functioning was lower in both FHR-SZ children (CGAS mean score = 68.2; 95% CI: 66.3-70.2, p < 0.0001) and FHR-BP children (73.7; 95% CI: 71.2-76.3, p < 0.05) compared with controls (77.9; 95% CI: 75.9-79.9). In conclusion, already at the age of seven, FHR-SZ and FHR-BP children show a higher prevalence of a broad spectrum of categorical and dimensional psychopathology compared with controls. These results emphasize the need for developing early intervention strategies towards this vulnerable group of children.
Association of breast cancer disease free survival (DFS) with omeprazole use.
Authors: Josiah An, Adithya Chennamadhavuni, Sarah L Mott, Rohan Garje, Jose Pablo Leone
Journal: Journal of Clinical Oncology (2018)

e12544 Background: Recent studies indicated that aryl-hydrocarbon receptor (AHR) modulators - such as omeprazole - decrease breast cancer cell invasion among mice with estrogen receptor negative (ER-) or triple negative (TN) breast cancer. Yet, it is unknown whether omeprazole use decreases breast cancer metastasis and improves survival in humans. The aim of this study was to assess the potential benefit of omeprazole use on DFS in ER- and TN breast cancer patients (pts) at a large academic center. Methods: A retrospective chart review was conducted on pts with breast cancer diagnosed between 2008 and 2016. Pts were classified by omeprazole use ( > 30 days of use). To investigate differences in pt characteristics by receipt of omeprazole, chi-squared and t-tests were used. To examine whether ER or TN status modified the effect of receipt of omeprazole on DFS and overall survival (OS), Cox regression models were used. Results: A total of 1387 pts were included in the study (non-omeprazole n = 968, omeprazole n = 419). There were 285 ER-tumors and 183 TN tumors. After a median follow up of 4 years, 94% of pts had no recurrence of breast cancer and 88% of pts were still alive. Median duration of omeprazole use for omeprazole group was 227 days. Median age at diagnosis was 58 years. Treatments included surgery (98%), radiation (61%), hormone therapy (65%) and chemotherapy (45%). Utilization of hormone therapy was lower in pts receiving omeprazole (61 vs 66%, p = 0.04), but chemotherapy was higher (49 vs 44%, p = 0.05). No significant differences in terms of sex, race, ER, PR, HER-2, stage, radiation, surgery, and age between omeprazole groups were evidenced. Multivariable results for the interaction between omeprazole use and receptor status (ER or TN) on DFS and OS are reported in table. Conclusions: Omeprazole use in breast cancer did not confer a survival benefit in DFS and OS for tumor subtypes based on ER or TN status. DFS* OS* HR 95% CI P-value HR 95% CI P-value Omeprazole Use Yes vs No At ER = Negative 1.53 0.93 2.51 0.50 1.16 0.68 1.98 0.57 Omeprazole Use Yes vs No At ER = Positive 1.24 0.85 1.80 1.41 0.94 2.10 Omeprazole Use Yes vs No At TN = No 1.13 0.76 1.66 0.34 1.28 0.84 1.94 0.57 Omeprazole Use Yes vs No At TN = Yes 1.58 0.89 2.79 1.03 0.55 1.91 *Adjusted for chemotherapy and hormone therapy
PTH-049 Clinical outcomes of endoscopic submucosal dissectionfor colorectal neoplasms: a single UK referral centre experience
Authors: Vasilios Papastergiou, Ioannis Stasinos, Rajaratnam Rameshshanker, Aurelia Wawszczak, Ripple Man, Adel Polecina, Janindra Warusavitarne, Zacharias Tsiamoulos, Noriko Suzuki, Brian Saunders
Journal: Endoscopy (2018)

<h3>Introduction</h3> There is limited experience of endoscopic submucosal dissection (ESD) for resection of colorectal lesions in the West and outcome data tends to be worse than that reported from Japanese centres. We report the outcomes of ESD in a single, tertiary UK referral centre. <h3>Methods</h3> A prospective database was analysed including 165 consecutive patients (mean age: 64.6±12.6 years, 62.4% males) with 173 colorectal neoplasms resected by ESD between 3/2012 and 12/2017. Two experienced colonoscopists performed all procedures. <h3>Results</h3> The median (IQR) lesion size was 3.5 cm (2–5), and 140 (80.9%) were located in the rectum. Overall, 49.7% were granular-type laterally spreading tumours (LST), 19.7% were non-granular LST, and 30.6% were polypoid lesions. In 29 (16.7%) cases a flexible endosurgical platform was used to assist ESD of complex rectal polyps [median(IQR) size: 6 cm (5–8)] by dynamic trans-anal retraction (Trans-Anal Submucosal Endoscopic Resection; TASER). Histology showed low-grade adenoma/dysplasia in 83 (47.9%), high-grade adenoma/dysplasia in 52 (30%), T1 cancer (&lt;1000 µm) in 17 (9.8%), and T1 cancer (&lt;1000 µm) in 17 (9.8%) lesions. The en bloc, histological complete and curative (R0) resection rates were 97.7%, 80.3% and 76.3% respectively. Three (1.7%) cases of delayed bleeding occurred, with one case requiring transfusion. Perforation occurred in 2 (1.2%) cases: one was recognised and treated intraoperatively with endoclips; the other one was followed up and managed conservatively. Sixty (34.7%) patients were electively admitted to hospital post procedure, for a median duration of 1 day (range 1–5). Twenty patients (12.1%), at risk of lymph node metastasis, underwent additional radical surgery. Eighty-nine (51.4%) ESD cases had endoscopic follow-up data over a median duration of 12 months (range 3.4–51.3). The local recurrence rate was 4/89 (4.5%); all recurrent cases were managed endoscopically. The recurrence rate was lower in cases with en bloc compared with piecemeal resection (3.4% vs 50%, p=0.08), histologic complete compared with histologic incomplete resection (2.5% vs 22.2%, p=0.05), and R0 compared with non-R0 resection (2.5% vs 20%, p=0.06). After a median follow up of 14.6 months (range: 3–55.8), the overall and disease-specific survival in the study population was 98.8% and 100%, respectively. <h3>Conclusions</h3> The current study demonstrates favourable clinical outcomes of selected colorectal ESD in a Western endoscopy setting. Further studies addressing the cost-effectiveness of ESD and comparing its long-term outcome with endoscopic mucosal resection in the West are needed.
Clinical significance of the aspartate aminotransferase (AST) to platelet ratio index in assessing the degree of liver fibrosis in chronic hepatitis C
Authors: Marko Duvnjak, Ivan Lerotic, Lucija Virovic, Vedran Tomasic, Tajana Pavic, Drinko Balicevic
Journal: Gut (2005)

INTRODUCTION: Information on the stage of liver fibrosis is crucial in managing chronic hepatitis C (CHC) patients. Liver histology is considered the gold standard for assessing the degree of liver fibrosis. However, liver biopsy is invasive procedure associated with sampling error, interobserver variability and potential complications. Therefore, there is a need for simple, noninvasive blood test that could serve as a surrogate for biopsy to distinguish mild from significant fibrosis in CHC. Some recent studies have found AST to platelet ratio index (APRI) as an accurate predictor of fibrosis in CHC [1, 2]. AIMS & METHODS: The aim of this study was to evaluate clinical efficacy of APRI as a predictor of the degree of liver fibrosis in CHC patients. We retrospectively analysed 45 consecutive patients (22 male, 23 female, mean age 38.2 years) with CHC and no history of alcohol abuse, who underwent liver biopsy at the Charity Sisters University Hospital, Zagreb. The liver biopsy specimens were staged using the METAVIR scoring system. Significant (moderate/severe) fibrosis was determined as an METAVIR score F2-F4. APRI was calculated as AST value/upper limit of normal ×100/platelets. In previous studies of APRI, thresholds of 0.5 or lower were used to indicate mild fibrosis and 1.0 or higher to indicate significant fibrosis [1, 2]. Results obtained with APRI were compared with biopsy results. RESULTS: Of 45 patients studied, 32 (71.1%) had no/mild fibrosis (METAVIR score F0-F1) and 13 (28.9%) patients had significant fibrosis (METAVIR score F2-F4). For the prediction of mild fibrosis, when using a previously described cut-off of 0.42 (APRI up to 0.42), APRI had a sensitivity of 50.0% with a specificity of 84.6%, negative predictive value (NPV) was 40.7% and positive predictive value (PPV) was 88.9%. In predicting significant fibrosis, when using a cut-off of 1.0 (APRI more then 1.0), APRI showed a sensitivity of 53.9% and a specificity of 87.5%, PPV was 63.6% while NPV was 82.4%. But, when using a cut-off of 0.60 for significant fibrosis, NPV was 91.3%. CONCLUSION: This study confirms that APRI is an accurate index and can be used to differentiate mild from significant fibrosis in patients with CHC. If APRI is less then 0.60 there is a 91.3% chance that significant fibrosis does not exist. Application of this simple index alone, or in combination with other blood tests, can decrease the need for more invasive staging of CHC using liver biopsy.
Clinical benefit of tucatinib after isolated brain progression: A retrospective pooled analysis of tucatinib phase 1b studies in HER2+ breast cancer.
Authors: Rashmi Krishna Murthy, Erika Paige Hamilton, Cristiano Ferrario, Nathalie Aucoin, Carla Isadora Falkson, Marc C. Chamberlain, Todd Gray, Virginia F. Borges
Journal: Journal of Clinical Oncology (2018)

1015 Background: For MBC patients with isolated brain progression, current guidelines recommend treatment with CNS-directed therapy and continuation of current systemic therapy, although there are limited data evaluating this strategy. Two Phase 1b trials of tucatinib permitted patients with HER2+ MBC to continue study treatment following CNS-directed therapy in instances of isolated brain metastases (BM) progression. Methods: 2 Phase 1b studies of tucatinib were pooled to identify patients with isolated brain progression (defined as new or progressive BM with stable or responding systemic disease) while on study. In patients treated for isolated brain progression, the median time to any subsequent progression or death was determined. Results: 117 patients were analyzed, 57 in the 004 (tucatinib + T-DM1) and 60 in the 005 (tucatinib +/- trastuzumab +/- capecitabine) trials. 25 patients (21%) with isolated BM were identified and comprised 2 groups: 14 who discontinued study and 11 who continued study treatment following CNS-directed therapy. Median time to isolated brain progression differed between these groups (12.3 months in post-progression treated vs. 6.3 months). The median time to any second event was 8.3 months in the post-progression CNS-treated patients. Patients selected for post-progression treatment had less exposure to pertuzumab, were more frequently treated with the triplet combination, had a longer time from pre-study CNS-directed therapy, had better preserved performance status, and were less likely to have new neurologic adverse events compared to patients not treated post-progression. Conclusions: Patients with isolated BM progression treated post-progression with CNS-directed therapy and continuation of study therapy had a median of 8.3 months to any second event, suggesting a substantial benefit for this treatment strategy. The selection of patients with post-progression treatment appears to be a composite of characteristics both at baseline and at time of brain progression. These results support the further evaluation of this approach to patients with isolated brain progression in the ongoing randomized HER2CLIMB trial. Clinical trial information: NCT01983501 and NCT02025192.
Incidence of PI3K pathway aberrations and their impact on response to neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC) subtypes.
Authors: Reva K Basho, Alex Trevarton, Kenneth R. Hess, Chunxiao Fu, Rosanna Lau, Chih-Hsu Lin, Olivier Lichtarge, Wei Tse Yang, William Fraser Symmans, Stacy L. Moulder
Journal: Journal of Clinical Oncology (2018)

588 Background: TNBC cell lines characterized as mesenchymal (M) and luminal androgen receptor (LAR) commonly have aberrations in the PI3K pathway. However, the incidence in human tumors and impact on response to therapy is less clear. Methods: Pre-treatment biopsies were collected from TNBC patients (pts) prior to NACT. Tumors were categorized into 5 groups using the Pietenpol criteria (Lehmann JCI 2011): basal-like (BL) comprised of BL-1 and BL-2, M comprised of M and mesenchymal stem-like, immunomodulatory (IM), LAR, or unspecified (UNS). Using RNAseq data, variants were identified in 16 PI3K pathway genes: AKT1, AKT2, AKT3, CRKL, IRS2, MTOR, PIK3CA, PIK3CG, PIK3R1, PTEN, RICTOR, RPTOR, RNF43, TSC1, TSC2. Results: Data was available in 63 pts (N = 4 stage I; N = 41 stage II; N = 18 stage III). There was no significant association between stage and subtype. 67 PI3K pathway variants were identified in 39 (62%) tumors. The incidence of mutated tumors and their differential response to NACT defined by residual cancer burden (RCB) in each subtype is presented in the table. There was no significant association between subtype and incidence of mutated tumors (P = 0.10). However, there were more mutated tumors in the LAR compared to non-LAR subsets (100% vs 57%); the majority of LAR tumors (5/7) had a variant in the PIK3R1 gene. The incidence of mutated tumors in the M vs non-M subsets was similar (57% vs 63%). Pts with mutated tumors did not have a significantly worse response to NACT overall (46% vs 54%; P = 0.61) or within the M subset (25% vs 50%; P = 0.58). Conclusions: In this cohort of TNBC pts, the incidence of PI3K pathway aberrations was higher than previously reported, likely due to the comprehensive genes evaluated. There was no significant difference in incidence of aberrations across subtypes, and PI3K pathway aberration was not associated with altered response to NACT. Larger cohorts are needed to clarify the impact of PI3K pathway aberrations in TNBC subtypes. Subtype N PI3K Mutated Tumors N (%) RCB 0-I if PI3K Wild Type N (%) RCB 0-I if PI3K Mutated N (%) All 63 39 (62) 13 (54) 18 (46) BL 20 11 (55) 5 (56) 6 (55) M 14 8 (57) 3 (50) 2 (25) IM 12 9 (75) 2 (67) 6 (67) LAR 7 7 (100) - 2 (29) UNS 10 4 (41) 3 (50) 2 (50)
Predicting expected absolute chemotherapy treatment benefit in women with early-stage breast cancer using a 12-gene expression assay.
Authors: William John Gradishar, Mark E. Robson, Darl D Flake, Lee Steven Schwartzberg, Priyanka Sharma, Hatem Hussein Soliman, Anthony Martin Magliocco, Krystal Brown, Saskia Wehnelt, Alexander Gutin, Ralf Kronenwett, Johnathan M. Lancaster
Journal: Journal of Clinical Oncology (2018)

525 Background: Previous studies have validated the ability of a 12-gene expression assay to predict risk of distant recurrence (DR) in women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) early stage breast cancer. Here, we employed a mathematical approach to estimate an expected absolute chemotherapy benefit based on the 12-gene expression test results. Methods: Data was included for patients who had clinical testing with the 12-gene expression assay in the US (Myriad Genetic Laboratories Inc., Salt Lake City, Utah) or Germany (Myriad GmbH, Munich, Germany). FFPE breast resections of treatment-naïve ER+, HER2- breast tissue were tested to generate a combined molecular and clinical score (EPclin score). For the entire group, the relative chemotherapy benefit was assumed to be 30% based on meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group. This was used to calculate the expected absolute chemotherapy benefit across the EPclin score continuum. This was first done in a conservative scenario where chemotherapy benefit was assumed to be independent of EPclin score (no interaction). The degree of interaction between expected chemotherapy benefit and the EPclin score was then systematically increased until the maximum possible EPclin score was associated with the maximum chemotherapy benefit. The mean absolute benefit was calculated for patients at high risk (EPclin ≥3.3) or low risk (EPclin < 3.3) of distant recurrence. Results: Overall, 2,205 ER+, HER2- breast resections (303 tested in USA, 1902 tested in Germany) were included here [1286 samples (58%) with low EPclin scores; 919 (42%) with high EPclin scores]. The mean absolute benefit ranged from 1.5% to 1.8% (mean 10-year risk of DR 4.6% to 4.3%) for patients with low risk EPclin scores compared to 5.3% to 7.3% (mean 10-year risk of DR 14.7% to 12.8%) for patients with high risk EPclin scores. Conclusions: In this analysis, the 12-gene expression assay was able to predict absolute benefit from adjuvant chemotherapy in women with ER+, HER2- early stage breast cancer, regardless of which EPclin score cohorts accrued maximal relative treatment benefit.
ERCC1 and XRCC1 as prognostic biomarkers for early HER2-positive breast cancer.
Authors: E. Lubennikova, Lyudmila Zhukova, Mikhail Lichinitser, E. Stepanova, Y. Vishnevskaya, D. Khochenkov, I. Ganshina, E. Borisova
Journal: Journal of Clinical Oncology (2018)

e12562 Background: A few prognostic factors are used to make decision on breast cancer (BC) treatment. Researches to identify novel prognostic and predictive factors are still actual. Two DNA repair proteins were studied as prognostic markers for patients with early HER2-positive BC, who received or not adjuvant trastuzumab (T). Methods: 103 patients with HER2+ BC, I-IIIa stage, treated with surgery in 3 Russian Cancer Centers . from 2002 to 2007 were included in analysis. Adjuvant treatment with trastuzumab was performed for 58 patients (56,3%) only. In all cases expression of ERCC1 and XRCC1 were immunohistochemistry studied. Patient characteristics at the time of BC diagnosis, expression of biomarkers, treatment options and their associations with overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. Results: 8-years PFS was 74,4%: 80,3 % for patients received adjuvant trastuzumab vs 60,9 % for patient without anti-HER treatment (p < 0,0001). 8-years OS was 81,9%: 88,4% vs 59,5% (p < 0,0001), respectively. Overexpression of XRCC1 was detected in 61,2% of patients and significantly correlated with poor PFS [HR = 7,181, 95% CI 2,149-24,00; p = 0,001]. The most significant differences were registered in target-therapy group: 8-years PFS for XRCC1-positive patients (n = 32) was 55,4% vs 96,2% for XRCC1-negative patients (n = 26) received trastuzumab (p < 0,0001). Overexpression of ERCC1 was detected in 65% of patients and significantly correlated with poor PFS [HR = 2,179, 95% CI 1,123-6,581; p = 0,027] and OS [HR = 3,071, 95% CI 1,017-9,269; p = 0,047] either. Adjuvant trastuzumab therapy significantly proof PFS and OS only in ERCC1-negative patients (p = 0,008 and p = 0,009, respectively). ERCC1-positive patients had poor prognosis independent of adjuvant T usage: 8-years PFS was 56,3% in trastuzumab group (n = 31) vs 73,1% in group without T (n = 36), p = 1,0; 8-y OS was 74,6% vs 76,8%, respectively, p = 0,45. Conclusions: Overexpression of XRCC1 and ERCC1 predict poor prognosis in early HER2-positive BC. We consider ERCC1 should be additional studied as a marker of trastuzumab resistance
Arterial spin labeling MR imaging for differentiation between high- and low-grade glioma—a meta-analysis
Authors: Alberto Falk Delgado, Francesca De Luca, Danielle van Westen, Anna Falk Delgado
Journal: Neuro-Oncology (2018)

Abstract Background Arterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) non-invasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma. Methods Cochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed. Results In total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79–0.90) and specificity 0.80 (0.72–0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71–0.91) and specificity 0.83 (0.69–0.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79–0.91) and specificity 0.80 (0.65–0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered. Conclusion Arterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.