bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term subjective memory after electroconvulsive therapy
Authors: Sigström Robert , Nordenskjöld Axel , Juréus Anders , Clements Caitlin , Joas Erik , Pålsson Erik , Landén Mikael 
Published: March 2020

Background
There have been reports of long-term subjective memory worsening after electroconvulsive therapy (ECT).

Aims
To study the prevalence and risk factors of long-term subjective memory worsening among patients receiving ECT in routine clinical practice.

Method
Patients (n = 535, of whom 277 were included in the final analysis) were recruited from eight Swedish hospitals. Participants' subjective memory impairment was assessed before ECT and a median of 73 days after ECT using the memory item from the Comprehensive Psychopathological Rating Scale. Participants also rated their pre-ECT expectations and post-ECT evaluations of the effect of ECT on memory on a 7-point scale. We used ordinal regression to identify variables associated with subjective memory worsening and negative evaluations of the effect of ECT on memory.

Results
Comparisons of pre- and post-ECT assessments showed that subjective memory worsened in 16.2% of participants, remained unchanged in 52.3% and improved in 31.4%. By contrast, when asked to evaluate the effect of ECT on memory after treatment 54.6% reported a negative effect. Subjective memory worsening was associated with negative expectations before ECT, younger age and shorter duration of follow-up.

Conclusions
Although subjective memory improved more often than it worsened when assessed before and after ECT, a majority of patients reported that ECT had negative effects on their memory when retrospectively asked how ECT had affected it. This might suggest that some patients attribute pre-existing subjective memory impairment to ECT. Clinicians should be aware that negative expectations are associated with subjective worsening of memory after ECT.
Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer
Authors: Gadgeel Shirish , Rodríguez-Abreu Delvys , Speranza Giovanna , Esteban Emilio , Felip Enriqueta , Dómine Manuel , Hui Rina , Hochmair Maximilian J. , Clingan Philip , Powell Steven F. , Cheng Susanna Yee-Shan , Bischoff Helge G. , Peled Nir , Grossi Francesco , Jennens Ross R. , Reck Martin , Garon Edward B. , Novello Silvia , Rubio-Viqueira Belén , Boyer Michael , Kurata Takayasu , Gray Jhanelle E. , Yang Jing , Bas Tuba , Pietanza M. Catherine , Garassino Marina C. 
Published: March 2020

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
Expression profiles can predict both general chemotherapy and gemcitabine-specific responses in breast cancer patients receiving neoadjuvant therapy
Authors: Oh D. S. , Carey L. A. , Fan C. , Sawyer L. , Hu Z. , Ma D. , Perou C. 
Published: March 2020

10008 Background: The identification of markers predictive of neoadjuvant chemotherapy response would be an important advance. Therefore, we sought to identify gene expression profiles predictive of neoadjuvant response and evaluated their drug specificity. Methods: DNA microarray analysis was performed on pre-treatment core biopsies from two different locally advanced breast cancer patient sets receiving neoadjuvant chemotherapy; the first set (L9819) was treated with 4 cycles of doxorubicin + cyclophosphamide (AC) followed by 4 cycles of paclitaxel (T) or paclitaxel + trastuzumab (TH). The second patient set (S329) received 4 cycles of gemcitabine + doxorubicin followed by 4 cycles of gemcitabine + cisplatin. Clinical response was based on RECIST criteria. Results: We obtained successful microarrays on 44 (L9819) and 46 (S329) of the patients enrolled. Ten-fold cross-validated supervised analyses separately performed on each dataset identified gene expression patterns that accurately predicted (75–85% accuracy) response (clinical complete responders vs. others) evaluated on those patients that completed all 8 cycles of chemotherapy. The predictive expression patterns from the L9819 trial were significantly enriched for apoptosis genes, while the predictive gene set from the S329 trial was enriched for nucleotide metabolism genes. The L9819 predictor was able to accurately predict (75% accuracy) response for the S329 patients, however, the S329 predictor was not able to predict response on the L9819 trial (50% accuracy). We speculate that the L9819 predictor was able to predict response on the S329 dataset (despite the fact that only doxorubicin was common to both trials) because this profile was enriched for apoptosis genes that may reflect a general mechanism of chemotherapy response/resistance, while the S329 predictor was more tuned to gemcitabine’s specific mechanism of action. Conclusions: This study may provide the means to predict response to AC-T(H) and GA-GC neoadjuvant chemotherapy. The ability of one predictor to work on the other dataset, but not vise versa, suggests that both general chemotherapy and drug specific response profiles may have been identified. [Table: see text]
Prostate cancer screening, treatment, and outcomes— A population-based study
Authors: Lu-Yao G. L. , Albertsen P. C. , Stanford J. L. , Stukel T. A. , Walker-Corkery E. S. , Barry M. J. 
Published: March 2020

10017 Background: It remains unknown whether more intense prostate cancer screening and treatment reduces prostate cancer mortality. We describe the experiences of two population-based cohorts with 15-years follow-up (1987–2001) to address the following questions: 1) does more intense screening and treatment for prostate cancer lead to lower mortality in community settings, and 2) do older men (age ≥75–79) benefit from more intense prostate cancer screening and treatment. Methods: Population-based cohort study consisting of white male Medicare beneficiaries who resided in the regions covered by the Seattle (N=88,863) and Connecticut (N=114,785) cancer registries. Inclusion criteria are age 65–79 and free of prostate cancer on January 1, 1987. All study subjects were followed through death or the end of 2001. The main outcomes are rates of screening for prostate cancer, treatment with radical prostatectomy, external beam radiotherapy, and prostate cancer specific mortality. Results: Between 1987 and 1990, compared to men in Connecticut, men in the Seattle region were 5.4 times (95% C.I. 4.8 - 6.1) more likely to undergo PSA testing, 2.2 times (95% C.I. 1.8 - 2.7) more likely to under go prostate biopsy, 5.9 times (95% C.I. 5.5 - 6.9) more likely to have radial prostatectomy, and 2.3 times (95% C.I. 2.2 - 2.5) more likely to have external beam radiation. The cumulative risk of radical prostatectomy or external beam radiation reached 9.1% in the Seattle cohort and 5.0% in the Connecticut cohort in 2001. After 15 years of follow-up, prostate cancer mortality rates were similar for subjects in the two study regions (hazard ratio of Seattle to CT: 1.01, 95% C.I. 0.93 - 1.09). For older men (aged 75–79 in 1987), however, the prostate cancer mortality rate was slightly higher in the Seattle than the Connecticut cohort (hazard ratio: 1.16, 95% C.I. 1.02 - 1.32). Conclusion: More intense screening for prostate cancer, surgery or radiation among a cohort of Medicare beneficiaries in the Seattle area compared with their counterparts in Connecticut has not lead to significantly lower mortality from prostate cancer over 15 years of follow-up. No significant financial relationships to disclose.
A novel role of DNA fragmentation factor as a tumor suppressor through maintaining genomic stability
Authors: Yan B. , Wang H. , Bedford J. S. , Dewhirst M. W. , Li C. 
Published: March 2020

10023 Background: DNA fragmentation is a hallmark of apoptosis. However, the biological function of apoptotic DNA fragmentation remains unclear. Genes encoding the nuclease responsible for DNA fragmentation, DFF40/CAD and DFF45/ICAD, are deleted, mutated, or aberrantly expressed in many human tumor types. Abnormalities in this gene are associated with aggressive tumors and poor prognosis in cancer patients. Tumor-specific DFF45 gene mutations were identified in human tumors, indicating the involvement of this gene in tumor development. Methods: We studied genetic instability, cellular transformation and tumorigenesis in cells and mice deficient in DNA fragmentation. We applied two methods to inhibit DNA fragmentation, overexpressing a modified ICAD which inhibits DNA fragmentation during apoptosis in stable cell lines and disrupting cad gene in transgenic mice. Genetic instability was studied by gene amplification assay, mutation assay and cytogenetic analysis including chromosomal aberrations and translocations. Cellular transformation was studied by soft agar assay using CAD-/- MEF cells. Tumorigenesis in DFF/CAD-knockout mice was studied by radiation carcinogenesis and two-stage skin chemical carcinogenesis. Results: (1) Human and mouse cancer cell lines with their CAD activity inhibited exhibited significantly more genetic instability under spontaneous or mutagen (ionizing radiation) induced conditions. These are reflected as elevated frequencies of chromosomal aberrations, gene amplifications, and gene mutations; (2) Mouse cells with targeted disruption of the cad gene exhibit a similar, increased level of genetic instability when the host animal is irradiated; (3) Mechanistically, CAD maintains genetic instability through the removal of cells with DNA damage, a role that is similar to genomic “gatekeepers” like p53; (4) CAD-null mouse embryo fibroblasts exhibited enhanced cellular transformation; (5) Significantly enhanced susceptibility to chemical and radiation-induced tumor development was observed in mice with targeted disruption of the CAD gene, indicating that it plays a role in suppressing tumor development. Conclusions: CAD plays an important role in maitaining genetic stability and suppressing tumor development. No significant financial relationships to disclose.
EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil
Authors: Na I. , Kang H. , Park Y. , Koh J. , Cho S. , Lee B. , Lee Y. , Shim Y. , Ryoo B. , Yang S. 
Published: March 2020

10027 Background: Some studies reported the presence of somatic mutation of EGFR in head and neck cancer. Human papillomavirus (HPV) was associated with some types of head and neck cancer. We performed this study to determine clinical significance of EGFR mutation and its association with HPV infection in patients with tongue and tonsil cancer. Methods: We sequenced exons 18–21 of EGFR TK domain and HPV typing was performed using the HPV DNA chip in tissues of patients with tongue and tonsil cancer. Univariate and multivariate analysis was performed. Results: Eighty-one patients were included. We detected EGFR mutation in 10 (12%) patients. Mutation was significantly frequent in never-smoker (21% versus 5%; P = 0.031). The mutation frequency did not differ between tongue and tonsil cancer (12% vs. 13%, respectively; P = 0.978). There was no difference between female and male (12% vs. 14%, respectively; P = 0.754). Eleven of 81 (14%) patients were HPV positive. HPV positivity was more common in young (<60 years) than older (≥60 years) patients (20% vs. 3%, respectively; P = 0.039). Patients with tonsil cancer showed more frequent HPV positivity than tongue cancer (42% vs. 2%, respectively; P < 0.001). There was no association between HPV positivity and EGFR mutation. In terms of disease-free survival, patients with EGFR mutation had better survival independently of stage and primary site (hazard ratio, 0.246; 95% CI, 0.075 to 0.802). Conclusions: We did not find association between EGFR mutation and HPV positivity. Patients with EGFR mutation showed better outcome in tongue and tonsil cancer. These results suggest that EGFR mutation may be a prognostic factor in patients with head and neck cancer. No significant financial relationships to disclose.
Multi-center prospective analysis of risk-reducing salpingo-oophorectomy to prevent BRCA-associated breast and ovarian cancer
Authors: Kauff N. D. , Domchek S. M. , Friebel T. M. , Lee J. B. , Roth R. , Robson M. E. , Barakat R. R. , Norton L. , Offit K. , Rebbeck T. R. 
Published: March 2020

1003 Background: Our groups previously reported on the efficacy of risk-reducing salpingo-oophorectomy (RRSO) for the prevention of BRCA-associated breast and ovarian cancer. (Kauff ND, et al. NEJM 2002; Rebbeck TR, et al. NEJM 2002) Limitations of those reports included relatively short prospective follow-up and lack of power to analyze the protection of RRSO when participants were stratified by BRCA1 vs. BRCA2. To address these limitations, we have pooled our updated datasets to provide robust estimates of the efficacy of RRSO. Methods: 886 women ≥ 30 years of age, with a deleterious mutation in BRCA1 or BRCA2 and ovaries in-situ at time of genetic test results, were enrolled on prospective follow-up studies at one of eleven centers from 11/1/1994 - 12/1/2004. Women chose to participate in either ovarian surveillance or undergo RRSO. Follow-up information was collected by questionnaire and medical record review. Follow-up time was counted from time of RRSO or from time of genetic test results for women who did not undergo RRSO. After excluding cancers diagnosed within the first 6 months of follow-up, the effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. Results: 559 (63%) participants underwent RRSO a median of 5 months after genetic test results. 12 occult ovarian or fallopian tube cancers were diagnosed at time of RRSO. During a mean 40 months follow-up, RRSO was associated with a 52% reduction in breast cancer risk and a 91% reduction in ovarian cancer risk (see Table ). When the cohort was stratified by mutation status, RRSO was associated with a reduced risk of BRCA1-associated ovarian cancer and BRCA2-associated breast cancer. Conclusions: The results confirm that RRSO is highly protective against BRCA-associated breast and ovarian cancer. These results also generate the hypothesis that the protection conferred by RRSO against specific cancers may differ between carriers of BRCA1 and BRCA2 mutations. [Table: see text] No significant financial relationships to disclose.
Promoter methylation and protein expression of the Slit2 and Robo1 genes in resected esophageal squamous cell carcinoma
Authors: Tzao C. , Hsu H. , Lee S. , Hsu W. , Sun G. , Cheng A. , Wang Y. 
Published: March 2020

10032 Background: Recent epigenetic studies suggest that the slit-robo pathway is involved in tumorigenesis of a number of human cancers and a role of SLIT2 as a tumor suppressor gene. In view of lack of epigenetic studies of SLIT2 and ROBO1 genes in squamous cell esophageal carcinoma (ESCC), we investigate whether promoter methylation is responsible for aberrant protien expression of SLIT2 and ROBO1 and whether promoter methylation and aberrant protein expression of these two genes are related to prognosis after resection for ESCC. Methods: We analyzed promoter methylation of SLIT2 and ROBO1 using methylation-specific polymerase chain reaction (MSP) and their protein expression using immunohistochemistry in 60 resected tumor specimens. The Pearson χ2 test was used to compare promoter methylation and protein expression of SLIT2 and ROBO1 among patients with different clinicopathological parameters. Concordance analysis was performed between promoter methylation and protein expression of these two genes. Results: Promoter methylation of SLIT2 and ROBO1 was observed in 43 (71.6%) and 16 (26.6%) of the 60 resected specimens, respectively (P = 0.002). Aberrant protein expression of SLIT2 and ROBO1 was observed in 51 (85%) and 23 (38.3%), respectively (P < 0.001). Promoter methylation of SLIT2 correlated well with smoking (P = 0.046), betel nut chewing (P = 0.032), staging (P = 0.018) and tumor (T) factor (P < 0.001) of the TNM system and its aberrant protein expression correlated well with betel nut chewing (P = 0.038), staging (P = 0.025) and nodal (N) involvement (P = 0.004). Promoter methylation and protein expression of ROBO1 did not correlate with any of these clinicopathologic parameters. A concordance rate of 88.2% and 74.2% was present between expression of SLIT2 and ROBO1 protein and their promoter methylation (P < 0.001) and (P = 0.004), respectively. Conclusions: Aberrant expression of SLIT2 and ROBO1 protein is frequently associated with the presence of ESCC, with SLIT2 a more predominant one. Promoter methylation is one of the major mechanisms responsible for aberrant protein expression of these two genes in resected ESCC. Promoter methylation and aberrant protein expression of SLIT2 may predict prognosis after resection for ESCC. No significant financial relationships to disclose.
Genetic models for estimating age-specific risk of sporadic breast cancer
Authors: Jupe E. R. , Ralph D. A. , Aston C. E. , Manjeshwar S. , Pugh T. D. , Gramling B. A. , Defreese D. C. , Shimasaki C. D. 
Published: March 2020

10038 Introduction: Accurately assessing individual risk of developing breast cancer is essential for early detection and prevention. The possibility exists to improve upon the widely used Gail model in predicting an individual’s risk of developing breast cancer, by incorporating both genetic and lifestyle information. Methods: We have developed a model with data from ∼7,000 Caucasian women (2,300 cases and 4,700 controls) enrolled in four geographically distinct regions of the US. Questionnaire-based information on clinical and lifestyle variables, including the Gail model questions, were collected. All samples were genotyped for 120 common, functional polymorphisms in candidate genes likely to influence breast carcinogenesis. The data were randomly divided into training (75%) and validation (25%) sets. Because of age-dependent genetic penetrance observed in the study, separate models were built for three age intervals (30–44, 45–54 and ≥ 55). Following assessment of Hardy-Weinberg equilibrium and linkage-disequilibrium, univariate and multivariate statistical analyses were performed to assess genetic main effects and epistatic interactions and define model terms. Models were evaluated by Receiver Operator Curve (ROC) analysis. Results: The riskprediction models developed for all three age intervals were informative with Area Under the Curve (AUC) that was consistently greater than expected by chance and exceeded the predictive power of the Gail model alone. No strong associations were found between scores derived from our models and the Gail model. The results suggest that the genetic markers examined contribute to breast cancer prediction independent of the Gail scores, and due to the improvement in the AUC, probably complement the Gail scores. The strongest genetic contributors to risk were identified in the youngest group where the AUC was 0.71 in the training set and 0.66 in the validation set. Estimated AUC values appear to be quite stable across 1,000 bootstrap samples of training and validation sets. Conclusions: The predictive power of these models integrating both genetic and epidemiological data provides an improved estimate of an individual’s breast cancer risk. [Table: see text]
Phase II trial of iboctadekin (rhIL-18) on a daily X 5 schedule in metastatic melanoma (MM)
Authors: Kirkwood J. M. , Kefford R. , Logan T. , Mainwaring P. N. , Millward M. , Pavlick A. C. , Dar M. M. , Kathman S. , Laubscher K. , Bell W. 
Published: March 2020

10043 Background: Interleukin-18 (IL-18) is an immunostimulatory cytokine with potent antitumor activity in preclinical models. Two phase I studies of recombinant human (rh) IL-18 explored a wide dose range (0.03–1.0 mg/kg) without reaching a maximum tolerated dose (MTD) on the daily × 5 schedule. Pharmacodynamic data including inflammatory cytokine production and activation of lymphocyte subsets revealed optimal biologic activity at the lower end of the dose range (0.01–0.2 mg/kg) as did 2 unconfirmed partial responses (PRs) in a MM and a renal cancer patient (pt) at 0.1 mg/kg. Methods: An open-label, randomized, phase II trial in 60 adult pts with previously untreated MM was conducted to evaluate the efficacy and safety of rhIL-18 administered as a 2-hour IV infusion daily × 5 every 28 days for 6 cycles. Pts with PS ≤ 1, without known CNS involvement, and with adequate end organ function were randomized in stage 1 to 3 dose levels of IL-18 stratified according to AJCC M stage 1a/b vs. 1c. Two confirmed responses for a given dose level in Stage 1 were required to enroll 20 additional pts/level in Stage 2. The 1° objective was determination of overall response rate (ORR) for each dose level. Progression-free survival (PFS), tolerability, and immunogenicity were 2° endpoints. Results: 64 pts were treated at 3 dose levels. Nine pts remain on study. One pt experienced a confirmed PR. Based on preliminary data, the difference in PFS 6 months (mos) was significant (p=0.03) for 0.01 vs 0.1 mg/kg. Most common toxicities were mild to moderate fever, rigors, chills, n/v, and headache. Anti-IL18 antibody (Ab) development correlated with dose level. No clinically significant adverse events were associated with Ab development. Conclusion: Iboctadekin has an acceptable tolerability profile and has activity in MM but insufficient confirmed responses have been observed at this time to initiate Stage 2. Preliminary PFS 6 months indicates an advantage for pts treated at the lowest dose. [Table: see text] [Table: see text]