tbuckley/cabot-search huggingface dataset:
Phase II/III randomized study of hyperfractionated radiotherapy with concomitant cetuximab versus concomitant platinum-based chemotherapy in advanced non-metastatic head and neck cancer: Update.
Authors: Khalid Al Saleh, Reham Safwat, Ahmed Bedair, Mustafa El-Sherify, Jitendra Shete, Amany AL Basmy
Journal: Journal of Clinical Oncology (2014)

e17044 Background: This is an update of a randomized study comparing the use of cetuximab versus platinum based chemotherapy with concurrent hyperfractionated radiation therapy (HRT) in locally advanced non metastatic head and neck carcinoma. Acute and late toxicity as well as progression free survival (PFS) were set as primary end points, while overall survival (OS) was set as secondary end point. Methods: Between December 2009 and August 2013, 37 patients were randomly assigned to HRT consisting of 120 cGy twice daily, to a total of 69.6-75.6 Gys in 58-63 fractions over 6 weeks, plus either platinum-based chemotherapy (Arm A: 22 patients) or weekly cetuximab (Arm B: 15 patients). The overall radiation dose was the same for the two groups. The median follow up time of the whole group was 19.3 months (IQR: 6.1- 37.1 ms). Results: The mean Overall treatment time was 62 days in both arms (p= 0.93). Skin toxicity (Grade >3) was experienced in 36.4% of patients in arm A and 40% in arm B (p= 0.82). Mucositis (Grade >3) was 54.5% in arm A and 60% in arm B (p=0.74). Hematologic toxicity of (Grade >3) occurred in 18.2% and 13.3% of the cases respectively (p= 0.9). The mean percent of weight loss was (9.2%, SD=5.8) in group A, and (13 %, SD=6) in group B respectively (p=0.06). Complete response was observed in 16 patients (72.7%) and 8 patient (53.3%) of arm A and B respectively p= 0.23. Partial response was achieved in 2 (9.1%) patients in arm A and in 6 (40%) in arm B. The 1-year PFS for the whole group, arm A, & arm B were 67.6%, 63.9% & 75% respectively (p= 0.37).The 2-year O.S was 88.9% and 90% for arm A and B respectively. Conclusions: When HRT is used, both platinum-based and cetuximab concomitant regimens seem to have equivalent PFS and OS. Moreover, the toxicity profile for both regimens is largely similar although a trend for less haematological but more skin and mucosa toxicities were noticed in the cetuximab arm. A larger patient’s cohort and longer follow up period is required to validate our findings.
A wide pharmacogenomic panel from a single oncology center in São Paulo: Data from 103 patients since 2005.
Authors: Luis Eduardo Werneck De Carvalho, Manoela Tavares Arruda Spada, Diogo Bugano, Paula Beatriz Tamura de Oliveira, Fabiana Seguin Anciaes, Aline Cristina de Oliveira Conceicao, Flavio dos Santos Silverio, Kleber Kobaiashi, Silvio Donatangelo, Eunice Cristina de Souza, Aluizio Augusto Pereira Semblano, Matheus Acacio Moreira, Nise Hitomi Yamaguchi
Journal: Journal of Clinical Oncology (2014)

e22050 Background: Pharmacogenomics has recently emerged as a major tool in the clinical analysis of cancer treatment efficacy. Understanding how mutations alter drug metabolism is crucial for both prognosis and choosing the most likely beneficial drug for each individual patient. Methods: 103 patients' files were studied and the most common malignancies were breast's (43 patients) and colorectal's (19 pts). The median age was 55 years (IQR 46-65), 32 (31%) were men. We performed a retrospective analysis of the pharmacogenetic-assay results and clinical files, which were recorded between 2005 and 2013. The goal of the study was to correlate the mutagenic profile of cancer patients, by identifying mutations in genes responsible for drug metabolism and DNA repair. Results: All distributions were in Hardy Weinberg, except for UGT1A1. The UGT1A1 analysis revealed that 14/51 patients were at increased risk of neutropenia during treatment with irinotecan due to mutations in that gene. Analysis of mutations affecting fluoropyrimidine metabolism, which upregulate both TS and DPD2A genes, yielded the following results: TS-TYMS mutations in 40/73 pts; MTHFR (55/ 89), and DPD2A (1/74), which were associated with higher toxicity in those patients. As for genes encoding DNA repair proteins such as XRCC1 Arg194, XRCC1 Arg 399 , XRCC3, XRCC7, 52/54 patients had mutations in this gene family. In the study of COMT Val, responsible for the proliferative potential and the carcinogenic effect, mutations were found in 30/45 patients. At least one mutation was found in 48/61 patients in genes encoding DNA-repair and cell detoxification enzymes, such as GSTM1, GSTT1 and GSTP1. As for the CYP2D6 family (variants 3,4,5,6,10), responsible for Tamoxifen metabolism, 12/31 patients presented at least one mutation. Conclusions: Most patients showed genetic variations in drug-metabolizing enzymes. Pharmacogenomics has become a useful tool in the selection of the best drug for each individual patient, thereby decreasing the probability of poor clinical responses and allowing a better control of side effects.
Limitations and Misinterpretations of E-Values for Sensitivity Analyses of Observational Studies
Authors: John P.A. Ioannidis, Yuan Jin Tan, Manuel R. Blum
Journal: Annals of Internal Medicine (2018)

The E-value was recently introduced on the basis of earlier work as "the minimum strength of association…that an unmeasured confounder would need to have with both the treatment and the outcome to fully explain away a specific treatment–outcome association, conditional on the measured covariates." E-values have been proposed for wide application in observational studies evaluating causality. However, they have limitations and are prone to misinterpretation. E-values have a monotonic, almost linear relationship with effect estimates and thus offer no additional information beyond what effect estimates can convey. Whereas effect estimates are based on real data, E-values may make unrealistic assumptions. No general rule can exist about what is a "small enough" E-value, and users of the biomedical literature are not familiar with how to interpret a range of E-values. Problems arise for any measure dependent on effect estimates and their CIs—for example, bias due to selective reporting and dependence on choice of exposure contrast and level of confidence. The automation of E-values may give an excuse not to think seriously about confounding. Moreover, biases other than confounding may still undermine results. Instead of misused or misinterpreted E-values, the authors recommend judicious use of existing methods for sensitivity analyses with careful assumptions; systematic assessments of whether and how known confounders have been handled, along with consideration of their prevalence and magnitude; thorough discussion of the potential for unknown confounders considering the study design and field of application; and explicit caution in making causal claims from observational studies.
Long-term survey of 443 cases of advanced-stage follicular lymphoma in Japan during the rituximab era.
Authors: Yasuo Hirayama, Kunihiko Ishitani, Shuithi Ohta, Mitsutoshi Kurosawa, Takeshi Kondo, Rishu Takimoto, Junji Kato
Journal: Journal of Clinical Oncology (2014)

e19504 Background: The proportion of follicular lymphoma (FL) among adult non-Hodgkin’s lymphoma cases in Japan or other Asian countries is only approximately 7-15%, a relatively low rate compared to that in the United States. The long-term overall survival (OS) rate of advanced-stage FL was expected to improve after the emergence of rituximab on the market, but there is a lack of large-scale survey data in Asia because of the relatively low FL incidence. Methods: We conducted a retrospective survey to assess the treatment outcomes of advanced-stage FL patients in 29 institutions in Hokkaido, a Japanese island, from January 2001 to December 2010. Results: The total number of patients was 443 (47.6% men, 52.4% women), with a median age of 55 years (range, 20–80 years). Of the cases, 42.2% were stage III, and 57.8% were stage IV. Further, 62.5%, 19.7%, 9.2%, 5.2%, and 3.4% had a performance status (PS) of 0, 1, 2, 3, and 4, respectively. Among a total of 443 cases, rituximab was administered in 427 (96.4%) as a single agent or combined with other therapies, the most common of which was R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; 281/443, 63.4%). The estimated 10-year OS was 77.1%. Seventeen patients experienced secondary malignancies (6 hematological diseases and 11 solid cancers, 8-years probability was 7.7%). Eighteen patients experienced transformation (8-years probability was 10.2%), among which 9 patients (50%) experienced disease-free survival for more than 3 years after therapy for transformation. Conclusions: Before rituximab, the 10-year OS of advanced FL patients with similar backgrounds in Japan was reported to be 40–60%. Although mentions of the above-described data are limited, improvements in OS were also observed in Japan during the rituximab era and post-transformation prognosis is better than described in older series.
Liver-transplantation-associated lung cancer: A comparison of clinical parameters and outcome.
Authors: Florian Kocher, Armin Finkenstedt, Michael Fiegl, Ivo W Graziadei, Gabriele Gamerith, Willi Oberaigner, Wolfgang Vogel, Wolfgang Hilbe
Journal: Journal of Clinical Oncology (2014)

e12531 Background: The incidence of lung cancer (LC) is increased in patients with history of liver transplantation (LT). The purpose of this study was to compare clinical characteristics and outcome of post liver transplantation lung cancer (PLTLC) patients with cohorts of “transplant naive” LC patients and LT patients without lung cancer. Methods: Patients who received a LT or were diagnosed with LC between December 1987 and August 2012 were included into analysis. PLTLC patients were compared to the total LT cohort (n=725) and the local LC registry (n=2,558) in regard to demographic parameters, risk factors, LC- and LT- characteristics and outcome. Standardized incidence ratios (SIR) were computed in the classical way after adjustment for sex, age and year of follow up. Results: Within the LT cohort 22 patients (17 men, 5 women, mean age LT: 58.4 years) developed PLTLC. SIR for PLTLC was 4.4 in women and 2.6 in men. Median time interval between LT and LC diagnosis was 6.5 years (range: 0.3-19.5 years). Pre-transplant hepatocellular carcinoma (46% vs. 31%) and alcoholic liver disease (50% vs. 24%) were more often seen in the PLTLC cohort compared to the control LT cohort. In comparison to non-LT associated lung cancer the PLTLC patients more frequently had a squamous cell carcinoma subtype (36% vs. 26%). Due to annual routine lung cancer screening 27% (n=6) of the PLTLC patients were detected at stage I with the option of a curative treatment (LC cohort: 5%; p <0.001). Median Survival was significantly inferior in the PLTLC cohort compared to the LT cohort (9.8 vs. 15.2 years; p=0.041) and LC patients at stages IIIB-IV (5.5 vs. 11.3 months; p=0.036). Conclusions: The Incidence of lung cancer is significantly increased in the LT population compared to an age and sex matched general population, suggesting that other risk factors of LC like smoking are involved. As the prognosis is dismal at advanced stages, a regular lung cancer screening is strongly recommended in LT patients.
Estimating the risk of PTSD in recent trauma survivors: results of the International Consortium to Predict PTSD (ICPP)
Authors: Arieh Y. Shalev, Martin Gevonden, Andrew Ratanatharathorn, Eugene Laska, Willem F. van der Mei, Wei Qi, Sarah Lowe, Betty S. Lai, Richard A. Bryant, Douglas Delahanty, Yutaka J. Matsuoka, Miranda Olff, Ulrich Schnyder, Soraya Seedat, Terri A. deRoon‐Cassini, Ronald C. Kessler, Karestan C. Koenen
Journal: World Psychiatry (2019)

A timely determination of the risk of post-traumatic stress disorder (PTSD) is a prerequisite for efficient service delivery and prevention. We provide a risk estimate tool allowing a calculation of individuals' PTSD likelihood from early predictors. Members of the International Consortium to Predict PTSD (ICPP) shared individual participants' item-level data from ten longitudinal studies of civilian trauma survivors admitted to acute care centers in six countries. Eligible participants (N=2,473) completed an initial clinical assessment within 60 days of trauma exposure, and at least one follow-up assessment 4-15 months later. The Clinician-Administered PTSD Scale for DSM-IV (CAPS) evaluated PTSD symptom severity and diagnostic status at each assessment. Participants' education, prior lifetime trauma exposure, marital status and socio-economic status were assessed and harmonized across studies. The study's main outcome was the likelihood of a follow-up PTSD given early predictors. The prevalence of follow-up PTSD was 11.8% (9.2% for male participants and 16.4% for females). A logistic model using early PTSD symptom severity (initial CAPS total score) as a predictor produced remarkably accurate estimates of follow-up PTSD (predicted vs. raw probabilities: r=0.976). Adding respondents' female gender, lower education, and exposure to prior interpersonal trauma to the model yielded higher PTSD likelihood estimates, with similar model accuracy (predicted vs. raw probabilities: r=0.941). The current model could be adjusted for other traumatic circumstances and accommodate risk factors not captured by the ICPP (e.g., biological, social). In line with their use in general medicine, risk estimate models can inform clinical choices in psychiatry. It is hoped that quantifying individuals' PTSD risk will be a first step towards systematic prevention of the disorder.
Assessment of patients' satisfaction of an innovative oncology telemedicine clinic.
Authors: Kim-Son Hoa Nguyen, Maryliza El-Masry, Maria Tham, Lonnie Howard, Renei Ventura, Karen Chwick, Millie Snigdha Das
Journal: Journal of Clinical Oncology (2014)

e17506 Background: Telemedicine has been used in various ways to improve patient access to care. However, telemedicine has rarely been applied within medical oncology. The Palo Alto (PA) Veterans Affairs (VA) oncology clinic serves veterans from a wide catchment area of over 13,000 square miles. The average round-trip commute to our clinic is 82 miles. In February 2013, we implemented a teleoncology clinic serving patients who do not live locally. Instead of traveling to PA, patients presented to a VA community-based outpatient clinic (CBOC), where teleconference equipment provided an audio and video linkage to the PA VA oncology clinic. Laboratory data and vital signs were obtained at the local CBOC. Methods: We evaluated all patients seen in the teleoncology clinic from February 1st, 2013 to January 1st, 2014. Descriptive statistics were performed for patient demographics, cancer type, cancer stage, and treatment. We performed a telephone survey of all patients who participated in the teleoncology clinic during this period. Results: There were 15 evaluable patients. All but one patient were male with an average age of 61.3 years. The most common cancers were lung (46.7%) and colon (20%). Most patients (66.7%) had stage IV. The most common treatments were chemotherapy only (53.3%), surgery plus chemotherapy (20%), and surgery plus chemotherapy plus radiation (13.3%). The average distance to a local CBOC was 14.5 miles, compared to the average distance to the PA VA clinic of 82.7 miles, corresponding with a round-trip saving of 136.4 miles/visit. On a scale of 1 (poor) to 4 (excellent), patients graded the quality of the audiovisual equipment a 3, the convenience of the local CBOC 2.8, the care team's ability to address patients' concerns 2.7, and the overall teleoncology experience 3. Although 40% of the patients preferred a face-to-face visit, 78.6% would recommend telemedicine to their family and friends. Conclusions: Our teleoncology clinic was well regarded by a majority of patients. Patients saved an average of 136.4 miles per visit. Teleoncology clinics can potentially improve access to care for VA cancer patients. An ongoing study is evaluating the clinical outcomes of patients participating in our teleoncology clinic.
Determination of serum levels of interleukin 6 (IL6), vascular endotelial growth factor (VEGF), and soluble receptor of interleukin 2 (srIL2) as a markers of tumor activity: A preliminary study.
Authors: Manuel Sureda, Belen Valenzuela, Begona Vazquez, Vanesa Escudero, Elena Ma Martínez, Joseba Rebollo, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2014)

e22198 Background: Previous studies have postulated the role of IL6, VEGF and srIL2 as indicators of disease activity in different morbid conditions including cancer. Methods: Serum samples from patients diagnosed of cancer, active or in remission, were obtained in order to evaluate IL6, VEGF and srIL2 as general markers of tumor activity. Additional samples were obtained from pts without neoplasia. Samples were assessed by enzyme-linked immunosorbent assay kits (ELISA; R and D systems, Minneapolis, MN). The assays were conducted according to the manufacturer's guidelines. Data are presented as mean ± standard error of the mean and corresponding range. Comparison between different groups was done using the Student's t-test, with SPSS version 13.0 (SPSS, Chicago, IL). All tests were two-sided with a significance level of 0.05. Results: From November 2005 to August 2013, 3,655 determinations were performed in different moments of the treatment of 844 cancer pts, covering a wide spectrum of diagnosis (25% breast ca, 24.2% GI tract ca, 19.8% GU tract ca, 6.8% lung ca, 21.8% others). Two main groups were defined: non active tumor (in complete response or cured) or active tumor (no treated or in response but no complete). Additionally, 93 determinations (2.5%) were performed in 66 non oncologic pts evaluated for checkup. Mean levels of IL6 were of 8.2±.36 pg/mL (range .25-316) in pts with no active tumor vs 22.5±.9 pg/mL (.87-323) in pts with active tumor (p<0.0005). Mean levels of srIL2 were 364.8± 4.6 pg/mL (92.16-2284.27) in pts with tumor vs 613.3±30.7 pg/mL (87.67-41292) in pts with active tumor (p<0.0005). Mean levels of VEGF were of 397.9± 5.8 pg/mL (17.53-1932) in pts with no active tumor vs 449.8± 10.4 pg/mL (10.79-3153.2) in pts with active tumor (p<0.0005). No significant differences were found between pts without neoplasia and no active tumor. For IL6 sensitivity was 41%, specificity 90%, positive predictive value 76% and negative predictive value 66%. Conclusions: Present data suggest that cytokine analysis (IL6, srIL2 and VEGF levels) may offer relevant information on the activity of a treated cancer in the follow-up period.
Lack of association between geographic factors and survival in hematopoietic cell transplantation.
Authors: Nandita Khera, Theodore Gooley, Fausto R. Loberiza, Stephanie Lee, Frederick R. Appelbaum
Journal: Journal of Clinical Oncology (2014)

e17676 Background: Information about the impact of geographic factors on outcomes of allogeneic hematopoietic cell transplantation (HCT) is conflicting. We examined whether remote (distance from primary residence to transplant center) or rural dwelling (vs. urban) is associated with survival after allogeneic HCT. Methods: We analyzed clinical data for 2413 patients who underwent first allogeneic HCT at Fred Hutchinson Cancer Research Center (FHCRC) from 1993 to 1997 and 2003 to 2007. Residential ZIP code was used to derive the distance from place of residence to FHCRC, household income and classify place of residence into urban or rural using rural urban commuting area code. Multivariable regression was used to analyze the association between distance (divided into quartiles) and overall survival while adjusting for clinical variables including Pretransplant Assessment of Mortality (PAM) score, median income, and rural vs. urban residence. A landmark analysis was also done for 1847 patients, alive at 100 days to assess the effect of distance on survivorship. Results: Median age of the patients was 40 years (range 1-79), 59% were males, 48% received HCT for AML/MDS, 35% had high risk disease, 50% had unrelated donor HCT and 89% got myeloablative conditioning. Median follow-up was 9.3 years (range 1.1 to 20.7). Median distance from FHCRC was 614 miles (range 0-2740). 83% were urban residents. Median income was $47,142 (range 6758 – 154,817). Increasing distance from FHCRC was not associated with worse survival for the entire cohort and in patients alive at 100 days. (Table) Results were similar for the two different time periods (interaction p=0.43 entire cohort, p=0.66 landmark cohort). Conclusions: Neither increasing distance from the transplant center, nor rural or urban residence was associated with worse survival after allogeneic HCT. Multivariable regression model. Quartile (miles) Entire cohort Landmark cohort HR (95% CI); p value Q1 (0-51) 1 1 Q2 (51-614) 1.0 (0.8-1.2); p=0.95 0.99 (0.8-1.2); p=0.9 Q3 (614-1977) 0.9 (0.8-1.1); p=0.74 0.98 (0.8-1.2); p=0.87 Q4 (1977-2740) 0.8 (0.7-0.9); p=0.01 0.86 (0.7-1.1); p=0.13 Rural vs. urban 1.1 (0.9-1.3); p=0.39 1.04 (0.8-1.3); p=0.74
Orthogonal assays for the identification of inhibitors of the single-stranded nucleic acid binding protein YB-1
Authors: AlexanderJ. Trevarton, Yan Zhou, Dehua Yang, Gordon W. Rewcastle, Jack U. Flanagan, Antony Braithwaite, Peter R. Shepherd, Cristin G. Print, Ming-Wei Wang, Annette Lasham
Journal: Acta Pharmaceutica Sinica B (2019)

We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches. YB-1 predominantly binds to single-stranded nucleic acids, adding further difficulty to drug discovery. Therefore, we have developed two novel screening assays to detect compounds that interfere with the transcriptional activation properties of YB-1, both of which may be generalizable to screen for inhibitors of other nucleic acid binding molecules. The first approach is a cell-based luciferase reporter gene assay that measures the level of activation of a fragment of the E2F1 promoter by YB-1. The second approach is a novel application of the AlphaScreen system, to detect interference of YB-1 interaction with a single-stranded DNA binding site. These complementary assays examine YB-1 binding to two discrete nucleic acid sequences using two different luminescent signal outputs and were employed sequentially to screen 7360 small molecule compounds leading to the identification of three putative YB-1 inhibitors.
Abstract 19852: PDE3A Binds Directly to and Inhibits SERCA2 Activity Independently of its Catalytic Activity
Authors: Jonas Skogestad, Jan Magnus Aronsen, Karina Hougen, Marianne Lunde, Gustav B Lothe, Ingrid Albert, Mira Børstad, Serena Marshall, Ana Isabel Costa Calejo, Per Kristian Lunde, Jens Preben Morth, Kjetil Tasken, Cathrine R Carlson, Ivar Sjaastad
Journal: Circulation (2017)

Introduction: SERCA2 controls cardiac contractility, and its activity is negatively regulated by the cAMP phosphodiesterase PDE3A through an unknown mechanism. Several preclinical trials have shown...