tbuckley/cabot-search huggingface dataset:
Personalized medicine and needs for predictive biomarkers that produce non-linear treatment interactions.
Authors: Howard M Mackey, Thomas Bengtsson
Journal: Journal of Clinical Oncology (2015)

e14000 Background: For predictive biomarkers that are not binary in nature (eg. non-mutation based), Mackey and Bengtsson (Contemporary Clinical Trials, 2013) illustrate the substantial statistical challenges in defining accurate biomarker thresholds for biomarker positivity. Indeed, predictive biomarkers that are continuous in nature (eg. percentage of cells with a particular IHC staining intensity) and interact linearly with an experimental treatment require large sample sizes for reliable threshold estimation. Methods: For time-to-event data under the Cox proportional hazards model, we investigate a range of non-linear biomarker by treatment interactions scenarios. For these models, we compare confidence intervals for the biomarker threshold to those of models with linear biomarker effects. Results: In the linear scenario, confidence intervals for the biomarker threshold often encompass at least 50% of the population, calling into question the clinical utility of such biomarkers. In contrast, models with non-linear interactions yielded smaller confidence intervals. In particular, steep `s-shaped’ efficacy-biomarker relationships yielded substantial increases in precision. Conclusions: When the biomarker by treatment interaction is linear, simultaneous investigation of an experimental therapy with a predictive biomarker often requires substantial sample sizes. Predictive biomarkers with strong, non-linear effects however, enable superior precision as well as superior clinical utility.
Comparison of five methods for detection of carbapenemases in Enterobacterales with proposal of a new algorithm
Authors: L. Lucena Baeza, N. Pfennigwerth, C. Greissl, S. Göttig, A. Saleh, Y. Stelzer, S.G. Gatermann, A. Hamprecht
Journal: Clinical Microbiology and Infection (2019)

ObjectivesThe aim of this study was to evaluate the performance of five different carbapenemase tests and to develop an algorithm which will permit the detection of most common and rare carbapenemases in routine microbiology laboratories.MethodsThe immunochromatographic tests CARBA-5 (NG), RESIST-4 O.K.N.V. (Coris), the colorimetric β-CARBA (BioRad), a newly developed carbapenem-inactivation method (CIM) supplemented with zinc (zCIM), and the Xpert Carba-R (Cepheid) were challenged with a collection of 189 molecularly characterized Enterobacterales isolates, including 146 carbapenemase producers (CPE): VIM (n = 48), OXA-48-like (n = 40), NDM (n = 29), KPC (n = 13), IMI (n = 9), IMP (n = 9), OXA-58 (n = 2), and GES (n = 2).ResultsThe overall sensitivity/specificity values for the five carbapenemase detection tests were 84.2% (CI 77.6–89.2%)/100% (CI 91.8–100%) for RESIST-4, 88.2% (CI 82.1–92.4%)/100% (CI 91.8–100%) for CARBA-5, 88.2% (CI 82.1–92.4%)/100% (CI 91.8–100%) for Xpert Carba-R, 73.7% (CI 66.2–80.0%)/100% (CI 93.4–99.0%) for β-CARBA, and 97.4% (CI 87.9–99.6%)/97.7% (CI 87.9–99.6%) for zCIM. The four common carbapenemases (KPC, OXA-48-like, NDM, and VIM) were detected with ≥97.6% sensitivity by all tests except for β-CARBA (76.6% (CI 68.4–83.2%)). IMI and GES were only detected by zCIM (sensitivity 90.9% (CI 62.3–98.4%)). Based on these results a new algorithm was developed, consisting of an immunochromatographic assay as the first test followed by zCIM, which allows detection of 99.3% of all carbapenemases assessed.ConclusionsExcept for β-CARBA, all methods showed excellent sensitivity/specificity for the detection of the four most frequent carbapenemases. With the new algorithm, rare variants can also be detected. It is rapid, simple, and inexpensive and can be performed in any microbiology laboratory, as no PCR equipment is required.
Phase I study of PM00104, a novel cytotoxic anti-cancer drug, administered to patients with advanced solid tumors or lymphoma
Authors: E. Gallerani, T. A. Yap, A. Lopez, C. Coronado, H. Shaw, A. Florez, B. de las Heras, H. Cortes-Funes, J. de Bono, L. Paz-Ares
Journal: Journal of Clinical Oncology (2007)

2517 Background: PM00104 (Zalypsis [Z]) is a novel synthetic alkaloid related to the marine compounds Jorumycin and the family of Renieramycins. Preliminary analyses of its mechanisms of action suggest effects on the cell cycle, DNA binding properties, as well as transcriptional inhibition. Z has shown antitumor activity in vitro (IC 50 =10 -8 M) and in xenografts models, and an acceptable toxicology profile. Methods: Patients (pts) with advanced cancers or lymphoma were enrolled to determine the safety, tolerability, maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK) and antitumor activity of Z administered as a 1- hour IV infusion every 3 weeks. Sequential cohorts of 3–6 pts received the following doses: 0.225, 0.45, 0.9, 1.8, 3.0 and 3.6 mg/m 2 . Results: 27 pts were treated (19 M; median age: 58, range: 39–79; ECOG PS =2). 2 of 6 pts at 3.6 mg/m 2 experienced dose-limiting toxicities (DLT), defining the MTD; 1 pt with colorectal cancer with extensive liver metastases developed grade 4 thrombocytopenia and neutropenia, grade 3 transaminase elevation, and grade 4 troponin I rise without cardiac symptoms or electrocardiogram alterations. These toxicities all resolved. Another pt with adrenal carcinoma developed grade 3 nausea, vomiting and asthenia despite anti-emetics, which resolved with dexamethasone 2 days after infusion. Other toxicities were =grade 2 and included: nausea, vomiting, transient transaminase elevation and asthenia at doses =0.225 mg/m 2 and myelosuppression (neutropenia and leukopenia) at doses =3.0 mg/m 2 . No DLTs were seen in 6 pts at a dose of 3.0 mg/m 2 , establishing this dose as the RD. 3 more pts were added to complete the expanded cohort at this RD. To date, 2 pts have SD lasting &gt;3 months. PK data indicate that drug AUC and C max increase proportionally across the dose range until doses =3.0 mg/m 2 , when a disproportionate increase in AUC and C max was seen. Z has a long half-life (=50 hours) and wide volume of distribution (Vss ∼500 l/m 2 ). Conclusions: Z has a favorable safety profile. The MTD on this schedule has been established at 3.6 mg/m 2 . Alternative schedules are being evaluated to try and increase dose intensity. No significant financial relationships to disclose.
Abstract P020: Novel Serum Metabolites Associate With Grip Strength Among Bogalusa Heart Study Participants
Authors: Jovia L Nierenberg, Jiang He, Changwei Li, Xiaoying Gu, Shengxu Li, Lydia A Bazzano, Wei Chen, Jason Kinchen, Tanika N Kelly
Journal: Circulation (2019)

Introduction: Hand grip strength is a simple and non-invasive measure for frailty and pre-frailty in aging populations. It has been shown to predict cardiovascular disease events, disability, fracture risk, and all-cause mortality. However, the biological pathways underlying frailty remain largely unknown. Hypothesis: Serum metabolites may associate with grip strength, among a middle aged biracial population. Methods: Untargeted ultrahigh performance liquid chromatography-tandem mass spectroscopy was used to detect and quantify serum metabolites among 825 white and 436 African-American participants of the Bogalusa Heart Study. Grip strength was measured in kg, and was averaged between both hands. We used race stratified and combined multivariate adjusted linear regression to examine associations between single metabolites and grip strength (mean: 35.14 kg, standard deviation: 11.85 kg), adjusted for age, sex, body mass index, kidney function, education, cigarette smoking, alcohol drinking, and race (in combined analyses). Significant metabolites were identified as those achieving Bonferroni corrected significance (P&lt;4.16х10 -5 ) in one race group and the entire cohort, with a similar trend observed in the other race group. Results: Six novel associated metabolites were identified, comprised of amino acid (polyamine), carbohydrate (aminosugar), and nucleotide (purine metabolism, adenine containing, and pyrimidine metabolism, cytidine or uracil containing) subpathways ( Table ). Participants with higher levels of these metabolites had lower grip strength. Conclusions: This analysis identified novel metabolites associated with grip strength, providing insight into the biological pathways of frailty.
Abstract 14811: A Clinical Risk Scoring Tool to Predict Readmission After Discharge From Cardiac Surgery: An Administrative and Clinical Database Study
Authors: Derrick Y Tam, Jiming Fang, Jack Tu, Dennis Ko, Andrew Tran, Saswata Deb, Stephen E Fremes
Journal: Circulation (2017)

Introduction: Reducing readmission after cardiac surgery remains a quality improvement priority. Most readmission risk models examine only coronary artery bypass grafting (CABG). We elucidate the pre- and peri-operative risk factors for readmission after CABG and/or valve surgery using administrative databases in Ontario, Canada. Methods: Adults >18 years undergoing isolated CABG, isolated/multiple valve (aortic, mitral or tricuspid) or combined CABG/valve surgery from 2008-2016 in Ontario were eligible. Risk factors for 30-day readmission after discharge were obtained through linkages of Ontario administrative databases. Hazard ratios for risk factors were calculated using Cox proportional hazards regression. We developed a clinical risk scoring tool weighted by beta-coefficients from the final model. Discrimination and calibration was performed using c-statistics and comparing the predicted to observed probabilities across deciles of predicted risk. Results: 63,336 patients underwent CABG and/or valve s...
Evolving patterns of metastatic renal cell carcinoma: A meta-analysis.
Authors: Justin Lin, William K. Oh, Bobby Chi-Hung Liaw, Matt D. Galsky, Che-Kai Tsao
Journal: Journal of Clinical Oncology (2019)

563 Background: Advances in diagnostic and treatment modalities have resulted in better outcomes in metastatic renal cell carcinoma (mRCC) patients. With new therapies extending survival, we hypothesize that pattern of metastatic disease has evolved over time. We assessed the pattern of metastases as reported in baseline characteristics of prospective clinical trial patients between 1990 and 2018. Methods: This study identified all phase I-III mRCC therapeutic clinical trials published between January 1990 and July 2018 in PubMed and ClinicalTrials.gov. Studies that included patients with other cancers or did not report metastases were excluded. Data was stratified to examine differences in three listed treatment eras for first-line therapy. Linear regression models were used to evaluate temporal trends and subcategorized as either First Line Only treatments (FLO) or Second-Line and Beyond (SLB). Results: 127 clinical trials encompassing 16534 subjects were identified. Between 1990 and 2018, rates of lymph node metastases in the FLO population increased significantly at 1.03% per year ( P &lt; 0.05). The rate of lung and liver metastases in FLO showed a trend of increase at 0.48% and 0.04% per year, respectively, but decreased -0.73% and -0.15% per year in the SLB population. Moreover, rate of bone metastasis showed a trend of increase in both populations, particularly between the VEGF/TKI and Immunotherapy/TKI eras in the SLB population (18.89% to 29.19%). Conclusions: Notable changes were found in the pattern of metastasis in patients with mRCC. Increasing rate of bone metastasis may warrant dedicated bone imaging for routine staging in patients with mRCC. These evolving patterns may have important implications in treatment selection and prognosis in this patient population. [Table: see text]
KRAS, NRAS, and BRAF mutations are highly enriched in trisomy 12 chronic lymphocytic leukemia and are associated with shorter treatment-free survival
Authors: Elena Vendramini, Riccardo Bomben, Federico Pozzo, Dania Benedetti, Tamara Bittolo, Francesca Maria Rossi, Michele Dal Bo, Kari G. Rabe, Gabriele Pozzato, Francesco Zaja, Annalisa Chiarenza, Francesco Di Raimondo, Esteban Braggio, Sameer A. Parikh, Neil E. Kay, Tait D. Shanafelt, Giovanni Del Poeta, Valter Gattei, Antonella Zucchetto
Journal: Leukemia (2019)

KRAS mutations are among the most common oncogenic events in human carcinomas of endodermal origin, whose presence predicts for resistance to several target therapies [1].Conversely, little is known regarding the role and/or clinical impact of KRAS mutations in the setting of the hematological malignancies, including chronic lymphocytic leukemia (CLL), and only in recent years extensive sequencing data have highlighted the recurrent mutations of genes affecting the Ras-MAPK pathway in CLL [2,3].These mutations, by leading to a constitutive activation of MAPK signaling pathway, have emerged as relevant in driving impaired clinical responses to lenalidomide and chlorambucil, and acquired resistance to fludarabine as well as to .In this context, some studies pinpointed a higher frequency of mutations in members of the Ras-MAPK pathway in CLL cases with specific clinico-biological features [6,7], including the presence of trisomy 12, a cytogenetic aberration associated with a unique pathophysiology among CLL [8,9], and/or an unmutated (UM) configuration of IGHV genes, although a dedicated and comprehensive analysis of these aspects is still missing.This study, approved by the IRB of the Aviano Centro di Riferimento Oncologico (Approvals n.IRB-05-2010 and n.IRB-05-2015), included 534 primary CLL from treatmentnaive patients.The cohort was purposely enriched in trisomy 12 CLL by including 110 cases from the Mayo Clinic, Rochester, MN [8] to better evaluate the incidence of mutations of the Ras-MAPK pathway in these subsets.Overall, out of 534 cases, trisomy 12 CLL accounted for 300 cases (190 with trisomy 12 as the sole abnormality [trisomy 12-only], and 110 with trisomy 12 plus another abnormality on FISH [trisomy 12-plus]), 332 cases had UM IGHV genes, and 214 cases had NOTCH1 aberrations (details in Table S1).CLL patients were diagnosed and treated according to the current iwCLL 2018 guidelines [10], and all samples were collected at diagnosis from treatment-naive patients.In 442/534 cases (clinical cohort),
Determining a correlation between certain multimolecular markers and pathologic complete response for ER-positive breast cancer.
Authors: Kun Wang, Teng Zhu, Yi-Fang Zhang, Chunling Liu
Journal: Journal of Clinical Oncology (2015)

e11523 Background: Pathological complete response (pCR) after neoadjuvant chemotherapy is an independent predictive factor. This study was to evaluate the correlation between multimolecular markers and pCR rates after neoadjuvant chemotherapy. Methods: Patients with previously untreated, non-metastatic, stage II-III breast cancer were enrolled. Immunohistochemistry was used to examine multimolecular markers expression in breast cancer biopsies. Patients were treated for 4 cycles with paclitaxel (175 mg/m2 biweekly) and carboplatin [area under the curve (AUC) 5 biweekly]. Patients with HER2-positive disease received trastuzumab (6 mg/kg initial dose with subsequent doses of 4 mg/kg biweekly) simultaneously. The primary end point was pathologic complete response (pCR). The correlation between multimolecular markers and pCR rates was evaluated by multivariate analysis. Results: Between 01/2009-02/2014, 131 patients were enrolled. Eighty-nine patients were estrogen receptor(ER) positive, 50 were HER2 positive. The overall pathologic complete response (pCR) rate was 34.4% (45 out of 131). In univariate analysis, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67 and tau were found to be significantly predictive of a PCR (p = 0.000, 0.000, 0.000, 0.048, 0.003, respectively). ER-negative [OR = 0.207, 95%CL (0.087-0.493), P = 0.000], and HER2-positive [OR = 5.451, 95% CL (2.312-12.850), P = 0.000] achieved higher PCR in multivariate analysis. HER2 [OR = 5.746, 95% CL (1.669-19.778), P = 0.006] and tau [OR = 0.154, 95%CL (0.038-0.627), P = 0.009] were significant for pCR in multivariate analysis in ER-positive tumors. Conclusions: In univariate analysis, patients with estrogen receptor (ER) negative, progesterone receptor (PgR) negative, HER2 positive, high level of Ki67 and tau were more likely to achieve pCR after neoadjuvant chemotherapy. ER-negative and HER2-positive achieved higher pCR on multivariate analysis. Higher pCR rates occurs in HER2-positive and tau-negative in patients with ER-positive tumors. Additional study about the postoperative follow-up of this regimen is warranted. Clinical trial information: NCT02059876.
Co-Expression of CD56 and Production of Transforming Growth Factor Beta By Foxp3 Regulatory T Cells from Langerhans Cell Histiocytosis Lesions
Authors: Jenee Mitchell, Egle Kvedaraite, Tatiana von Bahr Greenwood, Jan-Inge Henter, Daniel G Pellicci, Stuart P Berzins, George Kannourakis
Journal: Blood (2018)
Induction of acute myeloid leukemia (AML) with idarubicin, cytarabine and cladribine (ICC).
Authors: Eric Wiedower, Omer HASSAN Jamy, Michael Gary Martin
Journal: Journal of Clinical Oncology (2015)

e18048 Background: Seven plus 3 has long been considered the standard of care for the induction of AML. The addition of Cladribine to Daunorubicin 60 mg/m2 and Cytarabine has been shown to increase complete remission (CR) rate and median overall survival (OS) but whether the addition of Cladribine to 7 + 3 with other anthracyclines is beneficial is unknown. Methods: A retrospective study was conducted evaluating patients with AML induced with ICC between January 2010 and December 2014 at Methodist University Hospital in Memphis, TN. Approval for the study was obtained from the IRB. Patient and disease characteristics and outcomes were analyzed with GraphPad Prism, Microsoft Excel and SPSS version 19.0. Results: Twenty-two patients diagnosed with AML that received ICC were identified. Patient and disease characteristics are summarized in table 1. Twelve patients (54.5%) had at least 1 high-risk feature. All patients achieved hypoplastic bone marrows on Day 14 and seventeen (77.3%) achieved CR. Thirty day mortality was 9.1% (2 patients). One patient died from typhlitis and the other patient died secondary to complications from pulmonary leukostasis which was present upon presentation prior to initiation of induction chemotherapy. Twenty-four month OS and disease-free survival were 53.4% and 35.4%, respectively. Conclusions: Induction of AML with ICC was associated with a high CR rate and OS in our older and high-risk population. Further studies of ICC are reasonable. Patient and Disease Characteristics Total Number of Patients: 22 Median age : 58 years (range 24-68) Characteristics No. of Patients (%) Males/Females 14 (63.6)/ 8 (36.4) White/Black 10 (45.5)/ 12 (54.5) History of MDS 5 (22.7) Cytogenetics Favorable 2(9.1) Intermediate 13(59.1) Poor 4(18.2) Unknown 3(13.7) Flt3 Positive* 1 (4.5) NPM1 Positive** 2 (9.1) *Isolated occurrence with intermediate risk cytogenetics **Isolated occurrence with intermediate risk cytogenetics
Epicardial fat: the role of testosterone and lipid metabolism in a cohort of patients with Klinefelter syndrome
Authors: S. Granato, G. Barbaro, M.R. Di Giorgio, F.M. Rossi, C. Marzano, F. Impronta, M. Spaziani, A. Anzuini, A. Lenzi, A.F. Radicioni
Journal: Metabolism (2019)
The dynamics of biomarkers and bone imaging associated with oral cabozantinib therapy in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Ulka N. Vaishampayan, Izabela Podgorski, Jawana Lawhorn-Crews, Lance K. Heilbrun, Elisabeth I. Heath, Kimberlee Dobson, Daryn W. Smith, Anthony Frank Shields
Journal: Journal of Clinical Oncology (2015)

e13547 Background: Cabozantinib (C) is a c-met and vascular endothelial growth factor receptor inhibitor that demonstrated remarkable responses on bone scan. We studied the dynamics of these changes with imaging and biopsies pre- and post-therapy with C. Methods: 20 mCRPC patients (pts) with normal organ function and performance status 0-2 with maximum of 1 prior chemotherapy were enrolled. C 60 mg orally was administered daily. Pre-therapy conventional 99mTc-labeled bone scintigraphy (BS), positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) thymine (FMAU-PET) scans were conducted a mean of 6 days pre-therapy and 17 days post therapy. The maximum tumor standardized uptake values (SUV) were measured for the 5 most active lesions in at least 3 skeletal areas with each tracer. Tumor biopsies were conducted pre and 2 weeks post therapy. 3 bone markers were measured: serum bone specific alkaline phosphatase (BSAP), serum N-terminal telopeptide of collagen type 1 (NTx), and urine NTx. Results: 19/20 pts are evaluable.5 had visceral involvement. 11 and 6 pts required dose reduction to the 40 mg daily dose and 20 mg daily dose respectively. 7 patients had a PSA decline, of which 2 had a decline > 50%. The NaF-PET demonstrated a change in mean tumor SUV of -59% (range -85 to -5%, n = 9) and -43% (range -60 to -25%, n = 10) for the pts who were clinically stable and remained on therapy for > 4 or < 4 cycles, respectively. The FMAU-PET demonstrated a change in mean tumor SUV of -41% (-60 to -14%) and -34% (-63 to -23%) for these groups. Imaging analysis patterns were similar in pts maintaining stable disease for more, or less than 8 cycles. A 50% decrease in serum BSAP was associated with a hazard ratio (HR) for progression of 0.89 (90% confidence interval [CI]: 0.68 – 1.16). For serum NTx and urine NTx, the analogous HR’s were 0.82 (90% CI: 0.63 – 1.06) and 1.07 (90% CI: 0.63 – 1.84), respectively. Conclusions: Early changes in imaging and bone markers were not predictive of clinical benefit with C. Tissue C-met expression will be correlated with PFS and OS. Clinical trial information: NCT01812668.
CD8+ T cells expand stem and progenitor cells in favorable but not adverse risk acute myeloid leukemia
Authors: Ramin Radpour, Carsten Riether, Cedric Simillion, Sabine Höpner, Rémy Bruggmann, Adrian F. Ochsenbein
Journal: Leukemia (2019)

CD8+ T cell immunosurveillance is crucial in solid tumors and T cell dysfunction leads to tumor progression. In contrast, the role of CD8+ T cells in the control of leukemia is less clear. We characterized the molecular signature of leukemia stem/progenitor cells (LSPCs) and paired CD8+ T cells in patients with acute myeloid leukemia (AML). Epigenetic alterations via histone deacetylation reduced the expression of immune-related genes in bone marrow (BM)-infiltrating CD8+ T cells. Surprisingly, a silenced gene expression pattern in CD8+ T cells significantly correlated with an improved prognosis. To define interactions between CD8+ T cells and LSPCs, we performed comprehensive correlative network modeling. This analysis indicated that CD8+ T cells contribute to the maintenance/expansion of LSPCs, particularly in favorable risk AML. Functionally, CD8+ T cells in favorable AML induced the expansion of LSPCs by stimulating the autocrine production of important hematopoietic cytokines such as interleukin (IL)-3. In contrast, LSPCs in aggressive AML were characterized by a higher activation of stemness/proliferation-related pathways and develop independent of BM CD8+ T cells. Overall, our study indicates that CD8+ T cells support and expand LSPCs in favorable risk AML whereas intermediate and adverse risk AML possess the intrinsic molecular abnormalities to develop independently.