tbuckley/cabot-search huggingface dataset:
Prognostic impact of estrogen receptor (ER) level changes during progression for patients with both ER-positive (ER+) primary breast cancer and paired recurrence.
Authors: Maria Vittoria Dieci, Elena Barbieri, Aicha Goubar, Fabrice Andre, Claudia Omarini, Stefania Raffaella Bettelli, Federico Piacentini, Guido Ficarra, Pier Franco Conte, Valentina Guarneri
Journal: Journal of Clinical Oncology (2013)

556 Background: We have previously reported that ER+ breast cancer (BC) patients (pts) who become ER-negative at relapse have a poorer overall survival (OS) as compared to those still ER+ at relapse [Dieci et al., Ann Oncol 2013]. Our aim is to evaluate whether, among the group of patients with an ER+ status on both primary and recurrence, changes in the level of ER expression may be of prognostic value. Methods: A total of 81 pts with ER+ primary BC and ER+ paired recurrence who underwent relapse biopsy at Modena University Hospital were studied. ER status was assessed by IHC and the cutoff for ER-positivity was &gt;=10%. Samples were defined as ER-high (&gt;50%) and ER-low (&gt;=10% and &lt;=50%). HER2-status was defined according to IHC and/or FISH results. OS was calculated as the time interval between primary BC diagnosis and death or last follow up. Results: Biopsied recurrences were: distant (86%) and local relapses (14%). Fifteen percent of primary and 21% of recurrent tumors were HER2-positive. Sixty-two pts maintained the same ER level (i.e. high or low) on both primary and relapse (ER-level concordant), whereas 19 changed from ER-high to ER-low or viceversa (ER-level discordant). No difference in OS was observed between the ER-level concordant and the ER-level discordant groups (p=0.3). However, we identified those pts whose ER-high primary BC turned into ER-low as having a particularly poor outcome. Indeed, 10yrs-OS rates were 51% for the ER-level concordant group, 50% for pts changing from ER-low to ER-high and 14% for pts changing from ER-high to ER-low (p=0.0019). Finally, we focused on the subset of pts starting from an ER-high primary BC and showing an ER+/HER2-negative phenotype on both primary and relapse (n=51). The drop of ER-level expression below the 50% cut-off at relapse was confirmed as a poor prognostic factor, as compared to pts maintaining an ER-high level (10yrs-OS 53% vs 17%, p=0.0063). Conclusions: We demonstrated that, even in the case of maintenance of the same single-receptor status (ER+) and/or tumor phenotype (ER+/HER2-negative) between primary BC and recurrence, relapse biopsy may provide relevant prognostic information.
Association of aspirin use with improved 5-year survival in colorectal cancer patients with PIK3CA mutation.
Authors: Nishi Kothari, Timothy Joseph Yeatman, Kate Fisher, Michael J. Schell, Richard D. Kim
Journal: Journal of Clinical Oncology (2013)

3644 Background: Recent work has shown an association between longer survival and aspirin use in colorectal cancer (CRC) patients with mutated PIK3CA. It has been hypothesized that this survival advantage could occur via blocking the PI3K pathway and allowing apoptosis of mutated cancer cells. The goal of this work is examine the use of aspirin and outcome in CRC patients with PI3KCA mutation. Methods: PIK3CA mutation status was assessed in paraffin-embedded tumor samples from 471 CRC patients between 1998-2010. PIK3CA mutation was assessed by exome sequencing using an Illumina Next Generation (NGS) platform with 50-100X coverage on all patients. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. The usage of aspirin was collected retrospectively with electronic chart review. Results: Out of 471 patients, 73 were found to have unique PIK3CA mutations by NGS (15.4%). The most common mutations were found at codon 9 (38%) and codon 20 (21%). Patients had a median follow up of 47 months. Initial stage at diagnosis for PIK3CA mutants were as follows: 11 pts were stage I, 31 pts were stage II, 24 pts were stage III and 16 patients were stage IV. Of patients who died, those taking ASA had a 5% cancer related mortality compared to 23% cancer related mortality in non-ASA users. In contrast, the non-cancer related mortality was 25% in ASA users and only 8% in non-ASA users. Cancer specific rates for five year survival were 90% in the ASA group and 57% in the non-ASA group for all stages. In stage IV patients, there was 80% five year survival in the ASA users and 32% in the non-ASA group. Conclusions: There was a trend toward improvement in five year survival for colorectal cancer patients with PIK3CA mutations who used ASA. This trend persisted even in stage IV patients. Notably, non-cancer related deaths were higher in the ASA users, most likely secondary to medical comorbidities that necessitated ASA use. As follow up continues and this data set matures, future work will focus on validating these preliminary results and relating specific PIK3CA mutations to ASA response.
A phase I/II, first-in-human dose-escalation study of GSK2636771 in patients (pts) with PTEN-deficient advanced tumors.
Authors: Hendrik-Tobias Arkenau, Joaquin Mateo, Charlotte Rose Lemech, Jeffrey R. Infante, Howard A. Burris, Yung-Jue Bang, Joseph Paul Eder, Roy S. Herbst, Sunil Sharma, Hyun Cheol Chung, Shaun Decordova, Karen E Swales, Michelle D Garrett, Jill I Loftiss, Michael Durante, Mark W. Russo, Benjamin B. Suttle, Monica Motwani, Rakesh Kumar, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2014)

2514^ Background: GSK2636771 is a potent, orally bioavailable and selective inhibitor of PI3Kβ (0.89 nM), with >900-fold selectivity over PI3Kα/PI3Kγ and >10-fold over PI3Kδ. It inhibits AKT phosphorylation and downstream signalling measured as decrease of PRAS40-, GSK3β-, and RPS6-phosphorylation in PTEN mutant cell lines. Methods: An ongoing phase-I/IIa FTIH, open label dose escalation study of GSK2636771, once daily (QD), is being conducted to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy in pts with advanced tumors deficient in PTEN. The study comprised 3 parts: starting-dose selection, 3+3 dose escalation and phase-2 expansion. Backfill cohorts with mandatory, paired biopsies were opened to evaluate PD. The DLT period was 28 days. Results: As of 01/2014, 53 pts (35 m: 18 f, mean 60 yrs) were enrolled into 7 dose escalation (25 -500 mg) and 4 PD cohorts (50-350 mg). In total 5 DLTs (3x hypophosphatemia/ 2x hypocalcemia G3) were observed in 3 pts at 500 mg, defining MTD. AEs >20% (all grades) included diarrhoea, nausea, vomiting, fatigue, abdominal pain, anemia and decreased appetite - hyperglycemia was infrequent (4%). Cmax was reached 4-6 h after single and repeat dosing, with a t1/2 of 17-38.6 h across cohorts. Increases in Cmaxand AUC(0-24 h) were dose-proportional up to 350 mg, but less than proportional at 400 and 500 mg. Phosphorylated AKT analysis in surrogate tissue among 20 pts across cohorts revealed a >50% (18 pts) and >80% (12 pts) decrease, 1-10 h post dosing, suggesting target engagement. One pt (prostate) had a RECIST PR and 13 pts had SD, 6 of whom were on study for ≥6 months. Conclusions: MTD and recommended phase-2 dose of GSK2636771 was 400 mg QD. PD effects on AKT and downstream proteins were observed and early efficacy signals suggest anti-tumor activity in pts with PTEN deficient tumors. Recruitment into the phase-2 part is ongoing. Clinical trial information: NCT01458067.
The role of whole body <sup>18</sup>F-FDG PET/CT scan in patients with carcinoma of unknown primary
Authors: M. Hu, J. Yu, N. Liu, L. Kong, P. Zhang
Journal: Journal of Clinical Oncology (2009)

e22051 Background: Carcinoma of unknown primary (CUP) is a heterogeneous group of tumors and usually follows an aggressive biological and clinical behavior. Difficult challenges in oncology which the identification of the primary tumor and a complete disease staging could offer a more rational and efficient treatment in order to improve the survival time. Our aim was to evaluate the role of 18 F-FDG PET/CT scan with two aspects: detection of the primary site, and estimation of tumor biological behavior which essential for the development of new, individual and targeted effective therapies. Methods: One hundred and seventeen patients presenting with histologically confirmed metastatic carcinoma (76 lymph nodes, 41 visceral biopsy proven) of unknown primary site were included in this retrospective study. The evaluations as follows had not revealed a primary site: detailed medical history, full physical and laboratory examinations, and diagnostic imaging methods. All patients underwent PET/CT. Results: In 42 (35.90%) patients, a primary tumor site which was confirmed by follow-up or surgery was showed by PET/CT. In 15 (12.82%) patients, the primary tumor site was suggested by PET/CT but not confirmed. In 60 (51.28%) patients, the primary tumor site was not localized modifying the stage of disease. In the other 17 (14.53%) patients, PET/CT scan identified further unexpected metastases. Overall, the following oncological treatment was influenced by the PET/CT scan, in a total of 38 (32.47%) patients. Between the adenocarcinoma and squamous cell carcinoma groups, no significant difference in SUVmax was found ( t=1.191, p = 0.244). A significantly higher SUVmax was found among patients with poorly or undifferentiated carcinoma compared with patients with well to moderately ( t=4.013, p&lt;0.01) differentiation; In 42 patients with a confirmed primary tumor site, the SUVmax of Metastatic tumours have a closely relationship correlate with those of primary tumours, ( r=0.738, p&lt;0.01). Furthermore, a significantly higher SUVmax was found among metastases compared with primary tumors ( t=3.470, p&lt;0.01). Conclusions: Our data strongly support 18 F-FDG PET/ CT imagings not only provide new insights in the diagnosis and staging of patients with CUP, but also evaluate biologic characters of tissue. 1 No significant financial relationships to disclose.
Activation by zoledoronic acid and IL-18 of γδ T cells from early-stage breast cancer patients in the context of helper NK cells.
Authors: Tomoharu Sugie, Kaoru Murata-Hirai, Masashi Iwasaki, Craig T Morita, Wen Li, Haruki Okamura, Nagahiro Minato, Masakazu Toi, Yoshimasa Tanaka
Journal: Journal of Clinical Oncology (2012)

e21004 Background: Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. Methods: Breast cancer patients (n=80) were enrolled after institutional review board approval and with written informed consent. Peripheral blood mononuclear cells (PBMC) were purified and stimulated with Zol/IL-2 or Zol/IL-2/IL-18 for 2 to 10 days. The expanded cells were assessed on flow cytometry and the production of IFN-γ and TNF-α measured through ELISA. Results: The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2T cells and helper NK cells (CD3 - CD56 bright CD11c + CD14 - CD16 + NKGD2 + NKp44 low ) from patients with either low or high frequencies of Vγ2Vδ2 T cells. Cell-to-cell contact between γδ T and helper NK cells appeared to promote expansion of γδ T cells. Exogenous IL-18 markedly enhanced IFN-γ and TNF-α production from PBMC stimulated by Zol/IL-2, whereas the addition of an anti-IL-18Rα mAb reduced cytokine production. Conclusions: These results demonstrate that Zol elicits immunological responses by γδ T cells from early-stage breast cancer patients and IL-18 enhances proliferative responses and effector functions of γδ T cells in the context of helper NK cells.
Muscle-invasive bladder cancer: Molecular subtypes and response to neoadjuvant chemotherapy.
Authors: Roland Seiler, Brian Winters, James Douglas, Bas W.G. van Rhijn, Gottfrid Sjödahl, Seth P. Lerner, Katherine A. Hoadley, Scott A. North, David James McConkey, Woonyoung Choi, William Y. Kim, Kim E.M van Kessel, George N. Thalmann, Elai Davicioni, Simon J. Crabb, Joost L Boormans, Marc Dall'Era, Jonathan Lawrence Wright, Michiel Simon Van Der Heijden, Peter C. Black
Journal: Journal of Clinical Oncology (2017)

281 Background: Molecular subtypes of muscle-invasive bladder cancers (MIBC) have recently been discovered based on gene expression. We investigated the impact of different subtyping methods on response to neoadjuvant cisplatin-based chemotherapy (NAC) and developed a single sample model for subtyping. Methods: Transcriptome-wide microarray analysis was conducted on pre-NAC transurethral resection (TUR) specimens of 223 patients with MIBC who received NAC followed by cystectomy at 5 centers. The specimens were classified according to four published methods for molecular subtype (UNC, MDA, TCGA, Lund). Overall survival (OS) for each subtype was compared between NAC patients in this study and non-NAC patients from the provisional TCGA. A genomic classifier (GSC) was trained to predict subtype in a single sample model and validated in independent NAC (2 centers) and non-NAC datasets. Results: The models generated subtype calls similar to previously published ratios. Concordance of a given subtype between the different methods was high. Luminal tumors had the best OS independent of NAC. Patients with tumors classified as UNC basal, MDA basal and TCGA cluster III experienced the greatest improvement in OS after NAC compared to surgery alone. Tumors assigned as UNC claudin-low had the worst OS irrespective of treatment regimen (p=0.005). GSC accurately predicted four classes (luminal, luminal-infiltrated, basal, claudin-low) and the differential impact of a basal subtype on patient OS in NAC (3-yr survival of 75.2%; p=0.001) and non-NAC (3-yr survival of 42.4%; p=0.014) cohorts could be validated. Conclusions: The benefit of NAC varies between molecular subtypes. The good prognosis of luminal/cluster I tumors could not be improved with NAC, which suggests these patients may be managed best with surgery alone. The prognosis of patients with basal tumors improved the most when treated with NAC compared to surgery alone. Poor OS of claudin-low tumors even after NAC implies that these tumors are resistant to cisplatin-based chemotherapy, and these patients should be included in protocols investigating alternative treatment options like immunotherapy. Further validation prior to clinical implementation is needed.
Predictors for individual patient antibiotic treatment effect in hospitalized community-acquired pneumonia patients
Authors: A.F. Simonetti, C.H. van Werkhoven, V.A. Schweitzer, D. Viasus, J. Carratalà, D.F. Postma, J.J. Oosterheert, M.J.M. Bonten
Journal: Clinical Microbiology and Infection (2017)
Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease
Authors: Gearoid M. McMahon, Shih-Jen Hwang, Clary B. Clish, Adrienne Tin, Qiong Yang, Martin G. Larson, Eugene P. Rhee, Man Li, Daniel Levy, Christopher J. O'Donnell, Josef Coresh, J. Hunter Young, Robert E. Gerszten, Caroline S. Fox
Journal: Kidney International (2017)
Comparing health-related quality of life (HRQL) of cancer patients undergoing chemotherapy with family members in a tertiary hospital
Authors: A. Papadopoulos, I. Vrettos, K. Kamposioras, D. Charitos, G. Giannopoulos, D. Pectasides, D. Niakas, T. Economopoulos
Journal: Journal of Clinical Oncology (2009)

e20535 Background: In Greece there is limited information concerning the HRQL of cancer patients undergoing chemotherapy. The aim of this study was to estimate and compare the HRQL of cancer patients and their relatives during the period of chemotherapy and to investigate potential differences in HRQL. Methods: 122 family members (45 men and 77 women) of mean age 48.3 ±14.5 and 122 cancer patients undergoing chemotherapy (49 men and 73 women) of mean age 56.6 ±15.4 1SD completed the SF-36 health survey by personal interview. The SF-36 health survey was used to evaluate and compare HRQL which contains eight scales measuring physical functioning (PF), role physical (RP), bodily pain (BP), general health perception (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH), with higher scores (0–100 range) reflecting better-perceived health. Two component summary scores capture the overall physical and mental health (Physical Component Summary or PCS and Mental Component Summary or MCS). Data analysis was performed with SPSS version 13.0 while statistical analysis was performed with Wilcoxon signed ranks test. Results: The table below summarizes the results of our study. Conclusions: Although the physical health was significantly higher in the family members as it was expected for a healthy population, the mental health and especially MCS was significantly lower from the cancer patients undergoing chemotherapy. It seems that medical condition of the patients affects severely the mental HRQL of family members. Supportive psychological programs for both the patients and the family members seem mandatory. [Table: see text] No significant financial relationships to disclose.
Phase II multi-institutional prospective trial of nab-paclitaxel as second-line chemotherapy for advanced gastric cancer refractory to fluoropyrimidine with modified dose reduction criteria (CCOG1303).
Authors: Yoshinari Mochizuki, Daisuke Kobayashi, Hiroshi Kojima, Hiroshi Nakayama, Yoshihisa Kawase, Kiyoshi Ishigure, Toshio Shikano, Koji Torii, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2017)

91 Background: Nab-paclitaxel (nab-PTX) is a candidate as second-line chemotherapy for gastric cancer, with the response rate (RR) of 28% and overall survival (OS) of 9.2 months in that setting in Japan (J-0200). Adverse events (AE) of grade 3 or more were frequent and included neutropenia in 49%, leucopenia in 20% and peripheral nerve disorder (PND) in 24%. Modified dose reduction criteria to manipulate the doses earlier might be more practical, given the relative dose intensity (RDI) of paclitaxel (PTX) in the conventional weekly regimen. Phase II prospective trial was conducted to explore the efficacy and safety of nab-PTX with modified dose reduction criteria. Methods: Patients with histologically confirmed metastatic or recurrent gastric adenocarcinoma that progressed during the fluoropyrimidine-containing first-line chemotherapy were eligible. Patients pretreated with PTX were excluded. Nab-PTX (260 mg/m 2 ) was administered triweekly. Dose reduction was regulated according to predefined toxicity criteria which included neutropenia &lt; 1000/mm 3 and/or PND with grade 2 or more. Treatment was to be continued until PD, unacceptable toxicity, or patient’s refusal. The primary endpoint was progression free survival (PFS). Secondary endpoints were OS, RR and toxicity. Results: A total of 50 patients were enrolled from 14 institutions, 47 of whom were eligible for efficacy analyses. The median number of treatment given was 4 cycles (range, 1-25). Of total administration throughout the trial of 280 cycles, dose reduction was needed in 52 cycles (22%). The RDI was 80%. The median PFS was 3.5 months (range, 0.4-20.2) that was equivalent to the expected value designed in the study. The median OS was 9.0 months (range, 1.4-22.1) and RR was 16% (95%CI 2-30). AE of grade 3 or more included neutropenia in 49%, leucopenia in 21% and PND in 11%. Febrile neutropenia occurred in 1 patient (2%). The median time to treatment failure was 3.5 months (range, 0.4-18.0). Conclusions: The modified dose reduction criteria for triweekly administration of nab-PTX resulted in decreased incidence of severe PND without fall in efficacy. Clinical trial information: UMIN000012247.
Do host factors determine long-term survival in glioblastoma? A genome/transcriptome profiling study by the German Glioma Network.
Authors: Michael Weller, Ruthild Weber, Vera Riehmer, Kerstin Kaulich, Edith Willscher, Henry Wirth, Bettina Hentschel, Manfred Westphal, Matthias Simon, Gabriele Schackert, Michael Sabel, Dorothee Gramatzki, Joerg Felsberg, Joachim Peter Steinbach, Torsten Pietsch, Joerg Tonn, Andreas von Deimling, Hans Binder, Markus Loeffler, Guido Reifenberger
Journal: Journal of Clinical Oncology (2014)

2014 Background: The prognosis of glioblastoma remains poor: only a minority of patients experience long-term survival beyond three years after diagnosis. Previously identified predictors of long-term survival include younger age, gross total surgical resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase (IDH) 1 or 2 mutation (Hartmann et al. Clin Cancer Res 2013; 19:5146-5157), but these parameters do by no means fully account for long-term survival. Methods: Accordingly, to identify specific molecular signatures of glioblastomas with long-term survival, we performed genome- and transcriptome-wide molecular profiling of 94 glioblastoma samples, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS, and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups stratified by MGMT and IDH1/2 status. Results: Glioblastoma patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances differed between IDH1/2-mutant and IDH1/2-wildtype tumors, too, but not between survival groups of IDH1/2-wildtype patients. Conclusions: These data strongly suggest that host-derived rather than tumor-derived factors allow for long survival in glioblastoma. Ongoing studies on long-term survival in glioblastoma of the German Glioma Network therefore focus on immune responses, notably autoantibody profiling, to corroborate the hypothesis that immune control of glioblastoma may contribute to long-term survival.