tbuckley/cabot-search huggingface dataset:
Programmed death-1 blockade in mismatch repair deficient colorectal cancer.
Authors: Dung T. Le, Jennifer N. Uram, Hao Wang, Bjarne Bartlett, Holly Kemberling, Aleksandra Eyring, Nilofer Saba Azad, Dan Laheru, Ross C. Donehower, Todd S. Crocenzi, Richard M. Goldberg, George A. Fisher, James J. Lee, Tim F. Greten, Minori Koshiji, SoonMo Peter Kang, Robert A Anders, James R. Eshleman, Bert Vogelstein, Luis A. Diaz
Journal: Journal of Clinical Oncology (2016)

103 Background: Mismatch repair deficient (dMMR) colon cancers are densely infiltrated with CD8+T cells and regress when treated with anti-programmed death-1 (PD-1) antibodies. This anti-tumor response is thought to be potentiated by the thousands of somatic mutations that when expressed as proteins result in hundreds of potentially immunogenic neo-antigens that can be recognized by the patient's immune system. Methods: We previously reported a phase 2 study to evaluate the activity of pembrolizumab (pembro), a PD-1 antibody in treatment refractory dMMR colon cancers (NEJM 2015). We are reporting the expanded trial and updated data for the mismatch repair deficient CRC (dMMR, cohort A) and mismatch repair proficient CRC (pMMR, cohort B) cohorts. Pembro was administered at 10 mg/kg every 14 days in patients with 2 or more prior therapies. The co-primary endpoints were response and progression-free survival rate at 20 weeks. Secondary endpoints included disease control rate (DCR = CR + PR + SD), progression free survival (PFS), overall survival (OS) and safety. Results: A total of 53 patients (Cohort A: n = 28, Cohort B: n = 25) were treated. Median follow up time is 8.7 months. RR and DCR were 50% (14/28, 95% confidence interval (CI): 31-69%) and 89% (25/28) for dMMR CRC and 0% (0/25, 95% CI: 0-14%) and 16% (4/25) for pMMR CRC, respectively. Twenty-one of 28 dMMR CRC patients remain on study. Median PFS was not reached (NR) for dMMR CRC and 2.4 months for pMMR CRC (HR = 0.135; 95% CI 0.043 to 0.191; p=<0.0001). Median OS was NR for dMMR vs. 6 months for pMMR (HR = 0.247; 95% CI 0.117 to 0.589; p=0.001). For dMMR CRC, the PFS rates was 61% at 24 months and the OS rate was 66% at 24 months. Among patients with an objective response (n=14), only 1 has developed secondary resistance to pembro with a solitary brain metastasis after 4.6 months of therapy. Conclusions: Patients with dMMR CRC receive durable clinical benefit with pembrolizumab. Clinical trial information: NCT01876511.
Changing trends in utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Authors: Laura-Maria Krabbe, Mary Elizabeth Westerman, Vitaly Margulis, Ganesh Raj, Arthur I. Sagalowsky, Kevin Dale Courtney, Yull Edwin Arriaga, Yair Lotan
Journal: Journal of Clinical Oncology (2014)

e15518 Background: After reporting 17% of eligible patients with bladder cancer (BC) received neoadjuvant chemotherapy (NC) prior to radical cystectomy (RC) at this institution 2003-2008, we instituted a multi-disciplinary approach for our urologic oncology patients. We aimed to assess its impact on utilization of NC. Methods: A retrospective review of patients with BC undergoing RC between 2008 and 2012 at this institution was performed. Information on clinical and pathologic stage, renal function, perioperative chemotherapy (CTX) use and oncologic outcomes was collected. Primary outcome was use of CTX among eligible patients. Secondary measures were type of CTX, pathologic and survival outcomes. Results: Among 300 patients undergoing RC for BC, 197 had a clinical stage ≥T2 and 64% had adequate renal function (CrCl≥60ml/min). 42.1% received cisplatin-based NC (53/126 with CrCl≥60ml/min and 30/71 with CrCl<60ml/min). Patients given NC were more likely to be downstaged to non-muscle-invasive disease (35.8% vs. 9.8%) and had higher pT0 rates (12.6% vs. 1.5%). After RC 20% of high-risk patients (n=134) received adjuvant chemotherapy (AC). BMI (≤25kg/m2 vs. >25kg/m2) and clinical stage (T2 vs. >T2) were independent predictors of recurrence-free survival: Gender, age, GFR and application of NC were not predictors of recurrence. Conclusions: The rate of cisplatin-based NC use improved from 17% to 42%, whereas AC utilization decreased from 38% to 20%. Receipt of NC led to improved pT0 rates. Renal function did not influence the use of cisplatin based NC.
Abstract 1801: FOXA1, a novel regulator of neuroendocrine differentiation
Authors: Jung Kim, Hongjian Jin, Jonathan Zhao, Vamsi Parimi, Ximing Yang, Jindan Yu
Journal: Cancer Research (2016)

Abstract Neuroendocrine prostate cancer (NEPC) is a subtype of prostate cancer that is highly aggressive and exhibits a neuroendocrine phenotype, being distinct from prostate adenocarcinoma. Cases of NEPC are predicted to increase rapidly following broader use of new-generation hormonal therapies including abiraterone and enzalutamide. Although androgen deprivation and cytokine induction have been previously suggested to induce neuroendocrine differentiation of prostate cancer, little is known regarding the underlying molecular mechanisms. FOXA1 is a forkhead box family transcription factor that has been shown to act as a pioneer factor for androgen receptor (AR), thereby defining the prostatic transcriptional program. We have recently shown that FOXA1 plays an important role in suppressing epithelial-to-mesenchymal transdifferentiation, but is often downregulated in castration-resistant prostate cancer (CRPC). Along this line, in the present study, we showed that FOXA1 loss, achieved by shRNA-mediated knockdown, led to cell morphology changes typical of neuroendocrine differentiation, accompanied by a strong increase of NEPC marker enolase2 (ENO2), while ectopic FOXA1 overexpression reverses these alterations. This was further linked to ERK phosphorylation, which has been previously reported to be up-regulated following neuroendocrine differentiation. Moreover, to understand the mechanism underlying FOXA1 regulation of neuroendocrine differentiation, we performed bioinformatics analysis and nominated interleukin 8 (IL8) as a direct target of FOXA1 and its up-regulation is critical in mediating neuroendocrine differentiation of FOXA1-depleted cells. Finally, we validated a negative correlation between FOXA1 and neuroendocrine differentiation in primary prostate cancer specimens through analysis of publically available RNA-seq data as well as direct IHC staining of various NEPC markers. In summary, we report a new role of FOXA1 as a critical inhibitor of neuroendocrine differentiation and the importance of balanced FOXA1 expressing in the maintenance of the epithelial phenotype of prostate cancer. Citation Format: Jung Kim, Hongjian Jin, Jonathan Zhao, Vamsi Parimi, Ximing Yang, Jindan Yu. FOXA1, a novel regulator of neuroendocrine differentiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1801.
Residential Exposure to Natural Background Radiation and Risk of Childhood Acute Leukemia in France, 1990–2009
Authors: Claire Demoury, Fabienne Marquant, Géraldine Ielsch, Stéphanie Goujon, Christophe Debayle, Laure Faure, Astrid Coste, Olivier Laurent, Jérôme Guillevic, Dominique Laurier, Denis Hémon, Jacqueline Clavel
Journal: Environmental Health Perspectives (2016)

Background:Exposures to high-dose ionizing radiation and high-dose rate ionizing radiation are established risk factors for childhood acute leukemia (AL). The risk of AL following exposure to lower doses due to natural background radiation (NBR) has yet to be conclusively determined.Methods:AL cases diagnosed over 1990–2009 (9,056 cases) were identified and their municipality of residence at diagnosis collected by the National Registry of Childhood Cancers. The Geocap study, which included the 2,763 cases in 2002–2007 and 30,000 population controls, was used for complementary analyses. NBR exposures were modeled on a fine scale (36,326 municipalities) based on measurement campaigns and geological data. The power to detect an association between AL and dose to the red bone marrow (RBM) fitting UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) predictions was 92%, 45% and 99% for exposure to natural gamma radiation, radon and total radiation, respectively.Results:AL risk, irrespective of subtype and age group, was not associated with the exposure of municipalities to radon or gamma radiation in terms of yearly exposure at age reached, cumulative exposure or RBM dose. There was no confounding effect of census-based socio-demographic indicators, or environmental factors (road traffic, high voltage power lines, vicinity of nuclear plants) related to AL in the Geocap study.Conclusions:Our findings do not support the hypothesis that residential exposure to NBR increases the risk of AL, despite the large size of the study, fine scale exposure estimates and wide range of exposures over France. However, our results at the time of diagnosis do not rule out a slight association with gamma radiation at the time of birth, which would be more in line with the recent findings in the UK and Switzerland.Citation:Demoury C, Marquant F, Ielsch G, Goujon S, Debayle C, Faure L, Coste A, Laurent O, Guillevic J, Laurier D, Hémon D, Clavel J. 2017. Residential exposure to natural background radiation and risk of childhood acute leukemia in France, 1990–2009. Environ Health Perspect 125:714–720; http://dx.doi.org/10.1289/EHP296
Splenic Diffuse Red Pulp Small B Cell Lymphoma: Transformation To Diffuse Large Cells B Lymphoma
Authors: Evandro Dantas Bezerra, Leila Patricia Fontenele, Juliana Pereira, Luis Alberto de Padua Covas Lage, Felipe Maciel, Leticia Barquinero, Priscila R Carvalho, Scheila Siqueira, Elvira RP Velloso
Journal: Blood (2013)
Final results of ProGem1, the first in-human phase I/II study of NUC-1031 in patients with solid malignancies.
Authors: Sarah Patricia Blagden, Ivana Rizzuto, Chara Stavraka, Daniel O'Shea, Puvan Suppiah, Markand Patel, Ajithkumar Sukumaran, Naomi Loyse, Nishat Bharwani, Andrea Rockall, Hani Gabra, Mona El-Bahrawy, Harpreet Wasan, Robert C. F. Leonard, Nagy A Habib, John G. Gribben, Essam Ahmed Ghazaly, Christopher McGuigan
Journal: Journal of Clinical Oncology (2015)

2514 Background: NUC-1031 is a first-in-class nucleotide analogue utilising phosphoramidate chemistry to enhance anti-cancer efficacy and safety. In preclinical studies NUC-1031 demonstrated potent anti-cancer activity, generating high intracellular levels of the active cytotoxic di-fluoro-deoxycytidine triphosphate (dFdCTP) by overcoming key drug resistance mechanisms associated with nucleoside analogues. Methods: This study was comprised of 1) dose escalation part: 3–8 patients (pts) per cohort received 5-15 minute IV infusion of NUC-1031 starting at 500mg/m2 once weekly on days 1, 8, 15 in 4 weekly schedule (q4w), or 375mg/m2 twice-weekly on days 1 & 5, 8 & 12, 15 & 19 q4w and 2) expansion part at the recommended Phase II dose (RP2D). Endpoints were (primary) safety and tolerability, (secondary) pharmacokinetics (PK), pharmacodynamics and efficacy. Results: ProGem1 enrolled 68 pts, mean age 56 (20 - 83 yrs), average 2.7 prior lines of chemotherapy (range 1 - 6) with 16 primary cancer types. Dose-limiting toxicities occurred in 4 pts: G4 thrombocytopenia (2); G3 elevated ALT (2). 25 SAEs were ‘possibly/probably related’ to study drug, and 2 > G2: elevated ALT (4) and lung infection (3). Commonest AEs ≥ G3 ‘possibly/probably related’ were: neutropenia (16), fatigue (13), elevated GGT (10). NUC-1031 was stable, with plasma half-life of 8.3 hours. High intracellular levels of the active anti-cancer agent dFdCTP (Cmax = 475.5 µM/L) were rapidly achieved and maintained for 24 hours. Notable efficacy results were observed: 5 RECIST Partial Responses (10%); 33 Stable Disease (67%) for an ITT disease control rate (DCR) of 56% and on treatment analysis (OTA) DCR of 78%. PRs and SDs were observed in pts refractory/relapsed to prior nucleoside analogue therapy and were durable, mean PFS 6.1 months (range 2 – 20 mths). The RP2D was 825mg/m2 given on days 1, 8, 15, q4w. Conclusions: NUC-1031 has demonstrated impressive clinical activity with durable DCR (ITT 56%; OTA 78%) in a wide range of patients with advanced and rapidly progressing disease. NUC-1031 is well-tolerated at the RP2D. Phase III clinical studies in ovarian, pancreatic and biliary cancers are planned this year and combination studies are currently recruiting. Clinical trial information: NCT01621854.
NHS trust stands by doctors who set up clinic for private work
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Two consultants who started a private clinic that then took on overflow work from the NHS trust that employed them did not do anything wrong, the trust has said.

Steve Pandey, clinical director of colorectal surgery, and Stephen Lake, clinical director of endoscopy, from Worcestershire Acute Hospitals NHS Trust, registered the private Worcestershire Bowel Clinic in January 2012. The two consultants are directors of the clinic, which is based at the private Spire South Bank Hospital in Worcester and opened in October 2013. The clinic was subsequently contracted by the trust to treat NHS patients with bowel cancer through waiting list initiatives, to help the trust hit its waiting time targets.

However, last week the two doctors found themselves at the centre of an expose by the Birmingham …
Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients
Authors: Giovanni Caocci, Marianna Greco, Giuseppe Delogu, Christian Secchi, Bruno Martino, Claudia Labate, Elisabetta Abruzzese, Malgorzata Monika Trawinska, Sara Galimberti, Federica Orru, Claudio Fozza, Carlo Gambacorti Passerini, Francesco Galimi, Giorgio La Nasa
Journal: Journal of Hematology & Oncology (2016)

We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation.
Perforin Is Important For Both CD4+ and CD8+ T Cell-Mediated Graft-Versus-Tumor Effect But Plays Differential Roles In CD4+ and CD8+ T Cell Expansion After Allogeneic Transplantation
Authors: Nicholas Leigh, Guanglin Bian, Wei Du, George L. Chen, Hong Liu, Philip L. McCarthy, Xuefang Cao
Journal: Blood (2013)
Abstract 1658: M3814, a novel investigational DNA-PK inhibitor: enhancing the effect of fractionated radiotherapy leading to complete regression of tumors in mice
Authors: Frank T. Zenke, Astrid Zimmermann, Christian Sirrenberg, Heike Dahmen, Lubo Vassilev, Ulrich Pehl, Thomas Fuchss, Andree Blaukat
Journal: Cancer Research (2016)

Abstract Physical or chemical agents that damage DNA such as ionizing radiation are among the most widely used classes of cancer therapeutics today. Double strand breaks (DSB) generated in DNA by radiation induce multitude of cellular responses, including DNA repair, cell cycle arrest or cell death if the damage is left unrepaired. A complex set of molecular events are responsible for DNA repair via two major mechanisms - homologous recombination (HR) or non-homologous end joining (NHEJ). DNA-PKcs with its regulatory protein subunits, Ku70 and Ku80, is an integral component of NHEJ and considered an attractive intervention point to inhibit DNA repair. We have developed an orally bioavailable, highly potent, and selective inhibitor of DNA-PK, M3814, for cancer therapy in combination with DNA damaging modalities such as radiation, and radio-chemotherapy. Here, we present the preclinical characterization of M3814 using biochemical, cellular and human tumor xenograft models. M3814 sensitized multiple tumor cell lines to radiation therapy in vitro and strongly enhanced the antitumor activity of ionizing radiation in vivo with complete tumor regression applying a clinically relevant fractionated radiation regimen. These effects are due to inhibition of DNA-PK protein kinase activity as demonstrated by the levels of DNA-PK autophosphorylation in human tumor cell lines, and xenograft tumors M3814 is currently investigated in PhI clinical trials. Citation Format: Frank T. Zenke, Astrid Zimmermann, Christian Sirrenberg, Heike Dahmen, Lubo Vassilev, Ulrich Pehl, Thomas Fuchss, Andree Blaukat. M3814, a novel investigational DNA-PK inhibitor: enhancing the effect of fractionated radiotherapy leading to complete regression of tumors in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1658.
Fully Automated Evaluation of Total Glomerular Number and Capillary Tuft Size in Nephritic Kidneys Using Lightsheet Microscopy
Authors: Anika Klingberg, Anja Hasenberg, Isis Ludwig-Portugall, Anna Medyukhina, Linda Männ, Alexandra Brenzel, Daniel R. Engel, Marc Thilo Figge, Christian Kurts, Matthias Gunzer
Journal: Journal of the American Society of Nephrology (2016)

The total number of glomeruli is a fundamental parameter of kidney function but very difficult to determine using standard methodology. Here, we counted all individual glomeruli in murine kidneys and sized the capillary tufts by combining in vivo fluorescence labeling of endothelial cells, a novel tissue-clearing technique, lightsheet microscopy, and automated registration by image analysis. Total hands-on time per organ was <1 hour, and automated counting/sizing was finished in <3 hours. We also investigated the novel use of ethyl-3-phenylprop-2-enoate (ethyl cinnamate) as a nontoxic solvent-based clearing reagent that can be handled without specific safety measures. Ethyl cinnamate rapidly cleared all tested organs, including calcified bone, but the fluorescence of proteins and immunohistochemical labels was maintained over weeks. Using ethyl cinnamate-cleared kidneys, we also quantified the average creatinine clearance rate per glomerulus. This parameter decreased in the first week of experimental nephrotoxic nephritis, whereas reduction in glomerular numbers occurred much later. Our approach delivers fundamental parameters of renal function, and because of its ease of use and speed, it is suitable for high-throughput analysis and could greatly facilitate studies of the effect of kidney diseases on whole-organ physiology.
Which patient- and physician-related factors influence guideline adherence in adjuvant endocrine therapy?: Results of the prospective multi-center cohort study BRENDA II.
Authors: Lukas Schwentner, Reyn Van Ewijk, Rolf Kreienberg, Wolfgang Janni, Maria Blettner, Susanne Singer, Achim Wöckel
Journal: Journal of Clinical Oncology (2015)

e11544 Background: This study examined the question, which factors influence patients’ and physicians’ decisions associated with guideline adherent adjuvant endocrine therapy (ET). Methods: In a prospective multi-center study including 4 certified breast cancer centers in Germany, patients with primary breast cancer were sampled consecutively from 2009-2012. Patients completed a questionnaire prior to surgery and prior to adjuvant therapy, and after 6 months of adjuvant therapy. This questionnaire assessed health related quality of life (QoL) using the EORTC QLQ-C30, psychiatric comorbidity with the Patient Health Questionnaire (PHQ), demographic characteristics (age, education), and the intensity of fear for ET. Guideline adherence is based on internationally validated guidelines. Results: In 721 breast cancer patients an adjuvant ET was indicated adherent to the guideline recommendation. The tumorboard (TB) decided in 96.8% (n = 698) to indicate adjuvant ET. In only 3.2% the TB decided contra ET, this decision was significantly associated with somatic comorbidities (OR = 0.30; p = 0.04). After TB decision, 4.6% (32) of the patients decided against ET, whereas 95.4% (n = 666) started taking ET. This decision against ET was significantly associated with patients’ fear of ET (OR = 0.44; p = 0.05). Age (OR3.55; p = 0.11), psychiatric comorbidity (0.61; p = 0.25), socio-economic factors, and education were not associated with patients decision. Furthermore somatic comorbidity was not associated with patients’, but with physicians’ decisions for ET. Conclusions: Guideline adherence starting adjuvant ET is comparatively high with 92.3%. However in 3.2% the TB and in 4.6% patients decide against ET. Physicians’ decision against ET is mainly influenced by somatic comorbidities, whereas patients decision is mainly influenced by patient’s fear of ET.
Abstract 3408: Oncogenic SOX2 signaling in bladder cancer
Authors: Chia-Chang Wu, Yu-Fan Chiu, Yu-Ting Chou, Yuan-Hung Wang
Journal: Cancer Research (2016)

Abstract The intriguing phenomenon that cancer cells have biological features similar to stem cells suggests that cancer and stem cells may share the same regulatory signaling pathway. We found that SOX2, a master transcriptional factor controlling self-renewal of stem cells, was highly expressed in a subgroup of transitional cell carcinoma of bladder cancer, correlating with the advanced pathological grade. Moreover, SOX2 expression was associated with poor overall survival and recurrence-free survival outcomes in patients with bladder cancer. Knockdown of SOX2 in SOX2-high 5637 bladder cancer cells attenuated cell growth. Consistently, ectopic expression of SOX2 in SOX2-low T24 bladder cancer cells endowed cells with increased cell proliferation. Spheroid assay showed that SOX2 expression encouraged spheroid-forming ability of bladder cancer cells in low serum condition, demonstrating the involvement of SOX2 signaling in the maintenance of stemness in bladder cancer cells. Immunoblotting revealed that the expression of SOX2 induced phosphorylation of AKT in the serum-free condition, supporting that SOX2 regulates bladder cancer cell survival. Gene expression microarray analysis showed that SOX2 expression induced IGF2, which was further confirmed by Q-PCR analysis in bladder cancer cells. Chi-square test assay showed that IGF2 expression correlated with the advanced tumor stages in bladder cancer. Pharmacological inhibition of IGF2 signaling attenuated cell growth in SOX2-postive bladder cancer cells. Our findings support the notion that SOX2-IGF2 signaling axis confers aggressiveness in bladder cancer cells with potentials as biomarkers and therapeutic targets for bladder cancer intervention. Citation Format: Chia-Chang Wu, Yu-Fan Chiu, Yu-Ting Chou, Yuan-Hung Wang. Oncogenic SOX2 signaling in bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3408.
Nilotinib Or High-Dose Imatinib Compared With Standard-Dose Imatinib In Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses To Standard-Dose Imatinib: Including Updated Data From RE-Nice Study
Authors: Soo-Young Choi, Sung-Eun Lee, Yun Jeong Oh, Soo-Hyun Kim, Richard C. Woodman, Tomasz Szczudlo, Saengsuree Jootar, Hyeoung-Joon Kim, Sang Kyun Sohn, Joon Seong Park, Sung-Hyun Kim, Dae-Young Zang, Suk-Joong Oh, Dong-Wook Kim
Journal: Blood (2013)
Tools for opening new chapters in the book of Treponema pallidum evolutionary history
Authors: J.F. Gogarten, A. Düx, V.J. Schuenemann, K. Nowak, C. Boesch, R.M. Wittig, J. Krause, S. Calvignac-Spencer, F.H. Leendertz
Journal: Clinical Microbiology and Infection (2016)