tbuckley/cabot-search huggingface dataset:
Prescription compliance and persistency in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients (pts) on imatinib (IM)
Authors: J. Tsang, I. Rudychev, S. L. Pescatore
Journal: Journal of Clinical Oncology (2006)

6119 Background: IM (Glivec, Gleevec) is an oral targeted therapy with unprecedented efficacy in CML and GIST. Prescription compliance and persistency of pts receiving IM were measured by analysis of pt-level pharmacy claims data. Methods: Compliance and persistency were determined by analyzing the prescription-filling activity of pts (N=4043) compared with the prescribing activity of their physicians (N=3316) using pt pharmacy records accrued over 24 months (1/03–12/04). Observed average daily consumption (DACON) and average prescribed days of therapy were calculated and compared. Also, compliance and persistency were examined by pt demographics and initial IM dose prescribed. Results: Overall compliance (defined as medication possession ratio = apparent mg taken/mg prescribed) was 75%, with CML pts showing slightly greater compliance (78%) than GIST pts (73%). Fifty percent of pts were 100% compliant, the greatest compliance being found in pts initially treated with IM 300 or 400 mg/day (77%). Persistency (time on therapy without significant gaps in refills) averaged 255 days over 24 months. The most persistent pts were those initially given 300 or 400 mg/day (13.0 and 12.9 months, respectively). DACON was 400 mg/day for 65% of patients, but fluctuated above and below 400 mg/day in 18% and 17% of pts, respectively. Conclusions: This is the first assessment of pt compliance and persistency with prescribed IM therapy. Although less pronounced than with most other non-oncology products, suboptimal compliance and persistency with IM are a concern as doses &lt;300–400 mg may result in plasma levels lower than needed to eliminate cancer cells. Patient support programs and improved communication on the importance of adhering to recommended dosing could potentially optimize outcome and further reduce risk of relapse and progression. [Table: see text]
Case 51-1970
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Roman W. DeSanctis, Benjamin Castleman
Journal: New England Journal of Medicine (1970)

Presentation of Case First admission. A 53-year-old man was admitted to the hospital because of dyspnea.He had enjoyed excellent health until three years previously, when his physician made a diagnosis of anemia and administered injections. One month before admission there was the onset of progressive fatigue, and three weeks later exertional dyspnea developed. Three days before entry he stayed home from work because of fatigue and increasing dyspnea. Palpitation, orthopnea and paroxysmal nocturnal dyspnea occurred, and he came to the hospital.One brother had died at the age of 55 years as a result of heart disease. There was . . .
Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia in the Imatinib Era.
Authors: Jiri Pavlu, Matthias Klammer, Ian Gabriel, Richard Szydlo, Eduardo Olavarria, Dragana Milojkovic, Andrea Kew, Katy Rezvani, Francesco Dazzi, David Marin, John Goldman, Jane Apperley
Journal: Blood (2008)
Abstract 1282: Combination of PI3K targeting with cetuximab and irradiation: a preclinical study on an orthotopic xenograft model of head and neck cancer
Authors: Gérard Milano, Alexandre Bozec, Nathalie Ebran
Journal: Cancer Research (2016)

Abstract The PI3-kinase (PI3K)/AKT/mTOR signaling pathway is of particular interest in head and neck squamous cell carcinoma (HNSCC). Its activation has been identified as an important mechanism implicated in tumor progression and resistance to epidermal growth factor receptor (EGFR) inhibitors. The anti-EGFR monoclonal antibody cetuximab (Cet), radiotherapy (RT) and their combination are widely used in the therapeutic management of patients with HNSCC. Inhibition of the PI3K/AKT/mTOR signaling pathway has been shown to potentialize the effects of anti-EGFR agents and RT. We conducted a preliminary in vitro study demonstrating synergistic effects of Cet followed by the PI3K inhibitor BKM120 (Buparlisib) in both PI3KCA wild-type and mutated cells. The aim of the present study was to investigate the effects of combining BKM120 with Cet and RT on an orthotopic xenograft model of HNSCC. In the present study we have used an orthotopic (floor of the mouth) model of human HNSCC to measure the effects of a treatment including BKM120 (40 mg/kg, 5 days/week, p.o.), Cet (2,5 mg/kg/day, 1 day/week, i.p.) and RT (6 Gy/dose, 3 days/week), administered alone or in combination. Investigations were performed using the human PI3KCA-mutated (H1047R) HNSCC cell line, CAL33, injected into the mouth floor of nude mice. The tumor growth was followed by IVIS imagery on days 3, 7 and 12 and tumor size was checked with a caliper ruler on day 13 after animal euthanasia. As compared with the control, the BKM120-Cet and the BKM120-Cet-RT combinations led to the highest tumor inhibition and induced almost complete tumor growth arrest (p &amp;lt; 0.001). The addition of BKM120 and Cet to RT significantly enhanced the impact of RT alone on tumor growth (p &amp;lt; 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pERK labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the BKM120-Cet association. RT alone (p = 0.10) tended to activate the MAPK pathway but the association of BKM120 and Cet to RT inhibited the RT-induced activation of the MAPK pathway (p = 0.03). In conclusion, in this orthotopic HNSCC model, the combination of BKM120 with Cet and RT produced synergistic effects on tumor growth. These results could serve as a strong preclinical basis for innovative treatments combining PI3K inhibition with anti-EGFR therapies and RT in patients with HNSCC. Citation Format: Gérard Milano, Alexandre Bozec, Nathalie Ebran. Combination of PI3K targeting with cetuximab and irradiation: a preclinical study on an orthotopic xenograft model of head and neck 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 1282.
ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma: Five year follow-up.
Authors: John P. Neoptolemos, Daniel H. Palmer, Paula Ghaneh, Juan W. Valle, David Cunningham, Jonathan Wadsley, Tim Meyer, Alan Anthoney, Bengt Glimelius, Stephen Falk, Ralf Segersvard, Gary William Middleton, Paul J. Ross, Harpreet Singh Wasan, Alec McDonald, Tom David Lewis Crosby, Eftychia Eirini Psarelli, Pascal Hammel, Thilo Hackert, Markus W. Buchler
Journal: Journal of Clinical Oncology (2020)

4516 Background: The ESPAC-4 trial demonstrated that adjuvant GEM/CAP for pancreatic cancer significantly improved survival compared to GEM monotherapy. The aim of this study is to evaluate the long-term outcomes in the ESPAC-4 trial. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4-week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was five-year survival; secondary endpoints were toxicity and relapse free survival. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2-year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumor size was 30 mm, 61% were R1 resections, 80% were node positive and 40% were poorly differentiated. The data freeze was on 24 February 2020; median follow up was 60 months with 531 overall deaths, 280 in GEM, and 251 in GEM/CAP. Median (95% CI) survival (months) for patients treated with GEM/CAP was 27.7 23.3 – 31.2) and 26.0 (22.7 – 28.4) for GEM. Five-year (95% CI) survival rates were 20 (16 – 25) % for GEM and 28 (23 – 33) % for GEM/CAP. Stratified log-rank analysis revealed an HR=0.84 [95% CI, 0.70 – 0.99]; χ 2 (1) = 3.87, P=0.049. 70 out of 366 GEM patients in the safety set reported 101 grade 3/4 serious adverse events, while 65 out of 359 GEM/CAP patients reported 97 grade 3/4 serious adverse events ( P=0.724). Conclusions: Adjuvant GEM/CAP for pancreatic cancer had a statistically significant improvement in survival compared to GEM monotherapy. Clinical trial information: 96397434 .
Abstract 1438: Preserving genital nerve function in prostate cancer: imaging with a molecular imaging agent
Authors: Lucia Le Roux, Daniela Ramos, Leo Flores, Dawid Schellingerhout
Journal: Cancer Research (2016)

Abstract Purpose: To establish proof-of-concept for the use of a molecular nerve imaging agent in demonstrating nerve tissue at risk during prostate surgery, and thus preventing iatrogenic sexual dysfunction. Erectile Dysfunction (ED) is a common complication of all forms of prostate cancer treatment, with incidence varying from 13-97% depending on the series quoted. There is broad agreement that treatment related damage to the neurovascular bundles is a root cause of the condition, with strong indications from many studies that preservation of the neurovascular bundles avoids post-treatment ED. The goal of this study is to use a novel neural imaging agent based on the non-toxic Tetanus Toxin C-fragment (TTc) to allow the visualization of the anatomy of the genital nerves, thus facilitating nerve-sparing therapies. Materials and methods: C57 Black male mice were anaesthetized (1-2% isofluorane/oxygen) and injected with 40 μg/10 μl of fluorescently labeled TTc790 in the tunica albuginea of the left corpus cavernosum. Animals were imaged live over a period of 3 hours post injection with a Xenogen IVIS 200 small animal imager. Animals were then euthanized, and the complete male reproductive system was surgically exposed and imaged ex-vivo with a Zeiss AxioZoom16 dissection microscope. The cavernosal nerves, prostatic tissue with intact nerve plexi were dissected and prepared for cryo-sectioning followed by fluorescent immuno-histology using standard methods. Results: En bloc excision of the prostate with the penis allowed imaging of the genital nerves using the retrograde transported neural marker, TTc790. We noted fluorescent TTc-related signal uptake along the expected course of the nerve tract ipsilateral to the injection site, and were able to clearly demonstrate the pelvic ganglion within the capsule of the prostate. Immuno-histological assessment with post cryo-sectioning confirmed our surgical microscopy findings, including our demonstration of the pelvic ganglion. Conclusions: We demonstrate the use of TTc790 as a nerve imaging agent for showing the anatomy of the cavernosal nerves and pelvic ganglion complex by intra-operative fluorescent imaging. This suggests that, with further work, image guidance could be provided to physicians and surgeons to spare these nerves during prostate carcinoma treatments, allowing the preservation of genital nerve function and improving quality of life in prostate cancer survivors. Citation Format: Lucia Le Roux, Daniela Ramos, Leo Flores, Dawid Schellingerhout. Preserving genital nerve function in prostate cancer: imaging with a molecular imaging agent. [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 1438.
Phase 2 Trial of Entospletinib (GS-9973), a Selective SYK Inhibitor, in Follicular Lymphoma (FL)
Authors: Jeff P. Sharman, Leonard M. Klein, Michael Boxer, Kathryn S. Kolibaba, Michael J. Hawkins, Steve Abella, Meihua Wu, Christopher A. Yasenchak
Journal: Blood (2014)
Abstract 2737: Quantitative assessment of chromosome instability induced through chemical disruption of mitotic progression
Authors: Sarine Markossian, Alexei Arnaoutov, Nakhle S. Saba, Vladimir Larionov, Mary Dasso
Journal: Cancer Research (2016)

Abstract Most solid tumors are aneuploid, carrying an abnormal number of chromosomes, and they missegregate whole chromosomes in a phenomenon termed chromosome instability (CIN). CIN is associated with poor prognosis in many cancer types, and targeting of CIN is an attractive strategy for anti-cancer therapeutics. The mechanisms causing CIN and its contributions to tumor initiation and growth are not well defined, partly because there is no straightforward, quantitative assays for CIN in human cells. To address this problem, we have developed the first Human Artificial Chromosome (HAC)-based quantitative live-cell assay for mitotic chromosome segregation in mammalian cells, with which we can easily score the rates of CIN within one cell division under different experimental conditions. We have constructed a HAC encoding copies of enhanced green fluorescent protein (eGFP) fused to the destruction box (DB) of hSecurin, a substrate of the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase, which becomes active during anaphase to catalyze the proteolysis of critical mitotic target proteins. This HAC also contains tet operator (tetO) arrays and sequences encoding the tetracycline repressor fused to monomeric cherry fluorescent protein (tetR-mCherry). We have produced human U2OS cells (U2OS-Phoenix) carrying this HAC, in which we monitor HAC segregation in two ways: First, APC/C degrades the DB-eGFP fusion expressed from the HAC at anaphase onset, and DB-eGFP re-accumulates in the daughter cells after G1 phase, when APC/C becomes inactive. Daughter cells that do not obtain a copy of the HAC will thus be GFP negative in the subsequent interphase. Second, because tetR-mCherry binds to the tetO arrays, the HAC itself could be followed by live imaging. Following the HAC by live cell imaging experiments, we show that U2OS-Phoenix cells have low inherent levels of CIN, but HAC missegregation is markedly increased by treatment with Reversine, an inhibitor of Mps1, and microtubule agents Nocodazole and Paclitaxel. In summary, we have developed new assays to score CIN levels in human cells and have shown that CIN levels increase upon chemical disruption of mitotic progression, which makes our assays ideal for chemical screens. Citation Format: Sarine Markossian, Alexei Arnaoutov, Nakhle S. Saba, Vladimir Larionov, Mary Dasso. Quantitative assessment of chromosome instability induced through chemical disruption of mitotic progression. [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 2737.
Deaths at UK immigration detention centres are the result of avoidable systemic failures, report says
Authors: Nayanah Siva
Journal: BMJ (2016)

High numbers of avoidable deaths have continued to occur within UK immigration detention centres because the Home Office and NHS England have not tackled systemic failings in healthcare provision, a report has said.

The report by Medical Justice, an organisation that campaigns for health rights for detainees, included an extensive assessment of the 38 deaths in immigration detention centres in the UK that were reported between 2000 and 2015, and has said that some of these deaths were avoidable.

“In around half the investigations the Prisons and Probation Ombudsman directly criticised healthcare provisions with many of the same systemic failures repeated year after …
Abstract LB-234: A persistently activated signaling network regulates the DNA damage secretory program to promote cancer resistance driven by the therapeutically damaged tumor microenvironment
Authors: Yu Sun, Boyi Zhang, Fei Chen, Paul Chiao
Journal: Cancer Research (2016)

Abstract In cancer clinics, an in vivo form of the senescence-associated secretory phenotype (SASP) is driven by a DNA damage secretory program (DDSP) provoked by side effects of genotoxic therapeutics including chemotherapy and radiation which fuel advanced pathologies particularly cancer resistance. However, the complete mechanism underlying DDSP development in the tumor microenvironment (TME) remains unclear. Here we report that genotoxic agents frequently used in clinical oncology induce a gene expression pattern distinct from the one that is shaped by non-genotoxic drugs. Specifically, the zinc finger and scan domain containing 4 (Zscan4) is upregulated upon DNA damage in stromal cells and engaged in DNA damage response (DDR) in genotoxic settings. Apart from the established functions in telomere elongation and genomic integrity of stem cells, Zscan4 is central for the Rap1/TRF2 assembly and orchestrates the long term DDR signaling in differentiated stromal cells. In response to DNA damage, the mammalian target of rapamycin (mTOR) is phosphorylated in the cytoplasm of stromal cells and relays DDR signals, a phenomenon different from human cancer cells. There are physical interactions between the mTOR and the IKK complexes, events functionally implicating the NF-κB machinery that is regulated by both the IL-1α/IRAK1 and mTOR/Raptor axes. We determined that mTORC1 is a critical mediator of DDSP programmatic implementation by conducting signals from upstream molecules including p38 and PI3K/Akt, molecules activated in DNA damage events. We revealed that the ligand IL-1α signals through IL-1R and TAK1, the latter a member of the mitogen-activated kinase kinase kinase (MAPKKK) family that induces a proinflammatory cascade by activating JNK/p38 and NF-κB. Further, targeting p38, mTOR or TAK1 with small molecule inhibitors in vivo significantly abrogated cancer resistance acquired from the TME in chemotherapeutic cycles. Overall, our study substantiates p38, mTOR and TAK1 as a group of new candidates for future TME-oriented intervention to minimize resistance provoked by anticancer regimes, and suggests that anti-p38/mTOR/TAK1 agents may be repurposed to sensitize tumors by effectively targeting the TME. Our data disclose a novel mechanism of SASP (or DDSP) signaling in classical therapeutic settings, thus opening new avenues to improve clinical outcomes in the current era of precision medicine. Citation Format: Yu Sun, Boyi Zhang, Fei Chen, Paul Chiao. A persistently activated signaling network regulates the DNA damage secretory program to promote cancer resistance driven by the therapeutically damaged tumor microenvironment. [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 LB-234.
Case-Control Studies
Authors: Tony Blakely, Neil Pearce, John Lynch
Journal: JAMA (2019)

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Rougeole : une situation suboptimale en France
Authors: R Branchet, P Chauvin, A Flahault
Journal: Eurosurveillance (2000)

Le reseau Sentinelles a ete cree en 1984. Il est constitue de medecins generalistes volontaires et benevoles, repartis sur l’ensemble de la France metropolitaine (1). Les membres du reseau assurent la surveillance epidemiologique hebdomadaire de 10 indicateurs de sante (syndromes grippaux, rougeole, varicelle, oreillons, hepatites virales, diarrhees aigues, serologies VIH, uretrites masculines, suicides et hospitalisations). Les descriptions des cas sont recueillies par voie telematique, via Internet (http://www.b3e.jussieu.fr/sentiweb) ou Minitel, selon le choix du medecin generaliste Sentinelles.
Weibull and exponential proportional hazard modelling for optimizing economic evaluations of cancer treatments: FOLFIRINOX (FFX) vs gemcitabine (GEM) in metastatic pancreas cancer (mPC).
Authors: Mahdi Gharaibeh, Hitendra Patel, Ali McBride, J. Lyle Bootman, Ivo Abraham
Journal: Journal of Clinical Oncology (2016)

e15704 Background: Classical pharmacoeconomic analysis methods may prove insufficient for the economic evaluation of novel cancer treatments, esp. in advanced/metastatic setting as it is important to calculate a reliable and credible estimation of the total cost and outcomes. The application of different parametric models may impact economic evaluation estimates. Access to individual patient data from randomized controlled (RCT) trials is limited, hence digitization software is used to reproduce published Kaplan-Meier (K-M) curves and estimate distribution parameters. We compared the application of Weibull and exponential proportion hazard models to economic evaluation studies for FFX v. GEM in mPC. Methods: Weibull and exponential regressions were applied to progression-free (PFS) and overall (OS) survival data from digitization to derive the lambda and gamma parameters for Weibull and exponential models. Curves were estimated for FFX OS and PFS. Model selection was based on the value of R2and residual sum of squares (RSS). The proportional hazard assumption was tested by applying the RCT-reported (hazard ratio) HR on the chosen model curve. Results: Table 1 summarizes the data for both the Weibull and exponential models. Conclusions: Our application to FFX v. GEM in mPC shows that proportional hazard modeling using Weibull distribution yields the best model fit in the metastatic setting. Future studies should examine other treatment approaches for mPC and across other tumor types and disease stages. OS PFS Weibull Exponential Weibull Exponential R2 0.9870 0.9829 0.9858 0.9850 RSS 0.3124 1.0759 0.2175 0.8687 Lambda 0.9081 1.1126 1.8812 2.0600 Gamma 1.2567 - 1.3088 -