tbuckley/cabot-search huggingface dataset:
A multicenter randomized controlled trial of gemcitabine (G) alone versus gemcitabine and S-1 combination therapy (GS) in patients with unresectable advanced pancreatic cancer (PC): GEMSAP study.
Authors: Y. Nakai, H. Isayama, T. Sasaki, N. Sasahira, K. Hirano, T. Tsujino, M. Tada, M. Omata, K. Koike
Journal: Journal of Clinical Oncology (2010)

4037 Background: A pilot study of GS showed good results with median TTP of 10.0 months and OS of 20.4 months in unresectable PC (Oncology.2009;77:300-3). The aim of this study was to compare GS combination therapy to G monotherapy. Methods: Patients (pts) were randomized 1:1 to G (Gemcitabine 1,000 mg/m2 30min i.v. day 1, 8, 15, repeated every 4 weeks) or to GS (G 1,000 mg/m2 30 min i.v. day1, 15 and S-1 40 mg/m2 p.o. twice daily days 1-14, every 4 weeks). Eligible pts had unresectable locally advanced or metastatic pancreatic cancer without any prior treatment and ECOG PS 0-2. CT scans were performed every 8 weeks. The primary endpoint at this first analysis (6-months from the end of enrollment) was PFS. OS will be analyzed at the final analysis. Results: Between July 2006 and February 2009, 106 pts were enrolled in six hospitals, and the first analysis was done at September 2009. 1 pt in G (due to deteriorated PS) and 3 pts in GS (2 withdrew consent and 1 received G monotherapy) did not receive the allocated treatment. 10 pts in G and 19 pts in GS were alive at the time of this analysis. The median age, 67 and 63, male, 62% and 79%, PS = 0, 60% and 58%, locally advanced, 25% and 28% in G and GS, respectively. Objective response rate was 9.4% (95%CI, 4.1-20.3%) in G and 18.9% (95%CI, 10.6-31.4%) in GS (p = 0.265). Disease control rate was 56.6% in G and 79.3% in GS (p = 0.021). Median PFS was 3.6 months (95%CI, 2.0-4.8) in G and 5.4 months (95%CI, 3.7-9.2) in GS (HR 0.64, 95%CI, 0.42-0.97, p = 0.036). At the time of first analysis, median OS was 8.7 months (95%CI, 7.0-10.2) in G and 14.1 month (95%CI, 7.8-16.8) in GS (HR 0.69, 95%CI 0.43-1.08, p = 0.105), and 1-year survival rate was 32.0% in G and 50.1% in GS. Any grade 3-4 toxicities were comparable (48% vs. 40%) and the major grade 3-4 toxicities were neutropenia (35% vs. 34%) in G and GS. Conclusions: The addition of S-1 to G demonstrated longer PFS at the first analysis. OS in GS was longer than in G, but it was not statistically significant at this point. The assessment of OS will be planned at the final analysis. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Taiho Pharmaceutical Taiho Pharmaceutical
Anemia is related to blunted erythropoietin production and impaired renal function in chronic heart failure patients
Authors: BD Westenbrink, Tdj Smilde, E Lipsic, Gerarda Navis, Adriaan Voors, Hans Hillege, van Wiekert Gilst, van Dirk Veldhuisen
Journal: Journal of the American College of Cardiology (2006)
Phase I trial (VEG108925) of cetuximab, irinotecan, and pazopanib (GW786034) administered concurrently.
Authors: M. Deslandres, J. Delord, J. Bennouna, F. Ollivier, H. Senellart, C. M. de-Labareyre, F. C. Hagobian, R. Ruiz-Soto, C. L. Wixon
Journal: Journal of Clinical Oncology (2010)

e14052 Background: Pazopanib isan oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. The combination of cetuximab (C) and irinotecan (I) is approved for treatment of second line metastatic colorectal cancer. This trial aimed to assess the safety and tolerability of C, I and pazopanib (P) to define the maximum tolerated dose (MTD). Methods: Colorectal cancer patients (pts) who had received prior lines of I, C, and oxaliplatin were eligible for inclusion. C (250 mg/m2 weekly after 400 mg/m2 loading dose) plus I (120–180 mg/m2 biweekly) administered on Day 1 of each 14 day cycle plus escalating doses of P (400-800 mg/day)from Day 2 of each cycle were evaluated in cohorts of 3-6 pts to identify the MTD at which less than one third of the patients (no more than 1 out of 6) experience a dose limiting toxicity (DLT). 9 additional pts were enrolled at the MTD. Adverse events (AEs) were evaluated per NCI CTCAE v.3.0. Serial PK samples were taken on Day 1 and 8 of cycles 1, 2 and 3. Results: A total of 22 pts (median age 56 yrs) received C in combination with I/P at doses of 120 mg/m2/400 mg (Cohort [Ch] 1 n = 6), 120 mg/m2/800 mg (Ch2 n = 3) and 150 mg/m2/400 mg (Ch3 n = 13). The primary haematologic toxicity was neutropenia (n = 9) with grade 4 in 3 pts. The most frequent nonhaematologic AEs were asthenia (n = 15), diarrhea (n = 13), nausea (n = 12) and erythema (n = 5). The maximum toxicities were Gr 3 asthenia (n = 6), Gr 3 diarrhea (n = 1), Gr 2 nausea (n = 6) and Gr 2 erythema (n = 4). DLTs were: Ch1-Gr 3 asthenia, Ch2-Gr 4 neutropenia and Grade 3 ALT elevation, Ch3-Gr 4 neutropenia in 2 pts. Ch2 exceeded the MTD so Ch3 explored an increased dose of I and reduced dose of P. Coadministration of CIP resulted in ∼16% increase in I Cmax with no apparent effect on I AUC (0–24) compared to administration of CI. The MTD was defined as 250 mg/m2 weekly C, 150 mg/m2 biweekly I in combination with 400 mg daily P. Conclusions: Although P is a UGT1A1 inhibitor in vitro, the CIP regimen had no apparent effect on SN-38 (UGTIAI substrate) PK parameters. A combination of cetuximab, irinotecan and pazopanib is feasible with a manageable toxicity profile. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Favorable Outcome In Patients with Poor Prognosis Acute Myeloid Leukemia (AML) Using a 2-Day Induction Regimen Incorporating High Dose Cytarabine and Mitoxantrone.
Authors: Melissa L Larson, Sheena Sahota, Margaret C Keller, Bharathi Muthusamy, Allison Zindell, Jamile M. Shammo, Stephanie A. Gregory, Parameswaran Venugopal
Journal: Blood (2010)
Quality and Safety in Health Care, Part XVI
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2016)

As the result of a congressional mandate, the Veterans Health Administration (VA) undertook an initiative called the National VA Surgical Risk study. The purpose of this study was to collect information on its surgical patients to determine outcome data, adjusted for patient risk factors. In 1994, the VA started its National Surgical Quality Improvement Program (VASQIP). These efforts were one of the earliest well-done nationwide systems to study and improve outcomes in surgery adjusted for patient risk. Between 1991 and 2006, the VA hospitals observed a decrease of mortality of 47% and a decrease of morbidity of 43% of their patients in the first 30 days after an operation.
A Drug Screen in Zebrafish Identifies a New Therapeutic Agent Active in Acute Lymphoblastic Leukemia
Authors: Nikolaus Trede, Suzanne Ridges, Deepa Joshi, Jon Beck, Hossein Soffla, Kaveri Balan, Betsy Manos, Alexis Davis, Nathan Sweeney, Nathan Meeker, J. Kimble Frazer, Archana Agarwal, Radia Johnson, Irina Matei, Bertrand Montpellier, Cynthia Guidos, Matthew Sigman, David Jones
Journal: Blood (2010)
Вплив порушень нутритивного статусу на якість життя хворих на хронічні запальні захворювання кишечника
Authors: M.V. Stoikevych
Journal: GASTROENTEROLOGY (2016)

Стаття присвячена актуальній проблемі — впливу нутритивного статусу на якість життя хворих на хронічні запальні захворювання кишечника. Проведено анкетування 80 пацієнтів за допомогою загального (SF‑36) та спеціального (IBDQ) опитувальників. Проаналізовано отримані дані залежно від нутритивного статусу. Встановлено, що зниження нутритивного статусу негативно впливає на якість життя хворих на запальні захворювання кишечника, що обумовлено як кишковими розладами, так і порушенням психоемоційного стану та обмеженням соціальної активності. Найгірші показники якості життя спостерігались у хворих зі зниженим нутритивним статусом.
Characteristics and prognosis of patients (pts) with brain metastasis (BM) in advanced colorectal cancer (CRC) in the era of modern systemic chemotherapy (CT).
Authors: M. Kang, S. Kim, J. Baek, D. Kim, J. Oh, H. Yoo
Journal: Journal of Clinical Oncology (2010)

e14047 Background: We investigated the clinical outcomes of pts with BM from CRC to assess clinical benefit of CT administered after surgical or radiotherapeutic control of BM. Methods: Data of 63 consecutive pts who developed symptomatic BM from CRC and received cranial irradiation or craniotomy in National Cancer Center, Korea, between August 2001 and July 2009 were analyzed. Results: The median age was 56 years (range, 23–81); colon/rectum 28/35; M/F 33/30; metachronous/synchronous metastatic disease 29/34; ECOG performance status (PS) 1/2/3 or 4 25/23/15. Forty-six pts (73%) were treated with either whole brain radiotherapy or local radiation without surgery, and 17 pts (27%) received craniotomy with or without cranial irradiation. Frequent systemic metastatic sites other than brain were lung (70%), bone (44%), and liver (43%). Twenty-five pts (40%) were previously treated with all 3 drugs including fluoropyrimidine, oxaliplatin, and irinotecan; 37 (59%) were unexposed to either oxaliplatin or irinotecan; one pt was known for her previous CT history. The median survival after development of BM was 4.1 mo (95% CI 3.1-5.5). Pts who received CT after BM showed more improved survival compared to those who did not (11.4 mo vs. 3.1 mo, p<0.001). In multivariate analysis, CT after BM was still significantly associated with survival after BM; the adjusted hazard ratio was 0.34 (95% CI 0.13-0.89, p=0.027) (Table). Conclusions: Although BM has been known to be a late-stage phenomenon in CRC, about two-thirds of pts who developed BM was still unexposed to either irinotecan or oxaliplatin. CT after local control of BM could be beneficial for survival in selected pts. Hazard ratio (95% CI) P value CT after BM 0.34 (0.13-0.89) 0.027 Unfavorable histology 2.81 (1.01-7.83) 0.048 Previously treated with all 3 drugs 2.33 (1.02-5.34) 0.046 Sum of systemic metastatic sites >2 3.78 (1.84-7.76) <0.001 ECOG PS ≥ 2 3.51 (1.61-7.63) 0.002 No significant financial relationships to disclose.
Paediatricians criticise college survey on links with formula milk firms
Authors: Anne Gulland
Journal: BMJ (2016)

Paediatricians campaigning for their royal college to sever its links with infant formula milk manufacturers have criticised the wording of the college’s survey of members.

Delegates at the annual general meeting of the Royal College of Paediatrics and Child Health in April voted in favour of a motion urging it to “decline any commercial transactions or any other kind of funding or support” from all companies that market and manufacture breast milk substitutes.1

The college discussed the motion at its July council meeting and agreed to survey its members on the issue. The survey was sent to members in August.

Those campaigning for the college to change its policy say, however, that the wording of …
Migraine genetics: from genome-wide association studies to translational insights
Authors: Padhraig Gormley, Bendik S. Winsvold, Dale R. Nyholt, Mikko Kallela, Daniel I. Chasman, Aarno Palotie
Journal: Genome Medicine (2016)

Understanding the molecular mechanisms that precede and give rise to a migraine attack is key to developing new therapeutic strategies.Advances towards this goal have recently been made through genome-wide association studies, which have identified new genetic components of migraine that highlight vascular etiologies and underline the polygenic nature of this disorder.
Development of a clinical trial assay for PD-L1 immunohistochemistry (IHC) for use with pembrolizumab (pembro) clinical trials in melanoma.
Authors: Marisa Dolled-Filhart, Scot Ebbinghaus, Charlotte Roach, Gary Ponto, Grant Toland, Malinka Jansson, Kenneth Emancipator
Journal: Journal of Clinical Oncology (2016)

9571 Background: PD-L1 expression on tumors contributes to tumor escape from immune surveillance. In order to determine whether PD-L1 might be useful to identify those patients (pts) with melanoma most likely to respond to pembro, an IHC assay was developed for use in pembro clinical trials. Methods: The PD-L1 IHC assay was performed on the Dako platform using the 22C3 anti–PD-L1 antibody. In contrast to development of this assay for non–small cell lung cancer (NSCLC), scoring included mononuclear inflammatory cells intercalated and contiguous with tumor cells. A 6-point score was defined as: IHC0 (no staining), IHC1 ( < 1% staining), IHC2 (1%-9%), IHC3 (10%-32%), IHC4 (33%-65%), and IHC5 (66%-100% staining). The presence of distinct patterns (“interface” or “dendritic”) was also noted. Using data from 135 patients treated with pembro in KEYNOTE-001 (NCT01295827), 88 samples were evaluable for PD-L1 IHC and had central RECIST response data for use in a training set. Samples with obscuring melanin or insufficient tumor were “not evaluable.” Receiver operating characteristic (ROC) analysis was performed. Results: The ROC curve was somewhat flat. A score of IHC2 (1% staining) was chosen to optimize the true positive rate (clinical sensitivity) and negative predictive value. A 2 × 2 table is shown below comparing responders and nonresponders at the IHC2 cutoff. Assay performance could not be improved by incorporating the interface or dendritic patterns. Conclusions: PD-L1 is not a strong enough predictor of response to be used as a companion diagnostic for pembrolizumab monotherapy. However, PD-L1 testing could help guide treatment decisions in melanoma in clinical situations in which several treatment options are available. Although 66% of samples in this cohort were PD-L1–positive, higher prevalence (81%) was observed in the previously reported data from KEYNOTE-006 (NCT01866319), a randomized, controlled clinical trial for pembro in melanoma. Clinical trial information: NCT01295827. Responders Non-Responders PD-L1 IHC Score = 0,1 6 24 PD-L1 IHC Score = 2, 3, 4, 5 24 34
IgG4‐Related Disease: Retrospective Analysis of One Hundred Sixty‐Six Patients
Authors: Hiroshi Sekiguchi, Ryohei Horie, Mio Kanai, Reina Suzuki, Eunhee S. Yi, Jay H. Ryu
Journal: Arthritis & Rheumatology (2016)

To investigate clinical and pathologic aspects of IgG4-related disease (IgG4-RD) in non-Asian populations.We conducted a retrospective review of the medical records of patients with IgG4-RD who presented to an academic medical center from January 1994 to September 2012.Among 166 patients identified, the median age at diagnosis was 61 years (interquartile range [IQR] 49-70 years), 75% were male, and 80% were white. The median number of organs involved was 2 (IQR 2-3). When organs were grouped according to anatomic system, the hepatopancreaticobiliary system was most commonly involved (77%). The median highest serum IgG4 level during the clinical course was 215 mg/dl (IQR 122-466). Forty-three patients (26%) had a normal serum IgG4 level. Seventy-nine pathology specimens were available for immunostaining. The median number of IgG4+ cells was 37 (IQR 25-82) per high-power field, with an IgG4+:IgG+ ratio of 0.50 (IQR 0.32-0.68). Among 151 patients who received medical therapy, 72 (48%) received steroid-sparing agents because of relapse, recurrence, or corticosteroid intolerance. Of the 66 patients who were newly diagnosed, started on corticosteroid monotherapy as the initial treatment, and followed up at our institution, 30 (45%) experienced relapse or recurrence despite an initial favorable response. The number of organs involved had a significant impact on time to relapse or recurrence, with a hazard ratio of 1.48 (95% confidence interval [95% CI] 1.12-1.93) (P < 0.01) in multivariate analysis. The standardized incidence ratio of malignancy was 4.5 (95% CI 1.5-7.5).IgG4-RD is a multisystem disorder that commonly affects older men and has a propensity for relapse, recurrence, and malignancy.
Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells
Authors: Mei-Fong Pang, Michael J. Siedlik, Siyang Han, Melody Stallings-Mann, Derek C. Radisky, Celeste M. Nelson
Journal: Cancer Research (2016)

Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277-87. ©2016 AACR.
Azacitidine Treatment in High Risk Myelodysplastic Patients in Complete Haematological Remission Reverts Mesenchymal Stem Cells to a Normal Phenotype
Authors: Antonella Poloni, Giulia Maurizi, Domenico Mattiucci, Benedetta Costantini, Marianna Mariani, Stefania Mancini, Mirco Fanelli, Attilio Olivieri, Pietro Leoni
Journal: Blood (2014)
PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models
Authors: Fan Lin, Mark C. de Gooijer, Diana Hanekamp, Gayathri Chandrasekaran, Levi C.M. Buil, Nishita Thota, Rolf W. Sparidans, Jos H. Beijnen, Tom Würdinger, Olaf van Tellingen
Journal: Clinical Cancer Research (2016)

Purpose: The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs.Experimental Design: We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.Results: The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly, Abcb1a/b-/-;Abcg2-/- mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition. NVP-BEZ235 and ZSTK474 demonstrated antitumor efficacy with improved survival against U87 orthotopic gliomas, although the effect of ZSTK474 was more pronounced. Finally, ZSTK474 prolonged overall survival in Cre-LoxP conditional transgenic Pten;p16Ink4a/p19Arf;K-Rasv12;LucR mice, mainly by delaying tumor onset.Conclusions: PI3K/mTOR inhibitors with weak affinities for ABC transporters can achieve target inhibition in brain (tumors), but have modest single-agent efficacy and combinations with (BBB penetrable) inhibitors of other activated pathways may be required. Clin Cancer Res; 23(5); 1286-98. ©2016 AACR.
Case 5-1976
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Richard H. Meade, Walter G.J. Putschar
Journal: New England Journal of Medicine (1976)

Presentation of CaseA 65-year-old man was admitted to the hospital because of fever.At the age of 15 years an abscess developed in the vicinity of the right hip and was drained at this hospital. A presumptive diagnosis of bovine tuberculosis secondary to the ingestion of unpasteurized milk was made. He then felt well and had normal function of the hip, although there was intermittent drainage, especially during the winter months. Thirty-one years before entry he was admitted to another hospital, where a chronic sinus tract with a portion of the greater trochanter was excised. Two years later drainage . . .
Disease modifying therapies for relapsing multiple sclerosis
Authors: Dean M Wingerchuk, Brian G Weinshenker
Journal: BMJ (2016)

Multiple sclerosis (MS) is a common, disabling, putatively autoimmune neurological disease with worldwide distribution. It typically begins as a relapsing disorder that later evolves to a secondary progressive phase. Inflammatory and neurodegenerative mechanisms seem to operate in both phases, but their relative contributions and interactions are incompletely understood. Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. Benefits of longer duration of therapy on disability are less clear, as data beyond three years are largely limited to observational studies. However, current DMTs do not slow accrual of disability once progressive multiple sclerosis is established. This review summarizes the evidence about the use of approved DMTs and examines how to individualize treatment despite the absence of validated biomarkers to guide drug selection. Methods such as stratifying patients on the basis of estimated risk for future disability, weighing patient specific factors and preferences, and using objective outcomes to adjudicate treatment success are discussed. Emerging drug therapies and strategies are also reviewed.