tbuckley/cabot-search huggingface dataset:
Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including patients with brain metastases.
Authors: Sanjeev Deva, Richard D. Baird, Nicola Cresti, Javier Garcia-Corbacho, Linda Hogarth, Eugene P. Frenkel, Keiko Kawaguchi, Akinori Arimura, Kirsteen Donaldson, John Posner, Debashis Sarker, Duncan Ian Jodrell, Ruth Plummer, James F. Spicer
Journal: Journal of Clinical Oncology (2015)

2511 Background: S-222611 is an oral, reversible ErbB tyrosine kinase inhibitor of EGFR and HER2 with potent pre-clinical activity. MTD was not reached during dose-escalation, even at the maximum dose of 1600mg QD. PK and efficacy data supported a daily dose of 800mg. A further cohort has been treated to further explore safety and efficacy. Methods: Subjects with advanced solid tumors expressing EGFR and/or overexpressing HER2 were enrolled. S-222611 was administered until disease progression or unacceptable toxicity. Results: 76 patients (33 male/43 female; median age 62 years [range 31-81], ECOG PS 0/1/2: 24/51/1), were included in this expansion phase, including breast (27), esophago-gastric (30), head & neck (12) and renal (7). Dose reduction was required because of adverse events in 11 patients (14%); the most frequent of such being diarrhea and elevated bilirubin. Only 2 patients discontinued treatment due to drug-related adverse events. Of the 41 patients with HER2-positive cancers (26 breast, 13 esophago-gastric, 2 head & neck), 1 complete response (gastric-esophageal junction cancer) and 5 partial responses (4 breast cancer, 1 gastric cancer) were observed; all these patients had received prior HER2-directed therapy. Prolonged stable disease ( ≥ 6 months) was observed in 3 additional patients with breast cancer. 6 of the 25 breast patients had brain metastases, in whom 1 intracranial response and 2 prolonged SD ( ≥ 6mo) were observed. In the EGFR+ve/HER2-ve cohort (n = 35), no RECIST responses were seen, however 4 patients had prolonged stable disease ( ≥ 6mo). Conclusions: S-222621 was well tolerated at a dose of 800mg once daily. Anti-tumour activity, including shrinkage of brain metastases, was evident in a heavily pre-treated population of patients with HER2-positive breast and esophago-gastric cancers. Clinical trial information: 2009-017817-31.
Elevated CRP Is Associated with Longer Survival of PTCL-NOS in Peripheral T-Cell Lymphomas: A Single Institution Research
Authors: Tadahiro Gunji, Yasuhito Terui, Anna Takahashi, Norihito Inoue, Yoshiharu Kusano, Hideaki Nitta, Kyoko Ueda, Noriko Nishimura, Yuko Mishima, Masahiro Yokoyama, Kiyohiko Hatake
Journal: Blood (2015)
Targeting Of Leukemia Stem Cells By Interfering With Niches Using CD44 Variant 6 Chimeric Antigen Receptor Redirected Central Memory T Cells
Authors: Xiuli Wang, ChingLam W Wong, Ryan Urak, Armen Mardiros, Wen-Chung Chang, Ellie Taus, Lihua E Budde, Julie R Ostberg, Christine Brown, Stephen J. Forman
Journal: Blood (2013)
Corticosteroids for community-acquired pneumonia: a critical view of the evidence
Authors: James D. Chalmers
Journal: European Respiratory Journal (2016)

Community acquired pneumonia (CAP) remains a leading cause of morbidity and mortality, with mortality rates between 5% and 15% in hospitalised patients, rising to up to 30% in patients admitted to the intensive care unit (ICU) [1–3]. The current evidence raises more questions than answers, and does not support routine use of corticosteroids for CAP <http://ow.ly/t01g302QDhG>
MSI versus MSS sporadic colorectal cancers: Morphology, inflammation, and angiogenesis revisited.
Authors: Xavier Sagaert, Eric Van Cutsem, Sabine Tejpar, Hans Prenen, Gert De Hertogh
Journal: Journal of Clinical Oncology (2014)

495 Background: MSI is a well-documented pathway in the pathogenesis of colorectal cancer. A specific cphenotype has been associated with MSI tumors, as they tend to be more right-sided, have a better prognosis, mostly display a poor histologic differentiation and are marked by extensive inflammation. However, the biological basis and of all these features is still largely unknown. We hypothesize that MSI results in an accumulation of intratumoral mutations. Consequencely, lots of aberrant proteins are formed, probably resulting in a poor histologic differentiation but also evoking a strong immune response that may have the ability to limit tumor expansion (hence explaining a better prognosis) and to stimulate angiogenesis. Methods: To sustain this hypothesis we compared 35 MSI and 35 MSS tumors (matching for TNM staging) with respect to their morphology, inflammation and vessel density. Morphology was analyzed on HE stains. Immunohistochemical stainings for CD 3, CD4, CD8, CD20 and CD68 were performed to document the number of T-lymphocytes, B-lymphocytes and macrophages in relation to tumor location (intraepithelial, intratumoral, peritumoral). CD 31 staining was performed to highlight vessel density in the tumor and assess angiogenesis. Conclusions: (1) In accordance with literature, MSI tumors occured at younger age, with preponderance of the right colon and with a smaller likelihood of metastasis. (2) The most striking observation was the higher number of intra-epithelial T-lymphocytes in MSI tumors (not present in their microsatellite stable counterparts). No difference was found between MSI and MSS tumors in terms of intra/peritumoral B-cells, macrophages, and/or T-cells. (3) Half of the MSI tumors and none of the MSS tumors displayed different histological subtypes/patterns within one tumor. As such, we suggest that in daily routine practice, presence of morphologic tumor heterogeneity should initiate analysis for microsatellite instability. (4) MSI tumors had a statistically much higher (micro)vessel density as compared to their MSS counterparts, hence hinting at a potential application of anti-VEGF therapy in this subgroup of colorectal cancers.
Arsenic Trioxide-Mediated Growth Inhibition of Myeloma Cells Is Associated with An Extrinsic Signaling Pathway Involved in Caspase 3 and Caspase 8.
Authors: Jumei Shi, Yi Wu, Siqing Wang, Xiuqin Meng, Rong Wei, Xiaojing Hu, Maurizio Zangari, Guido J. Tricot, Fenghuang Zhan
Journal: Blood (2009)
P0285 : Inactivation of cyclin E1 acts pro-apoptotic and anti-proliferative in primary hepatoma cells and protects from hepatocarcinogenesis in mice
Authors: R. Sonntag, N. Moro, Y.A. Nevzorova, J.M. Bangen, D. Fahrenkamp, D. Lambertz, W. Hu, N. Gassler, G. Müller-Newen, R. Weiskirchen, M. Barbacid, P. Sicinski, C. Trautwein, C. Liedtke
Journal: Journal of Hepatology (2015)
GMC was wrong to release report on GP’s competence to patient, rules judge
Authors: Clare Dyer
Journal: BMJ (2016)

A High Court judge has ruled that a decision by the UK General Medical Council to release an expert report on a GP’s competence to the patient who complained about him was unlawful.

The patient, who had been given a diagnosis of bladder cancer, complained to the regulator about the GP, named only as DB. He claimed that his illness would have been recognised a year earlier had the doctor been doing his job properly.

The GMC commissioned a report from an expert, who decided that DB had fallen below the expected standard, “but not seriously below.” The expert concluded that most reasonably competent GPs would not have suspected …
Update: Interim Guidance for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus for Persons with Possible Zika Virus Exposure — United States, September 2016
Authors: Emily E. Petersen, Dana Meaney-Delman, Robyn Neblett-Fanfair, Fiona Havers, Titilope Oduyebo, Susan L. Hills, Ingrid B. Rabe, Amy Lambert, Julia Abercrombie, Stacey W. Martin, Carolyn V. Gould, Nadia Oussayef, Kara N.D. Polen, Matthew J. Kuehnert, Satish K. Pillai, Lyle R. Petersen, Margaret A. Honein, Denise J. Jamieson, John T. Brooks
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

CDC has updated its interim guidance for persons with possible Zika virus exposure who are planning to conceive (1) and interim guidance to prevent transmission of Zika virus through sexual contact (2), now combined into a single document. Guidance for care for pregnant women with possible Zika virus exposure was previously published (3). Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission (http://www.cdc.gov/zika/geo/index.html), or sex* without a condom† with a partner who traveled to or lived in an area of active transmission. Based on new though limited data, CDC now recommends that all men with possible Zika virus exposure who are considering attempting conception with their partner, regardless of symptom status,§ wait to conceive until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Recommendations for women planning to conceive remain unchanged: women with possible Zika virus exposure are recommended to wait to conceive until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Couples with possible Zika virus exposure, who are not pregnant and do not plan to become pregnant, who want to minimize their risk for sexual transmission of Zika virus should use a condom or abstain from sex for the same periods for men and women described above. Women of reproductive age who have had or anticipate future Zika virus exposure who do not want to become pregnant should use the most effective contraceptive method that can be used correctly and consistently. These recommendations will be further updated when additional data become available.
Obstructive sleep apnoea and bone health
Authors: Jia-Yu Zhong, Ling-Qing Yuan
Journal: European Respiratory Journal (2016)

We thank Liguori et al . [1] for sharing their interesting study about patients suffering from obstructive sleep apnoea (OSA) and their tendency towards lower bone mineral density (BMD) in the lumbar spine and femur compared with control subjects matched for age, body mass index and physical activity. The researchers defined "osteopenia" as a T-score value < −1 sd and "osteoporosis" as a T-score value < −2.5 sd. They also suggested that OSA could be detrimental to BMD, resulting in osteopenia and osteoporosis. However, there are some concerns with this study. To better understand the effect of OSA on bone health, fracture rate might be a more useful marker than BMD <http://ow.ly/h2vv3018gIg>
The association between overexpression of skp2 and the risk of recurrence following prostatectomy
Authors: P. L. Nguyen, J. Lei, E. Mueller, S. Signoretti, A. V. D’Amico, D. Lin, M. Pagano, M. H. Weinstein, M. Loda
Journal: Journal of Clinical Oncology (2008)

11052 Background: Decreased expression of the cell cycle inhibitor p27 is associated with a poor prognosis in several human cancers. Skp2 is a substrate recognition unit specifically targeting p27 for degradation and may therefore represent a therapeutic target in cancers with low p27. We sought to determine whether Skp2 overexpression is associated with p27 suppression and an increased risk of recurrence among men with prostate cancer treated with prostatectomy. Methods: We identified 110 men who received a prostatectomy for non-metastatic, node-negative prostate cancer from 1985–1996. Immunohistochemistry (IHC) staining for Skp2, p27, and MIB-1 were performed on paraffin-embedded material. Stains were scored based on the percent of cells showing nuclear staining, averaged by counting 100 tumor cells in 5 different areas. A threshold of >30% was used for high p27 staining, and a threshold of ≥5% was used for high Skp2 and high MIB-1. The primary endpoint was time to prostate-specific antigen (PSA) failure. Results: Overall 12 tumors (11%) had high Skp2 expression. These 12 all had correspondingly low p27 expression (p=0.006, Chi-Square). 40% of tumors with high Skp2 also had high MIB-1 expression, while only 13% of tumors with low Skp2 had high MIB-1 (p=0.035). Skp2 overexpression was associated with higher Gleason score (p=0.001) and more advanced pathological T-category (p=0.004). Median follow-up from the time of surgery was 67 months (range: 0.2 to 218 months). On Cox multivariable analysis, Skp2 overexpression was associated with a significantly shorter time to PSA failure (adjusted hazard ratio 5.2 (95% C.I. 1.9–14, p=0.001) after adjusting for PSA, pathologic T-category, and prostatectomy Gleason score. The median time to PSA failure was 4 months among those with Skp2 overexpression compared to 54 months among those who did not overexpress Skp2. Conclusions: Skp2 overexpression was associated with low levels of p27, poor prognostic features, and increased risk of recurrence. These results support the concept of Skp2-mediated degradation of p27, suggest a possible role for Skp2 in tumor progression, and raise the possibility that Skp2 could be a potential therapeutic target, particularly for tumors which underexpress p27. No significant financial relationships to disclose.
Final Results of the First-in-Human Clinical Study Incorporating Hyperbaric Oxygen into Umbilical Cord Blood Transplantation
Authors: Omar S. Aljitawi, Siddhartha Ganguly, Tara L. Lin, Shana Palla, Chris Lominska, Qing Yu, Singh Anurag, Sunil Abhyankar, Dennis Allin, Mary Eapen, Joseph McGuirk
Journal: Blood (2015)
Cardiac Soluble Guanylate Cyclase Protects Against Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice
Authors: Sara Vandenwijngaert, Melissa Swinnen, Peter Pokreisz, Hilde Gillijns, Ellen Caluwé, Jozef Bartunek, Kenneth D Bloch, Stefan Janssens
Journal: Circulation (2012)
Analyzing the MLL Recombinome.
Authors: Claus Meyer, Bjoern Schneider, Martin Reichel, Sieglinde Angermuller, Susanne Schnittger, Claudia Schoch, Mieke W.J.C. Jansen, Jacques J.. M. van Dongen, Rob Pieters, Oskar Haas, Sabine Strehl, Theo Dingermann, Thomas Klingebiel, Rolf Marschalek
Journal: Blood (2004)
Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction
Authors: Lei Wang, Xue-Chen Zhao, Wei Cui, Yong-Qiang Ma, Hua-Liang Ren, Xin Zhou, John Fassett, Yan-Zong Yang, Yingjie Chen, Yun-Long Xia, Jie Du, Hui-Hua Li
Journal: Circulation (2016)

The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown.Angiotensin II (490 ng·kg-1·min-1) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry.Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45+ CXCR2+ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+ proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20).Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
Impact of dihydropyrimidine dehydrogenase status of biopsy specimens on efficacy of irinotecan plus cisplatin, S-1, or 5-FU as first-line treatment of advanced gastric cancer patients in JCOG9912
Authors: Y. Yamada, S. Yamamoto, A. Ohtsu, Y. Suzuki, J. Nasu, K. Yamaguchi, T. Denda, A. Tsuji, Y. Hara, N. Boku
Journal: Journal of Clinical Oncology (2009)

4535 Background: JCOG9912 (randomized phase III trial) showed a significant non-inferiority of S-1 to 5-FU (P&lt;0.001); however, either S-1 or irinotecan plus cisplatin (IP) failed to show superiority to 5-FU (P=0.034 and 0.055, respectively) in overall survival. Excision repair cross-complementing group 1 (ERCC1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are reportedly related to outcome of advanced gastric cancer (AGC) patients (pts) treated with IP or 5-FU. Efficacy analyses are performed to evaluate the status of ERCC1, TS, DPD and 5 biomarkers related to anticancer drug sensitivity in first-line pts treated with IP, S-1, or 5-FU monotherapy under controlled conditions. Methods: Blocks from endoscopic biopsy specimens of primary lesions before chemotherapy were available from 365 of 704 pts in JCOG9912. Using laser-captured microdissection and real-time RT-PCR, we analyzed mRNA expression of ERCC1, TS, DPD in paraffin-embedded specimens. Expression levels of each gene were categorized into low and high values at each median. Results: The subjects with available tissue for analysis were representative of all randomized pts; 232 samples were assessable for TS, 168 for DPD, and 235 for ERCC1. There were no statistical differences in patient numbers between 3 arms. Pts with high TS showed worse progression-free survival (PFS) compared with those with low TS (hazard ratio (HR):1.26 [95%CI: 0.97–1.63]) in all pts; there was no difference in PFS between DPD and ERCC1 expression level. IP showed better PFS than S-1 in low DPD (HR: 0.57 [95%CI: 0.32–1.01]) but not in high DPD (HR: 1.24 [95%CI: 0.76–2.04]); there was no clear difference in PFS between pts treated with IP and S-1 regardless of TS and ERCC1 expression status. S-1 showed almost consistently better PFS than 5-FU regardless of mRNA expression status. Conclusions: This large analysis showed the prognostic value of TS status in AGC pts and the predictive value of DPD status for IP and S-1 as first-line treatment. Studies of DPD as a predictive marker for IP activity in AGC are warranted in future personalized phase III. [Table: see text]
The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells
Authors: Bryan King, Francesco Boccalatte, Kelly Moran-Crusio, Elmar Wolf, Jingjing Wang, Clarisse Kayembe, Charalampos Lazaris, Xiaofeng Yu, Beatriz Aranda-Orgilles, Anna Lasorella, Iannis Aifantis
Journal: Nature Immunology (2016)
BRIDGE: An open-label phase II trial evaluating the safety of bevacizumab (BV) plus paclitaxel/carboplatin (PC) as first-line treatment (tx) for patients (pts) with advanced, previously untreated, squamous non-small cell lung cancer (NSCLC).
Authors: L. Faoro, J. D. Hainsworth, D. A. Karlin, J. E. Huang, L. Fang, F. A. Scappaticci
Journal: Journal of Clinical Oncology (2010)

7583 Background: In a phase II study of first-line tx with BV + PC for NSCLC, squamous histology was found to be a risk factor for severe (Gr ≥ 3) pulmonary hemorrhage (PH). Subsequently, pts with predominantly squamous histology were generally excluded from phase III studies. This final analysis from the BRIDGE study assesses safety of delayed BV administration in pts with locally advanced or metastatic squamous NSCLC. Methods: BRIDGE was an open-label, single-arm, multicenter pilot study of PC alone in cycles 1 and 2, and PC + BV in cycles 3 to 6, followed by BV until progressive disease (PD) or unacceptable toxicity. Eligible pts had stage IIIb (with pleural effusion), stage IV, or recurrent squamous NSCLC. Pts with recent arterial thromboembolic events, gastrointestinal perforation, hemoptysis, untreated brain metastases, intrathoracic lesion(s) with cavitation, or anticoagulation therapy were not eligible. The primary endpoint was incidence of Gr ≥ 3 PH. Results: Forty- seven pts received 2 initial cycles of PC, and 31 continued on study to receive ≥ 1 dose of BV. Median age was 65 (range: 48-80); 96.3% had Stage IV disease. Pts received a median of 6.0 (range, 1-18) doses of BV, and 2 pts (6.5%) completed 12 mos of tx. Among the 31 pts who received BV, there were 3 reports of PH of any grade in 2 pts. One pt had Gr 1 PH during cycle 3, withdrew due to PD on the same day, and recovered from PH. A second pt developed Gr 3 PH after post-progression treatment, 44 days after the last BV dose; PH resolved 2 d later, but after another 55 d the pt developed Gr 4 PH, and subsequently died due to PD. Incidence of Gr ≥ 3 PH (1 pt) was 3.2% (90% CI: 0.3-13.5%). Nine pts (29.0%) experienced Gr 3 events, including 5 (16.1%) with hypertension; 5 experienced Gr 4 events (dyspnea, PH, basal ganglia infarction, cerebral ischemia and pain). Median progression-free survival (PFS) was 6.2 mos (95% CI: 5.32-7.62 mos); 57% of pts had PFS of ≥ 6 mos. Conclusions: The incidence of Gr ≥ 3 PH in this study was 3.2% (1 pt). No new safety signals were identified. Until further trials are conducted, tx of squamous NSCLC with BV should be considered experimental. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche
A pilot pharmacological study of twice-weekly paclitaxel therapy in advanced and recurrent gastric cancer
Authors: Y. Shima, A. Tsuji, S. Morita, T. Horimi
Journal: Journal of Clinical Oncology (2004)

4130 Background: Paclitaxel's efficacy can be adjusted by dividing its dose because its effects are time-dependent. Weekly paclitaxel therapy has been reported to be safe and useful for advanced, recurrent gastric cancer. In the present study, we administered paclitaxel twice a week to patients with previous chemotherapy with a 5-FU anticancer drug and evaluated the usefulness, tolerability and acceptability of this treatment regimen. Methods: Paclitaxel was administered twice a week at 40 mg/m2 (Level 0) or 32 mg/m2 (Level -1). One cycle consisted of 8 doses. Pharmacokinetic profile: Blood concentrations of paclitaxel were measured before and shortly after administration of each dose and 1, 2, 6, 12, 24, 36, 48, 60, 71 and 73 hrs after administration of the 1st and 5th doses. Results: Paclitaxel was administered twice a week to 7 patients. Level 0 and Level -1 treatments were completed in 3/4 and 3/3 patients, respectively. The tumor shrinking effect was PR in 2 patients and PD in the other 2 at Level 0 and PR in 1, NC in 1 and PD in the other at Level -1, resulting in an overall response rate of 42.9%. Adverse events observed included leukopenia, neutropenia, and general malaise. Grade 3 leukopenia and Grade 3 anemia occurred in 1/4 and 3/4 patients, respectively, in the 2nd and subsequent cycles at Level 0. No Grade 3 or severer adverse events were noted at Level 1. Paclitaxel was accumulated in 2/4 patients at Level 0 but no accumulation was noted at Level -1. Conclusions: Paclitaxel showed good antitumor effects when administered twice a week. Sufficient blood concentrations were achieved at Level -1 with only minor adverse events. Findings obtained in the present study suggest that the optimal dose of paclitaxel is about 32 mg/m2 when administered twice a week. No significant financial relationships to disclose.