tbuckley/cabot-search huggingface dataset:
Junior Doctors Committee proposed an academy in 1994
Authors: A Carney, D Wrede
Journal: BMJ (1996)

We were surprised to find a consultation paper on a possible British academy of medicine included in our copy of the BMJ at the beginning of June.1 We recognise the need for such a national academy but are concerned that this brief consultation paper was published by a group separate from and without representatives of the BMA.

The Junior Doctors Committee supports the formation of an academy, having published a discussion paper on the subject in 1994, which …
Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors
Authors: Marina N. Nikiforova, Abigail I. Wald, Melissa A. Melan, Somak Roy, Shan Zhong, Ronald L. Hamilton, Frank S. Lieberman, Jan Drappatz, Nduka M. Amankulor, Ian F. Pollack, Yuri E. Nikiforov, Craig Horbinski
Journal: Neuro-Oncology (2015)

Identification of genetic changes in CNS tumors is important for the appropriate clinical management of patients. Our objective was to develop a next-generation sequencing (NGS) assay for simultaneously detecting the various types of genetic alterations characteristic for adult and pediatric CNS tumors that can be applied to small brain biopsies. We report an amplification-based targeted NGS assay (GlioSeq) that analyzes 30 genes for single nucleotide variants (SNVs) and indels, 24 genes for copy number variations (CNVs), and 14 types of structural alterations in BRAF, EGFR, and FGFR3 genes in a single workflow. GlioSeq performance was evaluated in 54 adult and pediatric CNS tumors, and the results were compared with fluorescence in-situ hybridization, Sanger sequencing, and reverse transcription PCR. GlioSeq correctly identified 71/71 (100%) genetic alterations known to be present by conventional techniques, including 56 SNVs/indels, 9 CNVs, 3 EGFRvIII, and 3 KIAA1549-BRAF fusions. Only 20 ng of DNA and 10 ng of RNA were required for successful sequencing of 100% frozen and 96% formalin-fixed, paraffin-embedded tissue specimens. The assay sensitivity was 3%–5% of mutant alleles for SNVs and 1%–5% for gene fusions. The most commonly detected alterations were IDH1, TP53, TERT, ATRX. CDKN2A, and PTEN in high-grade gliomas, followed by BRAF fusions in low-grade gliomas and H3F3A mutations in pediatric gliomas. GlioSeq NGS assay offers accurate and sensitive detection of a wide range of genetic alterations in a single workflow. It allows rapid and cost-effective profiling of brain tumor specimens and thus provides valuable information for patient management.
Treatment continuum and not reinstitution should be the management strategy in non small cell lung cancer (NSCLC)
Authors: R. Taran, D. Pendharkar, I. Yasin
Journal: Journal of Clinical Oncology (2008)

18500 Background: Concurrent chemo-radiotherapy (CCRT) is accepted standard of care in nonsurgical stage IIB-IIIA patients with NSCLC. After CCRT follow-up observation is an average approach. Aim of the study was to analyze the importance of the continuity of treatment post CCRT or initial chemotherapy (CT). Methods: NSCLC stage IIB and above patients were randomized to arm A or B. Chemotherapy consisted of Cisplatinum 100 mg/m2 (day 1), Etoposide 200 mg (day 1–3) and CCRT consisted of radiation dose of 60 Gy given over 30 fractions with same drugs on day 1–3 and day 28–30. Arm A > CT 2 courses > First assessment > CCRT > Second assessment. Arm B > CCRT > First assessment > CT 2 course > Second assessment Results: There were 28 evaluable patients. Responses were seen as in Table. In arm A out of 15 patients 10 had shown response (all PR). On further continuation of treatment, the response progressed to CR in seven patients and another three patients progressed from status of stable disease to partial response status. Response continued to occur with continuation of treatment. In arm B, when treatment was not halted at level of CCRT and continued with additional chemotherapy, out of seven partial responders, three further converted to complete response. Overall 20/28 (71.43%) patients changed their degree of response with continuation of treatment. The level of response increased to higher level in both arms. In a standard scenario one would have stopped treatment post CCRT for observation. The analysis demonstrates that there are responses which continue to occur beyond. Conclusions: The concurrent chemoradiation or induction chemotherapy should be followed by “continued” treatment. The chances of response to such continuation are very high. Data from major trials should be looked from this angle. Prolonged continuous treatment probably could offer us better degree of response. Response Rate CR PR SD Arm A assessment (%) First 0/15 (0) 10/15 (66.7) 4/15 (26.7) Second 7/15 (46.7) 6/15 (40) 0/15 (0) Arm B assessment (%) First 3/13 (23) 7/13 (53.9) 0/13 (0) Second 6/13 (46.1) 4/13 (30.8) 0/30 (0) No significant financial relationships to disclose.
Abstract 56: Candesartan And Valsartan, Contrary To Irbesartan, Are Potent Biased Antagonists Of Adrenal (beta)arrestin-dependent, Angiotensin II Type 1 Receptor-induced Aldosterone Production And Improve Cardiac Function Post-myocardial Infarction
Authors: Anastasios Lymperopoulos, Karlee Walklett, Samalia Dabul, Ashley Siryk, Emmanuel Sturchler, Patricia McDonald, Giuseppe Rengo, Walter J Koch
Journal: Circulation Research (2014)

Introduction: The scaffolding protein βarrestin1 (βarr1) by the angiotensin II (AngII) type 1 receptor (AT 1 R) mediates AngII-induced aldosterone production in vitro and physiologically in vivo, thereby exacerbating heart failure (HF) progression post-myocardial infarction (MI). Herein, we sought to investigate the relative potency of various AT 1 R antagonist drugs (sartans) at inhibiting βarr vs. G protein activation and hence aldosterone production in vitro and in vivo. We also investigated the alterations in plasma aldosterone levels conferred by these agents and their impact on cardiac function of post-MI rats. Methods: For the in vitro tests, transfected CHO and adrenocortical H295R cells were used. For in vivo studies, post-MI rats overexpressing βarr1 in their adrenals received 7-day-long treatments with the drugs of interest. Results: Among the sartans tested, candesartan and valsartan were the most potent βarr activation and βarr-mediated aldosterone production inhibitors in vitro, as well as the most “biased” antagonists towards βarr vs. G-protein inhibition. Conversely, losartan and irbesartan were the least potent βarr inhibitors and the least “biased” antagonists towards βarr inhibition. These in vitro findings were corroborated in vivo, since candesartan and valsartan, contrary to irbesartan, caused significant plasma aldosterone reductions in post-MI rats. Accordingly, cardiac ejection fraction (EF) and contractility were significantly augmented in candesartan- and valsartan-treated rats (EF: 41.1±1% and 40±1% respectively, vs. 35±0.3% for saline-treated), but further deteriorated in irbesartan-treated post-MI rats (EF: 32±1%, n=7 rats/group). Conclusions: These findings provide important insights that might aid pharmacotherapeutic decisions (i.e. individual agent selections) involving this commonly prescribed cardiovascular drug class (sartans).
Transbronchial needle aspiration (TBNA) in the diagnosis and staging of lung cancer in a large cohort of patients
Authors: Sara Chiesa, Maria Majori, Rita Nizzoli, AnnaMaria Guazzi, Miriam Anghinolfi, Alfredo Antonio Chetta, Angelo Gianni Casalini
Journal: European Respiratory Journal (2011)

Introduction: TBNA is a minimally invasive bronchoscopy technique, that allows to examine mediastinal and hilar lymph nodes, avoiding surgical mediastinal exploration.

Objectives: The aim of this study was to assess the sensitivity and diagnostic accuracy of TBNA in a large cohort of patients. In addition, we appraised the relationships between TBNA yield and lymph node size and location.

Methods: Between March 2009 and November 2011, we prospectively examined 110 patients (age range: 30 to 87 yr, 31 F) with suspected lung cancer and enlarged mediastinal lymph nodes. Each patient performed TBNA during flexible bronchoscopy with rapid-on-site evaluation.

Results: TBNA was positive in 88 of 110 patients with suspected lung cancer (80%). No complications was observed. The lymph node size cut-off point, that better identified patients with positive aspirate was ≥ 24 mm (0.83 sensitivity and 0.51 specificity; AUC=0.681, p=0.018 by ROC curve analysis).

In all patients, the subcarinal and anterial carina limph node locations had the higher percentage and the left paratrachea limph node location had the lower percentage of patients with positive aspirates (98%, 75% and 50%, respectively).

Conclusions: Our results confirm that in a large cohort of patients conventional TBNA is a sensitive technique and an effective tool to diagnose and stage lung cancer and show that a ≥ 24 mm limph node size has a high likelihood to be associated to a positive aspirate. Additionally, the limph node location may play a role in the diagnostic yield of TBNA.
Abscopal Benefits of Localized Radiotherapy Depend on Activated T-cell Trafficking and Distribution between Metastatic Lesions
Authors: Jan T. Poleszczuk, Kimberly A. Luddy, Sotiris Prokopiou, Mark Robertson-Tessi, Eduardo G. Moros, Mayer Fishman, Julie Y. Djeu, Steven E. Finkelstein, Heiko Enderling
Journal: Cancer Research (2016)

It remains unclear how localized radiotherapy for cancer metastases can occasionally elicit a systemic antitumor effect, known as the abscopal effect, but historically, it has been speculated to reflect the generation of a host immunotherapeutic response. The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs. Here, we describe a mathematical model that incorporates physiologic information about T-cell trafficking to estimate the distribution of focal therapy-activated T cells between metastatic lesions. We integrated a dynamic model of tumor-immune interactions with systemic T-cell trafficking patterns to simulate the development of metastases. In virtual case studies, we found that the dissemination of activated T cells among multiple metastatic sites is complex and not intuitively predictable. Furthermore, we show that not all metastatic sites participate in systemic immune surveillance equally, and therefore the success in triggering the abscopal effect depends, at least in part, on which metastatic site is selected for localized therapy. Moreover, simulations revealed that seeding new metastatic sites may accelerate the growth of the primary tumor, because T-cell responses are partially diverted to the developing metastases, but the removal of the primary tumor can also favor the rapid growth of preexisting metastatic lesions. Collectively, our work provides the framework to prospectively identify anatomically defined focal therapy targets that are most likely to trigger an immune-mediated abscopal response and therefore may inform personalized treatment strategies in patients with metastatic disease.
A preliminary report of a double blind placebo controlled trial of gabapentin for control of hot flashes in women with breast cancer. A University of Rochester Cancer Center CCOP study
Authors: K. J. Pandya, J. Roscoe, E. Pajon, P. J. Kuebler, T. K. Banerjee, P. J. Flynn, J. Hickok, G. Morrow
Journal: Journal of Clinical Oncology (2004)

8017 Background: Hot flashes are experienced by a majority of women receiving systemic therapy for breast cancer. While estrogen replacement therapy can ameliorate these symptoms, controversy surrounds the use of estrogens in women with breast cancer. Based on initial observations by Thomas Guttuso (Neurology 2000;54:2161), and our pilot study (Breast Cancer Research and Treatment, in press), we conducted a double blind placebo controlled trial of gabapentin. Methods: Between June 2001 and July 2003, a total of 420 women with breast cancer on systemic therapy and having ≥2 hot flashes per day, were randomized from 18 participating CCOPs to placebo (P) or gabapentin (G) 100 mg or 300 mg po tid for 8 weeks. A self reported 1 week hot flash and other symptom inventory was kept by the patient prior to the start of treatment and during weeks 4 and 8 of the treatment. Results: Preliminary data are available on 360 women at week 4: P = 115, G100 = 123, G300 = 122 and 324 women at week 8: P = 103, G100 = 104, G300 = 117. All hot flashes were assigned a grade of 1, 2, 3 or 4 for mild, moderate, severe and very severe, respectively. A severity score was calculated by summation for each day (e.g., a woman who had 3 moderate hot flashes and 2 severe ones would have a severity score of 12 for that day). Neither mean hot flash severity nor mean frequency of hot flashes varied significantly at baseline. Analysis of Variance (ANOVA) at week 4 and at week 8 showed significant overall differences and significant linear trends in severity score and frequency of hot flashes, all ps≤0.005 (week 4 severity score: P=14.4, G100=12.2, G300=8.9; frequency: P=6.9, G100=5.9, G300=4.8, and week 8 severity score: P=13.4, G100=11.5, G300=8.6; frequency: P=6.7, G100=5.5, G300=4.6). This translates to a percent decrease in hot flash severity score from baseline as follows: week 4: P=23.3, G100=34.2, G300=48.1; week 8 P=18.0, G100=30.0, G300=45.6. Conclusions: This preliminary analysis suggests that gabapentin 300 mg po tid is effective in the control of hot flashes in women being treated for breast cancer. Supported by grant U10CA 37420 No significant financial relationships to disclose.
N-Benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells
Authors: N. J. Bahlis, Y. Miao, O. N. Koc, S. Gerson
Journal: Journal of Clinical Oncology (2005)

6503 Multiple myeloma is a clonal malignancy of plasma cells that invariably progresses to a chemoresistant state. The PI3K/Akt pathway mediates signals downstream of several growth factors involved in myeloma pathogenesis and constitutive activation of Akt was observed in myeloma cells. We now report that a staurosporine derivative, N-benzoylated staurosporine or PKC412, induces cell death in myeloma cell lines (RPMI8226S, U266, MM1S and MM1R) with loss of mitochondrial membrane potential ΔΨm, caspase 3, and PARP cleavage. ZVAD.fmk, but not IL-6 rescued these cells from PKC412 effects. Upstream of the mitochondria, PKC412 inhibited Bad phosphorylation and attenuated Akt kinase activity by suppressing its phosphorylation on serine residue in its activation loop. Reduced phosphorylation of downstream Akt substrates GSK3α/β and FKHR was also noted. Stable transfection of 8226S cells with constitutively active Akt (8226S-myAkt) partially protected against PKC412 cytotoxicity. Primary myeloma cells isolated from refractory myeloma patients (n=4), were equally sensitive to PKC412 treatment. More importantly, PKC412 did not affect CFU-GM or BFU-E colony formation. In summary, our results demonstrate that PKC412 suppresses Akt kinase activation and induces apoptosis in myeloma cell lines as well as primary resistant cells. PKC412 is an appropriate candidate for novel treatment protocols for multiple myeloma. No significant financial relationships to disclose.
Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non–Small-Cell Lung Cancer
Authors: Roelof W.F. van Leeuwen, Robert Peric, Koen G.A.M. Hussaarts, Emma Kienhuis, Nikki S. IJzerman, Peter de Bruijn, Cor van der Leest, Henk Codrington, Jeroen S. Kloover, Bronno van der Holt, Joachim G. Aerts, Teun van Gelder, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2016)

Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied.In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling.Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola.Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib.
Pegylated liposomal doxorubicin (PLD) and gemcitabine (G) in metastatic breast cancer (MBC) patients: A phase II study
Authors: A. Fabi, P. Papaldo, M. Ciccarese, N. Salesi, V. Lorusso, G. Ferretti, P. Carlini, I. Sacchi, F. Cecere, F. Cognetti
Journal: Journal of Clinical Oncology (2004)

813 Background: PLD and G have recently demonstrated a clinical efficacy in MBC in mono-chemotherapy. We conducted a phase II clinical trial to determine the activity and safety of the two drugs in combination either in untreated or previously treated metastatic breast cancer women. Patients (pts) received PLD 25 mg/m2 i.v on day 1 plus G 800 mg/m2 i.v. on day 1 and 8 of each 21-day cycle. Methods: Twenty-eight pts were entered into the study between January 2003 and December 2003. Median age: 55 years (range 33–71), median PS (WHO): 0 (0–2), predominant metastatic sites: lung (13 pts), liver (8 pts), bone (5 pts) and soft tissues (2 pts). The median number of previous chemotherapies given for metastatic disease was 1 (range 1–2). Fifteen women were chemotherapy naïve. Eleven pts (39%) were treated with anthracycline-containing regimen with a median anthacycline dose of 480 mg/m2. A median of 5 cycles were administered (range 1–8). Results: Twenty-one pts (1 early death, 6 too early) were assessable for response: 10 achieved partial response (47.6%), 5 (23.8%) stable disease, while 6 women (28.6%) experienced progressive disease. Among pretreated with anthacycline, 36% had a response. Among responders, 70% were chemotherapy naïve while 30% had previously received 1st or 2nd line chemotherapy. Median duration of response and time to progression were 6 months (range 4–9) and 5.8 months (range 1–9), respectively. Only grade 3–4 neutropenia was observed in 11 pts (39%); one case (3.5%) of febrile neutropenia occurred. Grade 3 mucositis and peripheral paresthesia were observed in 3 (11%) and 1 (3.5%) pts, respectively; one pt (3.5%) had a grade 2 hand-foot syndrome; seven pts (25 %) complained of moderate/severe asthenia. No case of cardiotoxicity or LVEF reduction was observed, even among pts previously treated with anthacyclines. Conclusions: The combination of PLD and G shows activity and a good tolerability. It seems to be no evidence of cross-resistance between classic anthracyclines and PLD. This regimen seems to be adequate even for heavily treated and elderly women. No significant financial relationships to disclose.
Specific Simian Virus 40 (SV40)-Induced Immunity Against Transplantable SV40 Tumor in Syrian Hamsters: Abrogation by BCG Vaccination
Authors: Gulnar T. Zhalgasbayeva, Galina I. Deichman
Journal: JNCI Journal of the National Cancer Institute (1977)

Syrian hamsters were immunized with simian virus 40 (SV40) and/or BCG (in different time and sequence combinations) and were subsequently challenged with SV40-induced transplantable tumor cells. Immunization of hamsters with some but not all BCG preparations alone induced high levels of resistance to SV40 transplantable tumor cells. The immunization with SV40 of hamsters preliminarily inoculated with BCG induced antitumor immunity, the level of which was equal to resistance induced by immunization of normal animals with SV40. No cumulative effects of BCG and SV40 immunizations were noticed in any of our experiments even when BCG prepartions alone induced considerable increase of antitumor resistance. Inoculation of animals with the mixture of SV40 and BCG was generally less effective than that with SV40 alone. Inoculation of BCG preparations into hamsters preimmunized with SV40 resulted in the complete or partial abrogation of the resistance induced by SV40. All preparations of BCG, independent from their antitumor activity per se, decreased the resistance induced by SV40. The effect of this BCG-induced abrogation of resistance was observed in animals immunized with SV40 7-427 days before inoculation of BCG. The effect was not short-term, as it was still observed 3 months after BCG inoculation.
Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian Testicular Cancer Group.
Authors: O Klepp, A M Olsson, H Henrikson, N Aass, O Dahl, A E Stenwig, B E Persson, E Cavallin-Ståhl, S D Fosså, L Wahlqvist
Journal: Journal of Clinical Oncology (1990)

Between 1981 and 1986, 279 consecutive patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT) of the testis underwent pathological staging (PS) with retroperitoneal lymphadenectomy (RPLND). Patients with retroperitoneal metastases (PS2) received adjuvant chemotherapy. The median follow-up time after RPLND was 50 months (range, 30 to 90). Clinical and histopathologic features were registered prospectively and analyzed for association with risk of having PS2, relapse despite pathological stage 1 (PS1) or the combined risk of either event, metastatic disease (MET). Seventy-five (26.9%) of the patients had PS2 disease, and 30 (14.7%) of the 204 PS1 patients relapsed, indicating that at least 105 (37.6%) of this CS1 population had subclinical MET at the time of orchiectomy. Four (1.4%) of the 279 CS1 patients died of testicular cancer. Multivariate analyses showed several variables to be significantly associated with outcome for the CS1 patients; vascular invasion in primary tumor and normal preorchiectomy serum alpha-fetoprotein (Pre-AFP) level indicated PS2 disease. If Pre-AFP was excluded from the model, the absence of teratoma or yolk sac elements in the primary tumor became significant predictors of PS2. Vascular invasion, absence of teratoma, and a short interval between orchiectomy and RPLND indicated increased risk of relapse in PS1 patients. Vascular invasion, normal Pre-AFP, absence of teratoma elements, and a short orchiectomy to RPLND interval were predictive of MET. Our results indicate that prognostic factors useful for stratification of CS1 patients with NSGCT to different treatment options may be established.
John Gavin Craig
Authors: Hannah Davidson
Journal: BMJ (2015)

John Gavin Craig graduated from Queen’s University Belfast in 1970 and spent the next three years working there in hospital medicine, when the Troubles were at their height. He returned to his home county of Yorkshire and worked as a hospital registrar in Leeds, where his gained his membership of the Royal College of Physicians. He went on to join his father, John G Craig, and Robert Murdoch in their practice …