tbuckley/cabot-search huggingface dataset:
Testing a prognostic model in patients with metastatic castrate resistant prostate cancer (MCRPC) treated prechemotherapy with abiraterone.
Authors: Shermaine Pan, Kellati Prasad, Emma Hall, Ric Swindell, Natalie Charnley
Journal: Journal of Clinical Oncology (2015)

283 Background: There is a need for prognostic models in metastatic prostate cancer to determine optimal treatment pathways on development of castrate resistance. Abiraterone is an androgen biosynthesis inhibitor. Efficacy was proven in patients with MCRPC prechemotherapy in the COU-AA-302 trial with PSA PFS 11.1 months (Raj et al New Eng J med 2013). We have previously investigated prognostic factors in MCRPC (Charnley et al J Clin Oncol 2014). We reported a prognostic model which predicts that if alk phos rise ≥100 in the preceding 3 months and/or Hb&lt;11 there is no response. The model was correct in 78.9% of responders and 55% of non responders (overall 66.7%). We test the model in an independent group of 81 patients prechemotherapy, some from a different treating centre. Methods: 81 patients with metastatic CRPC received abiraterone 1g daily prechemotherapy. Response to abiraterone was defined as a 50% reduction in PSA. Alk phos rise ≥100 in the previous 3 months and Hb&lt;11 were related to PSA response. Results: 19 patients had both alk phos rise ≥100 in the preceding 3 months, and Hb&lt;11. None of these patients had a PSA response. For the 31 patients with no risk factors 66% of cases responded. The predictive model was correct in 66% of true responders, and 85.3% of non responders, 74.1% overall. Conclusions: In this group of 81 patients with castrate resistant metastatic prostate cancer a previously defined model, which incorporates alk phos rise ≥100 in the preceding 3 months and/or Hb&lt;11 is 74.1 % accurate in an independent group of patients. No patients with both alk phos rise&gt;100 in the preceding 3 months, and Hb&lt;11, responded to abiraterone. The model has potential in guiding treatment pathways on development of castrate resistance in prostate cancer, but needs to be tested in a greater number of patients.
Gemcitabine (G) given as a prolonged infusion in patients (pts) with advanced solid tumors: A phase I study with intra-pt dose escalation (DE) and pharmacokinetic (PK) / pharmacodynamic (PD) analysis
Authors: P. Soulié, D. Luet, S. Dupuis, M. Boisdron-Celle, V. Guérin-Meyer, S. Abadie, B. Leproust, P. Maillart, R. Delva, E. Gamelin
Journal: Journal of Clinical Oncology (2006)

12029 Background: Optimizing drug delivery based on pharmacokinetic data is an important research issue. Previous studies have demonstrated a pharmacological advantage for infusions of G with a fixed dose rate to maximize cellular accumulation of G active metabolite (GTP), despite high interindividual PK variability. Methods: To develop a PK-guided G dosing schedule, we conducted an intra-pt G DE trial to determine: (1) maximum tolerated dose level (MTD) and dose-limiting toxicity (DLT), (2) plasma G and peripheral mononuclear cell GTP post-infusion levels. G was administered over 150 min on day 1, 8 and 15, q4w. The initial dose level (DL) was 1000 mg/m 2 , escalated by 250 mg/m 2 every cycle (cy) if no limiting toxicity occurred. Results: From 09/2003, 30 pts entered the study. Pts’ characteristics: 16 men/14 women; median age 66 years (49–81); tumor type: pancreas (10 pts), lung (7 pts), others (13 pts); prior chemotherapy (15 pts). A total of 109 cy were given (median: 3 cy/pt). Tolerance: Number of pts/DL: DL1 = 7 pts, DL2 = 5 pts, DL3 = 11 pts, DL4 = 5 pts, DL5 = 2 pts. Main reasons for stopping DE were: disease progression/early death (15 pts), DLT (4 pts), investigator’s decision (8 pts). DLT were: haematological (1 pt), asthenia (2 pts) and infection (1 pt). Most common grade (gr) 1–2/3–4 toxicities (% cy) included: nausea/vomiting (38%/2%), asthenia (56%/11%), neutropenia (29%/27%) and thrombocytopenia (42%/1%). Activity: 26 pts are evaluable (radiological assessment every 3 cycles) showing 5 partial response (2 unconfirmed), 7 stabilization and 14 progression. Conclusions: The main reason for DE failure was early progression, stressing the importance of an early individual dose adjustment. PK and PK/PD correlation analyses are ongoing to confirm our hypothesis. No significant financial relationships to disclose.
Retrospective mortality comparisons of cancer patients with sepsis syndromes.
Authors: D. Joyce, V. Holly, R. Dukes, E. Trueblood
Journal: Journal of Clinical Oncology (2010)

9066 Background: Cancer patients experience infectious side effects including sepsis and severe sepsis. In this single institution retrospective analysis 1,499 patients with sepsis with or without cancer were compared. The purpose of this study is to determine mortality and disposition of patients with the diagnosis of sepsis and cancer compared to no cancer sepsis patients. Methods: Hospitalized patients from the Bloomington Hospital, Bloomington, IN (1/2002 to 2/2008) were coded as sepsis (N=1,499). Four groups were compared: sepsis, sepsis-cancer, severe sepsis, and severe sepsis-cancer. Cancer diagnoses were confirmed by the cancer registry; study was IRB approved. Mortality, length of stay, discharge disposition and hospital charges were assessed among the four groups using one and two way ANOVA. Results: Of the 1,499 sepsis cases reviewed 57% (863) had sepsis alone, 11.8% (175) had sepsis and cancer. In the group of severe sepsis 25.8% (388) had severe sepsis alone and 4.8% (73) carried the diagnosis severe sepsis and cancer. Of all cases only 31% of patients were discharged directly to home. Severe sepsis patients had a significantly longer stay than sepsis patients (10.45 vs. 8.6 days, p=0.001). Length of stay for cancer vs. no cancer patients were not different. In subgroups cancer-severe sepsis length of stay was no different than cancer-sepsis. Mortality analysis demonstrated a higher mortality of cancer vs. no-cancer (32% vs. 23%, p=0.003) and severe sepsis vs. sepsis (47% vs. 15%, p=0.001). In subgroups the severe sepsis-cancer mortality was significantly higher than severe sepsis (56% vs. 46%, p=0.001). Sepsis-cancer mortality was more than sepsis (22% vs. 13%, p=0.038). A cost analysis of mean charges per hospital stay was highest in the severe sepsis groupings. Conclusions: Cancer patients with sepsis syndromes have a higher mortality than noncancer patients. Of significance was a cancer-severe sepsis mortality rate over 50%. Per patient cost and mortality were high for severe sepsis groupings. Further identification of morbidity and cancer-specific factors may aid in better triage and treatment approaches for cancer patients with sepsis syndromes. No significant financial relationships to disclose.
Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors
Authors: J. Nemunaitis, R. Eager, T. Twaddell, A. Corey, K. Sekar, K. Tkaczuk, J. Thompson, P.M. Hoff, R. Pazdur
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m 2 orally [PO] tid; cohort 2, 200 mg/m 2 PO tid; cohort 3, 200 mg/m 2 bid; and cohort 4, 250 mg/m 2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was ≥ 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.
Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of SU11248 in patients (pts) following failure of imatinib for metastatic GIST
Authors: G. D. Demetri, A. T. van Oosterom, M. Blackstein, C. Garrett, M. Shah, M. Heinrich, G. McArthur, I. Judson, C. M. Baum, P. G. Casali
Journal: Journal of Clinical Oncology (2005)

4000 Background: Inhibition of aberrant kinase signalling through the KIT or PDGFRα receptors with imatinib therapy has improved survival for pts with metastatic GIST, but over time, clonal evolution leads to imatinib-resistant disease. Imatinib resistance may be due to several mechanisms, including complex patterns of secondary kinase mutations. SU11248, an oral multitargeted tyrosine kinase inhibitor, has antiangiogenic and antitumor activity due to inhibition of signalling by VEGFR, PDGFRα and KIT. Prior studies have demonstrated clinically relevant activity in pts with imatinib-resistant GIST, including those associated with acquired secondary kinase mutations (Demetri et al. Proc ASCO 2004; 22: abstr 3001). Methods: A double-blind, phase 3 trial is being conducted to evaluate the efficacy and safety of single-agent SU11248 (50 mg once daily for 4 wks followed by a 2-wk break in each 6-wk cycle) compared with placebo in pts with GIST following documented failure of imatinib (due to objective progression or intolerable adverse effect of prior imatinib). Pts are initially randomized 2:1 to SU11248 or placebo. Treatment of pts who exhibit RECIST-defined progression of GIST is unblinded, and these pts are crossed over to unblinded SU11248 therapy. The primary study endpoint is TTP. Secondary endpoints include OS, ORR, time to tumor response, duration of response, duration of performance status maintenance and clinical benefit-related parameters (McGill Pain Questionnaire, investigator-rated changes in severity of signs and symptoms and other pt-reported outcomes). Based on a planned sample size of 357 pts (238 SU11248, 119 placebo), the trial was designed to have a 90% power to detect a 50% improvement in median TTP from 4 to 6 mos (2-sided unstratified log-rank test; significance level 0.05). A prospectively planned interim analysis will be performed after the first 141 events (objective progression of GIST). Results: Results of the interim analysis will be submitted by the late-breaking abstract deadline. Conclusions: Conclusions will be submitted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Novartis, Pfizer Novartis, Pfizer Pfizer Pfizer
BREAK-MB: A phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets).
Authors: John M. Kirkwood, Georgina V. Long, Uwe Trefzer, Michael A. Davies, Paolo Antonio Ascierto, Paul B. Chapman, Igor Puzanov, Axel Hauschild, Caroline Robert, Richard Kefford, Vicki L. Goodman, Julie C. Switzky, R. Suzanne Swann, Anne-Marie Martin, Mary E. Guckert, Michael R. W. Streit, Dirk Schadendorf
Journal: Journal of Clinical Oncology (2012)

8501 Background: Melanoma brain mets carry a poor prognosis (median survival ≤4 months), for which more effective therapies are needed. Dabrafenib is a potent, selective oral inhibitor of mutated BRAF that has demonstrated clinical efficacy in pts with BRAF V600E/K mutant melanoma and previously untreated brain mets in a phase I study. Therefore, a phase II study (BREAK-MB) was initiated. Methods: Stage IV pts with ≥ 1 intracranial met (0.5 cm–4 cm assessed by MRI) without prior brain therapy (Cohort A) or with progression following prior brain therapy (Cohort B) were eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The primary endpoint was investigator-assessed OIRR among V600E mutation-positive pts. Results: Overall, 172 pts were recruited. At interim analysis, of 127 pts enrolled (safety population), 41 (Cohort A n=24; Cohort B n=17) had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15 (53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4 (5%). The most common AEs were headache (21%), hyperkeratosis and rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3 (19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea (22% each) and pyrexia (17%). Conclusions: Dabrafenib shows high clinical activity both in pts with intra- and extracranial mets with acceptable toxicity. Final data will be presented.
Clinical Impact of Germ Cell Tumor Cells in Apheresis Products of Patients Receiving High-Dose Chemotherapy
Authors: C. Bokemeyer, A. J.M. Gillis, K. Pompe, F. Mayer, B. Metzner, N. Schleucher, J. Schleicher, G. Pflugrad-Jauch, J. W. Oosterhuis, L. Kanz, L. H.J. Looijenga
Journal: Journal of Clinical Oncology (2001)

High-dose chemotherapy (HD-Ctx) followed by autologous peripheral-blood stem-cell (PBSC) transplantation is currently investigated in patients with poor prognosis or relapsed metastatic germ cell tumor (GCTs). This study analyzed the presence and the clinical importance of contaminating tumor cells in PBSC preparations used to support HD-Ctx in GCT patients.Seven targets for reverse transcription polymerase chain reaction (RT-PCR)-based detection of GCT cells were able to detect seminomatous and different histologic variants of nonseminomatous tumor cells. PBSC preparations from 57 patients were investigated for the presence of contaminating tumor cells using this set of targets, including beta human chorionic gonadotropin (beta-hCG), fibronectin (EDB variant), epidermal growth factor receptor (EGFR), CD44 (v8 to 10 variant), germ cell and placental alkaline phosphatase (AP), human endogenous retrovirus type K (ENV and GAG), and XIST. Samples of PBSC preparations from four healthy donors for allogenic transplantations as well as blood specimens from 10 healthy volunteers served as negative controls.Fifty patients (43 first-line and seven second-line Ctx) were assessable. Combining all RT-PCR results, 29 PBSC preparations (58%) were positive for tumor-specific amplification products (HERV-K 0, fibronectin 4, XIST 14, beta-hCG 19, AP 19, CD44 24, EGFR 26). Ten (35%) of 29 patients who underwent transplantation with positive PBSC preparations and seven (33%) of 21 patients with negative PBSC preparations have suffered relapse or progression (not significant [ns]). With a median follow-up of 22 months (2 to 66) post-HD-Ctx projected 3-year survival rates are 68% (RT-PCR+) and 58% (RT-PCR-) (ns). None of the 10 control peripheral-blood samples showed positivity for any of the targets studied.GCT cells can be detected in more than 50% of PBSC preparations using a RT-PCR approach with multiple targets. Despite the presence of tumor cells, retransplantation of the PBSC products did not effect long-term outcome. Factors such as responsiveness to chemotherapy and tumor mass seem to overcome the importance of potentially re-infused tumor cells.
Five minutes with Mark Britnell: Does a perfect health system exist?
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

The chairman of KPMG Global Health talks to The BMJ about his new book

“The people of the UK are right to treasure their NHS,” writes Mark Britnell in his new book In Search of the Perfect Health System (Palgrave Macmillan). Currently chairman of KPMG Global Health, Britnell has worked in healthcare systems in over 60 countries. For his book he analysed 25 healthcare systems in search of what was working and what wasn’t in times of challenging demographic and economic change. He doesn’t find perfection, but against the others the NHS measures up pretty well.

“After …
Blood pressure and pulse changes in hyperactive children treated with imipramine and methylphenidate
Authors: L M Greenberg, A M Yellin
Journal: American Journal of Psychiatry (1975)

The authors found significant increases in systolic and diastolic blood pressure and pulse rate in hyperactive children treated with imipramine. Methylphenidate-treated children showed significant weight loss but no significant changes in blood pressure or pulse. The authors recommend caution in the use of imipramine and suggest the need for further study to determine short- and long-term effects of imipramine on blood pressure.
Induction &lt;italic&gt;In Vitro&lt;/italic&gt; by Autonomic Drugs of Cytoplasmic Vacuoles in Ascites Tumor Cells
Authors: Morris Belkin, Walter G. Hardy, Henry C. Orr, Alan B. Lachman
Journal: JNCI Journal of the National Cancer Institute (1962)

Cells of 4 mouse ascites tumors were immersed in balanced salt solution containing an autonomic drug. These experiments were performed in vitro at room temperature. When cell samples were examined microscopically at intervals, it was observed that certain autonomic drugs induced numerous, large, cytoplasmic vacuoles. Cells of the following mouse ascites tumors were used: Sarcoma 37 carried in the (BALB/c × A)F1 mouse; the Ehrlich carcinoma and Hepatoma 129P maintained in the C3H/HeN strain; and Leukemia L1210 carried in the (BALB/c × DBA)F1 mouse. In addition, a number of cell lines grown in tissue culture were employed: human malignant lines HeLa and D189, and normal cells of human lung, kidney, skin, and muscle, and mouse embryo. Fourteen of 36 drugs, belonging to various autonomic groups, induced vacuoles in concentrations of m/250 to m/1000. A maximum effect was usually obtained in about 3 hours. Autonomic drugs producing a strong vacuolar response included atropine, Inversine, Orthoxine, pilocarpine, physostigmine, and Priscoline. Induction of cell vacuoles in the peritoneal cavity was not successful, due to host toxicity of the drugs. When vacuolating cells were washed free of the drug and placed in normal balanced salt solution, reversal of the phenomenon occurred, the vacuoles progressively disappearing in 3 to 4 hours. Experiments, at incubator temperature (37° C) with selected drugs, on cells of the 4 mouse ascites tumors resulted in a pronounced increase in the rate and number of induced vacuoles in 3 of these tumors, compared to the response at room temperature (22–25° C).
Results of autologous transplantation for multiple myeloma (MM) in Austria. An analysis based on data from the Austrian Stem Cell Transplantation (ASCT) Registry
Authors: H. Ludwig, N. Zojer, W. Linkesch, P. Kahls, O. Krieger, H. T. Greinix, W. Hinterberger, E. Pittermann, T. Bauernhofer, G. Gastl
Journal: Journal of Clinical Oncology (2004)

6657 Background: Median survival with conventional therapy in MM is usually less than 40 months. Two prospective randomised trials (IFM 90 and MRC trial) showed superiority of high-dose therapy with autologous SCT over conventional treatment, although other trials were unable to confirm a statistical significant benefit. Here we report the results of high dose chemotherapy in all patients (> 99.5%) with MM treated in Austria. Methods: 324 patients treated with autologous SCT from 1989 onwards have retrospectively been analysed. Median age: 55.6 years (range 24.6 –70.7 years). Peripheral blood stem cells were used in 317 and bone-marrow derived stem cells in 7 patients. 170 patients were treated with single (ST) and 98 with double transplantation (DT), while all other patients received >2 autografts during the whole course of their disease. The influence of total body irradiation (TBI) and interferon (IFN) maintenance was also analysed. All but one patient were evaluable for survival, and 265 patients were evaluable for response. Results: A CR (without proof of negative immunofixation) was achieved in 37% and a PR in 53% of patients ( OR 90% ). TRM was 2.5% at 3 months, and median survival 66.5 months at a median follow-up of 14.2 months. DT yielded a significantly longer overall survival as compared to ST (p< 0.05; survival at 1 year 86% vs. 71%, respectively). There was a tendency for a shorter survival in patients with TBI as compared to those without TBI (survival 51 months vs. not reached, p=n.s.). Preliminary analysis shows significant prolongation of maintenance duration and survival with IFN maintenance treatment, but final analysis of a matched pair analysis will be presented. Conclusions: High dose chemotherapy with autologous SCT revealed a favourable survival (66.5 months) in patients with multiple myeloma of which only a minority have been treated in clinical trials in Austria. DT was associated with a significantly longer survival, while use of TBI was associated with a tendency towards shorter survival. Preliminary data suggest beneficial effects of IFN on maintenance duration and on survival. No significant financial relationships to disclose.
Direct Analysis of Differentiation Proteins in Normal and Leukemic Human Granulocytes by High-Performance Liquid Chromatography
Authors: W H Evans, J M Bednarek, V L Alvarez, D G Wright, H R Terebelo, G Taylor
Journal: JNCI Journal of the National Cancer Institute (1985)

The feasibility of the use of reverse-phase high-performance liquid chromatography (RP-HPLC) for detecting differences in the protein phenotypes of highly purified fractions of normal and chronic myelogenous leukemic (CML) mature granulocytes isolated from peripheral blood was determined. At least 21 protein peaks were consistently and reproducibly detected in the RP-HPLC profiles of acetonitrile-trifluoroacetic acid extracts of normal granulocytes. This assay takes only 60 minutes to perform and can be done on 4 X 10(6) granulocytes (approximately the number of granulocytes in 1 ml normal blood). Furthermore, sodium dodecyl sulfate-gel electrophoresis of the RP-HPLC fractions provides a second dimension to the analysis of the polypeptide pattern of these cell lysates. Analyses of subcellular fractions by these methods revealed that most of the major peaks in the RP-HPLC profiles of intact granulocytes originate mainly from the granule and membrane fractions. Although the protein phenotypes of mature granulocytes were remarkably uniform among normal individuals, those of mature granulocytes obtained from the blood of CML patients were consistently abnormal and varied considerably among individual patients. The results indicate that the approach used here could have useful application in the study of abnormal granulocyte differentiation in leukemia.