tbuckley/cabot-search huggingface dataset:
Recombinant human interleukin-3 to dose-intensify carboplatin and cyclophosphamide chemotherapy in epithelial ovarian cancer: a phase I trial.
Authors: G J Veldhuis, P H Willemse, M M van Gameren, J G Aalders, N H Mulder, B Mull, B Biesma, E G de Vries
Journal: Journal of Clinical Oncology (1995)

PURPOSE To define the optimal dose of recombinant human interleukin-3 (rhIL-3) required to intensify the dose of carboplatin and cyclophosphamide for advanced epithelial ovarian cancer. PATIENTS AND METHODS Seventeen patients were treated on day 1 with carboplatin (dose adjusted for creatinine clearance: range, 257 to 385 mg/m2; median, 300 mg/m2) and cyclophosphamide (750 mg/m2). rhIL-3 5 micrograms/kg/d (n = 10) or 10 micrograms/kg/d (n = 7) was administered subcutaneously (SC) on days 2 through 11. Carboplatin dose was escalated if no postponement of cycles 1 to 3 had occurred. RESULTS A 3-week interval was achieved in 62% of cycles and a 4-week interval in 81%, with no difference between the rhIL-3 doses. A neutrophil nadir less than 0.5 x 10(9)/L occurred in 35% of the cycles at 5 micrograms/kg/d and in 52% at 10 micrograms/kg/d of rhIL-3 (nonsignificant difference). The mean platelet nadir in cycle 1 was 173 +/- 78 x 10(9)/L at 5 micrograms/kg/d and 340 +/- 152 x 10(9)/L at 10 micrograms/kg/d of rhIL-3 (P &lt; .05), with a faster recovery of platelets at 10 micrograms/kg/d (P &lt; .05). Progressive myelotoxicity occurred for leukocytes and platelets at both rhIL-3 doses and required chemotherapy postponement in later cycles. The planned six cycles were completed by 41% of patients. Fever (&gt; or = 38.5 degrees C) occurred in 38% of cycles at 5 micrograms/kg/d and in 97% at 10 micrograms/kg/d (P &lt; .0005); headache and myalgias occurred in 30% and 44%, respectively. After two cycles, diffuse erythema, facial edema, and urticaria were observed in two patients at 5 micrograms/kg/d and in five patients at 10 micrograms/kg/d of rhIL-3. This resolved after discontinuation of rhIL-3 and administration of corticosteroids and antihistamines. CONCLUSION A dose of 5 micrograms/kg/d of rhIL-3 proved to be optimal to intensify the carboplatin and cyclophosphamide regimen. It permitted the administration of carboplatin and cyclophosphamide combination therapy every 3 weeks in 62% of cycles.
Age Is Not a Prognostic Variable With Autotransplants for Multiple Myeloma
Authors: D.S. Siegel, K.R. Desikan, J. Mehta, S. Singhal, A. Fassas, N. Munshi, E. Anaissie, S. Naucke, D. Ayers, D. Spoon, D. Vesole, G. Tricot, B. Barlogie
Journal: Blood (1999)
Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults
Authors: Connor A Emdin, Simon G Anderson, Thomas Callender, Nathalie Conrad, Gholamreza Salimi-Khorshidi, Hamid Mohseni, Mark Woodward, Kazem Rahimi
Journal: BMJ (2015)

<b>Objectives</b> To determine the subgroup specific associations between usual blood pressure and risk of peripheral arterial disease, and to examine the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort. <b>Design</b> Cohort study. <b>Setting</b> Linked electronic health records from 1990 to 2013 in the United Kingdom. <b>Participants</b> 4 222 459 people aged 30-90 years, registered at a primary care practice for at least one year and with a blood pressure measurement. <b>Main outcome measures</b> Time to first diagnosis of new onset peripheral arterial disease and time to first diagnosis of 12 different vascular events. <b>Results</b> A 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63, 95% confidence interval 1.59 to 1.66). The strength of the association declined with increasing age and body mass index (P&lt;0.001 for interaction) but was not modified by sex or smoking status. Peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease (1.68, 1.58 to 1.79), heart failure (1.63, 1.52 to 1.75), aortic aneurysm (2.10, 1.79 to 2.45), and chronic kidney disease (1.31, 1.25 to 1.38), but not haemorrhagic stroke. The most common initial vascular event among those with peripheral arterial disease was chronic kidney disease (24.4% of initial events), followed by ischaemic heart disease (18.5% of initial events), heart failure (14.7%), and atrial fibrillation (13.2%). Overall estimates from this cohort were consistent with those derived from traditional studies when we pooled the findings in two meta-analyses. <b>Conclusions</b> Raised blood pressure is a strong risk factor for peripheral arterial disease in a range of patient subgroups. Furthermore, clinicians should be aware that those with established peripheral arterial disease are at an increased risk of a range of other vascular events, including chronic kidney disease, ischaemic heart disease, heart failure, atrial fibrillation, and stroke.
Efficacy and toxicity of limited field concurrent chemoradiotherapy (CRT) with capecitabine for locally advanced pancreatic cancer (LAPC)
Authors: P. Jain, G. Watkins, A. Jackson, C. Dickinson, G. Whitfield, A. Rembielak, J. W. Valle, M. B. Taylor, P. M. Price, A. Saleem
Journal: Journal of Clinical Oncology (2008)

15586 Background: Treatment outcome in LAPC remains poor. As treatment-related toxicity limits CRT dose-intensification, we evaluated the efficacy/toxicity of capecitabine based CRT in LAPC patients using limited field irradiation, excluding elective nodal areas. Methods: 25 consecutive LAPC patients eligible for CRT were treated at a single institute. Capecitabine was administered at 500–600 mg/m2/b.i.d continuously (including weekends) from day one to completion of radiotherapy (RT). RT was delivered conformally to a dose of 50.4Gy in 28 fractions over 5.5 weeks. The gross tumour volume consisting of the pancreatic tumour and any involved peri-pancreatic nodes was isometrically expanded by 0.5 cm to generate the clinical target volume (CTV). The planning target volume (PTV) comprised the CTV plus a 1cm margin AP/LR and a 1.5 - 2 cm margin SI. Patients were reviewed weekly to monitor weight and collect toxicity data. Time to disease progression and survival were calculated from diagnosis. Results: Median age of the 25 patients (17 M; 8 F) was 66 years (range 45- 74). Tumour was located in the pancreatic head in 23 patients (92%) and histology available in 17 patients (68%). The median (range) PTV volume was 378 (146–860) cc. 2 patients did not complete treatment due to disease progression and post-surgical complication. Treatment was well tolerated with nausea and fatigue being the most common toxicities. Only one patient developed any grade 3 toxicity (nausea). With a median follow up of 8.3 months, the median time to progression was 9.7 months, with 25% remaining progression-free at 1 year. All patients had progressed by 2 years. Isolated loco-regional relapse was observed in only one patient. At progression, six patients were suitable for palliative chemotherapy. The median overall survival for all patients was 11.6 months with 1 year survival of 38%. Median survival for the 6 patients who received palliative chemotherapy at disease progression was 17 months. Conclusion: Limited field CRT using capecitabine 500–600 mg/m2 twice daily in LAPC is very well tolerated, with similar efficacy to historical CRT regimens. Avoiding elective nodal irradiation may allow CRT dose-intensification and combination with other anti-cancer agents. No significant financial relationships to disclose.
Disease-Free Survival Advantage of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil in Patients With Node-Negative, Rapidly Proliferating Breast Cancer: A Randomized Multicenter Study
Authors: Dino Amadori, Oriana Nanni, Maurizio Marangolo, Paolo Pacini, Alberto Ravaioli, Andrea Rossi, Angelo Gambi, Giuseppina Catalano, Davide Perroni, Emanuela Scarpi, Donata Casadei Giunchi, Amelia Tienghi, Aldo Becciolini, Annalisa Volpi
Journal: Journal of Clinical Oncology (2000)

According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy.Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery +/- radiotherapy.The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P: =.028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P: =.037) and third tertiles (58% v 78%, respectively; P: =.024).The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.
Characteristics of Cytotoxic Antibodies Against Neuraminidase-Treated Lymphocytes in Man
Authors: R Johannsen, H H Sedlacek, R Schmidtberger, H J Schick, F R Seiler
Journal: JNCI Journal of the National Cancer Institute (1979)

The serologic specificity of cytotoxic antibodies in human serum directed against Vibrio cholerae neuraminidase (Nase)-treated lymphocytes (V. cholerae Nase-ly) was investigated. With the use of the two-step cytotoxicity test, antibody activity was found to occur in 48% of healthy young adults, 43% of elderly persons, 39% of patients with multiple sclerosis, 30% of patients with tumors, and in no newborns. The antibodies could be absorbed with blood cells, tumor cells, and fetal tissues only if the cells had been previously treated with Nase; untreated cells did not react in our test systems. Moreover, antibodies could be absorbed with V. cholerae Nase bound to polyhydroxymethylene particles or to Sepharose 4B. The adsorbed antibodies against V. cholerae Nase-ly could be eluted effectively with 0.2 M lactose, which represents a β-D-galactosyl-containing inhibitor of the antibody. By immunadsorptlon and elullon processes with lactose, purification of cytotoxic antibodies against V. cholera Nase-ly up to 200-fold could be achieved. Analogous experiments with rabbit antiserum against V. cholera Nase showed that, due to pH stability and probably due to a higher binding affinity, the heterologous antibodies could be eluted with glycine-HCI buffer at pH 2.5 but not with 0.2 M lactose. Results showed that cytotoxic human antibodies against V. cholera Nasa-ly are “natural” antibodies cross-reacting with Nase. From results obtained with cytotoxicity, agglutination, and enzyme inhibition tests, strong evidence was provided for the presence of heterogeneous antibodies that differ in their capacity to activate complement, agglutinate V. cholera Nase-coated latex, or inhibit the enzymatic activity of V. cholerae Nase. V. cholera Nase remained firmly attached to the cell membrane after incubation and thus might represent an exogenous neoantlgen. The immunochemical relationship between attached V. cholera Nasa and “cryptic” struelures on target cells unmasked by V. cholera Nase would, therefore, have to be considered in further studles.
Autologous stem cell transplant in peripheral T cell lymphomas: Single institution 10-year retrospective analysis
Authors: C. E. Vigil, E. Ayala, L. Sokol
Journal: Journal of Clinical Oncology (2009)

e19538 Background: Peripheral T-cell lymphoma is a rare entitydisease, compromising 10% of non-Hodgkin's lymphoma worldwide and 5% of all lymphoid neoplasms in the United States. The long-term survival of conventional therapies has led the exploration of alternatives. High-dose chemotherapy followed by autologous haematopoietic stem cell transplantation, has been explored in recent years with little experiences. We are reporting our single-institute data in this population. Methods: A retrospective analysis on patients with diagnosis of peripheral T-cell lymphoma receiving autologous stem cell transplant was conducted (January 1997 to July 2008). The patients were stratified according to their International Prognostic Index (IPI), disease status at the time of transplant and histology type. Results: Twenty-nine subjects were identified, with a median age of 51; 13 patients had Anaplastic T cell, 18 patient had PTCL-nos, and 6 patients with angioimmunoblastic T cell lymphoma. Seventeen patients (58.62%) presented with an aa IPI score greater than 2.4 patients were in complete remission, 15 at first relapse, 4 in greater than 1 episode, and 6 with refractory disease at the time of transplantion.Kaplan Meier overall survival (OS) 72 and relapse free survival (RFS) was 62 at 1 year respectively. A multivariate analysis and new risk stratification based on the IPI score system and disease status at time of transplant were employed. We found that the lower risk category demonstrated a higher likelihood of longer survival HR 3.4. However, such outcome was not statistically significant (p = 0.1360). Conclusions: The status at time of transplant with new methods for evaluation of minimal residual disease may help in assessing outcome. Larger prospective studies investigating innovative regimens is warranted. No significant financial relationships to disclose.
Using established forums to improve difficult doctor-patient relationships
Authors: Clare Lister, Joe Reilly, Helen Beckwith
Journal: BMJ (2016)

We read Cocksedge’s personal view with interest, having recently completed a systematic review into this area ourselves.1 The idea of difficulty within the doctor-patient relationship is not new. Doctors are trained to care for and treat patients to cure or improve their symptoms, yet it can be a struggle to fulfil …
Growth factor gene expression in kidney of murine polycystic kidney disease.
Authors: T Nakamura, I Ebihara, I Nagaoka, Y Tomino, S Nagao, H Takahashi, H Koide
Journal: Journal of the American Society of Nephrology (1993)

The DBA/2FG-pcy mouse has a form of slowly progressive kidney disease that appears similar in many respects to that seen in the autosomal dominant form of human polycystic kidney disease. The aim of this study was to examine the mRNA expression of growth-related proteins in kidney obtained from DBA/2FG-pcy mice and control DBA/2 mice at 8, 16, and 30 wk of age. The mRNA levels encoding for proliferating cell nuclear antigen (PCNA), transforming growth factor (TGF)-beta, platelet-derived growth factor (PDGF)-A and PDGF-B chains, insulin-like growth factor (IGF)-I, and basic fibroblast growth factor (bFGF) were increased with the progression of cystic lesions in the kidneys of DBA/2FG-pcy mice. At 30 wk of age, mRNA levels of PCNA, TGF-beta, PDGF-A and PDGF-B chains, IGF-I, and bFGF were increased 5.4-fold, 4.8-fold, 4.4-fold, 3.8-fold, 3.7-fold, and 4.6-fold, respectively, compared with those of control DBA/2 mice. In contrast, mRNA levels for epidermal growth factor in kidney of DBA/2FG-pcy mice decreased with age as compared with those of DBA/2 mice. These results suggest that decreased epidermal growth factor mRNA expression and increased expression of PCNA, TGF-beta, PDGF-A and PDGF-B chains, IGF-I, and bFGF mRNA may contribute to the progression of cystic lesions in DBA/2FG-pcy mice.
Evaluation of the NKD-1 mutation in carcinoma of the uterine endometrium.
Authors: M. L. Tyndall, D. H. Castrillon, C. Pena, K. Wharton
Journal: Journal of Clinical Oncology (2010)

e15537 Background: Misregulation of the WNT/β-catenin pathway is characteristic of some cancers, most notably colorectal and endometrial cancer. For example, mutations in the CTNNB1 gene occur in at least 15% of endometrial cancers. However, stabilization of the β-catenin protein occurs more frequently in endometrial cancers (∼40% of cases) suggesting that mutations in other WNT pathway components may lead to misregulation of this pathway in endometrial cancer. Naked cuticle (NKD) proteins inhibit WNT signaling, and hence, alteration of NKD gene activity in mammals might activate WNT. A recent study showed that NKD1 exon 10 mutations were frequent in colorectal cancers (primary tumors and cell lines) that did not harbor mutations in other WNT/β-catenin pathway components, raising the question as to whether mutations in NKD1 gene might also be significant in endometrial carcinogenesis. We thus sought to evaluate whether NKD1 mutations also characterize endometrial adenocarcinoma. Methods: Genomic DNA was extracted from 3 endometrial cancer cell lines and 53 primary endometrial tumor samples from patients at UT Southwestern hospitals. Exon 10 of the NKD1 gene was subjected to bidirectional PCR sequencing. Automated base calls generated by sequence analysis software were visually inspected to confirm accurate variant detection. Results: Of the 53 endometrial tumor samples evaluated, 29 were endometrioid, 10 carcinosarcoma, 3 clear cell, 4 mixed, and 7 were of unclassified histology. No NKD1 mutations including single base insertions or deletions of the exon-10 poly-(C)7 tract were identified that would result in the synthesis of truncated NKD1 protein, as has been shown to occur in colorectal adenocarcinomas. Conclusions: No NKD1 gene mutations were found in any uterine cancers, arguing that other defects in this pathway account for the frequent stabilization of β-catenin. No significant financial relationships to disclose.
Ifosfamide and mesna: marginally active in patients with advanced carcinoma of the pancreas.
Authors: J A Ajani, J L Abbruzzese, P Goudeau, J S Faintuch, A C Yeomans, B M Boman, C Nicaise, B Levin
Journal: Journal of Clinical Oncology (1988)

Ifosfamide, an analogue of cyclophosphamide, has therapeutic activity against a wide variety of human malignancies. In a phase II trial in carcinoma of the pancreas, we treated 31 patients who had not received prior chemotherapy with a median ifosfamide dose of 2 g/m2/d (range, 1.5 to 2 g/m2/d) administered intravenously (IV) over one hour for five consecutive days every 3 weeks. 2-mercaptoethane sulphonate (mesna), an acrolein antagonist with known uroendothelial protective properties, was administered IV at a dose of 400 mg/m2 over 15 minutes before the daily dose of ifosfamide and repeated every four hours for two additional doses. Among 30 evaluable patients, one patient achieved a complete remission (26+ months) and another patient had a partial remission (4 months). The median duration of survival of all patients from the start of ifosfamide therapy was only 3 months (range, 1 to 26+ months). Treatments were generally well tolerated. The most common toxic effects included granulocytopenia, nausea and vomiting, malaise, anorexia, and mild hematuria. Mesna offers an adequate protection against uroendothelial injury caused by ifosfamide. Despite the previously reported response rate of greater than 20% at the same or lower doses of ifosfamide in other studies, our data suggest that ifosfamide is only marginally active against cancer of the pancreas and appears to be of minimal value in the treatment of patients with this tumor.
Phase II and pharmacogenetic study of docetaxel (D) and capecitabine (C) in chemonaive non-small cell lung cancer (NSCLC) patients (pts)
Authors: M. B. Lustberg, T. S. Bekaii-Saab, R. Diasio, H. Ezzeldin, S. L. Starrett, G. A. Otterson, M. A. Villalona
Journal: Journal of Clinical Oncology (2008)

19090 Background: D is believed to synergize with C through up-regulation of thymidine phosphorylase (TP). TP activation is the last metabolic step in the conversion of C into 5-FU. We have conducted a phase II trial of D 36 mg/m2/wk × 3 every 4 wks and C 625 mg/m2 orally twice a day × 14 days starting on day 5 in pts with previously treated NSCLC, showing promising efficacy and acceptable tolerability. We showed that TP, TS and DPD expression in lung tumor specimens may have predictive value for the regimen. Methods: We conducted a phase II trial of D + C with the above schedule and doses in chemonaive NSCLC pts in a Simon 2 stage phase II study. ORR was the primary endpoint. All patients were required to have tumor blocks available for measurement of TP, thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) expression. DPD activity in mononuclear cells was measured to assess correlation to toxicity. Patients with DPD levels <.07 nmol/min/mg protein were excluded. Results: 29 pts (20 M, 9 F), ages 39 to 72 received treatment. 8 pts never received treatment because of: Low DPD (1), insufficient tumor tissue (2) and other (5). The overall RR was 18% (5/28) and not supportive of moving to the second stage of the trial (8/28 required). 14/28 patients had SD (50%; 32% with SD > 12 weeks). Time to progression ranged from 1 to 13+ m. Toxicities included: Grade 3 fatigue (3), leukopenia (3), mucositis (2), dehydration (2), vomiting (2), grade 4 stomatitis (1) and myocardial infarction (1). DPD levels ranged from .06 to .26. The majority of responders (4/5) had DPD levels ≤ .1. Most of the responders (4/5) experienced grade 3 toxicities including leukopenia, dehydration, fatigue, and diarrhea. None of the patients (0/4) with DPD levels >.2 had a response. Tumors have been procured and enzymatic studies are under way. Conclusions: The combination of D + C in the treatment of chemonaive patients with NSCLC in the schedule studied was well tolerated, but did not meet the prospectively set endpoint. In future studies, DPD levels can help stratify patients who may benefit from higher doses of C. Subgroup analyses based on tumor tissue potential predictors are under way. Supported by R21CA108157, Roche and Sanofi Aventis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis Roche, sanofi-aventis
Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial
Authors: Michael D Privitera, Timothy E Welty, Barry E Gidal, Francisco J Diaz, Ron Krebill, Jerzy P Szaflarski, Barbara A Dworetzky, John R Pollard, Edmund J Elder, Wenlei Jiang, Xiaohui Jiang, Michel Berg
Journal: The Lancet Neurology (2016)