tbuckley/cabot-search huggingface dataset:
Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias.
Authors: M A Schwartz, D R Lovett, A Redner, R D Finn, M C Graham, C R Divgi, L Dantis, T S Gee, M Andreeff, L J Old
Journal: Journal of Clinical Oncology (1993)

PURPOSE Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues. A therapeutic dose-escalation study of M195 labeled with iodine 131 was conducted in patients with relapsed or refractory myeloid leukemias. METHODS Twenty-four patients (16 relapsed or refractory acute myeloid leukemias, five blastic myelodysplastic syndromes [MDS], two chemotherapy-related secondary leukemias, and one blastic chronic myelogenous leukemia [CML]), including seven who had failed to respond to prior bone marrow transplantation (BMT), received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. RESULTS In 22 patients, whole-body gamma-imaging demonstrated marked uptake of antibody into all areas of bone marrow. Twenty-three patients (96%) demonstrated decreases in peripheral-blood cell counts, with decreased percentage of bone marrow blasts seen in 83% of cases. Eighty-nine percent of bone marrow biopsies examined quantitatively demonstrated substantial decreases in the number of blasts, with greater than 99% of blasts killed in some patients. The two cases that failed to demonstrate leukemic cytoreduction occurred in the first two dose levels. For 131I doses of 135 mCi/m2 or greater, pancytopenia was profound and lasted for at least 12 days. Eight patients had sufficient marrow cytoreduction to proceed to BMT. Three of these achieved marrow remission, one of 6+, and one of 9 months' duration. Two patients in blastic phase temporarily reverted to their original myelodysplastic states. Thirty-seven percent of assessable patients developed human anti-mouse antibody (HAMA). In two patients with HAMA who were re-treated, plasma 131I-M195 levels could not be maintained and no therapeutic effect resulted. Significant nonhematologic toxicity (hepatic) was seen in one patient and the maximum-tolerated dose (MTD) was not reached. CONCLUSION These data suggest that safe leukemic cytoreduction can be achieved with 131I-M195 even in multiply relapsed or chemotherapy-refractory leukemias. This agent may be useful as part of a preparative regimen for BMT.
Long-term follow-up in patients with metastatic renal cell cancer not treated with IL-2
Authors: V. K. Chand, J. Sidloski, G. Clamon, R. J. Hohl
Journal: Journal of Clinical Oncology (2005)

4597 Background: Metastatic renal cell cancer (RCC) is associated with a <10% 5-year survival and response rate to standard chemotherapy. Excellent performance status, LDH < 1.5x ULN, normal Hgb, corrected calcium, and prior nephrectomy have been associated with prolonged survival. Follow-up of 255 select patients from seven phase II trials treated with high-dose interleukin-2 (IL-2) that had no control groups suggest durable responses at 5–10 years of follow-up in about 7% of patients and significant acute toxicity. Since RCC is reported to regress spontaneously and long term survival of RCC patients treated with or without immunotherapy is limited to <5year follow-up we sought to retrospectively create a control group of patients with metastatic RCC that would have been eligible for enrollment on trials with IL-2 and assess their long-term survival. Patients and Methods: From 1980–1993, 267 patients presented to our institution with metastatic RCC. Included were relatively asymptomatic patients with no significant co-morbidities. Those with CNS metastases or previous treatment with IL-2 were excluded. The main endpoint was survival after a 10+year follow-up. Results: 100 patients were found to be eligible. Median overall survival for these patients was 18 months. Only 2 patients had no evidence of disease after at least 10 years of follow-up. The median survival in patients <71 years old and still alive at least 9 months after metastatic diagnosis was 28 months. Patients found to have a single, non-hepatic metastasis at initial presentation lived significantly longer than all other patients (48.5 mos. vs. 10 mos., p<.001). Conclusion: Survivals of highly selected patients with metastatic renal cancer are similar whether they received high-dose IL-2 or not. Patients initially presenting with single, non-hepatic metastases have the potential for long-term survival with local therapy only. Patients with excellent performance status, initially found to have a combination of metastatic sites or any hepatic involvement, should be considered for a clinical trial or high-dose IL-2. Prospective, randomized studies are needed to determine if patients truly benefit from high-dose IL-2 therapy. No significant financial relationships to disclose.
Somatic Mosaic Mutations in<i>PPM1D</i>and<i>TP53</i>in the Blood of Women With Ovarian Carcinoma
Authors: Elizabeth M. Swisher, Maria I. Harrell, Barbara M. Norquist, Tom Walsh, Mark Brady, Ming Lee, Robert Hershberg, Kimberly R. Kalli, Heather Lankes, Eric Q. Konnick, Colin C. Pritchard, Bradley J. Monk, John K. Chan, Robert Burger, Scott H. Kaufmann, Michael J. Birrer
Journal: JAMA Oncology (2016)

Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established.To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95% CI, 6.80-43.69; and primary OC postchemotherapy OR, 4.82; 95% CI, 1.43-16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%).Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk.
Metabolic Shift In Hypoxia-Adapted CML Cells and Mechanisms Of Acquired Dasatinib Resistance Uncovered By Proteomic iTRAQ Profiling
Authors: Yoko Tabe, Linhua Jin, Hiroko Iwanami, Hiromichi Matsushita, Saiko Kazuno, Tsutomu Fujimura, Takashi Ueno, Takashi Miida, Michael Andreeff, Marina Konopleva, Shinya Kimura
Journal: Blood (2013)
Blocking Plasma Factors of Migration Inhibition Factor Production in Patients With Cervical Carcinoma. A Possible Role In Vivo&lt;xref rid="FN1" ref-type="fn"&gt;2&lt;/xref&gt;
Authors: L Favila, L Jiménez, M E Casto, G García-García, A Gutiérrez, I Pulido
Journal: JNCI Journal of the National Cancer Institute (1978)

The blocking activity was studied of plasma from patients with cervical carcinoma in a model of migration inhibition factor (MIF) production by normal human leukocytes. At the same time, the patients' in vivo (intradermal reactivity) and in vitro (MIF assay) responses were studied with two common antigens (streptokinase-streptodornase and purified protein derivative). The plasma of 15 of 27 patients with carcinoma was capable of blocking the MIF test of human normal leukocytes. Twelve of 15 patients with blocking factor in their plasma had no or only a slight in vivo response, although they had a good in vitor response. Two patients had blocking factor without any in vivo or in vitro response. Six patients who had in vitro responses and slight or no in vivo responses had no plasma blocking activity. Three patients had neither in vivo nor in vitro responses and lacked blocking activity in their plasma.
Programmed death ligand-1 (PDL1) and CD3 co-expression in patients with advanced stage EGFR mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKI)
Authors: R.A. Soo, H.R. Kim, B.R. Asuncion, Z. Fazreen, M.F.M. Omar, M.C. Herrera, J.S.Y. Lim, G. Sia, R. Soong, B.-C. Cho
Journal: Annals of Oncology (2015)
Analysis of cytokines in ECOG E4Z02: A phase III randomized study of l-carnitine supplementation for fatigue in patients with cancer
Authors: T. A. Rich, M. J. Fisch, J. Manola, D. Cella, B. Ansari, M. Koc, R. Cruciani
Journal: Journal of Clinical Oncology (2009)

9635 Background: The purpose of the study was to investigate associations between fatigue, depression and pain and serum levels of proinflammatory cytokines among pts randomized to l-carnitine supplementation or placebo. Methods: 376 cancer pts with normal hemoglobin and fatigue assessed as moderate or severe were randomized to 4 wks of supplementation with oral carnitine (n=189) or placebo (n=187) 1000 mg bid. Serum levels of 10 inflammatory cytokines and growth factors were measured with Luminex bead ELISA at baseline and 4 wks for 98 pts. Wilcoxon rank sum tests were used to compare cytokine levels between arms and between pts with/without symptoms. Multivariable models of fatigue, depression and pain at 4 wks were examined, adjusting for treatment arm, baseline symptoms and baseline cytokine levels. Results: There were no statistically significant differences in cytokine levels between pts with or without severe fatigue, pain, or depression at baseline. Levels of IL-1rα were higher at baseline among pts randomized to placebo (p=0.01) and increased after 4 wks, while levels among pts randomized to l-carnitine declined (p &lt;0.001). Levels of IFN-γ, TGF-α, IL-6, and TNF-α decreased more among pts randomized to placebo (p=0.008, p=0.006, p=0.01, and p=0.05, respectively). Pts with severe pain at 4 wks had greater declines in levels of EGF, IFN-γ, IL-1α, and IL-1rα than pts without (p=0.05, 0.05, 0.02 and 0.03, respectively). Reductions in IL-1α and TGF-α predicted lower pain severity at 4 wks (p=0.02 and p=0.04, respectively). Conclusions: Levels of proinflammatory cytokines or EGFR ligands failed to distinguish between patients with moderate vs. severe fatigue or levels of depression and pain (severe vs. not) prior to treatment intervention. Lower levels of IL-1α and TGF-α appear to be associated with improvement of pain severity but are not associated with treatment. Mechanisms for these findings require exploration. No significant financial relationships to disclose.
Comprehensive spa treatment in the Czech Republic
Authors: Katerina Neumannova, Jakub Zatloukal, Vitezslav Kolek
Journal: European Respiratory Journal (2011)

Introduction:  Patient with asthma (AB) can receive a comprehensive care treatment in specialized centres (Spa9s) in the Czech Republic.   Aim:  To evaluate an effect of the comprehensive spa treatment (CST) on ventilatory parameters, chest mobility and posture in children with AB.   Methods:  The examined group consisted of 50 medically stable children with AB (aged 11.6±2.5 years) who underwent a 4-week treatment in the Luhacovice Spa. The assessment was performed at baseline and after the treatment and it included lung function tests, maximal inspiratory (MIP) and expiratory (MEP) mouth pressure examination, chest expansion (CE) and kinesiological examination (muscle strength and length). The CST included respiratory physiotherapy, postural exercise and regular physical activity.   Results:  Lung function tests showed normal values at the baseline and after treatment. A significant improvement was observed in all ventilatory parameters, respiratory muscle strength and CE at both levels. There was a lower presence of muscle imbalances (shortened and weakened muscles) after the treatment.   Conclusion:  Children with AB can benefit due to the combination of physiotherapeutic approaches and physical activity not only in ventilation and breathing mechanism, but also in improved posture.
Predictors of Increased Carotid Intima-Media Thickness in Youth With Type 1 Diabetes: The SEARCH CVD Study
Authors: Amy S. Shah, Dana Dabelea, Nora F. Fino, Lawrence M. Dolan, R. Paul Wadwa, Ralph D’Agostino, Richard Hamman, Santica Marcovina, Stephen R. Daniels, Elaine M. Urbina
Journal: Diabetes Care (2015)

OBJECTIVE Youth with type 1 diabetes have worse cardiovascular (CV) risk factors and higher carotid intima-media thickness (IMT) than their peers without diabetes. Whether the burden of CV risk factors over time is associated with carotid IMT at follow-up in youth with type 1 diabetes is not known. RESEARCH DESIGN AND METHODS Two hundred ninety-eight youth with type 1 diabetes (mean age 13.3 ± 2.9 years, 87.6% non-Hispanic white, 53.7% male) had two study visits 5 years apart. CV risk factors, including BMI, lipids, blood pressure, hemoglobin A1c, and smoking status, were assessed at both visits, and carotid IMT was measured at follow-up using B-mode ultrasonography. Linear regression models with an area under the curve measurement that incorporated the baseline and follow-up CV risk factors were used to evaluate the relationship with carotid IMT at follow-up. RESULTS All CV risk factors worsened significantly over time (except LDL cholesterol) (P &amp;lt; 0.05). From baseline to follow-up, the number of abnormal CV risk factors also increased (P &amp;lt; 0.05). Predictors of carotid IMT were older age, male sex, and higher BMI z score area under the curve (all P &amp;lt; 0.05). CONCLUSIONS The CV risk factor burden increases over time in youth with type 1 diabetes. BMI z score was the only modifiable CV risk factor that predicted carotid IMT. This study highlights the critical need to better understand the risk factors that influence carotid IMT early in the course of type 1 diabetes.
Abstract 15820: Vagal Nerve Stimulation Modifies Intrinsic Cardiac Local Circuit Neurons in the Suppression of Atrial Arrhythmias
Authors: Eric Beaumont, John A Armour, Siamak Salavatian, Alain Vinet, Vincent Jacquemet, Jeffrey L Ardell
Journal: Circulation (2013)

Background: Burst electrical stimuli delivered to intra-pericardial mediastinal nerves (MNS) reproducibly evoke atrial fibrillation (AF), an effect dependent upon heterogeneous activation of the in...
Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials
Authors: S.S. Ramalingam, K. O'Byrne, M. Boyer, T. Mok, P.A. Jänne, H. Zhang, J. Liang, I. Taylor, E.I. Sbar, L. Paz-Ares
Journal: Annals of Oncology (2016)

BackgroundThe irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases.MethodsThe ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib.ResultsOne hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib.ConclusionsDacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721).Clinical trials numberARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).
CDC updates Zika virus guidance to protect pregnant women
Authors: Michael McCarthy
Journal: BMJ (2016)

In response to reports linking Zika virus infection to fetal abnormalities, including microencephaly, and to the recent report of sexual transmission of the virus in Texas,1 the US Centers for Disease Control and Prevention has updated its guidance on the virus.

The updates, released on 5 February, recommended that men who reside in or who have traveled to an area where there is active transmission of the Zika virus and who have a pregnant sexual partner should either abstain …
Updated results from a phase I trial of the histone deacetylase (HDAC) inhibitor MS-275 in patients with refractory solid tumors
Authors: L. Gore, S. N. Holden, M. Basche, S. K. S. Raj, I. Arnold, C. O'Bryant, S. Witta, B. Rohde, C. McCoy, S. G. Eckhardt
Journal: Journal of Clinical Oncology (2004)

3026 Background: Inhibition of HDACs in vitro has resulted in tumor cell growth arrest, differentiation and/or tumor apoptosis. This report evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of MS-275, an orally active synthetic benzamide derivative HDAC inhibitor, and presents updated clinical data from this phase I trial. Methods: MS-275 was given orally to 3–6 fasting patients per dose level with refractory/relapsed solid tumors or lymphoma. The plasma PK profile of MS-275 was analyzed using a validated, quantitative method. Histone H3 and H4 acetylation was analyzed in peripheral blood mononuclear cells (PBMCs) by immunohistochemical detection. Results: Seventeen pts have been enrolled on 3 schedules (Schs): 2–6 mg/m2 biweekly (n=10, Sch A); 2 mg/m2 twice weekly for 3 weeks with 1 week rest (n=6, Sch B); 4 mg/m2 weekly for 3 weeks with 1 week rest (n=1, Sch C). Eighty cycles have been administered on Sch A and 13 on Sch B. No drug related grade (gr) 4 adverse events (AEs) have been reported. The most common drug related AEs were gr 1–3 hypophosphatemia, asthenia, nausea and anorexia. The maximum tolerated dose was not reached on Sch A. Dose escalation of Sch B was not pursued due to laboratory abnormalities resulting in dose delays/omissions. The plasma profile of MS-275 demonstrates rapid absorption, with a Tmax of 0.5–2.0 h, and a dose-dependent increase in systemic exposure over the dose range 2–6 mg/m2. A biphasic elimination was noted, with an estimated T1/2 of 100 hours. Preliminary PD analyses indicate an increase in histone H3 and H4 acetylation in PBMCs, compared with pretreatment. One pt with melanoma continued to exhibit a partial response (Sch A), and 1 pt each with Ewing's sarcoma (Sch A), rectal carcinoma (Sch A) and melanoma (Sch B) had stable disease after 60+, 38+ and 20+ weeks of therapy, respectively. Conclusions: PK analyses indicate that MS-275 is rapidly absorbed, with a T1/2 of 100 h, and preliminary evidence of increased H3 and H4 histone acetylation has been observed. Potential antitumor activity has been noted in 4 pts and enrollment on MS-275 4 mg/m2 weekly for 3 weeks with 1 week rest is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Berlex; Schering AG Schering AG
Phase I/II study of cyclophosphamide, carboplatin, and etoposide and autologous hematopoietic stem-cell transplantation with posttransplant interferon alfa-2b for patients with lymphoma and Hodgkin's disease.
Authors: D P Schenkein, P Dixon, J F Desforges, E Berkman, J K Erban, J L Ascensao, K B Miller
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate the safety and toxicity of interferon alfa-2b (IFN) following an intensive preparative transplantation regimen in patients with relapsed Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirty-two patients with NHL or HD underwent autologous transplantation following cyclophosphamide 7,200 mg/m2, carboplatin 1,600 mg/m2, and etoposide 1,600 mg/m2 (CCV). Fourteen patients received an escalating dose of IFN. IFN was started at 1 x 10(6) U/m2 subcutaneously (SC) three times per week with a monthly dose escalation to a maximum of 3 x 10(6) U/m2 SC three times per week. IFN was continued for a total of 6 months. RESULTS The preparative regiment was well tolerated. Renal dysfunction was noted more frequently in patients with a history of pretransplant cisplatin treatment, and cardiac dysfunction was responsible for the single transplant-related death (3%). IFN was well tolerated with no serious complications. Transient neutropenia and thrombocytopenia were noted in several patients. The mean maximal-dose IFN achieved was 2 x 10(6) IU/m2. The median duration of treatment with IFN was 5.2 months. The overall probability of survival (OS) and event-free survival (EFS) at 36 months, with a median follow-up duration of 18 months, was 42% OS and 14% EFS in HD and 70% OS and 56% EFS in NHL. The EFS at 36 months was 73% for all NHL patients who received IFN and 50% for patients who refused IFN treatment (P = .12), with OS estimates of 100% in the IFN group and 35% in the untreated group (P = .0002). CONCLUSION CCV is a safe, effective conditioning regimen in patients with NHL or HD. Posttransplant IFN can be safely administered at 2.0 x 10(6) U/m2 three times per week for 6 months and may have a meaningful antitumor effect.
Pruning the ricket thicket
Authors: Valentin David, Myles Wolf
Journal: Journal of Clinical Investigation (2016)

Overexpression of FGF23 results in hypophosphatemic rickets, which is characterized by renal phosphate wasting, inappropriately low circulating levels of the active form of vitamin D, and skeletal abnormalities. The precise mechanisms of how excess FGF23 leads to hypophosphatemic rickets are not clear. In this issue of the JCI, Bai and colleagues demonstrate that deletion or inhibition of CYP24A1, which initiates degradation of the active form of vitamin D, ameliorates skeletal abnormalities in two mouse models of hypophosphatemic rickets. While this work supports an important role for excess CYP24A1 activity in the pathogenesis of FGF23-mediated hypophosphatemic rickets, more work will need to be done before CYP24A1 inhibition can be integrated into the management of patients living with these diseases.
Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: a National Cancer Institute of Canada Clinical Trials Group Study.
Authors: M Blackstein, E A Eisenhauer, R Wierzbicki, S Yoshida
Journal: Journal of Clinical Oncology (1990)

The Clinical Trials Group of the National Cancer Institute of Canada (NCIC) studied single-agent epirubicin in 40 previously untreated patients with extensive small-cell lung cancer (SCLC). The starting dose of epirubicin was 100 (eight patients) or 120 (32 patients) mg/m2 administered intravenously every 3 weeks. Twenty patients (50%) achieved an objective response (95% confidence limits, 33% to 66%) and three of the 20 had complete responses (CRs). The median survival of all 40 patients was 8.3 months (35.4 weeks). Myelosuppression, mild or moderate nausea and vomiting, and hair loss were commonly seen. There was one chemotherapy-related death. This drug is active and well tolerated in SCLC and the use of it as first-line therapy did not appear to compromise survival in this group of patients.