tbuckley/cabot-search huggingface dataset:
A pilot, pharmacokinetic (PK), and pharmacodynamic (PD) study to determine the feasibility of intrapatient dose escalation to tolerable rash and the activity of maximal doses of erlotinib (E) in previously treated patients with advanced non-small cell lung cancer (NSCLC)
Authors: C. A. Mita, G. Schwartz, M. M. Mita, K. Papadopoulos, L. Wood, M. de Jonge, S. Yancik, M. Hamilton, P. Santabarbara, E. Rowinsky
Journal: Journal of Clinical Oncology (2005)

3045 Background: The recommended dose of the epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor E may have been based in part on skin rash grade, which may not reflect maximal tolerability. Moreover, since clinical benefit with E and other EGFR inhibitors appears to correlate with the dose-dependent rash, this trial sought to determine the feasibility of intrapatient dose escalation to achieve a maximally tolerated “target” rash and to determine the antitumor efficacy of E at its true maximally tolerated dose in patients with advanced NSCLC. PK and PD studies of signal transduction elements related to EGFR were performed in skin, hair follicles, serum, and tumor. Methods: The starting E dose, 150 mg/day, was increased step-wise in each patient to 200 mg and then in 25 mg increments every 14 days unless an intolerable rash occurred (as defined by: requirement for narcotics or systemic corticosteroids; desquamation of >25% of body-surface area; generalized urticaria; or if the rash was considered intolerable by the patient) despite treatment with minocycline, or if another dose-limiting toxicity occurred. Results: To date, 26 patients (median age 65, [range 44–76]; 12 M/14 F) have been treated. Dose-escalation to 200–350 mg of E was possible in 21 patients. Worst grades of rash were 3, 2 and 1 in 2 (10%), 9 (50%) and 6 (33%) of the 18 evaluable patients, respectively. Other toxicities were grade 2–3 diarrhea (3 patients), grade 2–3 fatigue (5 patients) and grade 1–2 nausea (14 patients). Five patients had grade 2–3 thromboembolic events. Partial responses occurred in 2 (9%) of 22 evaluable patients, and 4 (18%) patients had stable disease >3 months. PK and PD studies will be presented. Conclusions: Intrapatient dose escalation of E was feasible, and further accrual to 50 patients is ongoing to determine the clinical benefit associated with higher doses of E. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI Genentech, OSI OSI
Nanotechnologies in Cancer Treatment and Diagnosis
Authors: Stephanie A. Morris, Dorothy Farrell, Piotr Grodzinski
Journal: Journal of the National Comprehensive Cancer Network (2014)

Despite significant efforts toward research and treatment development, cancer continues to be a major health problem in the United States that is only further enhanced by the heterogeneous nature of the disease. Nanotechnology has evolved as a technology with applications to medicine and the potential to improve clinical outcomes, with its application to cancer garnering much attention recently. In particular, through the generation of novel nanoscale devices and therapeutic platforms, nanotechnologies have emerged as innovative approaches that enable the detection and diagnosis of cancer at its earliest stages, and the delivery of anticancer drugs directly to tumors. This article highlights recent advances in the development of nanotechnologies for cancer therapeutics and diagnostics, and focuses on the potential future of cancer nanotechnology and the challenges this young field faces as it continues to move toward clinical translation.
Induction of Hepatic Glutathione Transferase and Suppression of 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene-Induced Chromosome Aberrations in Rat Bone Marrow Cells by Sudan III and Related Azo Dyes&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Yoshiaki Ito
 5, Sakan Maeda, Kazuhiko Souno, Norifumi Ueda, Taketoshi Sugiyama
Journal: JNCI Journal of the National Cancer Institute (1984)

Noninbred Long-Evans rats fed the reduced form of glutathione (GSH) 2 hours before injection with 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6)] showed a significant suppression of DMBA-induced chromosome aberrations (CA) in bone marrow cells. However, rats given injections of ethyl maleate [(EM) CAS: 141-05-9; (z)-2-butenedioic acid diethyl ester] 0.5 or 2 hours before being killed showed a remarkable fall in the hepatic GSH level. Furthermore, the administration of EM and bromosulfophthalein [CAS: 71-67-0; 3,3'-(4,5,6,7-tetrabromo-3-oxo-1(3H)-isobenzofuranylidene) bis(6-hydroxy)benzenesulfonic acid disodium salt] shortly before the DMBA injection inhibited the suppressive effects of Sudan III on DMBA-induced CA. A clear positive correlation was found between the capacity of Sudan III and related azo dyes to protect against DMBA-induced CA in bone marrow cells and glutathione transferase (GST) activity toward 1-chloro-2,4-dinitrobenzene in the liver cytosol induced by these azo dyes. DMBA activation with hepatic S-9 obtained from rats treated by polychlorinated biphenyls (PCB), phenobarbital, and Sudan III in the Ames system was high in this order as was also the case for the cytochrome P450 content. The addition of GSH to the Ames system containing S-9 from PCB-treated rats resulted in a substantial loss in the mutagenicity of DMBA. The present results suggest that GST and GSH play important roles in DMBA inactivation in rats previously administered Sudan III.
Prognostic serum markers in malignant pleural mesothelioma: Epidermal growth factor and platelet-derived growth factor
Authors: P. Betta, R. Libener, S. Orecchia, M. Salvio, F. Schillaci, R. Filiberti, R. Puntoni, M. Paganuzzi, P. Marroni
Journal: Journal of Clinical Oncology (2007)

18097 Background: While no previous data has so far shown any difference between the efficacy of serum platelet-derived growth factor (PDGF-AB) and serum epidermal growth factor (EGF) in distinguishing MPM from benign pleural diseases, some pilot studies have shown the potentiality of both these markers in the prognosis of MPM patients. This study investigates this capacity by analyzing survival in a series of MPM patients. Methods: Using an ELISA method, EGF (ng/ml) baseline serum was determined in 83 newly diagnosed MPM patients, and in 62 cases PDGF-AB serum levels were also measured. After a median follow-up time of 11.8 months (range 0.4–52.1 months), the log-rank test was used to compare the survival curves, and Cox’s regression analysis was also performed. Results: Median serum values were 0.56 ng/ml (range 0.09–2.05) for EGF and 43.0 ng/ml (range 0.1–145) for PDGF-AB. Patients with EGF levels higher than the median level of 0.56 ng/ml had an average survival time of 9.4 months (95%CI: 5.7–13.2), while the average survival time of patients with below-median EGF levels was 13.2 months (95%CI: 10.6–15.8); a statistically significant difference (p=0.005). For patients with PDGF-AB levels higher than an assumed cut-off of 49.8 ng/ml, (above 75 th percentile of MPM marker concentration) average survival was 7.9 months (95%CI: 4.5–11.3) as against the 14.9 months (95%CI: 10.3–18.7) in patients with below cut-off marker levels, again statistically significant (p=0.02). Cox’s regression analysis was performed on 42 patients in whom data on age, sex, histology, stage and platelet count were available. EGF and PDGF-AB levels higher than the selected cut-offs were confirmed as independent predictors of poor survival (HR=1.49; 95% CI: 1.04–2.13; p=0.03 and HR=1.96; 95% CI: 1.23–3.13; p=0.005, respectively). Conclusions: Our data suggest that circulating PDGF-AB and EGF levels are promising markers for clinical monitoring of MPM patients. No significant financial relationships to disclose.
Lung function decline predicts disability in valued life activities, which in turn predicts impaired quality of life in COPD
Authors: Paul D. Blanc, Jonathan Singer, Theodore A. Omachi, Gabriella Sanchez, Carlos Iribarren, Miriam Cisternas, Patricia P. Katz
Journal: European Respiratory Journal (2011)

Background: Interrelationships among lung function, disability, and health-related quality of life (HRQL) in COPD need clearer delineation.  Methods: We carried out baseline/follow-up interviews, spirometry, and 6 minute walk tests (6MWT) for 646 participants in a COPD cohort (42% male; age 59±6; median follow-up 2.1 years). Valued Life Activities (VLA) disability was scored with a validated instrument; VLA increased disability [VLA-ID]=0.5 standard deviation increase in score baseline-follow-up (14.6% disability). We assessed respiratory-specific HRQL with the Airways Questionnaire 20-Revised. Logistic regression (including age, sex, height) estimated risk by change in absolute values of FEV1 and 6MWT for VLA-ID; linear regression (including the same covariates, VLA-ID, and baseline HRQL) predicted follow-up HRQL.  Results: Mean decline in FEV1=-91 ml; mean decline in 6MWT=-37 M. VLA-ID predicted worsened HRQL (p  Conclusion: VLA-ID, but not FEV1 or 6MWT decrements, predicted HRQL impairment. Although FEV1 decline was associated with VLA-ID, worsening respiratory status did not directly account for HRQL changes.  Clinical Relevance: Interventions directly focused on attenuating disability are likely to be critical in preserving HRQL, independent of respiratory function or exercise capacity.  Support: NIH HL077618, FAMRI CoE2007.
The Tie receptor tyrosine kinase is expressed by human hematopoietic progenitor cells and by a subset of megakaryocytic cells
Authors: P Batard, P Sansilvestri, C Scheinecker, W Knapp, N Debili, W Vainchenker, HJ Buhring, MN Monier, E Kukk, J Partanen, MT Matikainen, R Alitalo, J Hatzfeld, K Alitalo
Journal: Blood (1996)
Pilot cross-over study to evaluate Regenecare topical gel in patients with epidermal growth factor receptor (HER1/EGFR) inhibitors-induced skin toxicity: The final analysis
Authors: S. Wong, K. Osann, A. Lindgren, T. Byun, M. Mummaneni
Journal: Journal of Clinical Oncology (2008)

20507 Background: Papulopustular rash is a dose-limiting toxicity of HER1/EGFR inhibitors. Secondary skin infection can occur from itching. Studies suggested that grade 2 rash might be a surrogate marker for HER1/EGFR inhibitor efficacy; better symptomatic management is desirable to promote optimal use of these agents. Regenecare contains 2% lidocaine for local pain management, marine collagen to promote tissue formation, aloe vera to enhance circulation and promote emollient effect, and sodium alginate to absorb exudates. This study evaluates the effectiveness of Regenecare in relieving the clinical symptoms of HER1/EGFR inhibitors-induced skin rash. Patient tolerability and satisfaction were assessed. Methods: Single center, prospective cross-over study of cancer patients treated with HER1/EGFR inhibitor. At the occurrence of symptomatic skin rash, subjects started applying study gel on the right side of the face and then crossed-over to both sides of the face after 1 week. Weekly facial evaluations with photographs for up to 6 weeks. Tolerability and satisfaction assessed by patient questionnaire. Results: Nineteen patients (M: F = 11:8; Mean age = 54.2 yrs) enrolled with 13 evaluable (9 cetuximab, 3 panitumumab, 1 erlotinib). Repeated Measures Analysis of Variance Model was used. For itch, a significant improvement over time was noted for the right compared to left side as evidenced by the significant interaction effect. For pain, the interaction effect did not reach statistical significance. All patients tolerated the study gel without any adverse effect and were very satisfied with the outcomes produced by the gel. Conclusions: Regenecare Gel appears effective in relieving rash-associated itching and pain in patients receiving EGFR inhibitors based on this pilot study. No Treatment Treatment Repeated Measures F-test p-value Left (Baseline) (n=13) Left (Week1) (n=13) Right (Baseline) (n=13) Right (Week 1) (n=13) ITCH Mean 1.538 1.577 1.538 0.615 R vs L: p=0.051 SE 0.268 0.225 0.243 0.180 T0 vs T1: p=0.232 Interaction: p=0.159 SE 0.377 0.345 0.211 PAIN Mean 1.385 1.269 1.308 0.731 R vs L: p=0.004 SE 0.311 0.257 0.308 0.257 T0 vs T1: p=0.126 Interaction: p=0.006 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MPM Medical Inc MPM Medical Inc
Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study
Authors: G. M. Bartelds, C. A. Wijbrandts, M. T. Nurmohamed, S. Stapel, W. F. Lems, L. Aarden, B. A. C. Dijkmans, P. P. Tak, G. J. Wolbink
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objective</h3> To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to adalimumab in rheumatoid arthritis (RA). <h3>Methods</h3> This cohort study consisted of 235 patients with RA, all treated with adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab ('switchers'), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and adalimumab were assessed. Clinical response to adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-adalimumab antibody status. <h3>Results</h3> After 28 weeks of adalimumab treatment the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-adalimumab and 0.6±1.3 in patients with anti-adalimumab (p&lt;0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). ΔDAS28 was greater for anti-TNF naive patients (1.7±1.5) than for switchers without anti-infliximab antibodies (ΔDAS28=0.9±1.4) (p=0.009). ΔDAS28 for switchers with anti-infliximab was 1.2±1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). <h3>Conclusion</h3> Switchers with anti-infliximab antibodies more often develop antibodies against adalimumab than anti-TNF naive patients. Response to adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
Clinical Effects of Infusions Into Chimpanzees of Primed Autologous Cultured T-Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: R B Slease, D M Strong, K E Gawith, G D Bonnard
Journal: JNCI Journal of the National Cancer Institute (1981)

As a model to study the possible early side effects of cultured T-cells (CTC) as a potential for adoptive cellular immunotherapy of human tumors, chimpanzees received iv infusions of 109 autologous, mixed lymphocyte culture-primed CTC. Complete blood counts, urinalyses, chest X-rays, blood chemistries, and serum immunoelectrophoresis were normal, and serologic studies were negative throughout the 3 weeks of observation. Serial transaminase levels were followed in 2 chimps, and mild increases in serum glutamic-oxaloacetic transaminase were seen in both and serum glutamic-pyruvic transaminase in 1 at 24 hours following each CTC infusion, but the levels returned to normal within 7 days. A liver biopsy specimen was normal. Fluorescence-activated cell sorter analysis of cells incubated with day 28 serum revealed weak labeling of only phytohemagglutinin (PHA)-stimulated Iymphoblasts and of CTC, suggesting that a weak anti-PHA antibody was generated. These studies indicate that infusions of autologous, in vitro-primed CTC are accompanied by little clinical toxicity in the chimp model but that they may be weakly immunogenic.
Final report of a phase I clinical study of biweekly pemetrexed and gemcitabine in patients with advanced solid tumors: Second dosing schedule &amp; response
Authors: A. S. Melemed, T. Larson, A. Z. Dudek, C. E. Mellskog, L. P. Bloss, Z. Ye, C. K. Obasaju
Journal: Journal of Clinical Oncology (2005)

7257 Background: Pemetrexed (Alimta), a multi-targeted anti-folate, is synergisitic with gemcitabine in preclinical models. The optimal sequence and schedule of both drugs is currently unknown. This is the first study examining a biweekly schedule. The first dosing schedule (cohort level 1–5) has established a maximum-tolerated dose (MTD) of Gemcitabine (G) 1500mg/m2 plus Pemetrexed (P) 600mg/m2 and a phase 2 recommend dose (P2RD) of G 1500mg/m2 followed by P 500mg/m2. Methods: An attempt was made to escalate G (cohort level 6–7), while maintaining P at a constant level, to further refine the P2RD. Escalating doses of G were infused over 30 minutes, followed immediately by P 500mg/m2 given IV over 10 minutes once on day 1 every 14 days. Results: The dose levels examined are shown in the Table. MTD was observed at cohort level 7. P:G dose intensity averaged 92%: 91%, with no. of doses ranging from 1 - 5. There was a suggestion of efficacy in all cohort level, with cohort level 5 having the highest number of PRs. Discussion: The P2RD was validated at G 1500mg/m2 + P 500mg/m2 every 14 days. This dose was chosen because multiple cycles could be given without dose reduction or delay and 5 PRs were seen out of 9 pts at this dose level whereas further escalation was shown to compromise dose intensity (levels 6–7) with no responses noted. Additional safety and efficacy data will be forthcoming. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly
Alterations in Sensitivity to Nonspecific Cell-Mediated Lysis Associated With Tumor Progression: Characterization of Activated Macrophage- and Natural Killer Cell-Resistant Tumor Variants23
Authors: Frederick P. Nestel, Peter R. Casson, Robert H. Wiltrout, Robert S. Kerbel
Journal: JNCI Journal of the National Cancer Institute (1984)

Certain “membrane-mutant,” lectin-resistant (Lecr) variants derived from the highly metastatic and poorly immunogenic DBA/2 mouse tumor MDAY-D2 previously were found to differ substantially in their ability to grow and to metastasize. In the present study, the parental MDAY-D2 tumor and several wheat germ agglutinin-resistant (WGAr) variants were examined for alterations in sensitivity to activated macrophage (Mø)- and natural killer cell (NK)-mediated lysis. The results indicated that selection in WGA after mutagenic treatment of a metastatic parental tumor cell line (MDAY-D2), which was Mø-sensitive (Møs) and NK-resistant (NKR), can result in the isolation of a significantly Mø-resistant (MøR) and NK-sensitive (NKS) tumor variant, MDW4. The in vivo hybridization of the MøR, NKS, Lecr MDW4 variant with a normal host-derived cell within a primary subcutaneous tumor, previously demonstrated to result in the progressive and selective outgrowth and metastasis of hybrid products, was found to be associated directly with reversion to the Møs, NKR phenotype of the metastatic parental MDAY-D2 cell line. DBA/2 mice given iv injections of 105 MøR, NKS cells (MDW4 or MDW4-110c1, a cloned line isolated from a subcutaneous primary tumor of an MDW4-injected animal) survived for a significantly prolonged period as compared to animals given injections of either the parental tumor or Møs, NKR hybrid products isolated from a MDW4 subcutaneous primary tumor (MDW4-110c2) or visceral metastases (MDW4-24a, MDW4-24b, and MDW4-24c). The results clearly indicate an inverse relationship among the tumor variants in their ability to be lysed by either Mø or NK and suggest a central role for NK rather than Mø surveillance in this tumor system.
The lack of evidence based knowledge of metabolic syndrome in obesity hypoventilation syndrome
Authors: Alinda G. Vos, Alex F. Muller, Folkert Brijker
Journal: European Respiratory Journal (2011)

Introduction:  The obesity hypoventilation syndrome (OHS) is a severe sleep related breathing disorder, with obstructive sleep apnea syndrome (OSAS) as the predominant sleeping pattern. It is often accompanied by multiple organ tract involvement. In OSAS, the interaction with metabolic syndrome is well studied. In OHS however, it is unclear whether the severity of disease has consequences for the occurrence and severity of metabolic syndrome. We evaluated the presence of evidence based knowledge.   Methods:  A systematic Pubmed and Cochrane search was performed, final check 24th February 2011, for metabolic syndrome in concurrence with OSAS and OHS, and related terms and synonyms in title and abstract (exclusion criterion: duplicates). The final data set was achieved by elimination of studies that contained predefined criteria: animal studies, studies    Results:  767 initial hits were found in OSAS, versus 273 for OHS. After the predefined elimination strategy, 171 remained, containing 5 RCT9s for OSAS, versus 6 studies, without any RCT, for OHS (Fischer exact p   Conclusion:  A markedly lower number of hits was found for metabolic syndrome in OHS, as compared to OSAS. Within the complexity of clinical features in OHS, the metabolic syndrome seems to be an unexplored area in research.
Promising effect of PMX-DHP absorption therapy for acute exacerbation of IPF
Authors: Arata Azuma, Shinji Abe, Takashi Ogura, Hiroshi Mukae, Hiroyuki Taniguchi, Masashi Bando, Yukihiko Sugiyama
Journal: European Respiratory Journal (2011)

Background:  Idiopathic pulmonary fibrosis (IPF)- acute exacerbation (AE) is poorly prognostic and devastating disorder in the IPF management. PMX-DHP (Toraymyxin) is indicated SIRS for endotoxin absorption therapy in Japan, which is widely used with extra cooperative hemo-perfusion and nafamostat mesilate. We tried to use of PMX-DHP for IPF-AE.   Methods:  The example of enforcing IPF-AE by PMX-DHP in multicenter experiences (n=73 for IPF in 160, all cases) was retrospectively analyzed. All cases that have P/F data before and after PMX-DHP, and are able to pursue the prognosis until the 90 days, indicated analytical objects.   Results:  In comparison of baseline and after PMX-DHP, P/F ratio significantly improved in case of P/F  Survival rate indicates 66.2% (30d), 30.1% (90d) in all cases, and 70.1% (30d), 34.5% (90d) in IPF. These results suggested to improve survival of IPF-AE in comparison with those reported in the past.   Conclusion:  PMX-DHP is possibly beneficial for the prognosis of IPF-AE.