tbuckley/cabot-search huggingface dataset:
Safety and pharmacokinetics (PK) of AMG 706 in combination with panitumumab and gemcitabine-cisplatin in patients (pts) with advanced cancer
Authors: J. Crawford, H. Burris, J. Stephenson, G. Otterson, M. Stein, J. McGreivy, Y. Sun, M. Ingram, L. Yang, L. S. Schwartzberg
Journal: Journal of Clinical Oncology (2007)

14057 Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 plus panitumumab and gemcitabine-cisplatin. Objectives are to establish the maximum tolerated dose and to assess safety, objective response and PK of AMG 706 with this regimen. Pts =18 yrs with advanced cancer, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti EGFR therapy, received panitumumab (9mg/kg IV day 1 of each 3-wk cycle) plus gemcitabine (1250mg/m 2 IV days 1 and 8) and cisplatin (75mg/m 2 IV day 1), and escalating doses of AMG 706 given continuously from day 1 of cycle 1. Assessments included dose-limiting toxicities (DLT; cycle 1), PK and tumor response (every 6–9 wks from wk 6). Results: As of Nov 2006, 36 pts (NSCLC n=19; pancreatic cancer n=4; other n=10; unknown primary n=3) were enrolled; 42% had prior chemotherapy. There was 1 DLT: pulmonary embolism, grade 5 (50mg QD). Selected treatment-related adverse events in =10% of pts are shown in the table . 39% of pts receiving AMG 706 had thromboembolic events (TE); 25% receiving study therapy without AMG 706 had TEs. There was 1 case of cholecystitis (grade 1), 1 of gallbladder pain (grade 3). Preliminary data showed that AMG 706 PK at 125 mg QD was comparable to data from monotherapy studies at the same dose level. Based on 29 pts with available response data (too early to evaluate/data unavailable n=7), objective tumor responses per RECIST were: CR n=1, 3% (breast cancer); PR n=9, 31% (NSCLC n=6; pancreatic cancer n=2; unknown primary n=1); SD n=17, 59%; PD n=1, 3%. Conclusions: In this study of pts with advanced cancer, AMG 706 was tolerable when combined with panitumumab and gemcitabine-cisplatin, with little effect on AMG 706 PK. Further studies need to determine if the observed TE rate exceeds gemcitabine-cisplatin background rates. [Table: see text] No significant financial relationships to disclose.
Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy.
Authors: W H Wilson, S E Bates, A Fojo, G Bryant, Z Zhan, J Regis, R E Wittes, E S Jaffe, S M Steinberg, J Herdt
Journal: Journal of Clinical Oncology (1995)

PURPOSE Overexpression of the multidrug resistance gene (mdr-1) is present in up to 60% of relapsed lymphomas. To study its role in lymphomas, we conducted a controlled trial of dexverapamil, an inhibitor of the mdr-1 gene product, P-glycoprotein (Pgp), in lymphomas refractory to etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS Eligible patients had recurrent Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL) and measurable disease. Patients initially received EPOCH alone and those with stable tumor over two cycles or progressive disease crossed over to receive dexverapamil and EPOCH on subsequent cycles. Dexverapamil was escalated eight dose levels, from 240 to 1,200 mg/m2/d. When possible, serial biopsies were obtained to measure mdr-1 expression by quantitative polymerase chain reaction (PCR). RESULTS Of 154 patients entered onto the trial, 109 had NHL and 45 had HD. The median age was 44 years, 67% had stage IV disease, and the median number of prior regimens was two (range, one to 12) in NHL and one (range, one to four) in HD. Sixty-four patients (42%) crossed over, of which eight were not assessable. The maximum-tolerated dose of dexverapamil was 900 mg/m2/d. Among 41 NHL patients (excluding mycosis fungoides), there were three complete responses (CRs) and two partial responses (PRs) (12%) and five minor responses (MRs); two of 10 HD patients achieved PRs. The mdr-1 level was measured in 44 biopsies from 19 patients. Pretherapy, mdr-1 was low (median, 2.5 U) but increased (median, 12.2 U) at crossover. Of six patients with mdr-1 levels greater than 15 U, three responded to dexverapamil, while only one of eight patients with mdr-1 levels less than 15 U responded. EPOCH and dexverapamil were well tolerated, but compared with EPOCH alone, produced more hematologic toxicity. CONCLUSION These results suggest that Pgp plays a role in clinical drug resistance of lymphomas. However, they also suggest that mechanisms other than Pgp are prominent in heavily pretreated patients and that, although Pgp inhibition may be necessary, it is probably insufficient. Earlier intervention with dexverapamil may be more effective and warrants further study.
Analysis of amylase rich pleural effusions
Authors: Suna Turkeli, Atilla Atici, Servet Kayhan
Journal: European Respiratory Journal (2013)

Background:  A rapid evaluation of pleural fluids is needed in differential diagnosis of pleural diseases.   Aim:  The aim of the study is to analyze the clinical utility of the measurement of pleural amylase levels and pleural fluid/serum amylase ratio in pleural effusions.   Material and methods:  Totally 115 patients with pleural effusion were enrolled in this prospectively designed study. Pleural fluids and serum samples were analyzed for transudate or exudate classification. Amylase levels were measured in vitro by Roche/Hitachi cobas-c systems in biochemical laboratory.   Results:  The mean age was 62.2 ± 15.3 and the range of age was between 20 and 94. Of the pleural fluids, 26 (22.6%) were determined as transudate and 89 (77.4%) were as exudate. As a common reason of pleural effusions, 61.5% of the transudates were originated from heart failure and 32.5% of the exudates were originated from lung cancer. The ratio between the serum amylase level and pleural fluid amylase level was not different between transudates and exudates caused by tumors or any other situations. Seven (6.1%) of pleural effusions were amylase rich and 4 of them were tumoral origin, the other 3 of them caused by extratumoral causes. Amylase rich effusions were found as a significant differential factor for malignant effusions (p=0.028). Amylase rich pleural fluids were determined more frequently in malignant effusions than paramalignant effusions in the present study (p 0.05).   Conclusion:  The predominant reason of amylase rich pleural effusions was malignant diseases and adenocarcinoma was the most common type among the lung cancers.
A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions.
Authors: S P Creekmore, J E Harris, T M Ellis, D P Braun, I I Cohen, N Bhoopalam, P F Jassak, M A Cahill, C L Canzoneri, R I Fisher
Journal: Journal of Clinical Oncology (1989)

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.
Degrees of Malignancy in Human Primary Central Nervous System Tumors: Ornithine Decarboxylase Levels as Better Indicators Than Adenosylmethionine Decarboxylase Levels&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: G Scalabrino, D Modena, M E Ferioli, M Puerari, G Luccarelli
Journal: JNCI Journal of the National Cancer Institute (1982)

The levels of activity to ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase (AMD) were measured in various types of primary human tumors of the central nervous system (CNS) and whenever possible were related to the malignancy of the tumor graded according to histopathologic criteria. In astrocytomas ODC levels increased linearly and progressively from infratentorial pilocytic astrocytoma (grade I) to glioblastoma multiforme (grade IV) and corrected well with the degree of histologic malignancy of the tumor. AMD activity levels, however, correlated with tumor malignancy only up to grade III astrocytoma. Medulloblastomas exhibited an unusual dichotomy with regard to the levels of polyamine biosynthetic decarboxylases (PBD): Medulloblastomas had the highest ODC activities of all the CNS tumors tested but had low AMD activities. In tumors of neuroepithelial tissue ODC level increases and, when present, AMD level increases were not due to proliferation of new blood vessels, because CNS hemangioblastomas had very low levels of both PBD activities. No significant differences in either of the PBD levels were observed among the several variants of meningiomas tested, the meningotheliomatous, the transitional, and the fibrous meningiomas. However, atypical forms of meningioma, i.e., those with mitotic figures, whatever the histologic variants, had higher levels of ODC, but not of AMD, than the typical forms, i.e., those without mitotic figures.
Association of a germ-line variant in the <i>K-ras</i> 3’ untranslated region with response and progression-free survival in patients with mCRC treated with single-agent cetuximab (IMCL-0144) or in combination with cetuximab (EPIC) independent of <i>K-ras</i> mutation status
Authors: T. Winder, W. Zhang, A. El-Khoueiry, D. Yang, A. Pohl, G. Lurje, E. Rowinsky, S. Khambata-Ford, C. Langer, M. Awad, H. Lenz
Journal: Journal of Clinical Oncology (2009)

4061 Background: Recent studies have found K-ras mutation status predicts response to EGFR inhibitors in mCRC. An in vitro study demonstrated let-7 microRNA family can regulate RAS expression by binding to the 3’UTR of RAS gene. Chin et al found a SNP in a let-7 microRNA complementary site (LCS) in the K-ras 3’ UTR increases cancer risk in NSCLC. We tested the hypothesis whether this SNP may be associated with clinical outcome in 130 mCRC patients enrolled in IMCL-0144 trial and in 186 pts enrolled in EPIC trial independent of K-Ras mutation status in the tumor. Methods: K-ras lcs 6 SNP was tested in 130 mCRC patients enrolled in IMC-0144 phase II clinical trial (single agent cetuximab) and in 186 mCRC patients enrolled in a second line phase III trial of cetuximab plus irinotecan versus irinotecan alone (EPIC). Genomic DNA was extracted from dissected formalin fixed paraffin embedded tumor tissue and K-ras mutation status and the polymorphism were analyzed using direct sequencing and PCR-RFLP technique. Results: The G harboring allele frequency in K-ras lcs6 was 8% in IMC-0144 and 11% in EPIC. K-ras lcs6 polymorphism was significantly associated with tumor response in patients with wild type K-ras in IMC-0144. The 12 pts harboring a G allele (TG+GG) had a 42% partial response (PR) rate compared to 55 pts with TT genotype with only 9% PR.(p=0.02, Fisher's-exact test). However, pts with TT genotype enrolled in EPIC treated with CPT-11 and cetuximab with mutant K-ras had a significantly better PFS of 12 weeks (95% CI 6.4–18) compared to those harboring the a G allele with median PFS of 6.4 weeks (95% 5.7–7) (p=0.037. log-rank test). There was no association between this polymorphism and clinical outcome in patients with wild type K-ras enrolled in EPIC. In a multivariate analysis the polymorphism remained independently associated with PFS in EPIC. Conclusions: Our data suggest for the first time that the functional germline polymorphism in K-ras lcs6 may be a potential predictive marker in mCRC patients treated with cetuximab-based chemotherapy independent of K-ras mutation status. This finding warranted further confirmative clinical trials. [Table: see text]
Subjective Global Assessment as an independent predictor of survival in patients with stage IIIB and IV non-small cell lung cancer
Authors: C. Lammersfeld, D. Gupta, S. Dahlk, P. G. Vashi, A. Aslam, C. G. Lis
Journal: Journal of Clinical Oncology (2008)

17552 Background: The Subjective Global Assessment (SGA), a well-validated tool for screening of malnutrition, assesses nutritional status based on features of the history and physical examination. Since malnutrition is a frequent manifestation in advanced lung cancer, we investigated the prognostic role of SGA in patients with stage IIIB and IV non-small cell lung cancer (NSCLC). Methods: We evaluated a case series of 162 histologically confirmed stages IIIB and IV NSCLC treated at Cancer Treatment Centers of America. Using SGA, patients were classified as well nourished (SGA A), moderately malnourished (SGA B) or severely malnourished (SGA C). Kaplan Meier method was used to calculate survival. Cox proportional hazard models were constructed to evaluate the prognostic effect of SGA independent of stage at diagnosis and prior treatment history. Results: Of 162 patients, 90 were males and 72 females. 76 were newly diagnosed at our hospital while 86 had received prior treatment elsewhere. 59 had stage IIIB disease at diagnosis while 103 had stage IV. The median age at diagnosis was 56 years (range 30-79 years). 78 patients were well-nourished (SGA A) while 84 were malnourished (SGA B or C). Well nourished patients had a median survival of 15.5 months (95% CI: 9.7 to 21.2), while malnourished patients had a median survival of 6.8 months (95% CI: 5.3 to 8.3); the difference being statistically significant (p = 0.01). Multivariate Cox modeling, after adjusting for stage at diagnosis and prior treatment history found that malnourished status was associated with a relative risk (RR) of 1.5 (95% CI: 1.03 to 2.2, p = 0.03). Stage at diagnosis was associated with a RR of 2.0 (95% CI: 1.3 to 3.0; p= 0.001) and prior treatment history was associated with a RR of 1.8 (95% CI: 1.2 to 2.7; p = 0.004). Conclusions: In this cohort, we found that low SGA scores (well-nourished status) versus high SGA scores (moderate to severe malnourished status) identified patients with better survival outcomes. At our center, we continue to investigate the role of nutritional intervention in improving prognosis in patients with NSCLC. No significant financial relationships to disclose.
Temporary high dose rate (HDR) brachytherapy and androgen deprivation for intermediate and high risk for biochemical failure –this is not the answer
Authors: A. C. A. Pellizzon, J. Salvajoli, P. Novaes, M. Maia, R. Ferrigno, R. Fogarolli, R. Pellizzon
Journal: Journal of Clinical Oncology (2004)

4664 Introduction: Prostate brachytherapy (BT) has reemerged during the 1990s. The use of temporary high dose rate (HDR) BT is based on the dissipation of radiation energy in tissues decreases exponentially in surrounding normal tissues. Intermediate and high risk tumors for biochemical failure (BF) encompass those with any of the following characteristics: T2 or more, Gleason score 7 to 10 and initial PSA dosage above 10 ng/ml. HDR-BT can be used to boost EBRT. Material and Methods: From March 1997 through February 2000, a total of 66 patients were considered intermediate or high risk for BF and were subject of this analysis. At the discretion of the referral urologists, patients received a course of NAAD, Results: Median age of patients was 67 years-old (range 56–76). 6-year acturial bNED survival for the entire group was 43.1%. 17 patients (25.8%) presented BF in median time of 21months. Neither NAAD nor time interval between EBRT and BT were predictive factors for BF, p= 0.812 and p=0.166, respectively. Discussion: There are some questions not answered till today when treating prostate cancer: one is if the interval between the end of EBRT and BT can influence on BC. The 2nd is if we really should use NAAD when using HDR-BT. Of importance is to note that the potential doubling time for prostate cancer was not yet established, and more, for slowly proliferating tumors, especially prostate adenocarcinoma, the intracellular repair is large, so larger doses per fraction would be necessary, what suggests a benefit of the use of HDR-BT.Our study failed to show relation between NAAD and treatment interval of more than 15 days between EBRT and BT a predictive factor for BF. No significant financial relationships to disclose.
Evaluation of the hedgehog signaling pathway as a therapeutic target for dendritic cell-based immunotherapy against patients with cancer.
Authors: T. Ogino, H. Onishi, H. Suzuki, A. Yamasaki, M. Katano
Journal: Journal of Clinical Oncology (2010)

e13061 Background: We are now doing moncyte-derived dendritic cells (Mo-DCs)-based vaccine therapy for advanced cancer patients. It has been shown that hedgehog (Hh) pathway contributes to tumor progression. We know that microenviroment of tumor tissue is hypoxic condition. So, we hypothesized that hypoxic condition affects the functions of both Mo-DCs and tumor cells, and that Hh pathway contributes to their functional changes. Methods: Peripheral blood moncytes were cultured with GM-CSF and IL-4 for 7 days in a 1% O2 (hypo-DCs) or 20% O2 condition (normo-DCs). Human pancreatic cancer cells were cultured for 7 days in a 1% O2 (hypo-Tu) or 20% O2 condition (normo-Tu). Antigen presentation-related functions of Mo-DCs, including proliferation. Phagocytosis, IL-12 or VEGF secretions, migration, maturation, and allo T cell stimulating capacity were estimated by FACS, ELISA, random migration assay, Matrigel invasion assay, and 3H thymidine uptake. Expressions of Hh-related molecules were determined by real time PCR and immunofluorescent staining. A Smo inhibitor, cyclopamine, was used to inhibit Hh pathway. Results: (A) Mo-DCs: 1) Proliferation, migration, invasion, and allo T cell stimulating capacities in hypo-DCs were significantly lower than those in normo-DCs (p<0.01). 2) Phagocytosis and IL-12 or VEGF secretions in hypo-DCs were significantly higher (p<0.01). 3) The expressions of Hh- related molecules in hypo-DCs were significantly higher (p<0.01) 4) VEGF secretion in hypo-DCs was suppressed by cyclopamine. (B) Tumor cells: 1) Invasion and expression of Hh-related molecules in hypo-Tu were higher than those in normo-Tu (p<0.05). 2) Proliferation of hypo-Tu was lower than that of normo-Tu (p<0.05). 3) Increased invasion of hypo-Tu was suppressed by cyclopamine. Conclusions: Hypoxia environment at the tumor site induces the decreased of antigen-presentation abilities of Mo-DCs but induces increase of tumor cell invasion ability. Importantly, increased VEGF secretion of hypo-DCs was suppressed by cycolpamine. On the other hand, the increased invasionin hypo-Tu was decreased by cyclopamine. Thus, Hh pathway may be a valuable therapeutic target for DC-based immunotherapy. No significant financial relationships to disclose.
National epidemiology of carbapenem-resistant and extensively drug-resistant Gram-negative bacteria isolated from blood samples in China in 2013
Authors: A. Xu, B. Zheng, Y.-C. Xu, Z.-G. Huang, N.-S. Zhong, C. Zhuo
Journal: Clinical Microbiology and Infection (2016)

Although antimicrobial resistance poses a great challenge to clinicians in China, there are limited antimicrobial resistance data on Gram-negative bacteria nationwide. We investigated the phenotypic characteristics of carbapenem-resistant Escherichia coli (CREC) and Klebsiella pneumoniae (CRKP) as well as extensively drug-resistant strains of Pseudomonas aeruginosa (XDRPA) and Acinetobacter baumannii (XDRAB) isolated from blood cultures in China. Data were collected on 24113 isolates from the China surveillance of antimicrobial resistance program in 2013, which comprised 208 hospitals located in all seven administrative regions of China. Minimum inhibitory concentrations (MICs) for common antimicrobials were determined by commercial automated systems available at local hospitals, and associations with geographic and clinical distributions was further studied. The overall prevalence of CREC, CRKP, XDRAB and XDRPA strains was 1.0, 5.5, 13.7 and 4.2%, respectively. Except for CREC, which did not differ greatly by region, the prevalence of the remaining three strains varied significantly across regions. The highest prevalence of CRKP (10.6%) and XDRAB (13.1%) were found in the pediatric group, and higher prevalence of all four target strains was found in the intensive care unit. For imipenem, 55.8% of CREC and 22.9% of CRKP strains had MICs of ≤4 μg/mL, while 97.4% XDRAB and 84% XDRPA isolates had MICs of ≥16 μg/mL. All CREC, CRKP and 81.2% of XDRAB strains were susceptible to tigecycline, with MIC90 values of 0.5, 2 and 4 μg/mL, respectively. In conclusion, a high prevalence of CRKP and XDRAB has emerged in China, especially in children and in the intensive care unit.
Early and long-lasting protection from arthritis in tumour necrosis factor (TNF ) transgenic mice vaccinated against TNF 
Authors: L Delavallee, H Le Buanec, N Bessis, E Assier, A Denys, B Bizzini, D Zagury, M-C Boissier
Journal: Annals of the Rheumatic Diseases (2007)

To evaluate the effect in mice with arthritis of active anti-tumour necrosis factor (TNF)alpha immunotherapy based on a keyhole limpet haemocyanin-human TNFalpha heterocomplex (hTNFalpha kinoid or TNFK) adjuvanted in incomplete Freund adjuvant. Immunotherapy was evaluated also with methotrexate.Human TNFalpha-transgenic mice received TNFK with or without methotrexate. Follow-up ranged from 6 weeks (short term) to 17 weeks (long term). Arthritis was evaluated clinically and histologically. Monitoring included titration of anti-hTNFalpha antibodies by ELISA and neutralisation assay.Vaccination with TNFK was associated with rapid-onset, long-lasting protection. Long-term results showed significantly milder arthritis in vaccinated animals than in control animals at the peak of the disease. Vaccination was followed by resolution of the clinical evidence of arthritis, contrasting with severe progressive arthritis in the control group. Histological improvements with decreased inflammation and destruction were noted in all immunised groups, even after the shortest follow-up (6 weeks). High titres of neutralising anti-hTNFalpha antibodies were detected as early as the fifth week post immunisation and persisted over time. Methotrexate given concomitantly with the vaccine did not influence either the effect on arthritis or the anti-hTNFalpha antibody titres.Anti-cytokine induction of autoimmune protection against chronic hTNFalpha overproduction is an efficient alternative to TNFalpha blockade in experimental arthritis and can be achieved using a TNFK vaccine.