tbuckley/cabot-search huggingface dataset:
Safety, tolerability and activity of gefitinib (ZD1839) in combination with tamoxifen in ovarian cancer patients refractory to platinum-taxane based therapy – a Phase-II study of the Ovarian Cancer Study Group (AGO Ovar 2.6)
Authors: S. Loibl, A. Du Bois, J. Pfisterer, J. Huober, H.-J. Lueck, J. Sehouli, U. Wagner
Journal: Journal of Clinical Oncology (2004)

5016 Background: To evaluate safety and tolerability of the combination of tamoxifen and gefitinib (‘Iressa’, ZD1839) in pts with refractory ovarian cancer.Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor, which in preclinical studies has demonstrated involvement in the inhibition of tamoxifen resistance. Patients and Methods: In this Phase II study, 57 pts with epithelial ovarian carcinoma refractory to platinum- and taxane-based therapy received oral tamoxifen (2 x 20 mg/day) and gefitinib (2 x 250 mg/day) until progression or unacceptable toxicity. Refractory pts are defined as those who progress or relapse during or within 6 mos after platinum- and taxane-based therapy. This interim analysis was based on data from 47 pts. Results: The median age was 60 years (37–80 yrs). 12 pts had received only first-line treatment with platinum/taxane, and 35 had received 1 or more further chemotherapy regimens. Gefitinib dose reductions to 250mg/day were carried out in 7 pts (14.9%) mainly due to diarrhea. Five pts prematurely discontinued trial medication due to adverse events (AEs). 26 pts (55.3%) stopped treatment due to disease progression. The most frequent drug related AEs were diarrhea 53.1% (40.4% grade 1/2, 10.6% grade 3/4, without grading 2.1% ) and acne-like skin rash 38.3% (23.4% grade 1/2, 4.3% grade 3/4, without grading 10.6%). Median time to progression was 58 days (95% CI: 55–70 days). One pt (2.1%) showed a complete response and 9 pts (19.1%) achieved stable disease. The proportion of pts alive after 6 mos was 56.6%. Conclusion: This first trial showed the combination of tamoxifen and gefitinib being relatively well tolerated in pts with refractory ovarian cancer. These preliminary data provide evidence that the combination showed some clinical activity in pts with platinum- and taxane refractory ovarian cancer, and therefore, should be further evaluated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Intracellular acidification mediates the inhibitory effect of peritoneal dialysate on peritoneal macrophages.
Authors: A Douvdevani, J Rapoport, A Konforty, R Yulzari, A Moran, C Chaimovitz
Journal: Journal of the American Society of Nephrology (1995)

Commercial peritoneal dialysis solution (CDS) is known to have a detrimental effect on the capacity of peritoneal macrophages (PM phi) to kill bacteria and produce acute phase cytokines. This cytotoxic effect is largely caused by the low pH of CDS. Because the cytoplasmic pH (pHi) is an important determinant of cellular function, the effect of CDS on the pHi of PM phi from continuous ambulatory peritoneal dialysis patients was studied. The pHi of PM phi was measured fluorometrically in N-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered salt solution (HBSS) or CDS at pH values of 5.3, 6.5, and 7.0, values that represent the pH existing in dialysate during the first 30 min of dwell time. For any given pH of the experimental medium, the pHi was always more acidic in CDS than in HBSS. When PM phi were incubated with a lactate-containing HBSS, a cellular acidification was observed that was similar to that attained by exposure to CDS at the same pH. This supports the hypothesis that the decrease in pHi was due to the influx of lactic acid from the CDS into the PM phi. In order to demonstrate a causal association between the CDS-induced cellular acidification and a defect in phagocytosis and cytokine production, these functions were studied after pHi clamping by means of K+/nigericin. It was found that clamping pHi to values below 6.5 led to a markedly reduced tumor necrosis factor-alpha production and phagocytosis. However, at values of pHi > 6.5, these functions were normal. (ABSTRACT TRUNCATED AT 250 WORDS)
Weekly paclitaxel/5-fluorouracil for recurrent ovarian cancer-A pilot study-
Authors: H. Watari, Y. Yamada, J. Kanazawa, Y. Oda, M. Hosaka, N. Kobayashi, Y. Todo, M. Takeda, Y. Ebina, R. Yamamoto, N. Sakuragi
Journal: Journal of Clinical Oncology (2005)

5160 Background: Standard chemotherapy regimen for recurrent ovarian cancer has not been established. Weekly paclitaxel (PTX) has been reported to be effective for recurrent ovarian cancer. In breast and gastric cancer, PTX combined with 5-fluorouracil (5-FU) has been reported to be highly effective. We, therefore, performed basic and clinical study on this combination therapy to evaluate its efficacy for recurrent ovarian cancer in a preliminary manner. Methods: Ovarian cancer cell lines (OVCAR-3, PA-1) were exposed to PTX for 24 h followed by 5-FU for 1 h with higher dose or 24 h with lower dose and then incubated in drug-free medium for 95 h or 72 h, respectively. Cell growth inhibition was determined by MTT assay. The effects of drug combinations were analyzed by combination index (CI) based on median effect principle. Ten patients with recurrent ovarian cancer, who were pretreated with taxane and carboplatin and gave their informed consent to receive this combination therapy, were eligible. A fixed dose of PTX (80 mg/m2) on day 1, 8, and 15 was combined with bolus injection of 5-FU, at a starting dose of 250 mg/m2 per week on day 2, 9, and 16. The maximum dose of 5-FU was set at 500 mg/m2 in this preliminary study. Chemotherapy was given every four week. Response and toxicity was evaluated by RECIST and CA-125 criteria described by Rustin et al., NCI-CTC, respectively. Results: Combination treatment with PTX and 5-FU revealed synergistic cytotoxic effect against two ovarian cancer cell lines in vitro irrespective of administration schedule of 5-FU. A pilot study for patients with recurrent ovarian cancer revealed that one of five patients (20%) with measurable disease showed complete response with eight months of duration of response and four patients revealed stable disease. Two of five patients (40%) without measurable disease showed 75% response evaluated by CA-125 criteria. Major side effects were hematologic toxicity (grade 3–4 leukopenia: 7 cases), which was, however, easily manageable by G-CSF. Conclusions: Weekly PTX/5-FU could be safely administered for patients with recurrent ovarian cancer and can be involved in sequential chemotherapy followed by platinum-containing regimen for prolongation of platinum-free interval. No significant financial relationships to disclose.
Clinical profile, outcomes, and ivabradine effects in patients with chronic obstructive pulmonary disease and chronic heart failure: The SHIFT trial analysis
Authors: Mitja Lainscak, Luigi Tavazzi, Karl Swedberg, Michel Komajda, Michael Böhm, Jeffrey Borer, Michele Robertson, Ian Ford
Journal: European Respiratory Journal (2013)

Introduction. Concomitant chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) is frequent, but prognostic and therapeutic implications remain poorly defined. This analysis of the SHIFT trial investigated: 1) the clinical profile and outcomes, and 2) the safety and efficacy of ivabradine.

Methods. Patients with stable systolic CHF in sinus rhythm of ≥70 bpm (N=6505) were randomized to placebo or ivabradine (2.5 to 7.5 mg bid). We report hazard ratios (HR) with 95% confidence intervals (CI) from multivariate Cox model analyses comparing the COPD (N=730) and non-COPD patients, and treatment effects of ivabradine vs placebo in both subgroups.

Results. COPD patients were older (65 vs 60y), more often men (82% vs 76%), and had more comorbidities. Beta-blockers were prescribed to 69% and 92% of COPD and non-COPD patients, respectively, with lower daily doses in COPD cohort (p<0.001). Composite primary endpoint (PE), (cardiovascular [CV] death and hospitalisation for worsening heart failure [HFH]), as well as HPH were more frequent in COPD patients (PE: 1.22, 1.06–1.40; HFH: 1.34, 1.14–1.57), while CV death was not. All were reduced similarly by ivabradine in both COPD (14%; 17%, 24%); and non-COPD (18%;27%, 7%) patients. Adverse events (AE) were more common in COPD patients (83% vs 73% in placebo arms), but AE rate was similar in the ivabradine and placebo arms of both subgroups.

Conclusions. COPD reduced the beta-blocker therapy implementation and worsened the prognosis in CHF. Ivabradine efficacy and safety were similar in COPD and non-COPD patients, and combination with beta-blockers was safe.
Toxicity of Nitro Compounds Toward Hypoxic Mammalian Cells In Vitro: Dependence on Reduction Potential
Authors: Adams, G. E., Stratford, I. J., Wallace, R. G., Wardman, P., Watts, M. E.
Journal: JNCI Journal of the National Cancer Institute (1980)

Fifteen nitroaromatic and nitroheterocyclic compounds that can act as "radiosensitizers" were tested for their cytotoxicity toward hypoxic Chinese hamster V79 cells in vitro. The cytotoxicity increased markedly as the electron affinity, measured as a one-electron reduction potential, increased. Non-nitro-containing compounds of similar electron affinities (such as quinones) that also act as radiosensitizers did not exhibit this specific toxicity toward hypoxic cells. The implications of the presence of the nitro group as a prerequisite for the hypoxic cell toxicity were discussed, and the mechanism of the cytotoxicity was compared with that of hypoxic cell radiosensitization.
Effect of bevacizumab and chemotherapy on serum levels of sVCAM-1 in patient with inflammatory and locally advanced breast cancer
Authors: N. Denduluri, S. B. Wedam, S. X. Yang, A. Parr, A. Berman, S. Steinberg, S. M. Swain
Journal: Journal of Clinical Oncology (2005)

611 Background: Levels of serum vascular cell adhesion molecule (sVCAM-1), a potential surrogate marker for angiogenesis, are elevated in breast cancer. This study aims to assess changes in sVCAM-1 after anti-angiogenic therapy and correlate changes with clinical response.Methods: 21 patients (pts) with inflammatory (IBC) and locally advanced breast cancer (LABC) underwent neoadjuvant treatment with bevacizumab (BV alone) for cycle (C) 1 followed by 6 C of BV and chemotherapy (CTX) with doxorubicin, docetaxel, and G-CSF. Blood samples were collected at baseline (BL), post-BV alone, and post-BV/CTX. sVCAM-1 levels were measured by ELISA. Changes from BL to post treatment levels were evaluated using the Wilcoxon signed rank test. Values at each time point and the two changes from BL were compared between responders and non-responders using an exact Wilcoxon rank sum test. P-values are two-tailed, with a p<0.025 required for significance in view of two primary comparisons being made. Results: There were 14 pts with partial response (PR), 5 pts with stable disease (SD) and 2 pts with progressive disease (PD). Serum concentrations (Mean ± SEM) of sVCAM-1 were 630.8 ± 83.4 ng/ml (n = 19) at baseline, 775.7 ± 85.2 ng/ml post-BV (n = 20) and 941.1 ± 112 ng/ml post-BV/CTX (n = 15). sVCAM-1 values rose from BL to post BV by a mean of 172.3 ± 23.3 ng/ml (p<0.0001) and rose from BL to post-BV/CTX by a mean of 284.7 ± 33.2 ng/ml (p<0.0002). The mean change from BL to post BV was 141.3 ± 25.3 ng/ml among responders (PR), and was 252.7 ± 32.4 ng/ml among non-responders (SD/PD) (p=0.026), exhibiting a borderline statistical significance in view of multiple comparisons. The mean change from BL to post BV/CTX was 275.1 ± 25 ng/ml in pts with PR and was 316.6 ± 136.5 ng/ml in pts with SD/PD (p=0.57). Conclusions: sVCAM-1 values increased significantly after treatment with BV alone and BV/CTX. Patients whose disease responded tended to have lower rise in the sVCAM-1 level after BV alone, but this differential effect disappears after the combination of BV/CTX. sVCAM-1 does not appear to be a surrogate marker for the anti-angiogenic effects of BV and BV/CTX in this small study population. No significant financial relationships to disclose.
Phase I/II study of weekly paclitaxel (P), UFT and leucovorin in patients with metastatic breast cancer (MBC)
Authors: A. Y. Chang, J. Beith, W. Yeo, M. Boyer, J. Wong, S. E. Lim, A. T. Chan
Journal: Journal of Clinical Oncology (2005)

726 Background: Weekly P is active against MBC and may be more efficacious than P given every 3 weeks. UFT is a combination of uracil and tegafur which is a pro-drug of 5-FU and is commonly used in patients with MBC outside USA. We designed a sequential weekly therapy of P and UFT/leucovorin (LV) to explore potential synergistic effect. Methods: In phase I we studied a fixed dose of P (80mg/m2) I.V. day 1 and escalated doses of UFT (125, 150, 175 mg/m2) with LV 30 mg p.o. bid on days 2 to 6 weekly for 3 weeks. Cycle repeats every 4 weeks. The Phase II study started after MTD of UFT was established and response was evaluated every 2 cycles and toxicity weekly. Eligibility criteria included no prior chemotherapy for measurable MBC, ECOG PS ≤ 2 and adequate organ functions. Results: Total of 53 patients has been entered: 16 in phase I, and 37 in phase II. Phase I study established MTD of UFT to be 300mg/m2. The dose limiting toxicities were diarrhea, neutropenic fever and fatigue. The efficacy of both phase I and II were similar and the results were pooled together. 45 patients were evaluable for response so far. The mean age was 54, PS0 77%, 1–20%, 2 -3%. Nine had disease in one organ, thirteen in 2 organs and twenty-four in more than 2 organs. CR6 (13%), PR25 (56%), SD8 (18%) and PD6 (13%), the overall response rate is 69%. Only 15 patients died, the median time to progression and survival has not been reached with 15 months of median follow-up. The grade ¾ toxicities included fatigue (16%) Diarrhea (16%) Vomiting (9%) neutropenia (4.5%), neutropenic fever (2%) peripheral neuropathy (4.5%). Conclusions: Combination of weekly paclitaxel and UFT/LV is well tolerated and highly active as the first line treatment for patients with MBC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Bristol-Myers Squibb
EGFR expression by immunohistochemistry (IHC) and response to chemotherapy and cetuximab in squamous cell carcinoma of the head and neck (SCCHN)
Authors: M. S. Kies, M. S. Ghebremichael, T. L. Katz, R. S. Herbst, H. Youssoufian, B. Burtness
Journal: Journal of Clinical Oncology (2007)

6024 Background: There is modest activity for cetuximab in recurrent SCCHN. Molecular markers for patient selection are desirable. Burtness et al (JCO 23:8646, 2005) reported that high EGFR expression predicted for tumor resistance to chemotherapy (CT) with or without cetuximab. We have studied an independent cohort of patients from the IMC-9816 study (Herbst et al, JCO 23:5578, 2005) using the same EGFR immunoreactivity staining technique. Methods: Slides were prepared from formalin fixed paraffin embedded tissue with the DAKO kit, with staining intensity graded on an ordinal scale 0–3 and staining density assessed according to the percentage of cells stained. High expression was defined as staining intensity 3 + on = 80% of cells. Tumor samples were available in 77 pts from the initial cohort of 132 patients with recurrent SCCHN who received cisplatin-based CT. Of the latter, 76 patients were assessed to have stable (SD 51) or progressive disease (PD 25) and then treated with cetuximab and cisplatin. An amendment permitted further enrollment of patients with PD after off study cisplatin therapy (N 54). Of a total of 130 pts who received cetuximab and cisplatin, tumor samples were available from 86. Results: There was no association of response with EGFR expression. Responses to CT are tabulated. Of the 86 SD and PD pts receiving CT and cetuximab, responses were observed in 3 of 44 and 7 of 42 pts with low and high EGFR expression, respectively (p=0.191). In a survival analysis of patients treated with cetuximab, the hazard ratio for subjects with high EGFR was 0.835, p=0.40. Conclusions: Conventional IHC, even when supplemented by staining intensity and staining density, does not predict for responsiveness of SCCHN to CT, with or without cetuximab. Future studies may require more quantitative methods, possibly subcellular localization, and measurement of other EGFR pathway targets, ligand content and probably “down-stream” effectors. No significant financial relationships to disclose. [Table: see text]
Analysis of therapy of community-acquired pneumonia (CAP) at the COPD patients
Authors: Hanna Demchuk, Yuriy Mostovoy
Journal: European Respiratory Journal (2011)

To assess extent, accuracy and efficiency of therapy of CAP at patients (PT) with COPD case histories of 252 inpatients (54,4% males, mean age 59,03±13,75) admitted due to CAP and COPD exacerbation were analyzed. PT with non-severe CAP were 94,8%. Moderate COPD had 54,4% PT, severe COPD – 34,1%, very severe COPD - 4%. Cardiovascular diseases were more than 60% PT. Analysis of therapy revealed average amount of prescribed medicines was 11,72±3,24. The most frequently used antibiotics was cephalosporines of third generation (61,9%), macrolides (21,4%), ciprofloxacin (20,6%) and inhibitor-protected aminopenicillins (14,3%). Correct combination of beta-lactam+macrolide was prescribed 40,2%. Combinations of fluoroquinolone with beta-lactam received 12,1% or fluoroquinolone+amicacin - 7,5%. These combinations are alternative treatment for investigated PT. Non-recommended antibacterial therapy received 18,6%. Amoxicillin/clavulanate±macrolide, cefriaxon±macrolide and ciprofloxacin±beta-lactam or amicacin was the most effective treatment (in 99,6%, 95,0% and 95,2% PT, relatively). For COPD exacerbation9s therapy systemic theophylline and corticosteroids were prescribed 59,5% and 52,4%, relatively, nebulization of inhaled corticosteroids and beta2-agonists - 11,5% and 27,8%. Mucolytics received 90,5%. Medications with non-established efficacy for CAP and COPD exacerbation received 76,2% PT. Non-recommended medicines for cardiovascular diseases were used for 53,3%. Thus the most of CAP PT with COPD received recommended, effective antibacterial therapy. The additional studies are needed for creation of reasonable guidelines for management of CAP patient with multiple concomitant diseases.
Abstract 14648: Interleukin-18 Blockade Prevents Diastolic Dysfunction in a Mouse Model of Heart Failure With Preserved Ejection Fraction
Authors: Jessica A Regan, Adolofo G Mauro, Salvatore Carbone, Carlo Marchetti, Eleonora Mezzaroma, Donatas Krauskaus, Fadi N Salloum, Charles A Dinarello, Benjamin Van Tassel, Antonio Abbate, Stefano Toldo
Journal: Circulation (2015)

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.
Predictive factors of regresion grade in patients with locally advanced rectal cancer treated with preoperative radiotherapy and capecitabine
Authors: J. Salinas, J. Lujan, M. Porras, G. Valero, J. Alonso
Journal: Journal of Clinical Oncology (2008)

15081 Background: the aim of this study was to look for predictive factors of response in our series of patient treated at our institution with preoperative radiotherapy and capecitabine between 2003 to 2007. Methods: Seventy-eight patients with locally advanced rectal carcinoma (T3/T4 or N+) received 3D-radiotherapy (50,4–54Gy/28–30fractions) and chemotherapy with capecitabine (825mg/m2/12h on a continuous form). TME was performed 6–8 weeks after the end of the treatment. Results: There was 49 male and 29 female. Mean age 61,5 (range 26–85). ECOG 0:44p, 1: 33p, 2: 1p. Clinical stage (determined by EUS plus CT and/or MRI): cT2N1 1p, cT3N0 30p, cT3N1 38p, cT3N2 6p, cT4N1 2p, cT4N2 1p. Tumor location were inferior in 33p, medium in 37p and superior in 8p. Mean CEA level 17 (range 1–356). Radiotherapy dose was 50,4Gy in 45p and 54,4 in 33p. Surgery consisted of low anterior resection in 56p, and abdominoperineal resection in 20p (two patients were R2). Tumor downstaging was observed in 55p (70,5%), including 13p with complete pathological response (16,7%) and 19p with only microfoci of tumor remaining (24,4%). 66,7% received adjuvant chemotherapy. Main adverse event (CTC): diarrhea G3–4: 25,6%, skin G2–3: 9%, hemathologic G2–3: 5,4% and hand-foot syndrome 5%. Predictive factor analysis: only CEA level and clinical tumor staging showed significant correlation with tumor response. Conclusions: Preoperative chemoradiotherapy with capecitabine is an excellent tolerated regimen with high probability of tumor downstaging. Our results showed that CEA level and clinical tumor staging with EUS and CT/MRI were a significant correlation with grade of regresion. No significant financial relationships to disclose.