tbuckley/cabot-search huggingface dataset:
Integrated report of the phase 2 experience with XL999 administered IV to patients (pts) with NSCLC, renal cell CA (RCC), metastatic colorectal CA (CRC), recurrent ovarian CA, acute myelogenous leaukemia (AML), and multiple myeloma (MM)
Authors: L. Cripe, W. McGuire, M. Wertheim, P. Eisenberg, W. Stadler, R. Paquette, T. Logan, T. Zimmerman, D. Matei, U. Matulonis
Journal: Journal of Clinical Oncology (2007)

3591 Background: XL999 is a potent spectrum-selective inhibitor of tyrosine kinases including VEGFR2/KDR, FGFR1/3, PDGFR-β, FLT3, RET, KIT, &amp; SRC. A Ph 1 study in pts w/advanced malignancies has shown anti-tumor activity (3 PRs &amp;10 SD lasting 3–26 + months) DLTs were cardiac failure &amp; transaminase elevation. Methods: XL999 is being investigated in 6 Ph 2 trials. Pts w/histologically confirmed NSCLC, RCC, CRC, recurrent ovarian CA, AML, &amp; MM were enrolled. The primary objectives of these independent studies are to determine response rate and further evaluate safety and tolerability of XL999. The secondary objectives are to assess PFS, duration of response &amp; OS. Pts receive a once wkly 4hr IV administration of XL999 (2.4 mg/kg). Tumor response is assessed every 8 wks. Results: A total of 79 pts were treated. A confirmed PR was reported in 1/ 9 pts w/NSCLC. An additional 2 pts have SD at 2 &amp; 3 months w/1 showing tumor shrinkage (24%). Two of 11 pts w/RCC have SD at 2 &amp; 4 months. Of 14 pts enrolled w/AML, 1 of 3 with an activating FLT3 mutation had a PR, and 8 of 10 w/circulating myeloblasts had &gt;50% reduction in myeloblasts. AEs = Grade 2 in =10% of pts related to XL999 included N/V, constipation, diarrhea, dry mouth, oral hypoesthesia, fatigue, pyrexia, dizziness, dysguesia, &amp; hypertension. Cardiovascular (CV) events considered SAEs were reported in 11 pts (14%), and all but 1 occurred with the 1st dose of XL999.These events were characterized by ST /T wave changes in ECG,LVEF decreases and /or troponin elevation. Most pts with CV SAEs recovered to baseline within 2–3 wks upon withdrawl of further XL999. Conclusions: XL999 administered IV at a dose of 2.4mg/kg wkly was associated w/CV AEs, the majority of which were associated w/the 1st dose and were generally reversible upon XL999 discontinuation. XL999 shows preliminary evidence of anti- tumor activity in pts w/NSCLC &amp; AML. [Table: see text]
A prospective economic analysis of cost-effectiveness of cetuximab for metastatic colorectal cancer patients from the NCIC CTG and AGITG CO.17 trial
Authors: N. Mittmann, H. J. Au, D. Tu, C. J. O'Callaghan, C. S. Karapetis, M. J. Moore, J. Zalcberg, J. Simes, W. K. Evans, D. J. Jonker
Journal: Journal of Clinical Oncology (2008)

6528 Background: CO.17 study is the first intergroup (Canadian/Australian) trial, that prospectively collected resource utilization and utility data for cetuximab (N=283) vs. best supportive care alone (BSC; N=274) in advanced colorectal cancer patients. A cost-effectiveness analysis was conducted based on the improved survival, higher cost of cetuximab and variable costs across countries from the perspective of the Canadian health care system. Methods: The mean difference in trial survival times between cetuximab and BSC was calculated. Direct medical resource utilization data was collected during the trial from the time of randomization until death or study closure. Trial resources included medications physician visits, toxicity management, institutionalization, emergency department visits and hospitalizations. Mean overall incremental cost (2007 $CAN-provincial sources) was determined. Drug acquisition costs (DAC) for cetuximab, based on several countries, were used to determine the incremental cost effectiveness ratio (ICER) in dollars per life-year gained (LYG). Sensitivity analyses for cetuximab DACs were conducted. Bootstrapping (1,000 iterations) provided 95%CI. Results: Mean incremental trial survival was 0.12 years. Preliminary results showed variability in the ICER, where DAC was the cost driver. At the lowest DAC ($2.94/mg), overall incremental costs were $19,361 for cetuximab compared to BSC, with incremental values of $1,086 for toxicity management, $1,016 for hospitalization, and $410 plus $81 for oncologist and family physician visits respectively. The ICER for cetuximab was $183,287/LYG (95%CI: $114,139-$581,027) using a $2.94/mg DAC (Switzerland), $198,467/LYG ($123,509-$558,270; $3.24/mg-Canadian suggested) and $375,047/LYG ($237,139- $1,233,111; $6.73/mg US). Sensitivity analyses produced an ICER of $50,000/LYG at $0.28/mg; $100,000/LYG at $1.30/mg and $200,000/LYG at $3.27/mg. Cost per quality adjusted life year will also be determined. Conclusions: Cetuximab showed high and variable ICERs dependent on a range of DACs in CO.17 advanced colorectal cancer patients. Utility will impact the incremental value. No significant financial relationships to disclose.
Low ER level is one factor in the resistance of ER-positive and HER-2-positive tumors to hormone therapy
Authors: J. Horiguchi
Journal: Journal of Clinical Oncology (2004)

809 Introduction: Some clinical data have suggested that HER-2 overexpression might be associated with tamoxifen resistance in patients with hormone receptor-positive breast cancer. The purpose of this study was to evaluate the inter-site variation of ER and HER-2 expression and ER and HER-2 levels as identified using immunohistochemistry. Methods: A total of 227 women with invasive breast cancer undergoing surgical treatment between 1991 and 2001 were included in this study. Paraffin-embedded tumor tissues were used in immunohistochemical study. Double staining was performed using both ER and HER-2 antibody. ER expression was assessed using the Allred score. HER-2 score was determined using the HercepTest score. Both the ER- and HER-2-positive tumors were classified into two types; co-expressed type and separately expressed type. Results: HER-2 expression was inversely correlated with ER expression. When evaluated in ER-positive patients, HER-2 overexpression was associated with lower ER levels. ER and HER-2-positive tumors were observed in 22 (9.7%) of 227 tumors. The co-expressed type was found in 10 patients, and the separately expressed type was found in 12 patients. ER and HER-2 scores were significant prognostic factors, however, there was no difference in disease-free survival between patients with the co-expressed type tumors and the separately expressed type tumors. Conclusions: Low ER levels might be one factor in the relative resistance of ER-positive and HER-2-positive tumors to hormonal therapy. No significant financial relationships to disclose.
Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer.
Authors: S A Rosenberg, M T Lotze, J C Yang, W M Linehan, C Seipp, S Calabro, S E Karp, R M Sherry, S Steinberg, D E White
Journal: Journal of Clinical Oncology (1989)

We performed an escalating dose study of the combined administration of interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) in 94 patients with metastatic cancer. Patients received alpha-IFN at a dose of 3 x 10(6) U/m2 in conjunction with IL-2 at doses of either 1 x 10(6) U/m2 (six patients), 3 x 10(6) U/m2 (32 patients), or 4.5 x 10(6) U/m2 (26 patients). Thirty patients received alpha-IFN at 6 x 10(6) U/m2 plus IL-2 at 4.5 x 10(6) U/m2. Patients each received cytokine as an intravenous bolus infusion every 8 hours for up to 5 consecutive days and after a 10-day rest received a second cycle of combination cytokines. Of the 91 patients evaluable for response, seven patients had a complete regression of cancer, and 18 had a partial regression. At the four increasing dose levels used in patients with renal cell cancer (35 patients) or melanoma (39 patients), objective responses were seen in 17% (of six patients), 24% (of 25 patients), 38% (of 16 patients), and 41% (of 27 patients), respectively. Of the 25 total responding patients, 16 are still responding 5 to 14 months after treatment. The toxicities associated with the combined administration of IL-2 and alpha-IFN were similar to those expected from each agent alone. There was one treatment-related death in the 94 patients treated in this study. Thus, using increasing doses of the combination of IL-2 and alpha-IFN, it appears that response rates may be related to the doses of the cytokines used, and that at the highest doses of these combination cytokines, response rates may be higher than those for either cytokine alone. A prospective randomized trial comparing the cytokine combinations with each cytokine administered alone is necessary as is the extension of this combination cytokine treatment to patients with other types of solid cancer.
Bevacizumab (BEV) in combination with temozolomide (TMZ) and radiation therapy (XRT) followed by BEV, TMZ, and irinotecan for newly diagnosed glioblastoma multiforme (GBM).
Authors: J. J. Vredenburgh, A. Desjardins, D. A. Reardon, K. Peters, J. Kirkpatrick, J. E. Herndon, J. Marcello, L. Bailey, S. Threatt, H. S. Friedman
Journal: Journal of Clinical Oncology (2010)

2023 Background: The prognosis for newly diagnosed GBM remains poor. The addition of TMZ to radiation therapy improved the median progression-free survival (PFS) to 6.9 months and median overall survival to 15.8 months. GBMs have abundant neo- vascularization and the highest levels of vascular endothelial growth factor (VEGF). BEV is an antibody to VEGF and is the most active agent tested for recurrent GBM. Methods: 125 newly diagnosed GBM patients were enrolled between 8/07 and 3/09. Patients received radiation therapy and TMZ at 75 mg/m2/d beginning between 2-6 weeks post-craniotomy. BEV at 10 mg/kg every 14 days was added a minimum of 4 weeks post- op. Following radiation therapy, patients received 6-12 monthly cycles of TMZ at 200 mg/m2/d days 1-5, BEV at 10 mg/kg and irinotecan on days 1 and 15. The dose of irinotecan was 340 mg/m2 for patients on enzyme inducing anti-epileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAED. This efficacy analysis is based on the first 75 patients and the toxicity analysis includes all 125 patients. Results: The addition of BEV and irinotecan to standard therapy doubled the median PFS, 14 months vs. 6.9 months. The median overall survival has not been reached, but 56% of the patients are alive at a minimum follow-up of 18 months. In addition, 28% remain progression-free at a median follow- up of 23 months. The regimen was tolerable, 122 of 125 patients completed radiation therapy and 78 completed 6 cycles of post-radiation BEV, TMZ, and irinotecan. The toxicities are listed below (Table). There were 4 toxic deaths, MI, PE, PCP, and sepsis. A comprehensive analysis of tumor biomarkers is underway. Conclusions: The addition of BEV to TMZ and radiation followed by TMZ, BEV, and irinotecan is tolerable. The median progression-free survival is improved and the overall survival is prolonged. Toxicity No. CNS hemorrhage 1 PE/DVT 9 Wound dehiscence 2 Grade 4 heme tox 17 Bowel perforation 1 Secondary AML 1 PCP 2 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Roche Genentech Genentech
Effect of combined sequential treatment of sipuleucel-T followed by enzalutamide in metastatic chemo-naïve castration-resistant prostate cancer: Results of single center of large urology group.
Authors: Vladimir Mouraviev, Christopher Michael Pieczonka, Dimitios Telonis, David Albala
Journal: Journal of Clinical Oncology (2015)

241 Background: The timing and sequencing of combination therapy is becoming of outmost importance for the treatment of mCRPC patients. As a result our hypothesis has been to layer on enzalutamide very quickly after the completion of sipuleucel-T. Methods: We collected the data of 84 patients with chemo-naïve mCRPC treated with sipuleucel-T at our practice from September 2011 to January 2014. Prior to the initiation of treatment the baseline status was recorded in all patients. We then selected and analyzed outcomes of 19 patients who received sequential enzalutamide treatment after completion of sipuleucel-T. The average timing for the initiation of enzalutamide was 2.5±1.6 months after completion of the immune therapy. We believe this to be a very unique cohort as all of these patients were treated with enzalutamide off label (i.e. pre-chemo). Results: The median time of enzalutamide therapy was 5.4 months (range: 1-13). In our cohort of 19 patients: 1 case showed radiographic full regression of metastatic lesions in bone, lung and lymph nodes. Another case showed radiographic full regression of bony metastatic lesions. 2 other cases – showed a partial regression radiographically of bony metastatic disease. 13 cases showed stable disease according to RECIST-criteria. The remaining 2 patients were deceased due to progression of mCRPC. The patients with full and partial response were in the lowest quartile of our cohort as defined as a PSA ≤ 3.87 ng/ml. On the contrary, all cases of progression and death were documented in highest (last) quartile as defined by a PSA level more than 84 ng/ml. Conclusions: Our experience demonstrates a promising effect using sequential sipuleucel-T immunotherapy followed by enzalutamide for mCRPC. To our knowledge this will be the first case of complete radiographic regression of lung, bone, and extensive lymph node disease. Currently there are studies undergoing that will hopefully validate our experience with using enzalutamide at the initiation of sipuleucel-T.
Atrial fibrillation-induced electrical remodeling in humans What is the next step?
Authors: M Allessie
Journal: Cardiovascular Research (1999)

See article by Bosch et al. [1] (pages 121–131) in this issue. 

In the article elsewhere in this issue, “Ionic mechanisms of electrical remodeling in human atrial fibrillation”, Ralph Bosch and co-workers [1] describe the changes in atrial action potential characteristics and ion-channel densities in 8 patients with chronic atrial fibrillation (AF). The action potentials of single atrial cells isolated from patients in AF, showed a normal resting membrane potential more negative than −75 mV and amplitudes higher than 115 mV. However, compared to patients in sinus rhythm the repolarization phase was markedly changed. Both, the early rapid repolarization (phase 1), carried by Ito and the plateau of the action potential mainly carried by ICa,L(phase 2), were clearly attenuated or even abolished. As a result, atrial cells in AF patients seemed to repolarize almost exclusively by phase 3 repolarization. The total duration of the action potential was markedly decreased. At a pacing rate of 60 beats/minute, the duration had shortened from a control value of 255±45 ms to 104±9 ms (a reduction of 60%). In addition, also the physiological rate adaptation was reduced and the atrial action potentials showed almost no shortening anymore when the stimulation frequency was increased (98±8 ms at 240 beats/minute). An important consequence of this loss of the physiological rate adaptation is that chronically fibrillating atria can no longer be expected to prolong their action potentials when sinus rhythm is restored. Since short action potentials (and short refractory periods) facilitate the induction of atrial re-entry, this maladaptation may be the pathophysiological basis for the frequently observed early recurrences after cardioversion of AF [2,3].

Long-term shortening of the atrial refractory period by rapid pacing or atrial fibrillation has first been demonstrated in chronically instrumented dogs and goats [4,5]. In the goat, artificial … 

* Tel.: +043-388-1202-00; fax: +043-388-41-66
A Single Intravenous Dose of Murine Megakaryocyte Growth and Development Factor Potently Stimulates Platelet Production, Challenging the Necessity for Daily Administration
Authors: Najat C. Daw, Julie T. Arnold, Basel A. Abushullaih, Paula E. Stenberg, Melanie M. White, Deepthi Jayawardene, Deo Kumar Srivastava, Carl W. Jackson
Journal: Blood (1998)
Heart exposure in 100 consecutive, unselected patients treated with adjuvant 3D conformal radiotherapy for left-sided breast cancer.
Authors: Federico Lonardi, Gloria Gioga, Manuela Coeli, Franco Campostrini
Journal: Journal of Clinical Oncology (2013)

103 Background: Women treated with radiotherapy for left-sided breast cancer may have their heart exposed to doses ranging from 1 to 7 Gy on the average. This was confirmed by a recent study* focusing on the ischemic risk based on medical records dating back to 1950s. Modern 3D conformal radiotherapy (3D-CRT), however, may play a major role in heart-sparing irradiation. Methods: We reviewed the treatment planning records and dose-volume histograms of 100 consecutive, unselected patients (pts) affected with left-sided breast cancer who underwent adjuvant 3D-CRT after either quadrantectomy (90 pts) or mastectomy (10 pts) in our center during the year 2011. Median age was 52 (range 42-90). The whole breast (or chest wall) received 50 Gy / 25 fractions in 66 pts and 45 Gy / 18 fractions in 34. Boost to surgical bed (10 Gy / 4-5 fractions) was delivered by photons in 10 pts. Median number of tangential fields was 2 (range 2-4). All treatments were performed in the supine position. Results: The average of the median doses to the whole heart was 2.89 Gy (range 0.8 to 13.05). Median doses were: 1.15 to 1.99 Gy in 21 pts; 2.01 to 3.00 Gy in 32 pts; 3.06 to 3.98 Gy in 16 pts; 4.16 to 4.83 Gy in 13 pts. Median dose only exceeded 5 Gy in 17 pts. One pt received less than 1 Gy and one pt more than 13 Gy. Median volumes (mV) of heart exposed to 5 Gy, 10 Gy and 15 Gy were: mV5 ≤ 4% (range 1 to 42%), mV10 ≤ 3% (0 to 30%), mV15 ≤ 2% (0 to 24%). Conclusions: The average doses we registered are lower than those (4.9 Gy, range 0.03 to 27.72) reported in the large investigation by Darby et al.*. Although related to a small case series, our data confirm that contemporary 3D conformal techniques allow reduced median doses to the whole heart with potential favorable impact on the risk of radiation-induced cardiac disease in the coming decades. Estimate of cardiac involvement in breast cancer radiotherapy based on older case series and outdated treatment techniques may be misleading. *Darby SC et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. NEJM 368, 11, 2013.
The 4th Euro-Mediterranean Conference of Natural Products and Drug Discovery: Back to Mother Nature (BioNat-IV), Cairo/Sharm El-Sheikh, Egypt, March 3–7, 2015
Authors: Ashraf A. Khalil, Marwa M.S. Diab, Kamal D. Moudgil
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The 4th Euro-Mediterranean Conference of Natural Products and Drug Discovery: Back to Mother Nature (BioNat-IV) was recently (from March 3rd through 7th, 2015) convened in Cairo and Sharm El-Sheikh along the Red Sea coast of Egypt. Overall, the meeting provided a platform for scientists from different nations to discuss emerging ideas that focused on cell signaling in cancer; the pathogenesis of autoimmune diseases; the identification and use of natural products as well as novel drug delivery approaches for the treatment of cancer, arthritis, diabetes, tuberculosis, fungal infection, etc.; and untapped or unconventional sources for natural products. This fourth in a row conference tried to bridge the gap not only between basic research and clinical applications, but also between developed nations and developing countries. With the continuing success of these past meetings, the fifth Euro-Mediterranean Conference of Natural Products and Drug Discovery (BioNat-V) is slated to be in February 2017.
Factors influencing outcome after pulmonary resection for colorectal cancer (CRC) metastases in the current era
Authors: M. W. Onaitis, J. Haney, R. Petersen, L. B. Saltz, R. M. Flores, N. Rizk, M. S. Bains, T. D'Amico, N. E. Kemeny, V. W. Rusch, R. J. Downey
Journal: Journal of Clinical Oncology (2008)

4024 Background: We examined the role for surgery and factors associated with relapse-free and overall survival after pulmonary metastasectomy for CRC. Methods: A retrospective review of prospective databases at two tertiary-care centers was performed to identify patients who underwent complete resection of all macroscopic disease from 1998 to 2007. Results: 377 study patients were identified. The primary site of disease was rectum (52%), left colon (26%), right colon (16%), and other (6%). Before thoracic recurrence, 156 patients (41%) underwent resection of extrathoracic metastases. Median disease-free interval (DFI) was 24 months from time of primary operation. Resection was a single or multiple wedge resections in 72%, lobectomy in 19%, segmentectomy in 7%, and bilobectomy in 2%. Number of metastatic deposits resected was 1 in 60%, 2 in 20%, 3 in 10%, and 4 or more in 10%. Median size of the largest nodule was 1.5 cm. Pre-resection chemotherapy was administered to 87 patients (23%). Post-resection chemotherapy was delivered to 169 patients (45%). Kaplan-Meier recurrence-free survival was 28% and overall survival was 78% at 3 years. Regarding recurrence-free survival, univariate analysis revealed age <65 years, gender, DFI <1 year, number of metastases ≥3 as significant predictors, and presence of prior extrathoracic disease trended toward signficance. Multivariable analysis revealed age <65 years, female gender, DFI <1 year, and number of metastases ≥3 as independent predictors of recurrence. Of 44 patients with 3 or more lesions and <1 year DFI, none was cured by operaton. By contrast, recurrence-free survival was 49% at 3 years for those with 1 lesion and DFI >1 year. Conclusions: Age less than 65 years, female gender, DFI <1 year, and number of metastases 3 or greater are independent predictors of recurrence. Non-surgical management should be considered standard for patients who have both 3 or more pulmonary metastases and <1 year DFI. Recurrence-free Multivariable Analysis Hazard Ratio [95% CI] p Age>65 0.65 [0.47,0.90] 0.01 Male gender 0.64 [0.46,0.89] 0.009 DFI<1 year 1.57 [1.15,2.15] 0.005 No. mets ≥3 1.85 [1.28,2.69] 0.001 No significant financial relationships to disclose.