tbuckley/cabot-search huggingface dataset:
Absolute benefits of experimental medical therapies in phase III randomized clinical trials (RCTs) in breast and colorectal cancer
Authors: B. Seruga, P. C. Hertz, L. Wang, C. M. Booth, M. Krzyzanowska, D. W. Cescon, I. F. Tannock
Journal: Journal of Clinical Oncology (2009)

6513 Background: New treatments are approved based on results of RCTs, which have become larger and powered to detect smaller absolute benefits (Booth et al, J Clin Oncol 26, 2008).The purpose of this study was to evaluate temporal trends in absolute benefits of experimental medical therapies in RCTs. Methods: RCTs with 200 or more participants evaluating medical therapies for breast and colorectal cancer were identified by searching Medline from 1975 to 2007. For each trial, absolute benefits were determined as: (i) the difference in either 3-year event-free survival (EFS) or 5-year overall survival (OS) for adjuvant trials, or in median survival for metastatic trials, as per usual practice; and (ii) the area between time-to-event curves for the treatment arms relative to total area, up to a given time. Monthly incremental cost of new therapies approved by the FDA between 1995 and 2007 were determined for treatments for metastatic disease. Results: We identified 236 eligible RCTs, with 57% evaluating adjuvant treatments for breast (N=102) and colorectal cancer (N=33). Median absolute benefits of experimental treatments decreased substantially in the last decade (Table) and were in the range of only 1.3 to 2.7% when analyzed as the relative area between time-to-event curves. Among RCTs evaluating treatment for metastatic cancer there was no change in absolute benefits with time, but incremental monthly cost of new approved treatments increased with time (1995: median $U.S. 65; 2007: median $U.S. 6560, p&lt;0.0001). Conclusions: Evaluating absolute benefit as the relative area between time-to-event curves does not depend on the shape of the curves and is preferred. Over time, RCTs evaluating adjuvant treatment for breast and colorectal cancer show decreasing absolute benefit. New costly treatments may not assure meaningful clinical benefits. [Table: see text] No significant financial relationships to disclose.
Current practices in 1st- (1L), 2nd- (2L), and 3rd-line (3L) treatment for metastatic colorectal cancer (mCRC).
Authors: Stephen F Thompson, Sheikh Usman Iqbal, Sarah Naoshy, Daniel B Ng, Michael L Andria, Steven A Sherman, Elisabetta Malangone, Lee Stern, Magdaliz Gorritz-Kindu
Journal: Journal of Clinical Oncology (2012)

e14028 Background: Up-to-date information concerning the optimal regimen assignment and sequencing of therapies is lacking for the treatment of mCRC patients. By tracking trends in treatment choice, this retrospective, observational study assesses current treatment patterns in mCRC patients by line of therapy. Methods: Using electronic medical record data from one of the largest US oncology databases (SDI), treatment regimens for 1L, 2L, and 3L were assessed for patients age ≥18 yrs diagnosed with mCRC from 1/1/04-7/31/11 who received anticancer agents. Results: 1,793 stage IV patients were identified in 1L, 1,050 in 2L, and 504 in 3L. Overall mean age was 60.4 yrs, and 54.6% were men. The most common comorbidities were hypertension (18.0%), lipid metabolism disorders (10.6%), and diabetes (8.6%). 47.8% had commercial insurance, 37.2% Medicare, 8.5% Medicaid, and 4.6% self pay. 1,026 patients received bevacizumab (B) in 1L, 583 in 2L, and 204 in 3L. Patients were more likely to receive FOLFOX (FX) + B in 1L and 2L. The top 3 regimens are shown in the table below. For patients who began treatment with B and continued B in a subsequent regimen, mean dose of B increased from 443.7 mg/kg (1L) to 567.0 mg/kg (2L) and 618.1 mg/kg (3L). Conclusions: FX is the regimen of choice in mCRC. In terms of biologics, B is more commonly used in 1L/2L than 3L. Given that approximately half the mCRC patients progressed to 2L/3L treatment, this likely reflects an unmet need for advanced therapies for the effective treatment of the disease. Furthermore, consistent dose escalation with continued B use across 2L/3L was seen despite that use of B in 3L mCRC is inconsistent with NCCN guidelines. Additional research on outcomes implications is needed, including mortality, patient toxicity, and costs. [Table: see text]
Abstract 16013: Direct Nkx2-5 Transcriptional Repression of Isl1 Controls Cardiomyocyte Subtype Identity
Authors: Alexander Goedel, Tatjana Dorn, Jason T Lam, Franziska Herrmann, Jessica Haas, Karin Bundschu, Gergana Dobreva, Matthias Schiemann, Ralf Dirschinger, Susanne J Kühl, Daniel Sinnecker, Alessandra Moretti, Michael Kühl, Karl-Ludwig Laugwitz
Journal: Circulation (2014)

During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the LIM-homeodomain transcription factor Islet-1 (Isl1) and the homeobox protein Nkx2-5. Here, we show that a direct repression of Isl1 transcription by Nkx2-5 is necessary for proper specification and maturation of ventricular and atrial chamber-specific myocardial lineages. Overexpression of Nkx2-5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in the Isl1+ precursor population. These effects were partially rescued by Isl1 overexpression. Embryos deficient for Nkx2-5 in the Isl1+ lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube (Figure 1A). We demonstrated that Nkx2-5 directly binds to an Isl1 gene enhancer and represses the transcriptional activity of Isl1. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, Isl1 overexpression in ESCs leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased number of cardiomyocytes (Figure 1B). Functional and molecular analysis of Isl1-overexpressing cardiomyocytes revealed higher beating frequencies in both ESC-derived contracting areas and Xenopus Isl1-gain-of-function hearts (Figure 1C), which was associated with upregulation of nodal-specific genes and downregulation of transcripts of working myocardium. Our findings provide an Isl1/Nkx2-5-mediated mechanism that coordinately regulates the specification of cardiac progenitors towards the different myocardial lineages and ensures proper acquisition of myocyte subtype-identity (Figure 1D).
A longitudinal pilot study to investigate whether hormonal therapy for prostate cancer affects cognition
Authors: D. J. Bloomfield, V. Shilling, T. Edginton, V. Jenkins
Journal: Journal of Clinical Oncology (2004)

4646 Background: Hormone therapies for prostate cancer block or lower the action of testosterone, and testosterone is related to cognitive ability (Wolf & Kirschbaum 2002). Testosterone supplementation can improve spatial and verbal memory (Cherrier et al 2001). Cognitive functioning plays an important role in a patient's quality of life but few studies have investigated the potential effects of anti-androgen therapy on cognition. Methods: Patients (n=34) receiving temporary reversible medical castration with an LHRH agonist as neo-adjuvant hormone therapy prior to radical radiotherapy for localised prostate cancer. Healthy controls (n=18) similar in age and intelligence to calculate a reliable change index. Each participant was tested at baseline (T1) and followed up at three months (T2), and following the end of therapy at one year (T3). The same assessment of mood and cognition was made at every time-point. Serum testosterone and oestradiol were measured alongside psychometric testing. The Cognitive test battery included tests of spatial ability, visual memory, working memory, verbal memory and processing speed. FACT P and General Health Questionnaire 12 were also administered. Reliable Change Index is a method of defining change in neuropsychological test scores that accounts for test reliability and practice effects, calculated from the control group's T1-T2 performance on each task. We looked at an individual patient's change in scores to see whether scores fall outside the RC 90% CI Results: At T2 seven patients remained above threshold on GHQ12. There were no overall group differences on the tasks. Biochemistry showed a significant drop in total & free testosterone and oestradiol levels (all p<0.0001). 16 patients declined on the reliable change index as opposed to 3 controls. Of these 8/16 declined on one task, 6/16 declined on two tasks and 2/16 on three tasks. Conclusions: Changes are occurring for some patients. Interview data with the T3 results (to be presented) will provide us with further information. No significant financial relationships to disclose.
Incidence of bevacizumab (BE) related toxicities: Association of hypertension (HTN) and proteinuria (PTN), a BE toxicity syndrome (BETS)
Authors: C. L. Martel, B. Ebrahimi, R. C. Horns, G. H. Upadhyaya, M. J. Vakil, C. H. Yeon, L. D. Bosserman, C. A. Presant
Journal: Journal of Clinical Oncology (2005)

8062 Background: BE, a monoclonal antibody that inhibits VEGF, prolongs survival in patients (pts) with metastatic colorectal cancer treated with 5FU chemotherapy. However, BE is associated with HTN, PTN, and other unique toxicities (T). We examined the incidence and management of BE T since FDA approval. Methods: 31 consecutive pts in 6 cancer centers who received BE were evaluated. Incidence of HTN (BP >140 systolic or >90 diastolic), PTN (any degree measured by dipstick and/or 24 hr urine protein) and other T was analyzed. Results: New or worsened HTN developed in 6 pts (19%). Three pts with HTN pre BE developed grade 3 HTN, controlled with an increase in dose of prior antihypertensives (2 pt) or with no change in treatment (1). One pt had de novo grade 2 HTN controlled with antihypertensives and 2 pts had untreated de novo grade 1 HTN. PTN was seen in 6 pt (19%), 5 of whom also developed HTN. Four pts had trace or 1+ protein on dipstick. One pt had 2+ protein on dipstick but only 362 mg/24 hr. One pt had 2430 mg protein/ 24 hr, and BE was stopped. There was a statistically significant association of HTN and PTN (p<0.0005); 16% of pts developed a syndrome we call BETS with both HTN and PTN. Other T were perforated nasal septum (1), anal fissure (1), and gastrointestinal bleed (2); all of these pt discontinued BE. Total incidence of T was 11/31 (35%). Conclusions: The use of BE after FDA approval has been associated with acceptably low T rates. However, significant adverse events do occur. Because in clinical practice HTN and PTN appear to be associated, we suggest that management of BETS include antihypertensive drugs protective against progressive proteinuria and nephropathy, such as ACE inhibitors. Further, since BE may be increasingly used in pts with prolonged survival, early prevention of BETS may allow more prolonged BE usage. Consideration of ACE inhibitors at earliest sign of BP elevation or even trace proteinuria may enhance total cumulative BE dosage, which could potentially improve survival while decreasing T. Prospective trials of management of BETS are indicated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Clinical significance of ERCC1 expression in advanced squamous cell carcinoma of the head and neck treated with cisplatin- based concurrent chemoradiation
Authors: H. Jun, M. Ahn, H. Kim, B. Park, J. Han, Y. Ahn, H. Jeong, Y. Son, J. Baek, K. Park
Journal: Journal of Clinical Oncology (2007)

6061 Background: The cytotoxic effect of cisplatin is based on the DNA cross linking. Nucleotide excision repair is associated with resistant to platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in nucleotide excision repair pathway. We evaluated the expression of ERCC1 as a predictive factor for survival in patients of squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). Methods: We reviewed the clinical records and pathologic specimens of locally advanced SCCHN patients who had been treated with cisplatin-based definitive CCRT between 1995 and 2005. ERCC1 expression of the biopsy specimen was assessed by immunohistochemical (IHC) staining and a semi- quantitative grading system (H-score) was used for the evaluation. The median value of the H-score was chosen as the cutoff point for positive ERCC1 expression. Results: A total of 44 specimens and clinical data of the patients were reviewed. The median age was 59 years (range; 27–75), and 81.8% were male; 94.2% had ECOG performance status 0–1. The positive ERCC1 expression rate was 54.5% of all specimens (N=24/44). Overall tumor response rate for CCRT was 90.9% (CR=65.9%; PR=25.0%). With a median follow-up of 45.9 months (range; 5.4–133.0), 5-year progression free survival (PFS) rate was 58.0% and 5-year overall survival (OS) rate was 57.2%. Patients in group of positive ERCC1 expression showed poor survival in terms of PFS and OS (p=0.04; p=0.05), compared with negative ERCC1 expression group. Conclusions: The positive ERCC1 expression might be a predictive factor for poor survival and early progression in patients with locally advanced SCCHN treated with cisplatin-based CCRT. No significant financial relationships to disclose.
Increased blood levels of inflammatory cytokines CRP, TNF-α, CD40L, MCP-1 and Nitric Oxide in malignancy-associated thrombosis and their modulation by a low molecular weight heparin, Enoxaparin
Authors: J. Fareed, O. Iqbal, M. Tobu, D. A. Hoppensteadt, J. Cunanan, S. Cort, S. Deitcher
Journal: Journal of Clinical Oncology (2004)

6077 Background: Endogenous generation of inflammatory cytokines and induction of NO synthase (NOS, EC 1.1.4. 13.49) resulting in enhanced formation of NO free radicals contribute to the pathogenesis of vascular and thrombotic events in these patients. Patients recruited in an open label, multidose active comparator parallel design study were randomized to receive a low molecular weight heparin (LMWH) namely enoxaparin at a dose of 1–1.5 mg/kg SC for one week. Methods: Blood samples were collected prior to and 3–7 days after initiation of LMWH. These samples were analyzed for NO measurement utilizing a chemical method (Sievers 280i, Ionics Corp. Boulder, CO) and ELISA methods for MCP-1, CD40L, TNF-α (R&D Systems, Minneapolis, MN) and hsCRP (American Diagnostica, Stamford, CT). In addition to the control group (n=50), a group of medical patients with thrombosis without cancer were included (n=50). Results: The relative increase of these inflammatory markers in the cancer patients with thrombosis was higher in comparison to the two other groups. In particular, the CD40L levels were found to be 10-fold higher in comparison to normals. Patients with thrombosis without cancer exhibited only a 4-fold increase in comparison to normal. The MCP-1 levels showed a 5-fold increase in the cancer with thrombosis group, whereas cancer patients without thrombosis exhibited a 40% increase. HsCRP was much higher in the cancer patients with thrombosis when compared with cancer patients without thrombosis. The TNF-α levels were increased in both groups. Interestingly, the relative increase in the NO level was significantly higher in cancer patients with thrombosis 63.1± 50.1 μ M for ONCENOX and 39.8± 16.2 μ M for CORTES study. Cancer patients with thrombosis treated with LMWH for 3–7 days exhibited a marked downregulation of MCP-1, CD40L, hsCRP and NO. In the group of patients with thrombosis without cancer a decreased trend was noted. Conclusions: This observation clearly suggests that the pathogenesis of cancer-associated thrombosis is strongly influenced by inflammatory cytokines. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis; Mitsubishi; Pfizer
Registry of gastric cancer treatment evaluation (REGATE): Baseline characteristics of 10,299 patients from 22 countries
Authors: M. D. Ter-Ovanesov, Y. Bang, S. Yalcin, A. Roth, J. R. Zalcberg, V. Soloviev, M. K. Mallath, E. B. Ecstein- Fraisse, C. Wu
Journal: Journal of Clinical Oncology (2009)

4575 Background: Gastric cancer (GC) is the second most common cause of cancer death in the world. Recent advances in diagnosis and treatment provide new options in the management of this poor-prognosis disease. REGATE is an international disease registry designed to assess real-world practice patterns for patients (pts) with GC. Methods: Pts with newly diagnosed GC were enrolled. The target sample size was calculated according to the GC prevalence in participating countries. Data were collected at 2 visits occurring within a 10-month timeframe: baseline (pts and tumor characteristics, treatment plan) and after completion of initial treatment (actual therapy received). Characteristics of the patients at the time of enrollment are described. Results: From August 2004 to July 2008, 10,299 pts were enrolled by 223 investigators in 22 countries (Asia-Pacific 43%, Europe 31%, Latin-America 20%, and North Africa 6%). Characteristics are as follows. Median age 60 years (range: 18–104) with 23% of pts &lt;50 years. Male 65%, female 35%; 91% of pts were symptomatic; 8% had family history of GC; and 32% had H. pylori infection. GC was diagnosed by endoscopy in 95% of pts. Primary tumor location: antrum 39%, body 39%, proximal 17%. Histopathological type was assessed using WHO, Lauren, and/or Ming classifications in 75%, 60% and 31% of pts, respectively. The most common histopathological sub-types were diffuse (51%) and intestinal (44%) according to Lauren; signet ring cell (41%) and tubular (22%) according to WHO. Most patients (55%) had a poorly/undifferentiated tumor. AJCC stage at diagnosis: I-21%, II-20%, III-21%, IV-38%. Initial choice of planned therapy was mainly based on stage (69% of pts) and determined by either a multidisciplinary team (41%) or a surgeon alone (37%). Conclusions: REGATE is the largest prospective international disease registry that provides new insight into the characteristics of patients with newly diagnosed GC. Results including worldwide treatment patterns over time are expected after all patients have completed their initial treatment. [Table: see text]
Tuberculosis infection in chronic myeloid leukemia (CML) patients treated with imatinib.
Authors: N. Ghadyalpatil, K. Prabhash, H. Menon, R. Nair, S. Banavali, V. Noronha, V. Wabale, R. Singh, G. Goyal, V. Ostwal
Journal: Journal of Clinical Oncology (2010)

6594 Background: Imatinib (IM) is recommended as initial therapy for CML. However, concern exists regarding activation of tuberculosis secondary to IM induced immunosupression. There is little information about interaction of IM with antituberculosis drugs. Methods: We analyzed data of CML patients treated with IM. Past history of tuberculosis was noted. Patients were followed up for the reactivation of tuberculosis. Results: Data of 1100 patients of CML was analyzed. Records of 21 patients (9 females and 12 males) confirmed the history of tuberculosis (17 pulmonary, 4 extrapulmonary sites). Median follow-up of these patients was 49 months (range from 6-156 months). Importantly, no reactivation of tuberculosis was noted. One patient died due to disease progression. Interestingly, 3 other patients with no past history developed active tuberculosis on IM therapy. Mean duration for acquiring this infection was 17 months from the start of IM. This was confirmed by sputum examination 2 patients and radiological findings,lympocytosis and raised adenosine deaminase in the pleural effusion in another. None of these patients had neutropenia or lymphopenia at the time of reactivation. All 3 patients responded to the 4-drug antituberculosis therapy given for 6 months while IM was continued at increased dose of 600 mg due to the potential enzyme induction by Rifampicin. No patient developed drug induced hepatitis. Subsequent sputum for AFB was negative with clearance of radiological findings in all patients.These patients continued to be in molecular remission during and after antituberculosis therapy with no further activation of tuberculosis. Conclusions: The association of tuberculosis with CML is not common and the prevalence is same as with other haematolymphoid malignancies but higher as compared to general population. Prompt administration of antituberculosis therapy results in complete cure from infection while continuing imatinib therapy. Imatinib can be safely given in patients with past history of tuberculosis without concern of reactivation. Further pharmacological studies are required to understand drug interactions and to determine the optimum dose of imatinib during antituberculosis therapy. No significant financial relationships to disclose.
A dose-escalation trial of GM-CSF-gene transduced allogeneic prostate cancer cellular immunotherapy in combination with a fully human anti-CTLA antibody (MDX-010, ipilimumab) in patients with metastatic hormone-refractory prostate cancer (mHRPC)
Authors: W. Gerritsen, A. J. Van Den Eertwegh, T. De Gruijl, G. Giaccone, R. J. Scheper, I. Lowy, E. Levy, K. Hege, N. Sacks
Journal: Journal of Clinical Oncology (2006)

2500 Background: A Phase 1 trial is underway to study the combination of GM-CSF-gene-transduced allogeneic prostate cancer cellular immunotherapy (GVAX immunotherapy (IT) and ipilimumab in patients (pts) with mHRPC. Ipilimumab is a fully human IgG monoclonal antibody specific to the CTLA-4 receptor on T cells that augments immune responses by blocking the inhibitory CTLA-4/B7 interactions. Pre-clinical studies of antibodies to CTLA-4 in combination with GM-CSF secreting tumor cell vaccines demonstrate potent synergy. Methods: Eligible pts have documented mHRPC and are chemotherapy-naïve. All pts receive a 500 million cell priming dose of GVAX IT on day 1 followed by bi-weekly intradermal treatments (tx) of 300 million cells for a 24 week (wk) period. Ipilimumab is administered every 4 wks starting on day 1 for the same period. Pts are enrolled in cohorts of 3; each cohort is assigned an escalating dose of ipilimumab: 0.3, 1, 3 or 5 mg/kg. PSA is measured every 4 wks, and tumor assessments performed every 12 wks. 15 pts will be enrolled at the maximum tolerated dose. Pts are followed for disease progression and survival. Results: Ten pts have been enrolled. All 6 pts in Cohorts 1 and 2 have completed tx and are in follow-up; 5 of 6 completed all planned tx. Three pts in Cohort 3 have completed 75% of tx and are on-going. One pt in Cohort 4 has completed 25% of tx and is on-going. No dose-limiting or immune mediated toxicities have been observed. The most common adverse event is injection site reaction which occurs in 100% of pts. PSA responses by NCI working group criteria include 1 partial response (PR), 4 stable disease (SD), and 4 progressive disease (PD). Of note, 3 PD occurred in Cohort 1; 2 SD and 1 PD occurred in Cohort 2, and 1 PR and 2 SD occurred in Cohort 3. Any decline in PSA was evident within 2–4 wks of initiating tx. Conclusions: The combination of GVAX IT and ipilimumab appears well-tolerated in pts with mHPRC. These preliminary data suggest a relationship between PSA response and the dose level of ipilimumab in combination with GVAX IT. [Table: see text]