tbuckley/cabot-search huggingface dataset:
Final phase II safety and efficacy results of study MC0452: Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma.
Authors: J. R. Merchan, H. C. Pitot, R. Qin, G. Liu, T. R. Fitch, W. J. Maples, J. Picus, C. Erlichman
Journal: Journal of Clinical Oncology (2011)

4548 Background: Combined mTOR and VEGF blockade is a potentially promising and rational strategy for the treatment of advanced RCC. We previously reported the phase I safety and initial efficacy results of temsirolimus (T) +bevacizumab (B) in RTKI naïve stage IV RCC patients (pts) (J Clin Oncol 2007, 25(18S Suppl):5034). We now report the final results of the phase II study of T+B in RCC patients (pts) previously treated with VEGFR TKI. Methods: Design: Open label, phase I/II study of T+B in advanced RCC pts. Pts with measurable stage IV RCC with a component of clear/conventional cell type, performance status 0-2 and good organ function were eligible. Up to two prior treatment regimens were allowed (at least one prior RTKI). Phase II dose was T=25 mg IV weekly and B= 10 mg/kg every 2 weeks repeated in 4 week cycles. The primary objective (phase II portion): to assess the proportion of patients who were progression-free 6 months after study entry. Secondary objectives: assessment of response rates and toxicity. Results: Forty-six pts have been enrolled into the phase II portion (5 ineligible pts; 1 pt cancelled prior to starting treatment). Forty pts are evaluable for response assessment and 45 pts are evaluable for toxicity. Baseline characteristics (N: 46): median age: 62 (38-82); M/F: 35/11; number of met. sites: 1/2/3+: 19/9/18; prior nephrectomy: 42; number of prior RTKIs: 1= 40; 2=3. Most common (>5%) Gr 3-4 AEs (N=45) included fatigue (17.8%), hypertriglyceridemia (11.1%), stomatitis (8.9%), proteinuria (8.9%), abdominal pain (6.7%), and anemia (6.7%). Best responses were: PR/SD/PD= 9(23%)/25(63%)/6(14%). Six-month progression free rate: 40% (16/40 pts). Median time to progression: 7.6 (4-8.5) months. Median overall survival: 20.6 (11.5-23.7) months. Conclusions: T+B combination at the recommended phase II doses is feasible and active in RTKI treated RCC patients. The 6 month progression-free rate (40%) met the efficacy endpoint and warrants confirmatory studies for clinical activity. Correlative studies on available plasma, serum and tumor samples for angiogenic and molecular biomarkers are underway. Support: N01-CM62205, CA 119545-02, and Commonwealth Foundation.
Interdisciplinary community oncology clinic intervention to improve pain control for all patients.
Authors: Jeanne Elnadry, Tina Duarte, Gregory John C. Yang, Ambuga Badari
Journal: Journal of Clinical Oncology (2014)

63 Background: In rural Yuma, AZ there are too few palliative care specialists to meet the needs of the population. This report presents a unique approach to interdisciplinary care for pain management beginning early in cancer care. To address this need a palliative care specialist collaborated with the entire clinical staff of the community cancer center, including physicians, nurses, social worker, pharmacist, and medical assistants, to initiate a new distress screening tool and develop an interdisciplinary collaborative practice model for pain management. Methods: Data was analyzed from 274 consecutive patients using a review of systems form which was modified 3/2014 to include more information regarding pain, depression/anxiety, communication about illness, spiritual needs, and educational needs, and from 55 patients admitted to home hospice. All clinical staff reviewed the data together and mapped clinical processes. A pain assessment protocol was developed for nurses and medical assistants, who gave the assessment summary to the physician seeing the patient. Further training for nurses taught an algorithm to collaborate with physicians for pain medication orders driven by the assessment findings. Results: About 1/3 of patients had significant concerns about pain. End-of-life data showed that 31% of 55 patients admitted from the cancer center to a local hospice had moderate to severe pain (pain score 4-10) at the time of hospice admission. 88% of these patients’ pain was controlled within 48 hours of admission to home hospice, with pain score 0-3. Data for 274 consecutive clinic patients showed that 30% of patients had concerns about pain, 30% about advanced care planning and communication, and 32% about anxiety, depression, and coping. Of the 162 patients who reported distress, 57% reported distress in 2 or more domains. Conclusions: Hospice data showed that nearly all cancer patients with moderate to severe pain could have pain control within 48 hours. Patients undergoing treatment should be able to have similar results, but were not. Follow-up data collection to assess effect of the collaborative practice model intervention is planned for August 2014.
Inactivation of <i>BRCA1</i> by epigenetic gene silencing in human ovarian tumors.
Authors: Y. Kawakami, K. Miyamoto, K. Takehara, H. Nakamura, O. Samura, T. Mizunoe
Journal: Journal of Clinical Oncology (2011)

e15524 Background: Tumor suppressor gene silencing through promoter hypermethylation plays an important role in oncogenesis. BRCA1 is tumor suppressor gene that encodes proteins that function in the DNA repair process and approximately 10% of cases of ovarian cancer are due to germline mutations in BRCA1. It is also reported that BRCA1 expression is decreased in sporadic ovarian cancers by other mechanisms, such as epigenetic alteration, suggesting its important role in sporadic ovarian cancers. DNA methylation, a major epigenetic process, of BRCA1 and its contribution in sporadic ovarian tumors are not fully understood. Methods: We evaluated the DNA methylation status of the BRCA1 5' CpG island by methylation-specific PCR in 12 human ovarian cancer cell lines and 39 primary epithelial ovarian tumor specimens. After sodium-bisulfite treatment, the conditions for specific amplification of methylated or unmethylated DNA were determined, using DNA from normal blood and SssI methylase-treated DNA by methylation-specific PCR. Cases included the following: malignant (n = 16), borderline (n = 8), and benign (n = 16) tumors. The correlation between these results and clinicopathological features was examined. Results: BRCA1 was hypermethylated in one of 12 (8%) ovarian cancer cell lines and 15 of 39 (38%) primary ovarian tumors. Relative to clinicopathological features, BRCA1 methylation was detected in 39% of malignant and borderline tumors and in 38% of benign tumors, suggesting the importance of BRCA1 pathway in both types of tumors. Some adjacent nontumorous tissues also showed aberrant methylation. Conclusions: BRCA1 was found to be frequently hypermethylated both in benign and malignant ovarian tumors. Our results suggest that epigenetic alteration of BRCA1 might play a role in the development of benign and malignant sporadic ovarian tumors.
The association of very low PSA with increased cancer-specific death in men with high-grade prostate cancer.
Authors: Brandon Arvin Virgil Mahal, Ayal Aaron Aizer, Jason Alexander Efstathiou, Paul Linh Nguyen
Journal: Journal of Clinical Oncology (2015)

62 Background: It has been hypothesized that very low PSAs in men with high-grade prostate cancer could reflect dedifferentiation and a poorer prognosis, but clinical evidence to support this is limited. We sought to determine whether a very low-presenting PSA was associated with greater prostate cancer-specific mortality (PCSM) among men with Gleason score (GS) 8-10 disease. Methods: The Surveillance, Epidemiology and End Results Program was used to identify a national cohort of 328,904 men diagnosed with cT1-4N0M0 prostate cancer between 2004 and 2010. Multivariable Fine-Gray competing-risks regression analysis was used to determine PCSM as a function of PSA level (&lt;2.5 ng/mL, 2.6-4 ng/mL, 4.1-10 ng/mL, 10.1-20 ng/mL, 20.1-40 ng/mL, or &gt;40ng/mL) and GS (8-10 vs. &lt;=7). Results: Median follow-up was 38 months. Among men with GS 8-10 disease, using PSA 4.1-10 as the reference group, the Adjusted HR (AHR) for PCSM for men with PSA level &lt;2.5 was 1.86 (95% CI 1.51-2.29; P&lt;0.001), PSA 2.6-4 was1.44 (1.17-1.78; P&lt;0.001), PSA 10.1-20 was 1.58 (1.39-1.78; P&lt;0.001), PSA 20.1-40 was 2.04 (1.78-2.33; P&lt;0.001), and PSA&gt;40 was 3.19 (2.83-3.59; P&lt;0.001), suggesting a U-shaped distribution. There was a significant interaction between PSA level and GS (P interaction &lt;0.001) such that PSA &lt;2.5 only significantly predicted for poorer PCSM among patients with high grade GS 8-10 disease. Conclusions: Among patients with high grade GS 8-10 disease, patients with PSA &lt;2.5 and 2.6-4 appear to have a higher risk for cancer-specific death compared to patients with a 10.1-20 PSA level, supporting the notion that low PSA in GS 8-10 disease may be a sign of underlying aggressive and extremely poorly differentiated or anaplastic low PSA-producing tumors. Patients with low PSA GS 8-10 disease should be considered for clinical trials studying the use of chemotherapy and other novel agents in very-high risk prostate cancers.
A Mutation in the G-Protein Gene <i>GNB2</i> Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction
Authors: Birgit Stallmeyer, Johanna Kuß, Stefan Kotthoff, Sven Zumhagen, Kirsty Vowinkel, Susanne Rinné, Lina A. Matschke, Corinna Friedrich, Ellen Schulze-Bahr, Stephan Rust, Guiscard Seebohm, Niels Decher, Eric Schulze-Bahr
Journal: Circulation Research (2017)

Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved.We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB.Genome-wide linkage analysis mapped the SND+AVB disease locus to chromosome 7q21.1-q31.1 (2-point logarithm of the odds score: 4.64; θ=0); in this region, targeted exome sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the GNB2 gene that strictly cosegregated with the SND+AVB phenotype. GNB2 encodes the β2 subunit (Gβ2) of the heterotrimeric G-protein complex that is being released from G-protein-coupled receptors on vagal stimulation. In 2 heterologous expression systems (HEK-293T cells and Xenopus laevis oocytes), an enhanced activation of the G-protein-activated K+ channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gβ2 was coexpressed with Gγ2; this was in contrast to coexpression of mutant Gβ2-Gγ2 with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ2 to cardiac GIRK channels when compared with native Gβ2.A GNB2 gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity. Our findings describe for the first time a role of a mutant G-protein in the nonsyndromic pacemaker disease because of GIRK channel activation.
Assessing patient experience in an outpatient multidisciplinary clinic setting.
Authors: Diane Denny, Scott Hartman
Journal: Journal of Clinical Oncology (2016)

224 Background: Cancer Treatment Centers of America (CTCA), a national network of five hospitals, implemented a new survey instrument and methodology to gather patient experience data in the outpatient setting. While borrowing many questions from its vendors’ client base, the network also added questions considered pivotal to understanding the critical dimensions of care deemed most relevant to the oncology patient. Surveying includes 100% of all patients first contacted via the U.S. mail and subsequently using e-surveys. Methods: Data is collected, with the ability to be segmented by cancer type; for medical, surgical and radiation oncologists with respect to confidence and likelihood of recommending. For each specialty, an open ended question has been added for the patient to elaborate upon his/her rating. Further, several questions have been added to reflect key dimensions of care specific to the oncology such as emotional needs, family involvement and information, sensitivity to personal difficulties associated with treatment, drawing blood and IV discomfort, and involvement in care decisions, to name a few. Results: The revised approach has resulted in greater than a 200% increase in responses, at a cost reduction, cognizant of the growing sophistication of the population served in using technology as part of the patient experience feedback process. Results at three months post-implementation have yielded the findings in the Table. Conclusions: Since implementation, not only have completed surveys increased with respect to easily accessible discrete quantitative data, qualitative information has grown exponentially. This has resulted in more meaningful and robust data around which to focus, including specialty data at the disease and provider levels. The revisions also substantially support CTCA centers’ Magnet journey, including question dimensions and unit level reporting. [Table: see text]
Rolapitant for the prevention of nausea in patients receiving moderately or highly emetogenic chemotherapy.
Authors: Rudolph M. Navari, Cindy K Nagy, Sujata Arora, Daniel Powers, Rebecca Anne Clark-Snow
Journal: Journal of Clinical Oncology (2016)

224 Background: Nausea control remains an unmet need for patients receiving moderately or highly emetogenic chemotherapy (MEC, HEC). The objective of this analysis was to determine the effect of the neurokinin-1 (NK-1) receptor antagonist rolapitant (VARUBI) on the prevention of nausea in patients receiving either MEC or HEC. Methods: Post hoc analyses of nausea from three randomized, double-blind, active-controlled, phase 3 clinical trials were performed for carboplatin-based MEC (n = 401), non-carboplatin-based MEC (n = 228), total MEC (n = 629), anthracycline/cyclophosphamide (AC)-based chemotherapy (n = 703), and cisplatin-based HEC (n = 1070). Patients were randomized 1:1 to oral rolapitant 180 mg or placebo ~1–2 h before chemotherapy. All patients received active control: granisetron 2 mg oral or 10 mcg/kg IV and oral dexamethasone 20 mg. Granisetron was continued on days 2 and 3 for patients receiving MEC or AC-based therapy and dexamethasone 8 mg twice daily on days 2–4 for patients receiving HEC. Patients self-assessed nausea on days 1–6 using a 100-mm visual analog scale (VAS). Percentage of patients with no nausea (NN; maximum VAS &lt; 5 mm) or no significant nausea (NSN; maximum VAS &lt; 25 mm) was determined for overall, delayed, and acute phases of CINV in cycle 1. Results: Rates of NN in the carboplatin-based MEC and total MEC subgroups were significantly higher (P &lt; 0.05) with rolapitant than active control in the delayed and overall phases. In the cisplatin-based HEC subgroup, rates of NN and NSN were significantly higher (P &lt; 0.05) with rolapitant than active control in the delayed, acute, and overall phases. Conclusions: Rolapitant prevents nausea during all CINV phases in patients receiving cisplatin-based HEC, and during the delayed and overall phases in patients receiving carboplatin-based MEC. Clinical trial information: NCT01500226, NCT01499849, NCT01500213.
Clinical features of germ cell tumors (GCT) in men age 50 or older: Successful outcome and tolerability to chemotherapy for advanced disease.
Authors: M. H. Voss, E. P. Jacobsen, S. Patil, S. Turkula, X. Jia, J. Sheinfeld, D. F. Bajorin, G. J. Bosl, R. J. Motzer, D. R. Feldman
Journal: Journal of Clinical Oncology (2011)

4656 Background: Most patients with GCT are diagnosed and treated below age 50. For patients ≥50, less is known about possible differences in biology, outcome and tolerability of treatment. Methods: We reviewed histology, primary tumor site and outcome for 4,176 males (median age at diagnosis 30, maximum age 82) seen at our center from 1990 to 2010 for management of GCT. Individual chart review was performed on men ≥50 receiving 1st-line platinum-based chemotherapy at our center (regardless of age at diagnosis) to characterize chemotherapy tolerance and outcome. Results: 229 patients (5.5%) were diagnosed at ≥50 (median age ≥50 group: 54; median age <50 group: 30), with significant differences in primary site and histology between the 2 groups (see table below). 59 men ≥50 received risk-directed 1st-line platinum chemotherapy (47 etoposide, cisplatin [EP]; 8 bleomycin + EP [BEP]; 4 with other regimens) for advanced GCT (48 good-, 7 intermediate-, 4 poor-risk), and 1 patient ≥50 received adjuvant EP. 5-year overall survival for the chemotherapy group (n=60) is 87% (95% CI 74-94). 36 (60%) had a treatment delay (≥ 7 days) with ≥1cycle and/or required a regimen change due to adverse events (delay: 55%; regimen change: 12%). 46 / 48 patients (96%) completed their planned course of EP, 2 patients discontinued EP due to toxicity. 6 / 8 men (75%) were unable to complete 4 cycles of BEP (5 due to pulmonary toxicity). Neutropenic fever with ≥ 1 cycle occurred in 43.3% of patients (50% with BEP, 40% with EP). Conclusions: GCT diagnosed at ≥50 has a distinct distribution of histologies and primary sites. Although complications and dose delays were frequent in those men ≥50 requiring chemotherapy, overall prognosis remains excellent when risk-directed treatment is given with curative intent. Prophylactic growth factor support is recommended with cisplatin chemotherapy for men ≥50 to reduce the incidence of neutropenic fever. Diagnosis <50 (%) [N= 3,949*] Diagnosis ≥50 (%) [N= 229*] P value Histology Seminoma 36.5 67.3 <0.0001 Nonseminoma 63.3 31.0 Spermatocytic seminoma 0.2 1.8 Primary site Testis 92.8 90.0 <0.0001 Retroperitoneum 0.8 3.5 Mediastinum 4.3 4.8 CNS 1.7 0 Other 0.4 1.7 *Two had second primary.
AVASTERB OUEST: A prospective cohort study of unresectable metastatic colon cancer treated successively by FOLFIRI bevacizumab and cetuximab irinotecan
Authors: J. Metges, E. Gamelin, R. Faroux, V. Klein, G. Ganem, J. Douillard, C. Stampfli, S. Corbinais, C. Riche, F. Grude
Journal: Journal of Clinical Oncology (2009)

e15103 Background: Bevacizumab and cetuximab regimen are approuved since 2005 in Europe for Metastatic Colorectal Cancer Patients (MCCP). Very few studies have reported data concerning the sequence (FOLFIRI BEVA and after failure CETUXIMAB- CAMPTO) in MCCP from the real world. Methods: Since 2003, in west of France, (Bretagne-Pays de Loire),a network called OMIT(Observatoire des Médicaments et Innovations Thérapeutiques) directed by Regional Health Agencies has been created. This structure gathered prospectively data from MCCP treated with targeted therapies. Since 2006, a cohort of MCCP treated successively by FOLFIRI BEVACIZUMAB (same protocol : same dose) as first line to progression or unacceptable toxicity and CETUXIMAB- CAMPTO after the first line failure was constitued (AVASTERB cohort). Criteria for initial unresectability of metastic lesions was based on investigator's evaluations during local comitee (surgeons and oncologists). In order to have a large follow up, the 35 first patients of the cohort were studied in this abstract.Age, sex, response rate to the different regimens,secondary metastatic lesion resection, time to progression to the different regimens, follow up and overall survival are the criterias studied. Results: Median age 60 years (49–83), Males : 60%, colon 71%,rectum: 17%, colorectal jonction :12%.Response rate(OR+SD)with Folfiri Bevacizumab : 45.7%. 17% of the patients underwent hepatic surgery with curative intent (all during Folfiri bevacizumab) Time to progression with Bevacizumab : 6 months. Fifty eight percent of the patients are still alive with a median follow up of 25 months (11–29)Median overall survival was not reached.The 12 months and 24 months overall survival rates are respectively 71.4% and 45.7% (date of point: 01/01/2009). Actualisation of the data will be provided during the meeting Conclusions: The results from this prospective unselected cohort of MCCP treated with the sequence FOLFIRI BEVA and after failure CETUX-CAMPTO from the real world show promising TTP, and overall survival. The study of the Kras mutation and others biomarkers could improve these results by personalization of the treatment. This part of our study is actually ongoing. No significant financial relationships to disclose.
Prevention of mucositis with KGF in patients undergoing allogeneic stem cell transplantation.
Authors: J. D. Goldberg, J. Zheng, H. Castro-Malaspina, A. A. Jakubowski, G. Heller, M. R. M. Van Den Brink, M. Perales
Journal: Journal of Clinical Oncology (2011)

6543 Background: Prospective studies have shown that palifermin (keratinocyte growth factor, KGF) reduces the duration and severity of oral mucositis after auto hematopoietic stem cell transplant (HSCT). Methods: To test the hypothesis that KGF reduces mucositis following ablative allogeneic (allo)-HSCT, we conducted a retrospective study on 251 consecutive adult patients with hematologic malignancies who had a T cell depleted allo-HSCT from 2004-2009. 154 patients received KGF (TBI=77, chemo=77) and 97 patients did not receive KGF (TBI=44, chemo=53). The number of days of PCA and TPN use and length of hospital stay (LOS) were evaluated as clinical surrogates for mucositis severity. Outcomes were compared between KGF and non-KGF recipients using the Wilcoxon rank-sum test. Adjusting for age, ATG use and conditioning regimen, linear regression models evaluated the effect of KGF on each of these outcomes. Results: In the entire cohort, KGF was significantly associated in univariate and multivariate analysis with fewer days on PCA and TPN, and shorter LOS (Table). While the same significant association between KGF and outcomes was noted in recipients of TBI-based allo-HSCT, KGF did not affect mucositis severity in recipients of a chemo-based allo-HSCT. KGF did not affect overall survival, event-free survival, engraftment or acute graft-versus-host disease. Conclusions: Our data demonstrate that KGF decreases mucositis severity in recipients of TBI-based but not chemo-based allo-HSCT. We cannot exclude a benefit of KGF in other chemotherapy regimens. Prospective studies evaluating KGF’s impact on mucositis following allo-HSCT should preferentially focus on patients who receive TBI-based transplants. KGF P value Yes Median (range) No Median (range) Wilcoxon rank sum Adjusted test Entire cohort PCA days 2 (0-78) 7 (0-106) 0.002 0.023 TPN days 12 (0-53) 15 (0-63) 0.003 0.006 LOS 31 (11-89) 33 (15-128) 0.001 0.014 TBI regimens PCA days 5 (0-45) 11 (0-106) 0.011 0.033 TPN days 11 (0-51) 17 (0-32) <0.001 <0.001 LOS 31 (24-72) 37 (16-106) <0.001 0.001 Chemo regimen (busulfan/melphalan/fludarabine) PCA days 0 (0-78) 5 (0-34) 0.032 0.288 TPN days 12 (0-53) 13 (0-63) 0.573 0.490 LOS 31 (11-89) 32 (15-128) 0.696 0.459