tbuckley/cabot-search huggingface dataset:
Does unblinding of treatment assignment impact participant perceptions in clinical trials?
Authors: Ann H. Partridge, Karen Sepucha, Anne M. O'Neill, Kathy Miller, Christine Motley, Ramona F. Swaby, Bryan P. Schneider, Chau T. Dang, Donald W. Northfelt, George W. Sledge
Journal: Journal of Clinical Oncology (2012)

6025 Background: Blinding patients to treatment regimen is an important component of high quality randomized clinical trials although concern exists about how receipt of a placebo will impact participants’ views. In ECOG5103, patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo (arm A) or bevacizumab (arms B and C) and treatment assignment was unblinded by 24 weeks. We sought to determine if unblinding was associated with differential changes in participants’ views. Methods: The Decision-Making/Quality of Life component (DM-QOL) included all patients enrolling on E5103 between 1/5- 6/8/10. Women were surveyed pretreatment and after unblinding. Wilcoxon rank sum testing was used to examine differences. Results: 572 patients on DM-QOL started protocol therapy; 118 on arm A, 454 on arm B/C; the two groups (arm A vs. B/C) were well balanced. 516 patients participated in pretreatment, 514 in unblinding survey. Pretreatment, 32% reported &gt;moderate chance of recurrence in 5 years, 27% &gt;moderate chance of serious problem from treatment, 99% feeling at least somewhat informed, 98% at least somewhat confident in study participation, most “extremely” confident. Overall, median response scores did not change over time, with no statistically significant differences between the groups in changes in perceptions of: recurrence risk (p=0.45); chances of a serious problem (p=0.12), feeling informed (p=0.99). However, they differed in confidence about study participation (p=0.04): after unblinding, a higher % of placebo-treated patients had increased confidence (38% vs. 25%), and a higher % of bevacizumab-treated patients had decreased confidence (29% vs. 22%), although 44% across all arms had no change. Conclusions: In a placebo-controlled, double-blinded RCT, unblinding did not significantly affect most participants’ views, regardless of receipt of placebo or experimental drug. However, confidence in study participation may have been affected by knowledge of receipt of bevacizumab; publicity surrounding this experimental therapy may have affected results.
Phase Ib dose-escalation trial of the AKT inhibitor (AKTi) MK2206 in combination with paclitaxel (P) and trastuzumab (H) in patients (pts) with HER2-overexpressing (HER2+) cancer.
Authors: Amy Jo Chien, Thach-Giao Truong, Michelle E. Melisko, Mark M. Moasser, Robin Katie Kelley, Michael Korn, Andrew H. Ko, Norma Pantoja, Anne Reinert, Jennifer A. Grabowsky, Mark Jesus M Magbanua, Hope S. Rugo, Pamela N. Munster
Journal: Journal of Clinical Oncology (2013)

2605 Background: AKT plays a key role in the survival, resistance, and overall aggressive pathogenesis of HER2+ malignancies, suggesting that AKTis may be of therapeutic value. MK2206 is a selective allosteric AKTi that has demonstrated synergy in combination with both H and P in preclinical studies. Methods: We conducted a phase 1b study of MK2206 in combination with weekly P 80 mg/m2 and H 2 mg/kg in pts with HER2+ solid tumors. MK2206 was given orally at a starting dose of 135 mg once a week (QW). Dose escalation was performed using a modified Ji method. The maximum tolerated dose (MTD) was defined as the dose level resulting in 3 or fewer dose limiting toxicities (DLTs) in 11 pts, then confirmed in 4 additional pts. Circulating tumor cells and PK samples were collected for all pts. Results: A total of 17 pts were enrolled, and 15 pts were evaluable for toxicity. All pts had HER2+ tumors (11 breast, 3 gastric, 1 esophageal). Based on interim toxicity data from other studies, the dose of MK2206 was not escalated beyond 135 mg QW. All 15 pts were treated at this dose level which was determined to be tolerable. Two DLTs were observed including grade 3 rash and grade 3 neutropenia resulting in a &gt;7 day treatment delay. There were no severe adverse events (AEs) related to study treatment. Other grade 3/4 AEs were neutropenia (6 pts), febrile neutropenia (1 pt), peripheral neuropathy (1 pt), and depression (1 pt). The most common all-grade AEs include rash (13 pts), hyperglycemia (13 pts), neutropenia (13 pts), peripheral neuropathy (10 pts), diarrhea (9 pts), fatigue (9 pts), anorexia (9 pts), stomatitis (7 pts). Of the 14 pts evaluable for response, 9 pts (64%) had tumor response (2 CR, 7 PR), and 4 pts had SD. The median duration of response was 5.5 months. Pts were heavily pretreated (median lines of prior therapy 3, 11 prior taxane, 12 prior H). Conclusions: MK2206 at a dose of135 mg QW in combination with weekly P and H is safe and well-tolerated. 135 mg QW is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in pts with HER2+ tumors despite extensive prior therapy. MK2206 is now being tested in the neoadjuvant ISPY2 trial. Clinical trial information: NCT01235897.
Prospective exploratory analysis of the association between genetic polymorphisms and sunitinib toxicity and efficacy in metastatic renal-cell carcinoma.
Authors: Carlos Alberto Farfan, Juan Sepulveda, Julio Benitez, Guillermo de Velasco, Felipe Villacampa, Federico de la Rosa, Irene Canamares, Cristina Rodriguez de Antona, Hernan Cortes-Funes, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2012)

4620 Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor treatment that is approved for metastatic renal cell carcinoma (mRCC). However, several patients either do not respond to treatment or they experience significant toxicity.Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods: 30 patients with newly diagnosed mRCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU 50 mg/day, 4 wks on / 2 wks off treatment schedule. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1.a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction : 2.33 months vs NR; p&lt;0.006). Pts with CYP2C19*1/*1 , wild type genotype, had an increased risk of dose reductions due to toxicity vs. other genotypes (Median time to dose reduction: 2.8 vs 9.73 months; p&lt;0.021). Catechol-O-methyltransferase (COMT) V158M polymorphisms, was associated with PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 months; OS=17.2 months and Val/Val pts PFS=3.3 months; OS= 4.4 months ; p=0.005 for PFS and p=0.003 for OS). Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if these is confirmed, it could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011).
Patient-centered medical homes may improve breast cancer surveillance among survivors.
Authors: Stephanie B. Wheeler, Racquel Elizabeth Kohler, Ravi K. Goyal, Katherine Elizabeth Reeder-Hayes, Kristen Hassmiller Lich, Timothy Smith, Cathy Melvin, Alexis Moore, Marisa E Domino
Journal: Journal of Clinical Oncology (2012)

6029 Background: Community Care of North Carolina (CCNC) initiated a medical home (MH) program in the early 1990s focused on improving care in Medicaid-insured populations. CCNC has been successful in improving asthma, diabetes, and cardiovascular disease outcomes, but has not been examined in the context of cancer care. We sought to determine whether CCNC enrollment was associated with improved cancer surveillance among breast cancer survivors. Methods: Using state cancer registry records linked to Medicaid claims, we identified women ages 18-64 diagnosed with stage 0, I, or II breast cancer from 2003-2007. We included only cases insured by Medicaid for at least 12 of 15 months following the index cancer diagnosis. Reflecting ASCO guidelines for breast cancer surveillance for survivors (2006), we defined outcomes as time to first surveillance mammogram post-diagnosis and overall receipt of mammogram by 15-months post-diagnosis. Our primary independent variable was enrollment in CCNC, categorized as never enrolled, enrolled up to 6 months, and enrolled 7 months or more. We used multivariate Cox proportional hazards stratified by receipt of radiation therapy (RT) and logistic regressions. Results: 840 women were included in our sample. Approximately half were enrolled in CCNC for at least some time during the study period, 38% for more than 7 months post-diagnosis. Among women who received RT, being in a MH for at least 7 months corresponded to earlier follow-up mammogram (Hazard Ratio: 1.34; p=0.028), controlling for all other factors. Enrollment in a MH for at least 7 months post-diagnosis also was associated with overall receipt of mammogram by 15 months (p&lt;0.01). Interaction terms indicated that women enrolled in MHs and living in a rural area had a statistically significant higher likelihood of receiving mammography. Conclusions: Results suggest that MH enrollment is associated with improved cancer surveillance among breast cancer survivors insured by Medicaid. Given the growing population of cancer survivors and increased emphasis on MHs in the Affordable Care Act, more research is needed to explore how patient-centered medical homes can be enhanced to improve the transition from cancer patient to cancer survivor.
Inequities in cancer outcomes between different healthcare systems in Brazil.
Authors: Kimlin Tan Ashing, Cristiane Decat Bergerot, Errol James Philip, Getulio Okuma
Journal: Journal of Clinical Oncology (2017)

31 Background: Studies have shown a clear difference among minority and economically disadvantaged patients. Less is known about marginalized populations in Brazil, a country that possesses a two-tiered healthcare system, based on socioeconomic status. We sought to explore differences in quality of life (QOL) and distress among patients receiving care within these systems. Methods: 270 patients were assessed for distress (DT), anxiety/depression (HADS) and QOL (FACT-G). Half of them was recruited at a private institution (PRI) and the other at a public institution (PUB) (each group: n=135; 68.9% breast and 31.1% gynecological cancers). We calculated descriptive statistics and examined QOL and distress using T-test and ANOVA. Results: We found ethnic differences between PUB (50.4% white, 32.6% mulato and 14.1% black) and PRI patients (82.9% white), and income disparities (PUB patients report almost a third less monthly income than PRI patients). PUB patients were mostly late-stage diagnosed 70.4% compared to PRI counterpart 42.2% (p&lt;.001). In general PUB patients reported higher rates of distress and anxiety/depression (p&lt;.03); and poorer QoL outcomes (p&lt;.01). Conclusions: This preliminary study is one of the first to investigate inequities in cancer outcomes among patients in Brazilian healthcare settings. Analyses revealed notable differences between groups across demographic characteristics, while individuals of lower socioeconomic status reported significantly poorer psychosocial outcomes. These results suggest a complex interaction between ethnicity, access to care and cancer outcomes, and warrants further research to better understand and address these inequities. Further discussion of the role of psycho-oncology research and clinical practice in reducing disparate outcomes among Brazilian cancer patients is warranted.
The use of improved and complete enrichment co-amplification at lower denaturation temperature (ICE COLD-PCR) method for the detection of <i>EGFR</i> and <i>KRAS </i>mutations from cell-free plasma DNA of non-small cell lung cancer (NSCLC) patients.
Authors: Hai T. Tran, Benjamin L. Legendre, Edward S. Kim, George R. Blumenschein, Anne S. Tsao, Roy S. Herbst, Ignacio Ivan Wistuba, Marcia Lewis, Katherine Richardson, Waun Ki Hong, John Heymach
Journal: Journal of Clinical Oncology (2014)

8058 Background: Identification of specific molecular alterations from cell free plasma DNA (cfpDNA) holds tremendous potential as a noninvasive method to assess tumor genotype. We evaluated whether ICE COLD-PCR(ICP) can be used to identify EGFR and KRAS mutations from cfpDNA in patients enrolled in the BATTLE research clinical trial. Methods: Tissue genotyping of KRAS (Exons 2, 3) and EGFR (Exons 18 - 21) on DNA extracted form paraffin-embedded tumor tissue was determined using PCR-based sequencing analysis, with lower limit of sensitivity of detection of 20%. Genotyping of cfpDNA was determined using ICP for mutation enrichment followed by Sanger sequencing for mutation detection, with limit of detection of 0.05%. Results: DNA was isolated and extracted from 154 available plasma samples with matched tumor genotype; with volumes ranging 0.2–0.7 mL. For the overall population with or without mutations, a concordance of 92%, 91%, and 81% was observed with tissue genotypes for EGFR Exon 19, EGFR Exon 21 and KRAS Exon 2, respectively. Mutation specific sensitivities were 80% for EGFR-19del, 42.9% for EGFR-21-L858R, and 34.4% for KRAS-2. Conclusions: The use of cfpDNA for the determination of important EGFR and KRAS mutations provides a non-invasive method which may assist physicians with clinical care for cancer patients. The results from this analysis are encouraging, but, regardless of the methodology used for mutation detection in cfpDNA; additional assay standardization such as initial plasma volume for extraction, amount of extracted DNA and the influence of tissue heterogeneity versus cfpDNA in mutation detection are needed prior to routine clinical use. Overall, these results demonstrate the feasibility in the use of ICP for mutation determination from cfpDNA of NSCLC patients. Clinical trial information: NCT00409968, NCT00411671, NCT00411632, NCT00410059, and NCT00410189.
New negligence claims service aims to resolve cases more quickly
Authors: Clare Dyer
Journal: BMJ (2017)

The NHS Litigation Authority, which handles clinical negligence claims against the health service, will launch on 1 April as NHS Resolution, with a new mandate to resolve cases earlier and learn lessons to reduce mistakes in the future.

Instead of focusing strictly on claims management NHS Resolution will put more resources into intervening early, so that lessons to improve patient safety can be shared quickly to avoid unnecessary court action.

The reorganisation will focus particularly on injuries around the time of birth—the single most expensive source of claims against the NHS, costing around £500m (€580m; $625m) a …
Targeting <i>FGFR1</i>-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398.
Authors: Lucia Nogova, Lecia V. Sequist, Philippe Alexandre Cassier, Manuel Hidalgo, Jean-Pierre Delord, Martin H. Schuler, Wan-Teck Lim, D. Ross Camidge, Reinhard Buettner, Lukas Carl Heukamp, Masyar Gardizi, Matthias Scheffler, Kato Kambartel, Francois Philippe Ringeisen, Suman Sen, Randi Isaacs, Maud Joannaert, Caroline Lefebvre, Juergen Wolf
Journal: Journal of Clinical Oncology (2014)

8034 Background: Identifying molecular drivers in lung squamous cell carcinoma (SCC) is a major medical need since no targeted therapy is available yet for this subtype. Fibroblast growth factor receptors (FGFRs) are physiologically involved in cell proliferation and survival. Genetic alteration of FGFR genes leads to deregulated activation in various cancers, and FGFR1 amplification has been detected in lung SCC. Here, we report on patients (pts) with FGFR1-amplified lung SCC treated in a phase 1 study of BGJ398, a potent, selective pan-FGFR inhibitor. Methods: While this phase 1 dose-escalation study enrolled pts ≥ 18 years of age with any FGFR genetically altered tumor, we report here on the subgroup of pts with FGFR1-amplified advanced or metastatic lung SCC treated with 100 or 125 mg BGJ398 once daily in 28-day cycles. Pts who had progressed following at least 1 line of therapy, including platinum, were eligible for enrollment. FGFR1-amplified tumors were identified by fluorescent/chromogenic in situ hybridization (FISH/CISH) using, in most pts, a score recently established for lung SCC (Schildhaus, Mod Path 2012). Radiologic evaluation was performed every 8 weeks. Results: As of November 22, 2013, 21 pts with lung SCC were treated at the maximum tolerated dose of 125 mg/day (n = 19) or 100 mg/day (n = 2). Screening for FGFR1 amplification was most commonly performed locally (n = 17) vs centrally (n = 4) and was assayed by FISH in all but 1 case (CISH). Of 17 evaluable pts at data cutoff, 2 achieved partial responses (PR; 1 confirmed by RECIST). PRs were durable, lasting about 8 and 3 months, respectively. Of note, 2 additional pts achieved PR (1 confirmed) after the data cutoff date. Additionally, 3 pts had stable disease with tumor regressions noted (up to 11% reduction). The adverse event profile for pts in this study with lung SCC included manageable and reversible hyperphosphatemia, as well as stomatitis, alopecia, decreased appetite, and fatigue. Conclusions: Here we report on the first molecularly targeted therapy in lung SCC demonstrating clinical efficacy. These data encourage further development of BGJ398 in FGFR1-amplified lung SCC and efforts to optimize predictive biomarkers for FGFR inhibitor sensitivity. Clinical trial information: NCT01004224.
Role of LINE-1 methylation status of adjacent normal colonic mucus in the survival of Chinese patients with colon cancer.
Authors: Changhua Zhuo, Qingguo Li, Dawei Li, Peng Lian, Xinxiang Li, Yiwei Li, Guoxiang Cai, Sanjun Cai
Journal: Journal of Clinical Oncology (2015)

e14514 Background: As a global epigenetic change, LINE-1 hypomethylation in normal mucosa were reported to have a key role in forming a ‘field defect’ in colorectal carcinogenesis. We aimed to study its influence on the survival of Chinese colon cancer patients. Methods: Tissue samples of tumor or normal mucosa were utilized to detect certain genetic and epigenetic modifications. Prognostic variables for the patients’ survivals were determined and the influence of LINE-1 methylation rate (LMR) level was further analyzed by survival studies. Results: Overall, 127 patients, 83 males and 44 females, completed a median follow-up of 65 (3-85) months. It was revealed 14 (11.02%) and 5 (3.94%) cases mutated in KRAS and BRAF gene, respectively. Sixteen (12.60%) were confirmed as MSI-H, and 76 (59.84%) were found to have a loss of heterozygosity (LOH) at 18q. There were 26 (20.47%) cases defined as hypermethylation at hMLH1 gene promoter. A mean of 64.42 (9.45-86.93) % of LMRs were determined by pyrosequencing and further sub-grouped into high or low level by X-tile program. Cox multivariate analysis confirmed that the LMR level (high vs. low, HR = 0.396, 95% CI: 0.194-0.805, p = 0.011), MSI status (MSI-H vs. MSS or MSI-L, HR = 0.082, 95% CI: 0.011-0.629, p = 0.016), and distant metastases (M1 vs. M0, HR = 28.006, 95% CI: 11.380-68.920, p = 0.000) were the independent prognostic factors for colon cancer specific survival. Sub-layer analysis revealed that patient with lower LMR level had a significantly worse survival in the subgroups of M0, right-sized colon, size ≤ 5 cm, Stage I-III, MSI-L or MSS, serum CEA at normal level, age > 60 years, 18q LOH, BRAF gene wild-types, KRAS gene mutation, etc. (all with p < 0.05). Conclusions: Genetic and epigenetic alterations can concurrently exist in the complex mechanisms of colonic tumorigenicity. Hypomethylation of LINE-1 at adjacent normal mucosa might be associated with worse outcome in certain Chinese patients with colon cancer. Acknowledgements: This work was supported by the National Natural Science Foundation of China (No. 81372646 to Cai SJ, No. 81472222 to Li DW, and No. 51377024 to Li XX).
Contribution of tumor stroma ratio to a better selection of stage II colon cancer patients into high and low risk groups: A population based study.
Authors: Sanne Kjaer-Frifeldt, Gabi W. van Pelt, Rene dePont Christensen, Wilma E Mesker, Anders Kristian Moeller Jakobsen, Vincent T.H.B.M. Smit, Rob A.E.M. Tollenaar, Flemming Brandt Soerensen
Journal: Journal of Clinical Oncology (2016)

3582 Background: Despite the well-known uncertainty on efficiency, adjuvant chemotherapy is today offered to a subgroup of stage II colon cancer patients with high risk of recurrence, currently based on T-stage, lymphovascular invasion, malignancy grade, perforation and inadequate lymph node sampling. Recent research has focused on the stroma in epithelial tumors as a prognostic biomarker in various malignant epithelial neoplasms, including colon cancer. Patients with a high percentage of stroma within the tumor, determined by the Tumor-Stroma-Ratio (TSR), show a poor prognosis. Methods: The study included all patients diagnosed with stage II colon cancer in Denmark in 2003. Patients receiving adjuvant chemotherapy were excluded. The TSR was scored on routine H&E tissue sections. Stroma-high (> 50% stroma) and stroma-low (≤ 50% stroma) groups were evaluated regarding Overall Survival (OS) and Recurrence-Free Cancer Specific Survival (RF-CSS). The currently defined risk groups were stratified according to TSR, and a prognostic index was created using the coefficients obtained from a collective multiple Cox regression, based on RF-CSS data. Results: Of 580 patients, 107 (18.4%) were scored as stroma-high and 473 (81.6%) as stroma-low. TSR showed prognostic impact in both univariate (OS: p= 0.0075, HR = 1.58 (1.14-2.20), RF-CSS: p< 10-5, HR = 2.47 (1.53-3.98)) and multiple COX analyses (OS: p= 0.0007, HR = 1.66 (1.24-2.22), RF-CSS: p= 0.0001, HR = 2.22 (1.58-3.27)). When comparing the generated RF-CSS risk index based on traditional high-risk, and including the TSR, the TSR contributed significantly to the index, p= 0.0001. When stratifying according to TSR, stroma high patients showed significantly poorer 5 years RF-CSS in both low (stroma high: 76%, stroma low; 89%; p < 10-5) and high (stroma high: 49%, stroma low: 71%; p = 0.01) risk groups. Conclusions: This population based study confirms the prognostic importance of TSR in both uni- and multivariate analyses. Furthermore, including TSR in the current risk assessment of patients with stage II colon cancer, may contribute to a more appropriate definition of high and low risk groups than todays practice.