tbuckley/cabot-search huggingface dataset:
Effect of obinutuzumab (GA101), a type II glycoengineered monoclonal antibody targeting CD20, against rituximab resistant and sensitive cell lines in B-cell non-Hodgkin lymphoma.
Authors: Aradhana Tiwari, Janet Ayello, Carmella Van de ven, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2012)

e21150 Background: : Relapse or insufficient response or resistance to Rituximab (RTX) has evolved as a challenge in therapy of B-cell NHL. RTX in combination with FAB chemotherapy is a safe, well tolerated and associated with &gt; 90% EFS in children with advanced mature B-Cell NHL (Cairo M.S. et al, ASCO 2010). Obinutuzumab (GA101), a novel type II glyco-engineered CD20 antibody of the IgG1 isotype, demonstrates superior cell death induction and its glycoengineered Fc region has shown to cause significantly enhanced ADCC (Mössner et al, Bld 2010; Niederfellner G. et al, Bld 2011). We evaluated the efficacy of GA101 against Raji (Burkitt Lymphoma), a RTX sensitive cell line (RSCL) and RTX resistant cell lines(RRCL), Raji-2R and Raji-4RH, respectively (generously supplied by M. Barth, MD, Roswell Park Cancer Center, Buffalo, NY. Barth M. et al, ASH 2010). Methods: All cell lines were cultured in RPMI with 10% FBS and incubated with escalating doses of GA101 (1-1000 µg/ml) for 24 hrs (n=10), 48 and 72 hrs (n=6). Cell death was evaluated by staining with AnnexinV/7AAD and flow-cytometry. B-Cell Lymphoblastic Lymphoma (BLL) U-698-M cells (CD20 + ) were used as the positive and Loucy cells (CD20 - ) (T-ALL) were used as the negative controls. Results: At 48 hrs 100 µg/ml of GA101, Raji and U-698-M demonstrated highest cell death of 33.62±5.7% and 37.8± 3.9%, respectively; while Raji-2R and Raji-4RH cell death was 22.8±1.8% and 10.31±0.81% (p&lt;0.02) and (p&lt;0.001) respectively. At 1000 µg/ml of GA101 at 24 hrs, Raji demonstrated increased cell death 40.27±9.1% compared with Raji2R 14.1±0.07 and Raji4RH 20.3± 3.2 (p&lt;0.001) and (p&lt;0.001) respectively. Conclusions: GA101 represents a promising candidate for treating RTX resistant B-Cell Lymphomas and related CD20 + B-Cell malignancies. Further studies should aim to identify novel approaches such as combination with activated NK Cells or chemotherapeutic agents that may enhance or synergize with the efficacy of GA101. Further investigations aim to elucidate the mechanisms responsible for minimal cell death induction on the U698M and Raji cell lines.
Phase II trial of temsirolimus and bevacizumab for initial recurrence of endometrial cancer.
Authors: Mark H. Einstein, Robert M Wenham, Robert Morgan, Mihaela C. Cristea, Elizabeth Laureen Strevel, Amit M. Oza, Andreas Kaubisch, Briant Fruth, Rui Qin, Charles Erlichman
Journal: Journal of Clinical Oncology (2012)

5025 Background: We report the interim results of the endometrial arm of a multi-tumor protocol using temsirolimus and bevacizumab in endometrial cancer (EMCA) patients at the time of their initial recurrence. The primary aim of this trial is to assess treatment efficacy in terms of both confirmed tumor response and 6-month progression free survival (PFS). Methods: Women with a performance status of 0 or 1 who have had their first recurrence for EMCA were eligible. Subjects who had chemotherapy as part of their adjuvant treatment after front line surgical staging were also eligible. The regimen included Temsirolimus 25 mg IV weekly followed by bevacizumab 10mg/kg IV on days 1 and 15 of a 28 day cycle. A modified two-stage Simon design with fixed sample size was adopted with the null hypothesis being that the true tumor response rate is at most 25% and the true 6 month PFS rate is at most 50%. Results: We enrolled 26 evaluable subjects to the first stage of which one did not proceed with treatment. The median age at enrollment was 60 (range 40-80). 22 (85%) were white and 19 (73%) were not Hispanic/Latino. 19 (73%) of subjects had prior raditation therapy, with 4 having a prior para-aortic boost. 5 (20%) subjects had a confirmed PR and 12 (48%) were progression-free at 6 months, which fell short of the futility stopping rule. An additional 5 (20%) subjects had a best response of confirmed SD, so 10 (40%) had overall clinical benefit from this regimen. AEs attributable to treatment were modest and included 16 grade 3 adverse events, of which the most common ones included hypertension, hyperglycemia, and neutropenia. There were 2 grade 4 events that were possibly treatment related including a duodenal perforation and an anorectal infection. Conclusions: While there was clinical benefit of this regimen in women at the time of their first recurrence of EMCA, the combination of temsirolimus and bevacizumab did not achieve our prespecified efficacy assumptions. This differs from what has been reported with this combination as a second line therapy for recurrent EMCA, where prespecified response assumptions differ. Also, the regimen had comparable safety and toxicity to other cytotoxic chemotherapy regimens used in this setting.
Survival outcomes for African-American (AA) vs matched Caucasian (CAU) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T (sip-T).
Authors: David I. Quinn, Stephen J. Freedland, Elisabeth I. Heath, Ronald F. Tutrone, David G. McLeod, Nadeem Anwar Sheikh, Nancy N. Chang, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

192 Background: Prostate cancer risk and mortality is higher in AA vs CAU men. In an analysis of three phase 3 mCRPC trials, AA pts appear to derive greater survival benefit with sip-T, an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC. AA pts on sip-T had a 30.7-month (mo) median overall survival (OS) benefit vs control (AUA 2012 P953), in contrast to a 4.1-mo OS benefit with sip-T vs control for all pts in IMPACT (NEJM 2010;363:411). As the prior analysis did not adjust for baseline differences between races, we matched AA to CAU pts on sip-T to better assess racial differences in sip-T benefit and cumulative antigen presenting cell (APC) activation, which correlates with OS (CII 2013;62:137). Methods: Data were from phase 3 mCRPC trials that randomized pts 2:1 to sip-T or control (D9901 [NCT00005947]; D9902A [NCT01133704]; IMPACT [NCT00065442]). Thirty-three AA sip-T pts were matched with 66 CAU sip-T pts based on predicted Halabi survival. Data were evaluated by the Kaplan-Meier method (event rates) and ANOVA (APC activation). Results: Median follow-up was 23.2 mos. AA pts on sip-T had a 20.6-mo longer median OS (45.3 mos; 95% CI 23.4–NE) vs CAU pts (24.7 mos; 95% CI 18.1–29.4) (HR = 0.49; 95% CI 0.26–0.91; p = 0.02). Median event-free survival (time to death or anticancer intervention [ACI]) was 10.7 mos for AA pts (95% CI 8.5–21.5) vs 8.7 mos for CAU pts (95% CI 6.6–11.5) (HR = 0.74; 95% CI 0.47–1.18; p = 0.20). Median time to next ACI was 23.5 mos in AA pts (95% CI 9.4–NE) vs 16.3 mos in CAU pts (95% CI 9.7–25.6) (HR = 0.78; 95% CI 0.42–1.43; p = 0.42). In AA pts, median APC activation was higher with sip-T infusion 1 vs CAU pts (7.0 vs 5.5, p = 0.004). Median cumulative APC activation over the three infusions was 27.7 (22.6–42.4, AA) vs 25.7 (21.5–33.9, CAU) (p = 0.083). Conclusions: Prior studies found sip-T provides OS benefit to both AA and CAU mCRPC pts. Herein, for men treated with sip-T, AA had longer survival, suggesting sip-T may provide greater OS benefit in AA. The basis for this may be biologic (greater APC activation). Further studies with larger sample sizes are needed to confirm if AA pts derive greater OS benefit from sip-T. Clinical trial information: NCT00005947; NCT01133704; NCT00065442.
Melanoma risk in men with testicular germ cell tumors in the United States.
Authors: Brandon David Bernard, Sarah C. Markt, Laurence Albiges, Rowan Miller, Clair Beard, Christopher Sweeney
Journal: Journal of Clinical Oncology (2015)

e15554 Background: Prevalence of atypical nevi is thought to be higher in men with testicular germ cell tumors (GCT) possibly as part of the dysplastic nevus syndrome (DNS) (Raghavan, 1994; Sigg, 1988). DNS is associated with developing malignant melanoma. The aim of this study was to evaluate whether men with GCT in the USA are at increased risk of melanoma over the general population. Methods: The Surveillance, Epidemiology, and End Results (SEER) 9 registry was used to identify men with GCT and subsequent diagnoses of melanoma. Age-standardized incidence ratios (SIRs) were calculated by multiple outcomes analysis to account for those men with multiple diagnoses of melanoma after a diagnosis of GCT (multiple primary-SIRs), and were reported as excess risk per 10,000. Results: 107 diagnoses of melanoma were made in 102 men with GCT from 1973-2011. 101 men were white and 1was classified as other (American Indian/AK Native, Asian/Pacific Islander) for an overall SIR of 1.14. Mean age of diagnosis of GCT and melanoma was 35 and 54 years, respectively. Men diagnosed with GCT had a SIR of 1.85 (p<0.05) for a diagnosis of melanoma within 5 years after a diagnosis of GCT; men aged 20-24 had a SIR of 6.39 (p<0.05) by 5 years. There were no other statistically significant excess risks in other age groups or for greater than 5 years of follow-up. Conclusions: Overall, men with GCT are not at an increased risk for developing melanoma. However, this data suggests melanoma is diagnosed at a higher rate within 5 years of a diagnosis of GCT and the subset of men with GCT in their early 20s appears to be at highest risk. It is unknown whether regular follow-up after a diagnosis of GCT accounts for the early identification of melanoma or whether this phenomenon is due to the earlier development of melanoma itself. Regardless, frequent skin exams should be encouraged in this population given the poor prognosis of advanced disease. SIR for a diagnosis of melanoma in men with GCT. Total population Men aged 20-24 Number of melanoma diagnoses SIR (excess risk/ 10,000) Number of melanoma diagnoses SIR (excess risk/ 10,000) Years after a diagnosis of GCT 0-5 30 1.85* 4 6.39* >5 77 0.99 7 1.22 Total 107 1.14 11 1.73 *p <0.05.
<i>BRAF</i><sup>V600</sup> mutation levels and response to vemurafenib in metastatic melanoma.
Authors: Celeste Lebbe, Alexandre Howkit, Aurelie Sadoux, Marie Pierre Podgorniak, Maxime Battistella, Cécile Pagès, Jennifer Roux, Raphael Porcher, Jorg Tost, Samia Mourah
Journal: Journal of Clinical Oncology (2014)

9005 Background: Resistance mechanisms acquired during BRAF inhibitor (BRAFi) treatment were shown to involve multiple signalling pathways including MAPK, PI3K pathways and tumor microenvironment. They may also be complicated by intra-tumor heterogeneity of BRAF mutational status which paradoxically enhances wild-type BRAF cells proliferation. We therefore wanted to evaluate using a quantitative pyrosequencing assay whether the level of BRAFV600 mutation in tumor tissue could predict clinical response and outcome of BRAFV600melanoma patients treated with the BRAFi, vemurafenib. Methods: melanoma specimen from 44 patients with advanced melanoma treated with vemurafenib were available at abseline. The BRAFV600 mutation level was defined as the ratio of the BRAFV600 allele quantification to the percentage of tumor cells in the sample. The main end point were response according to RECIST, progression free survival, overall survival and ratio of the mutated allele to percentage of tumor cells. Results: The BRAFV600 mutation level was significantly associated with the best response rate to vemurafenib (BRAFV600E and BRAFV600K P=0.003; BRAFV600E only P=0.003). The median PFS and OS for all patients were respectively 4 (95%CI 3 to 6) and 13 (95%CI 6 to 15) months. Interestingly, until 10 months of treatment the PFS of patients with high ratio (≥ 0.5; median) was significantly better than those of patients with a low ratio) but the benefit did not last. Indeed the progression free survival (PFS) benefit in those patients with a high mutation levels (≥ 0.5) gradually decreased during the first 6 months of treatment as the risk of progression increased and, beyond 10 months of treatment, became even lower than in patients with low mutation level. Conclusions: We show that quantification of BRAF mutant allele (V600E and V600K) is a predictive marker of BRAFi response in metastatic melanoma patients. This preliminary study constitutes a first step in the identification of surrogate biomarkers of melanoma response to BRAFi and provides a promising tool that might help in the management of metastatic melanoma.
Caregiver preferences for increasing patient survival in advanced melanoma.
Authors: A. Brett Hauber, Juan M. González, Joshua Posner, Michael Lees
Journal: Journal of Clinical Oncology (2017)

185 Background: Patients with advanced cancer and their caregivers may often accept shorter life expectancy to ensure higher quality of remaining months of life. Our objective was to elicit caregiver preferences for quality-adjusted survival associated with treatments for advanced melanoma using a discrete-choice experiment. Methods: Adults in Germany and Sweden caring for people with diagnoses of advanced melanoma completed a web-enabled, discrete-choice experiment. The survey presented caregivers with a series of 10 choice questions, each including three profiles – a pair of hypothetical melanoma treatments and standard of care. Each profile was defined by survival time (24 months, 12 months, 6 months), severity (mild, moderate, severe) of melanoma symptoms, nausea and vomiting, diarrhea, skin problems, and out-of-pocket cost. Treatment profile pairs in choice questions were based on an experimental design with known statistical properties. Standard of care was constant across all choice questions. Regression analysis related respondents’ choice to treatment characteristics and estimate preference weights in each country. Results: 188 respondents in Germany and 202 in Sweden completed the survey. Caregivers choices were consistent with accepting tradeoffs among efficacy, symptom severity, severity of toxicities and cost. Severity of melanoma symptoms was the most important outcome for Swedish caregivers and was approximately as important as survival time for German caregivers. German caregivers placed positive value on each additional month of survival regardless of symptom severity. In Sweden, additional months of survival were of positive value to caregivers except when melanoma symptoms were severe or patients experienced severe nausea, vomiting, and diarrhea concurrently. In all cases where additional months of survival had positive value, the incremental value of each additional month diminished as overall survival increased. Conclusions: Additional months of life with severe symptoms or toxicities may not be viewed as unambiguously good outcomes. Quality of survival is not only a key consideration, but may determine whether a given treatment for melanoma is considered better or worse than standard of care.
Analysis of the prognostic role of plasmatic K-ras mutations in advanced non-small cell lung cancer (NSCLC) patients
Authors: R. Sirera, C. Camps, A. Berrocal, M. Muñoz-Navarro, R. Garcia-Gomez, N. Viñolas, A. Artal, M. Guillot, M. Taron, R. Rosell
Journal: Journal of Clinical Oncology (2007)

18009 Background: Qualitative analysis of circulating DNA in blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of K-ras mutations at codon 12 and several clinical variables in advanced NSCLC patients. Methods: We examined 451 NSCLC patients in stage IIIB and IV, treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. K-ras mutational status was determined by a method based in allelic discrimination with RT-PCR. Results: Median age was 61 years [35–82] and 84% were males. 99% had performance status 0–1. 84% were in stage IV and 16% in stage IIIB. The histological subtypes were: 32% squamous cell carcinoma, 50% adenocarcinoma, 14% anaplastic large cell, and 4% undifferentiated. 41% of the patients received second line chemotherapy. 1% achieved complete response (CR), 36% partial response (PR), 35% had stable disease (SD) and 28% progressive disease (PD). Here we present the results of the analysis of K-ras mutations in the plasma of 165 samples. 17 patients presented K-ras mutations (10.3%), being codon 12 TGT in 16 patients and GTT in 1 case. Plasmatic mutations were found either in patients presenting squamous cell carcinoma (n=3) and in patients with adenocarcinoma (14). Patients with K-ras mutations in plasma had a median time to progression (TTP) of 2.3 months (m) [0.5- 4.6] while for wild type K-ras was 4.1 m [3.3–4.8], (p=0.9). Overall Survival (OS) in K-ras mutated patients was 10.1 m [4.1–15.8] and in wild type K-ras was 9.0 m [6.9–11.1], (p=0.6). Conclusions: In advanced NSCLC, there were no significant differences between patients with K-ras mutations and those with wild-type genotype with respect to baseline characteristics, response rates, TTP, or OS. Data from the rest of the cohort will be presented at the meeting. No significant financial relationships to disclose.
Potentially preventable readmissions after complex cancer surgery: Analysis of the national readmissions dataset.
Authors: Syed Nabeel Zafar, Adil A Shah, Mustafa Raoof, Lori L Wilson, Nabil Wasif
Journal: Journal of Clinical Oncology (2017)

109 Background: Hospital readmissions following surgery are a focus of quality improvement efforts nationwide. Although some reflect appropriate care, others are potentially preventable readmissions (PPRs). We aim to describe the burden, timing, and factors associated with PPRs after complex cancer surgery. Methods: The National Readmissions Dataset (2013) was used to select patients undergoing a complex oncologic resection (defined as esophagectomy/gastrectomy, hepatectomy, pancreatectomy, colorectal resection, lung resection, and cystectomy). All Readmissions occurring within 30 days from discharge were analyzed. Causes for readmissions were categorized in eleven diagnostic groups and tabulated. ICD-9 primary diagnosis codes were reviewed to identify PPRs. Logistic regression analyses were used to identify demographic, clinical and hospital factors associated with PPRs. Results: We analyzed 60,970 patients with 92,260 admissions. A 30 day readmission occurred in 14% of patients, and was highest following cystectomy (25%) and lowest for lung resections (9%). Of all readmissions 82% were deemed to be PPRs. Half of PPRs occurred within the first 10 days of discharge. Infections, gastrointestinal complications and respiratory conditions accounted for 59% of PPRs. Other common causes included dehydration/electrolyte deficiencies (11%), exacerbation of comorbidity (9.2%), bleeding (5%), thromboembolism (3.5%), and wound complications (3.2%). Factors associated with an increased likelihood of PPRs include Medicaid compared with private insurance (OR 1.24, 95%CI 0.8-1.7), higher comorbid conditions (OR 1.44, 95%CI 1.32, 1.59), and discharge to a facility (OR 1.9, 95%CI 1.7-2.1). Patients with a prolonged hospital stay or a major complication during the index admission had a 34% (OR 1.34, 95%CI 1.3-1.4), and 64% (OR 1.64, 95%CI 1.5-1.7) higher likelihood of a PPR respectively. Conclusions: Most 30 day readmissions after complex cancer surgery are potentially preventable and occur within 10 days of discharge. We identify common causes of readmission and high risk populations to help physicians, administrators and policy makers develop strategies to decrease PPRs.
A phase I study of concurrent chemoradiotherapy with docetaxel-cisplatin followed by docetaxel consolidation therapy in inoperable stage IIIA/B non-small cell lung cancer (NSCLC)
Authors: A. Borgmeier, R. Huber, M. Flentje, J. Willner, M. Schmidt, C. Manegold, J. Debus
Journal: Journal of Clinical Oncology (2004)

7350 Background: Docetaxel-based concurrent chemoradiotherapy (CTRT) regimens have shown promising activity and acceptable toxicity in stage IIIA/B NSCLC. This study was designed to evaluate the optimal therapeutic dose of docetaxel as consolidation therapy (DCT) after docetaxel-cisplatin CTRT. Methods: Patients (pts) with inoperable NSCLC, stage IIIA/B, received chemotherapy with docetaxel (20 mg/m2) and cisplatin (25 mg/m2) on days 1,8,15,22,29,36, with concurrent radiotherapy (5 days per week; 2 Gy per day) starting day 1 for a total dose of 66 Gy. If restaging after CTRT demonstrated disease stabilization or partial/complete response, then DCT with docetaxel (75 mg/m2, day 71 and 92) was added. DCT dose escalation to docetaxel 85 mg/m2 was planned for day 92, and a third docetaxel administration planned for day 113. Results: Of 23 patients enrolled (mean age 58.8±7.0 y), all were evaluable and had NSCLC stage IIIB; 6 and 17 patients had Eastern Cooperative Oncology Group performance status 0 and 1, respectively. Partial response occurred in 10 pts, and 13 pts showed disease stabilization. 1 pt with a partial response had a complete tumor resection and left the study. No pts experienced disease progression. Median survival ± SD was 42.1 ± 24.3 weeks (18 pts are alive and under observation). The DCT dose was reduced to docetaxel 60 mg/m2 in all pts as the first 3 pts had grade 3/4 toxicity. Dose-limiting toxicities included grade 3 esophagitis and pneumonitis, observed in 26% and 13% of pts, respectively. Grade 3/4 hematologic toxicities were seen in 39% of pts. Grade 3 diarrhea and emesis occurred in 2 pts (9%). Conclusions: The optimal dose of docetaxel as consolidation therapy after CTRT is 60mg/m2. This regimen resulted in a high rate of tumor response in pts with good performance status. Schedule modifications are being studied as a result of observed toxicity with CTRT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Pharma
Octogenarian patients with colorectal cancer: Characterizing an emerging clinical entity.
Authors: Hadar Goldvaser, Noa Katz Shroitman, Irit Ben-Aharon, Ofer Purim, Yulia Kundel, Daniel Shepshelovich, Tzippy Shohat, Baruch Brenner
Journal: Journal of Clinical Oncology (2017)

552 Background: Colorectal cancer (CRC) in Octogenarians is an emerging clinical entity. It is currently unclear whether these patients have unique features and whether their treatment should differ from younger patients with CRC. The aim of this study was to better characterize this patients population. Methods: A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of ≥ 80 years between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Results: The study included 350 patients, followed for a median of 40.2 months (range 1.8-97.5). Several significant differences were noted. Elderly patients had a higher proportion of Ashkenazi ethnicity (p &lt; 0.001), lower rates of family history of any cancer (p &lt; 0.001) and family history of CRC (p = 0.006), and a higher rate of personal history of other malignancies (p = 0.035). CRC diagnosis by screening was less frequent in octogenarians (p &lt; 0.001) and their performance status at presentation was worse. Octogenarians were more likely to have tumors located in the right colon (p = 0.029) and had a lower prevalence of well differentiated histology (p = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of performance status. Their 5-year cancer specific survival was worse (63.4% vs.77.6%, p = 0.009), both for metastatic (p = 0.03) and for non-metastatic disease (p = 0.028). Conclusions: Elderly patients with CRC presented several differences in clinical and tumor characteristics compared to their younger counterparts. They were less likely to receive treatment and they had worse outcome. Further research is needed to better define this growing patient population and to establish their optimal treatment.