tbuckley/cabot-search huggingface dataset:
Lymphodepletion and tumor burden govern clinical responses in patients with B-cell malignancies treated with autologous, CD19-targeted T cells.
Authors: R. J. Brentjens, I. Riviere, J. Park, M. Davilla, X. Wang, R. Yeh, N. Lamanna, M. G. Frattini, M. Sadelain
Journal: Journal of Clinical Oncology (2011)

2534 Background: We have initiated phase I clinical trials treating patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) (IRB #06-138) and relapsed acute lymphoblastic leukemia (ALL) (IRB #09-114) with autologous T cells modified to express a chimeric antigen receptor (CAR) specific to the B cell tumor antigen CD19 (19-28z). Methods: T cells from patients with relapsed or refractory CLL and B cell ALL were retrovirally modified ex vivo to express the 19-28z CAR and infused into patients either directly or following prior cyclophosphamide chemotherapy. Results: In the absence of prior lymphodepletion, CD19-targeted T cells did not induce a measurable clinical response in CLL patients. In contrast, 2 of 3 evaluable patients who received prior cyclophosphamide chemotherapy exhibited either a marked reduction of peripheral lymphadenopathy at 3 months following therapy, or a mixed response with overall stable disease. Further, persistence of infused modified T cells was more readily detected in blood or bone marrow samples of the lymphodepleted cohort when compared to patients treated with modified T cells alone. The first ALL patient treated on the IRB #09-114 protocol, in remission following re-induction chemotherapy, treated with cyclophosphamide followed by infusion of 19-28z+ autologous T cells, similarly demonstrated evidence of modified T cell persistence in the blood and bone marrow and exhibited an anticipated B cell aplasia following therapy in the setting of otherwise normal bone marrow recovery. Conclusions: Infusion of modified T cells targeted to the CD19 antigen is well tolerated with enhanced persistence and clinical benefit following prior lymphodepleting chemotherapy. In the setting of advanced tumor burdens, clinical responses to modified T cell therapy are delayed over time and may be appreciated only over weeks to months following therapy. Finally, collective analyses of the 8 patients treated to date suggests a further correlation between tumor burden and modified T cell persistence, implying enhanced modified T cell survival, and potentially anti-tumor efficacy, in the setting of low disease burdens.
Locally advanced or metastatic pancreatic tumors: Molecular biology may help to know it and to select the optimal treatment.
Authors: Luca Faloppi, Kalliopi Andrikou, Cristian Loretelli, Alessandra Mandolesi, Maristella Bianconi, Mario Scartozzi, Rossana Berardi, Italo Bearzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2013)

201 Background: Pancreatic cancer have a multi step progression model with successive mutations like activation of KRAS and inactivation of SMAD 4. Various studies demonstrated that loss of SMAD 4 cooperate with an activating KRAS mutation to promote progression, leading to dysregulation of TGFb pathway. This plays a pivotal role in the formation of desmoplastic reaction by the activation of stellate cells. Stromal cells synthesize and secrete multiple proteins like SPARC which has been associated with worst prognosis. Early data have suggested that the identification of cancer stem cells in primary tumors is associated with shorter OS, resistance to therapy and metastatic potential. Emerging evidence suggest that the activation of the NOTCH 1 pathway is associated with molecular characteristics of stem cells. The aim of our study is to investigate the relationship and the potential prognostic role of these biomarkers. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed immunohistochemical evaluations of KRAS, and molecular biology assessment of NOTCH 1 CD133, OCT3/4, SMAD 4, SPARC. Results: Preliminary analysis showed lower rate of KRAS mutations (54%) and higher expression of NOTCH 1 in KRAS WT patients (57% vs 41%). Different expression of OCT3/4 and CD133 was found according to NOTCH1 expression. In patients with NOTCH1 overexpression, OCT3/4 is found overexpressed (59% vs 45%). Instead in patients with lower NOTCH1 expression CD133 is overexpressed (59% vs 42%). Furthermore KRAS WT compared to MT patients showed higher expression of SMAD4 (66% vs 37%) and lower expression of SPARC (44% vs 59%). Conclusions: Our data indicate that KRAS status can differentiate two prognostic categories of pancreatic tumors: one (KRAS MT) probably more aggressive and characterized by early metastatization, associated to desmoplastic reaction and stemness (higher SPARC and CD133), the other (KRAS WT) with a more favourable behavior, correlated with a prevalent local invasiveness, with lower desmoplasia and stemness profile (lower SPARC and higher OCT3/4). These data suggest that the latter tumors are good candidates to radiotherapy as a part of combinated treatment.
Evaluation of resource utilization using time-derived, activity-based costing (TDABC) to result in more effective processes and cost reduction.
Authors: Pamela T. Soliman, Elizabeth A. Garcia, Kai E. Lang, Valerie Villanueva, Shannon Neville Westin, Nicole D. Fleming, Thomas W. Feeley, Karen H. Lu, Larissa Meyer
Journal: Journal of Clinical Oncology (2016)

22 Background: Current changes in health care economics have led to a focus on value-based health care. TDABC is a systematic method to assess personnel utilization and the associated cost in the delivery of medical care. Based on baseline process maps and cost estimates in our outpatient center, cancer surveillance visits (CSV) were identified as inefficient, lengthy and high cost. The purpose of this study was to determine if reallocation of personnel was feasible, resulted in decrease cost and better value care. Methods: In 2014, a multidisciplinary team developed process maps for each visit type in the outpatient center. Maps included each step of clinical care from registration to check out and the personnel associated with that care. Total personnel costs were based on the estimated time spent with each patient and the average salary of the care provider. In 9/2014, we instituted an advanced practice provider (APP) independent practice initiative where CSV were done by either faculty or APP, no longer both. Billing codes were used to determine the % of CSV seen by APPs only. Patient and staff satisfaction were assessed pre- and post-implementation with validated measures. Results: At baseline, the estimated patient time and personnel cost for a CSV was 98 min and $380.79. The estimated patient time and personnel cost for an APP only CSV was 53 min and $132.60.; resulting in a potential savings of $249/CSV. Prior to 9/14 less than 21% were seen by APP’s only. After implementation of the initiative, the number of APP only visits increased each quarter to Q1 27%, Q2 38%, Q3 40% and Q4 41%. The estimated cost savings based on 4000 CSV/year was $354,000. Patient satisfaction remained the same (Press-Ganey). APP and physician engagement/satisfaction increased by 30% (Gallup Employee Survey). Conclusions: Evaluation of our outpatient clinic using TDABC allowed us to identify low efficiency, high cost processes. After implementation of a new process, patient wait times and personnel costs were significantly reduced resulting in better value care and improved provider satisfaction.
Evaluation of prognostic factors in gene expression and clinicopathologic characteristics in patients with adjuvant chemotherapy for advanced gastric cancer.
Authors: M. Azuma, K. Ishido, A. Takeuchi, A. Naruke, K. Higuchi, T. Sasaki, C. Katada, S. Sakuramoto, M. Watanabe, W. Koizumi
Journal: Journal of Clinical Oncology (2011)

61 Background: We reported TS expression is an independent prognostic factor in patients with gastric cancer who received postoperative adjuvant chemotherapy with S-1 at 2010 ASCO GI (abstract 32). These pharmacogenomic finding will help for choosing chemotherapeutic agents for personalized therapy in the future. Our aim was to indicate association of TS expression with clinicopathological characteristics in the same patient population. Methods: 39 patients with stage II or III advanced gastric cancer who underwent gastrectomy were analyzed. These patients received adjuvant chemotherapy with S-1 after surgery. Formalin-fixed, paraffin-embedded tumor tissues were dissected by the laser-captured microdissection technique and analyzed for target gene expressions using a quantitative real-time PCR. Results: There were no significant differences between stage II and III in TS gene expressions. TS expression (low ≤ 0.72, high &gt; 0.72) and histological type (intestinal and diffuse) are evaluated for PFS and OS. Patients were classified as Group I (n = 5); low TS and intestinal type, Group II (n = 14); low TS and diffuse type, Group III (n = 13); high TS and diffuse type and Group IV (n = 7); high TS and intestinal type. There were significant differences between these four groups (Kaplan-Meier survival analysis, log-rank test, PFS: p = 0.0112 OS: p = 0.0128). The survival curve showed longer survival both PFS and OS in Groups 1 &gt; 2 &gt; 3 &gt; 4. In low TS situation (responders as Group I and II), there is a trend in patients with intestinal type had a longer survival compared to diffuse type (Group I &gt; II). In high TS situation (non-responders as Group III and IV), the result are opposite, there is a trend in patients with diffuse type had a longer survival compared to Intestinal type (Group III &gt; IV). Conclusions: These data suggest that TS gene expression levels may be molecular markers of prognostic factor for patients with adjuvant chemotherapy for resectable gastric cancer. S-1 might be effect different behavior by both histological type and TS expression. Prospective studies are needed to validate these preliminary findings. No significant financial relationships to disclose.
Preliminary results of Ch.E.S.T.: A phase III study of surgery alone or surgery plus preoperative gemcitabine-cisplatin in clinical early stages non-small cell lung cancer (NSCLC)
Authors: G. V. Scagliotti
Journal: Journal of Clinical Oncology (2005)

LBA7023 Background: This phase III study tested the hypothesis whether 3 cycles of gemcitabine-cisplatin administered before radical surgery provides better progression-free survival than surgery alone in patients (pts) with early stages of NSCLC. Secondary endpoints include overall survival, assessment of response rate to chemotherapy, operative mortality and other chemotherapy-related toxicities. Methods: Chemonaive pts with clinical stage T2N0, T1–2N1, or T3N0–1, an ECOG PS 0–1, and adequate hematologic, renal and hepatic function were randomized to receive preoperatively either cisplatin 75 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8 every 3 weeks for 3 cycles (arm 2) or no chemotherapy (arm 1). Pts in arm 2 underwent surgery 2–6 weeks after the end of chemotherapy, and pts in arm 1 within 2 weeks after randomization. Pts were stratified according to stage IB/IIA versus IIB/IIIA disease. The original statistical plan considered the following assumptions: 3-year progression-free survival rate of 45%–55% in arm 1; a 20% reduction of event rate in arm 2; 3-year accrual; 3-year follow-up; α=0.05 (2-sided); β=0.20 using the log-rank test; and 390 events were requested for a total of 700 pts to be randomized. Results: From September 2000 to August 2004, 236 pts from 44 European centers were randomized (123 to arm 1, 113 to arm 2). Median age was 61.6/61.0 years, and the majority of pts were male (87.8%/80.5%) and in 70.7%/75.2% of pts ECOG performance status was 0. Stage IB/IIA disease was reported in 55.3% and 50.4% of pts, respectively. The commonest histology was squamous cell carcinoma (47.2%/35.4%), followed by adenocarcinoma (28.5%/34.5%) and large cell carcinoma (1.6%/5.3%). No severe drug or treatment-related toxicity has been reported so far. Final data on therapeutic compliance, detailed toxicities, and preliminary data on efficacy outcomes will be reported in the final abstract. Conclusions: Following the results of recent adjuvant trials the study will be prematurely closed at the end of December 2004 because many investigators involved in the study feel unethical to complete the study treating patients with surgery alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Eli Lilly AstraZeneca, Eli Lilly, Millenium
The regulation of clear cell renal cancer cells proliferation and tyrosine kinase inhibitors responsiveness by tumor micro-environmental factors.
Authors: Anna Malgorzata Czarnecka, Wojciech Solarek, Damian Matak, Mohammed Imran Khan, Anna Kornakiewicz, Lukasz Szymanski, Karolina Czarnecka, Slawomir Lewicki, Robert Zdanowski, Cezary Szczylik
Journal: Journal of Clinical Oncology (2014)

488 Background: Tumor microenvironment is a complex network of multiple cell types, paracrine and endocrine signaling molecules, ECM and physical factors, which orchestrate the fate of tumor progression. In the field of ccRCC little attention has been paid to non-immunologic factors in tumor niche. Objectives of this study include the analysis of hypoxia, triiodothyronine (T3), insulin, insulin-like growth factor-1 and -2 impact on ccRCC cells. The effect of above mentioned tumor niche factors on TKI activity on ccRCC cells was to be quantified. The study was initiated as ccRCC cells are known to harbor disrupted hypoxia response and TRbeta (TRβ) - T3 receptor - functions as a tumor suppressor with tissue hypothyroidism involved in maintaining a proliferative advantage, whereas hypothyroidisms was defined as biomarker of sunitinib treatment efficacy. Moreover obesity and diabetes (DM2) are considered risk factors for ccRCC and high IGF-I expression is associated with poor long-term patient survival. This research aims to find molecular background for clinically relevant observations. Methods: ccRCC cells from primary and metastatic tumors (ATCC, MSK collections) along with cancer progenitor cells (CD133+) were cultured in normoxic or hypoxic conditions; in defined media supplemented with T3, IN, IGF, TRβ inhibitor and TKIs (sunitinib, axitinib). Cell proliferation was evaluated using AlamarBlue and MTT. Colony formation potential was evaluated. TRβ gene expression was measured with RealTime-RT PCR and sequenced under standard protocol. Normal kidney proximal tube cells were used as negative control. Results: ccRCC TKI responsiveness is limited by hypoxia, at the same time tumor cell proliferation may be promoted by T3, IN and IGF. Colony formation potential of ccRCC cells under TKI treatment in hypoxic conditions is downregulated. Conclusions: Multiple micro-environmental factors modify the proliferation and/or differentiation of ccRCC cell populations. Understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment should aid the identification of novel targets for improving TKIs clinical management.
Molecular alterations in brain metastases from colorectal tumors.
Authors: M. G. Denis, D. Loussouarn, S. Theoleyre, S. Martin, M. Heymann, G. Aillet, N. Rioux-Leclercq, C. Magois, J. J. Auger, D. Vansteene, J. Bennouna
Journal: Journal of Clinical Oncology (2011)

e14082 Background: Brain metastases associated with colorectal cancer are relatively rare, but a frequent cause of death. The aim of our study was to analyze brain metastases from colorectal tumor, and identify cancer characteristics which were associated with their development. Methods: We performed a retrospective study of 19 patients (11 males and 8 females, 50-88 years, mean 67 years) who underwent brain surgery. DNA was extracted from FFPE sections following macrodissection using an automated iPrep system (InVitrogen). RNA was extracted from serial sections using the RNeasy FFPE kit (Qiagen), and cDNA was synthesized using the Quantitect reverse transcription kit (Qiagen). KRAS and BRAF mutations were tested using allele-specific PCR. PTEN expression was determined by immunohistochemistry. Amphiregulin expression was measured by real-time PCR. Results: KRAS mutations were found in 13 (68.4%) brain metastases : c.35G>T, c.35G>A, c.35G>C and c.38G>A mutations were found in 5, 3, 3 and 2 samples, respectively. One tumor (5.3%, KRAS wt) presented the BRAF p.V600E mutation. PTEN was detected by immunohistochemistry in 12 tumors (63.2%), but 7 cases (36.8%) were negative for PTEN expression. Of these 7 tumors, 5 presented a KRAS mutation, and 1 was BRAF V600E. Amphiregulin expression was found to be very low in 10 tumors, intermediate in 6 samples, and high in the remaining 3 tumors. Two of these 3 tumors presented a mutated KRAS and the third one was PTEN negative. KRAS, BRAF and PTEN status were fully concordant between primary cancer and brain metastasis from the same individual. However, we did not find any correlation in the expression level of amphiregulin between the primary tumor and the metastatic site. Conclusions: KRAS mutation prevalence was high in this series of patients presenting with cerebral metastases. Loss of PTEN was strongly associated with KRAS/BRAF alterations. Altogether, the overwhelming majority of the tumors tested (16/19, 84.2%) presented at least one molecular alteration. Further characterization of these tumors might yield better insight into their development, and potentially the treatment of these patients with poor prognosis.
Parenting experiences of cancer survivors with young children in the 2012 LIVESTRONG Survey for People Affected by Cancer.
Authors: Robin L. Whitney, Janice Bell, Sarah C. Reed, Emma Blackmon, Katherine K. Kim, Jill G. Joseph
Journal: Journal of Clinical Oncology (2016)

189 Background: When a parent is diagnosed with cancer, family functioning may be disrupted, placing children at risk. Little is known, however, about the parenting experiences of cancer survivors. Methods: Among cancer survivors with children age ≤ 20 years at diagnosis (n = 2,375) in the 2012 LIVESTRONG Survey for People Affected by Cancer, we used logistic regression to model the odds that 1) children were not fully emotionally supported or that 2) cancer affected survivors’ ability to provide care for their children. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Predictors included age of youngest child at diagnosis ( ≤ 10 years versus 11-20 years), survivor report of high distress, and confidence obtaining emotional support. Models also controlled for important sociodemographic covariates. Results: Among survivors, 50% reported that their children were not fully emotionally supported, and 58% reported that cancer affected their ability to provide care for their children. Significant predictors of children not being fully emotionally supported included: government insurance (OR 1.5; 95% CI 1.0-2.1); annual income ≤ $60,000 (OR 1.6; 95% CI 1.3-2.1); being retired (OR 1.7; 95% CI 1.2-2.4); or female (OR 1.4; 95% CI 1.1-1.7). Significant predictors of cancer interfering with the ability to provide care for children included: female sex (OR 2.2; 95% CI 1.8-2.7), survivor report of high distress (OR 1.6, 95% CI 1.4-2.0), having a child ≤ 10 years (OR 2.5; 95% CI 2.0-3.2), or a child who was not fully emotionally supported (OR 1.5; 95% CI 1.3-1.9). Survivors with confidence in their ability to obtain emotional support were less likely to report that cancer interfered with their ability to provide care (OR 0.8; 95% CI 0.6-0.9). Conclusions: Many cancer survivors with young children at diagnosis report that cancer or its treatment affects their ability to provide care, or that their children are not fully emotionally supported. Increased attention to the psychosocial needs of parenting cancer survivors is warranted, particularly among women, those with public insurance, lower incomes, children ≤ 10 years and survivors who report high distress levels or inadequate emotional support.
Bosutinib and exemestane (EXE) versus EXE alone in postmenopausal (postm) women with hormone receptor–positive (HR+) HER2-negative (HER2–) advanced breast cancer (ABC).
Authors: B. Moy, F. Lebrun, M. Bellet, L. Chow, I. Lang, B. Xu, R. A. Badwe, D. L. Hershman, E. Leip, N. Bardy-Bouxin, L. Duvillie, P. Neven
Journal: Journal of Clinical Oncology (2011)

631 Background: Third-generation nonsteroidal aromatase inhibitors (AIs) are used as adjuvant and 1st-line metastatic therapy for postm HR+ ABC. However, many patients (pts) subsequently experience disease progression. A phase 2 study of the Src/Abl kinase inhibitor bosutinib (BOS) as monotherapy (400 mg) in unselected, heavily pretreated ABC pts revealed an overall response rate (ORR) of 9.4% and 16-wk progression-free survival (PFS) rate of 29.8%, with a median PFS of 9.9 wks. As all responses were seen in HR+ pts, combination BOS and endocrine therapy was explored. Methods: This randomized, open-label, multicenter, phase 2 trial evaluated BOS and EXE vs EXE alone as 2nd-line therapy after AI failure in postm HR+ HER2– ABC. The primary end point was PFS. Prior to randomization, a 28-day safety lead-in phase was conducted; BOS 400 mg/EXE 25 mg was administered orally once daily, with reduction to BOS 300 mg if the higher dose had unacceptable toxicity. Results: 42 pts participated in the safety lead-in phase. 14 pts received BOS 400 mg/EXE 25 mg; common drug-related adverse events (AEs; any grade/grade ≥3) were diarrhea (93%/7%), nausea (79%/7%), vomiting (57%/0), increased alanine aminotransferase (ALT; 29%/29%), increased aspartate aminotransferase (AST; 21%/0), fatigue, (21%/0), and rash (21%/0). 5 of 13 (38.5%) evaluable pts experienced a dose-limiting toxicity (DLT) of increased ALT (n = 4), increased AST (n = 1), diarrhea (n = 1), and vomiting (n = 1). Therefore, another 28 pts were enrolled at a dose of BOS 300 mg/EXE 25 mg. At this dose level, grade ≥3 drug-related AEs included diarrhea (11%), nausea (7%), and ALT elevations (4%). Across dose levels, 5 pts discontinued due to diarrhea. All transaminase elevations were reversible upon BOS discontinuation. Median investigator-assessed PFS was 12.3 wks, and the ORR was 3.6%. Conclusions: The safety profile of BOS 300 mg/EXE 25 mg was generally manageable, albeit with limited efficacy. Because of the lower than expected efficacy and high rate of transaminase elevations, this study was stopped prematurely. Given prior evidence of efficacy of BOS monotherapy, new regimens with BOS should be explored for ABC.