tbuckley/cabot-search huggingface dataset:
ADAPT: An ongoing international phase III randomized trial of autologous dendritic cell immunotherapy (AGS-003) plus standard treatment in advanced renal cell carcinoma (RCC).
Authors: Robert A. Figlin, Christopher G. Wood
Journal: Journal of Clinical Oncology (2014)

449^ Background: AGS-003 is an autologous immunotherapy designed to induce an immune response to a patient’s own tumor. Sunitinib is a receptor tyrosine kinase inhibitor that has emerged as the standard of care in treatment-naïve RCC patients. The antitumor activity of sunitinib, together with its ability to reverse the immune suppression seen in RCC patients provided the rationale to combine sunitinib treatment with AGS-003 immunotherapy. In a single arm phase 2 study, AGS-003 in combination with sunitinib was safe and yielded a median overall survival (OS) of over 30 months in synchronous mRCC patients with one (DxTx&lt;1yr) or more RCC risk factors. Methods: The study is seeking to enroll adults with synchronous mRCC with a time from diagnosis to treatment of &lt; 1yr (DxTx&lt;1yr) who are good candidates for surgery and standard targeted therapy (initiating with, but not limited to sunitinib), clear cell histology, 1-4 Heng RCC risk factors, KPS ≥ 70%, life expectancy of at least 6 months and adequate end organ function. Exclusion criteria include prior systemic RCC treatment, brain metastases, or requirement for chronic immunosuppressive therapy. While therapy initiates with sunitinib for all subjects, changes to other TKIs or mTOR inhibitors is permitted for early progression or toxicity. Results: Currently 94 sites have been initiated with more than 120 patients consented for tumor collection and 35 randomized to treatment as of September 2013. To date, nearly 50% of patients consented for tumor collection have been excluded from participation in the treatment phase of the ADAPT study due to non-clear cell histology, cardiac history, thromboembolic disorders and other criteria making them unsuitable candidates to initiate standard TKI therapy. Conclusions: Patients with newly diagnosed, synchronous mRCC present with poor prognosis and other features which may prohibit the safe or effective initiation and administration of TKIs. Exclusion criteria have recently been amended to optimize enrollment. Further details regarding study progress, baseline patient characteristics, eligibility disposition and updated figures will be presented. Clinical trial information: NCT01582672.
The role of activating mutations of KRAS, BRAF, and PIK3CA pathway convergence at the transcriptional level and prediction of treatment response to cetuximab in colorectal cancer.
Authors: I. Simon, S. Tian, V. Moreno, P. Roepman, J. Tabernero, M. Snel, T. Macarulla, L. van't Veer, R. Bernards, G. Capella
Journal: Journal of Clinical Oncology (2011)

3534 Background: Several molecular alterations such as mutations in KRAS, BRAF or PIK3CA genes constitutively activate EGFR downstream pathways in colorectal cancer (CRC). In this study, we developed three gene expression profiles that characterize KRAS-, BRAF- or PIK3CA-activated-like tumors and show that a combined model might be used for identifying patients with activated EGFR signalling. Methods: Fresh frozen tumor samples from 381 patients were collected at four European hospitals. Mutations in KRAS, BRAF and PIK3CA were assessed by direct sequencing. Using whole genome microarray data, three mutation profiles were developed using a 10-fold cross validation method. The three profiles were validated in an independent set of 80 patients and in-silico in a dataset from metastatic CRC tumor samples from patients treated with cetuximab. Results: Overall 175 (45.9%) of the tumors harbored oncogenic mutations in KRAS (n = 115 cases; 30.2%), BRAF (n = 42; 11.0%) and PIK3CA (n = 44; 11.6%). An activating mutation signature for KRAS (75 genes, sensitivity 91.3%, specificity 61.7%), for BRAF (58 genes, sensitivity 90.5%, specificity 91.8%) and for PIK3CA (49 genes, sensitivity 75.0%, specificity 80.1%) were developed. Combined into an integrative 3-way classification model, tumors can be classified as "mutation-like" tumors or "non-mutation-like" tumors with a sensitivity of 90.3% and a specificity of 61.7%. The three mutation signatures and the combined model are associated with response to cetuximab treatment in patients with metastatic colorectal cancer (KRAS signature p=0.004, BRAF signature p=0.018, PIK3CA signature p=0.003 and combination model p=0.0009). Conclusions: The convergence of distinct oncogenic mutations in effector genes downstream of EGFR at the transcriptional level allows the discovery of activated profiles that includes both known and unknown activation in this pathway. The three profiles allow the identification of patients with activating mutations on EGFR pathway, which may not benefit from drugs that inhibit the EGFR receptor.
Quality of life (QOL) characteristics of patients with cervical cancer in the validation study of EORTC-QLQ-CX24.
Authors: V. Bjelic-Radisic, P. T. Jensen, A. Nordin, R. Galale, A. Costantini, K. Kuljanic, S. Singer, A. C. Waldenstrom, E. Greimel
Journal: Journal of Clinical Oncology (2011)

e19538 Background: Approximately 46% of patients with cervical cancer are younger than 50 years at the time of diagnosis. The aim of the study was to investigate the QOL of patients undergoing different treatment options. The sensitivity of EORTC-QLQ-CX24 and QLQ-C30 was also tested. Methods: In the validation study of QLQ-CX24 data of 343 patients from 13 countries were analyzed. Mean age was 49.77 (SD 13.28); mean follow-up time 2.54 years (SD 3.22). The QOL was assessed using the EORTC QLQ-C30 and the QLQ-CX24. The patients were divided in groups according to menopausal and treatment status, surgery versus no surgery, and irradiation versus no irradiation. Statistical analyses were performed using descriptive statistics, ANOVA and post-hoc test. Results: Premenopausal patients (28.3%) had significantly more financial difficulties, fatigue and appetite loss and fewer problems in body image and all scales related to sexuality compared to postmenopausal women (35.1%). Patients undergoing active treatment (38.9%) had lower QOL scores on all scales (except lymphoedema and peripheral neuropathy scale) compared to patients in follow-up (61.1%). Patient undergoing surgery only had less insomnia, nausea and emesis and were more sexually active compared with the other groups. Patients undergoing surgery and other treatment had more problems with lymphoedema, sexual worry and sexual/vaginal symptoms. Patients undergone irradiation alone or in combination with another treatment (56%) had more appetite loss, diarrhea and nausea/emesis, more problems in symptoms experience, sexual activity, and sexual/vaginal symptoms compared to patients without irradiation. Conclusions: The results revealed that patients with cervical carcinoma had different side effects with different impact on QOL dependent on the various therapy options. Despite sample heterogeneity the results indicate that the QOL assessment tools are able to discriminate between groups of patients. The QLQ-CX24 showed more sensitivity to assess the impact on QOL than the QLQ-C30. This confirms the construct validity of the instrument and underlines the necessity to use disease-specific questionnaire in specific patient populations.
Association of Elevated Reward Prediction Error Response With Weight Gain in Adolescent Anorexia Nervosa
Authors: Marisa DeGuzman, Megan E. Shott, Tony T. Yang, Justin Riederer, Guido K.W. Frank
Journal: American Journal of Psychiatry (2017)

Objective: Anorexia nervosa is a psychiatric disorder of unknown etiology. Understanding associations between behavior and neurobiology is important in treatment development. Using a novel monetary reward task during functional magnetic resonance brain imaging, the authors tested how brain reward learning in adolescent anorexia nervosa changes with weight restoration. Method: Female adolescents with anorexia nervosa (N=21; mean age, 16.4 years [SD=1.9]) underwent functional MRI (fMRI) before and after treatment; similarly, healthy female control adolescents (N=21; mean age, 15.2 years [SD=2.4]) underwent fMRI on two occasions. Brain function was tested using the reward prediction error construct, a computational model for reward receipt and omission related to motivation and neural dopamine responsiveness. Results: Compared with the control group, the anorexia nervosa group exhibited greater brain response 1) for prediction error regression within the caudate, ventral caudate/nucleus accumbens, and anterior and posterior insula, 2) to unexpected reward receipt in the anterior and posterior insula, and 3) to unexpected reward omission in the caudate body. Prediction error and unexpected reward omission response tended to normalize with treatment, while unexpected reward receipt response remained significantly elevated. Greater caudate prediction error response when underweight was associated with lower weight gain during treatment. Punishment sensitivity correlated positively with ventral caudate prediction error response. Conclusions: Reward system responsiveness is elevated in adolescent anorexia nervosa when underweight and after weight restoration. Heightened prediction error activity in brain reward regions may represent a phenotype of adolescent anorexia nervosa that does not respond well to treatment. Prediction error response could be a neurobiological marker of illness severity that can indicate individual treatment needs.
Value of close follow-up for “probably benign findings,” BIRADS category 3 (MR-Bi3), on magnetic resonance imaging of the breast (BrMR).
Authors: M. J. Janicek, V. M. Camaya, D. Naddaff
Journal: Journal of Clinical Oncology (2011)

e11060 Background: One of the objections to wider use of breast MRI, e.g. in high risk screening, is its relatively high false positive rate. Particularly for subtle findings such as small enhancing foci, there is a shift from more aggressive approach to observation and close follow-up with MRI, (MR-Bi3). Our pilot study analyzed clinical outcomes of MR-Bi3 pts and the added value of such close follow up (f/u). Proportion of MR-Bi3 and MR-Bi3 after
A fully automated capillary western system for absolute quantitation of endogenous PKC proteins: An approach to correlate protein quantity with function.
Authors: Jin-Qiu Chen, Madeleine Heldman, Michelle Herrmann, Noemi Kedei, Peter Blumberg, Paul Goldsmith
Journal: Journal of Clinical Oncology (2012)

31 Background: The human prostate cell line LNCaP and the human myelocytic leukemia cell line U937 differ dramatically in their responses to the two protein kinase C (PKC) targeted ligands phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 and show complex differences in the patterns of transcriptional responses that they induce. Quantitation of relative abundance of individual PKC isoforms in the two cell lines may help to link the downstream effects of the two compounds to these isoforms. Methods: Simple Western is a capillary-based automated Western system recently developed by ProteinSimple. All steps following sample preparation are fully automated in the Simple Western system, including sample loading, size-based protein separation, immunoprobing, washing, detection and data analysis. Simple Western is gel-free and blot-free, uses less amount of samples, and produces highly quantitative, reproducible information that cannot be generated using regular Western assays. Using the Simple Western system, we developed a method for absolute quantitation of endogenous proteins in cell lysates and quantified PKC isoforms in LNCaP and U937 cells. Results: PKC isoforms were measured at levels of picogram or sub-picogram per nanogram cell lysate. PKC delta was identified as the dominant PKC isoforms in both cell lines. In LNCaP cells, PKC delta expression is ~20-fold higher than PKC alpha, ~40-fold higher than PKC epsilon, and at least 20-fold higher than PKC beta. In U937 cells, PKC delta expression is similar to PKC beta, at least 200 fold higher than PKC alpha, and ~50-fold higher than PKC epsilon. Conclusions: The Simple Western system, with its high-quality data quantitation and excellent assay reproducibility, allowed us to detect both the relative abundance of the PKC isoforms and their absolute quantitation in the tested cells. It circumvents the problem that antibodies of different affinities for different proteins yield a misleading impression of relative abundance and it provides an approach to accurately correlate protein quantities with their function.
Healthcare utilization and quality among survivors of adolescent and young adult cancer.
Authors: Anne C. Kirchhoff, Sapna Kaul, Mark Fluchel, Christopher F Parmeter, Holly Lynn Spraker
Journal: Journal of Clinical Oncology (2016)

21 Background: To evaluate perceived health care quality among a national sample of survivors of adolescent and young adult (AYA) cancer relative to individuals from the general population. Methods: Using the Medical Expenditure Panel Surveys from 2008-2012, we identified 1,163 survivors diagnosed with cancer ages 15-39 who were at least five years from diagnosis and currently ages of 20-64. A comparison group with no history of cancer was created via propensity score matching on sex, age at study, race/ethnicity, census-region, and survey year. Participants with one or more health care visit in the past 12 months were asked to rate health care quality from all providers (0 = worst to 10 = best), which we categorized as low (0-4), moderate (5-7) and high (8-10). Among survivors, we identified factors such insurance and health status associated with health care quality using ordinal logistic regression. Results: Mean time since diagnosis was 18.3 years. A total of 18% of survivors of AYA cancer reported no health care visits in the previous 12 months compared to 25% of the comparison group (p &lt; 0.001). Survivors rated their health care quality lower than the comparison group (low/moderate: 30.8% vs. 22.5%, respectively, p = 0.003). Among survivors, those who were publicly insured (odds ratio (OR) = 0.62, 95% confidence interval (CI): 0.39-0.97, p = 0.04) and uninsured (OR = 0.25, 95% CI: 0.13-0.48, p &lt; 0.001) were more likely to provide lower health care quality ratings than privately insured survivors. Survivors in fair/poor health also reported poorer quality compared to those in excellent/very good/good health (OR = 0.43, 95% CI, p &lt; 0.001). Conclusions: Survivors of AYA cancer reported greater health care use and poorer health care quality compared to individuals without cancer. Our results call for targeted interventions to meet AYA cancer survivors’ health care needs and expectations.
A randomized, double-blind, placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.
Authors: Jeffrey R. Infante, Bradley G. Somer, Joon Oh Park, Chung-Pin Li, Max E. Scheulen, Saifuddin M. Kasubhai, Do-Youn Oh, Yuan Liu, Soumi Lahiri, Klaudia Steplewski, Ngocdiep T. Le
Journal: Journal of Clinical Oncology (2013)

291 Background: Trametinib, an oral MEK1/2 inhibitor, holds promise for tumors that frequently harbor RAS activating mutations, such as pancreatic cancer. Trametinib monotherapy or in combination with gemcitabine showed preliminary activity in patients (pts) with advanced pancreatic cancer. Methods: Eligible pts with untreated metastatic pancreatic cancer were randomized (double-blind, 1:1) to receive gemcitabine 1000 mg/m 2 intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks, plus either trametinib 2 mg or placebo daily. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR). OS and ORR were also analyzed based on baseline KRAS status as determined in plasma cell free DNA (cfDNA). Results: Baseline characteristics for the 160 randomized and treated pts were similar across arms. Skin related events (73% vs. 34%), diarrhea (54% vs. 28%), thrombocytopenia (40% vs. 28%), and stomatitis (36% vs. 8%) were more frequent with trametinib, as was grade 3/4 anemia (22% vs. 11%). However, rates of grade ≥ 3 thrombocytopenia, neutropenia and febrile neutropenia were similar between the arms. More pts on trametinib arm required dose reduction or interruption due to AEs (68% vs. 49% and 74% vs. 43%, respectively). Median OS was 8.4 months with trametinib compared to 6.7 months with placebo [HR 0.98 (95% CI: 0.67, 1.44, p=0.453)]. Median PFS was 16 weeks on trametinib and 15 weeks on placebo arm. ORRs and median DoRs were 22% and 23.9 weeks and 18% and 16.1 weeks on trametinib and placebo arm, respectively. The median OS and ORR in the subgroup of pts with KRAS mutations (n=143) was similar to OS and ORR for all randomized pts. Conclusions: This is first randomized, placebo-controlled trial evaluating the combination of gemcitabine with a MEK inhibitor. There was an increased incidence of skin, GI, and hematologic toxicities with trametinib compared to placebo. The addition of trametinib did not improve OS, PFS, or response rate. These outcomes remained independent of KRAS mutations based on cfDNA. Clinical trial information: NCT01231581.
Relevance of CEA and LDH in relation to KRAS status in patients with unresectable colorectal liver metastases.
Authors: Louise Catherine Connell, Joanne F. Chou, Taryn Mary Boucher, Marinela Capanu, Nancy E. Kemeny
Journal: Journal of Clinical Oncology (2016)

762 Background: While the significance of CEA, LDH and KRAS status as individual prognostic factors for patients (pts) with metastatic colorectal cancer (mCRC) has been addressed, the relationship and interdependence between these prognostic factors on overall survival (OS) is limited. Methods: A retrospective review of pts with unresectable liver metastases and no extrahepatic disease and known KRAS status and baseline CEA and LDH treated with hepatic arterial infusion (HAI) plus systemic therapy from 2002 to 2013. Baseline values were taken from start of HAI. OS was estimated using Kaplan-Meyer. Relationship between OS and markers were evaluated using Cox regression method. Results: A total of 75 pts were included: 54 pts were KRAS wildtype (WT) and 21 pts were KRAS mutant (MUT). Median follow-up was 88 months (mos) and median OS was 45.7 mos [95% CI: 32.1-68.8]. 27 pts (36%) underwent hepatic resection at 1-year, with 3-year OS of 85% [95% CI: 64%-94%] versus 31% [95% CI: 18%-44%] for pts who did not get to resection (p&lt;0.01). Univariate analysis of factors associated with OS are shown in Table 1. On multivariate analysis, pts with CEA &gt;200 ng/mL [HR 2.6, 95% CI: 1.2-6.0, p=0.018], KRAS MUT [HR 2.2, 95% CI: 1.1-4.3, p=0.018] and prior chemotherapy [HR 2.3, 95% CI: 1.1-4.5, p=0.017] had significantly lower OS. Pts who achieved hepatic resection had significant increase in OS [HR 0.4, 95% CI: 0.2-0.8, p=0.009]. Conclusions: This analysis verifies that high CEA, KRAS MUT, prior chemotherapy, and hepatic resection affect OS in pts with unresectable mCRC. This data also suggests that CEA is an independent predictor of survival. Although further investigation is needed, CEA is clinically relevant and should be included in standard laboratory testing. [Table: see text]
Transcription factors Stat5a and Stat5b: Favorable prognostic markers in breast cancer
Authors: A. Witkiewicz, A. Ryder, L. M. Neilson, F. E. Utama, T. H. Tran, T. Hyslop, H. Rui
Journal: Journal of Clinical Oncology (2008)

22071 Background: We have previously reported that presence of nuclear localized, tyrosine phosphorylated Stat5 in breast carcinoma cells is associated with a highly favorable prognosis in a material of 209 patients with node-negative breast cancer. This initial analysis was performed on tissue array sections and not on whole sections. Furthermore, the initial study did not distinguish between Stat5a and Stat5b, since the phosphotyrosine-motif recognized by the antibody is the same in Stat5a and Stat5b. Stat5a and Stat5b are highly homologous transcription factors with overlapping but distinct regulation and biological effects. It has remained unclear whether both Stat5a and Stat5b contribute to the favorable prognosis associated with positive anti-phospho-Stat5 status. Methods: We have now performed a retrospective follow-up analysis of nuclear localized, tyrosine phosphorylated Stat5 in whole sections of breast cancer from an independent material of 400 node-negative breast cancer specimens with outcome data provided by the National Cancer Institute's Cooperative Breast Cancer Tissue Resource (CBCTR). We also analyzed levels of Stat5a and Stat5b individually and performed survival analyses. Results: Nuclear localized, tyrosine phosphorylated Stat5 remained a significant favorable prognostic marker in this independent follow-up material of human breast cancer, validating our previous data. Furthermore, nuclear localized Stat5a and Stat5b both correlated with favorable prognosis. In contrast, nuclear localized phosphorylated Stat3 did not significantly correlate with prognosis. Conclusions: Levels of nuclear localized, tyrosine phosphorylated Stat5a/b, alone or in conjunction with levels of nuclear Stat5a or Stat5b proteins, could be a cost-effective test identifying a subset of node-negative breast cancer patients with excellent prognosis who may be managed less aggressively following surgery. No significant financial relationships to disclose.
Concurrent chemoradiotherapy and brachytherapy boost for base of tongue cancer treatment outcomes.
Authors: W. F. Mourad, K. Hu, M. Perksy, M. Urken, A. Jacobson, T. Tran, B. Culliney, P. Costantino, S. P. Schantz, L. B. Harrison
Journal: Journal of Clinical Oncology (2011)

e16026 Background: Concurrent chemo-radiotherapy (CCRT) and brachytherapy boost (BT) for base of tongue (BOT) cancers have been associated with high rates of organ preservation, swallowing function and better therapeutic ratio. We report our experience of long term outcomes for BOT patients (pts) treated with reduced dose CCRT with BT. Methods: Single institute retrospective study of 89 BOT cancer pts with characteristics as follows: median age 57 (41-82yr) Male: 89% and staged as follows: II 11%, III 10%, IVA/B 79%; T1:8%, T2:45%, T3: 30%, T4: 17%, N2/3 80%. Pts were treated initially with external beam radiation therapy (EBRT) to a median dose of 60Gy (45-72Gy) followed by a base of tongue brachytherapy boost [median dose 18Gy (9-30Gy)]. Concurrent chemotherapy or biologic therapy was given in 81% (mostly given as single agent Cisplatin and to lesser extent, Carboplatin, Erbitux, taxanes or combined). Planned neck dissection performed in 79%. EBRT was delivered with a 2D technique in 61% and IMRT in 39% with comparable median doses (63Gy vs 60Gy, respectively). Results: At a median follow up of 38 months, 3 yr local control (LC) was 97%, regional control (RC) 96%, locoregional control (LRC) 93%, distant-metastasis-free survival (DMFS) 91%, disease-free survival (DFS) 88% and overall survival OS 90%. The 3 yr incidence of PEG-dependence was 4% and grade 2 xerostomia 5%. No difference in 3 year LRC (94% vs 94%), DFS (89% vs 81%) or OS (85% vs 93%) could be detected between 2D vs IMRT treated pts. IMRT shows a trend towards improve grade 2 xerostomia (11% vs 2%) and PEG dependency rates (3% vs 7%) compared with 2D, respectively but was not statistically significant. Conclusions: CCRT combined with BT yields excellent LRC, OS, and DFS for pts with base-of-tongue cancer with low rates of PEG dependency and severe xerostomia due to dose escalation to the tumor and reduced dose to normal tissue such technique spares patients severe long term toxicity without compromise of organ function.