tbuckley/cabot-search huggingface dataset:
Positron emission tomography/computed tomography for early treatment response evaluation in metastatic colon cancer.
Authors: Bodil E. Engelmann, Annika Loft, Andreas Kjær, Hans J. Nielsen, Eric von Benzon, Nils Brünner, Ib Jarle Christensen, Thomas A. Gerds, Susanne H. Hansson, Niels Henrik Hollander, Michael Holmsgaard Kristensen, Johan Löfgren, Elena Markova, Carsten Sloth, Liselotte Højgaard
Journal: Journal of Clinical Oncology (2014)

614 Background: Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography/ computed tomography (PET/CT) and measurements of tissue inhibitor of metalloproteinases type 1 (TIMP-1), carcinoembryonic antigen (CEA) and urokinase plasminogen activator receptor domain I [uPAR(I)] for early assessment of treatment response in mCC patients. Methods: Thirty-three mCC patients scheduled for first line chemotherapy with capecitabine, oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1) and EORTC PET criteria. Plasma TIMP-1, plasma uPAR(I) and serum CEA were determined. Results: Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80 %, specificity of 69 % and an Odds Ratio of 13.9 [CI 1.9; 182]. Early metabolically stable or progressive disease was associated with shorter progression-free survival (PFS) (hazard ratio (HR) = 3.2 [CI 1.3; 7.8]). Biomarker levels at early evaluation were associated to shorter PFS (TIMP-1 per unit increase on a log-2 transformed ng/mL scale: HR = 2.23 [CI 1.20; 4.14]; uPAR(I) per 25 fmol/mL increase: HR = 1.36 [CI 1.03; 1.79]). Conclusions: This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP-1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP-1 and uPAR(I) guided early treatment adaptation in mCC.
Lapatinib plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer.
Authors: J. Watanabe, S. Hamauchi, Y. Higashi, Y. Onozawa
Journal: Journal of Clinical Oncology (2011)

e11003 Background: Lapatinib (L) is widely used in patients (pts) with trastuzumab (T)-pretreated HER2-positive metastatic breast cancer (HER2+MBC), although, we do not know upfront use of L is beneficial or not for HER2+MBC pts. Methods: T-pretreated HER2+MBC pts received L plus capecitabine (C). L was administered 1250mg/body daily and C was given 2000mg/m2/day from day 1 to 14 in a 3-week cycle. Clinical efficacy was assessed by 2 (or 3). Results: Thirty female HER2+MBC pts (29 immunohistochemically HER2-positive, 1 FISH-positive), median age of 54 (range 33-72) were treated with L+C. Twenty-four pts (80.0%) had visceral lesion(s) and 8 pts (26.7%) had histories of central nervous system involvement. Median T-based regimens pts received prior to L+C was 2.5 (range 1-7), and 15 pts (50.0%) were heavily (>2) pretreated. Of 23 pts who have complete history of previous therapies, exposed to T from 56 to 2226 (median 876) days prior to L+C. Twenty-two pts discontinued therapy because of disease-progression (20 pts) or toxicity (2 pts). Of 20 resistant pts, 9 re-challenged T-based therapies, 4 received HER2-nonspecific regimens including clinical trials and 7 underwent supportive care. Of 24 evaluable pts, 1 (4.2%) achieved complete response (CR), 2 (8.3%) showed partial response (PR) and 12 (50.0%) maintained stable disease (SD). Because only 8 pts has died during observation, median overall survival is not applicable. Median progression-free (PF) was 154.0 days (95% confidence interval 97.3-210.7). Pts heavily pretreated (2> T-based regimens) showed a trend of inferior PF (202.0 vs. 151.0), although, it was not statistically significant (p=0.25). Furthermore, numbers of prior regimens did not affect OS (p=0.66). Clinical benefit rates (CR+PR+SD) for each group were 61.5% in lightly-pretreated and 53.8% in heavily-pretreated respectively. Although it was very limited size to be analyzed, pts thought to be T-responder (exposed >300 days) had a better PF than non-responder. (median 412.0 vs. 151.0 days, p=0.0129) Conclusions: Within our observation, lapatinib plus capecitabine showed clinical effectiveness against patients with trastuzumab-pretreated HER2+MBC both in early and late phase of their clinical course.
MLN4924, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients (pts) with metastatic melanoma: Results of a phase I study.
Authors: S. Bhatia, O. Hamid, A. C. Pavlick, G. Mulligan, P. G. Smith, M. D. Pickard, M. Shultz, R. M. Walker, B. Dezube, S. O'Day
Journal: Journal of Clinical Oncology (2011)

8529 Background: MLN4924 is an investigational inhibitor of NAE; NAE is an essential controller of the NEDD8 conjugation pathway that is required for cullin-RING ligase (CRL) activity. MLN4924 prevents proteasomal degradation of CRL substrate proteins with important roles in cell-cycle progression (p27), DNA damage (Cdt-1), stress response (Nrf-2), and survival signaling (pIκBα), leading to apoptosis. MLN4924 has antitumor activity in preclinical models of several tumor types including melanoma. This phase I study investigates the safety of two schedules of MLN4924 in pts with metastatic melanoma. Methods: Pts aged ≥18 yrs with ECOG PS 0-2 and no symptomatic brain metastases received 1-hr IV infusions of MLN4924 on d 1, 4, 8, 11 (schedule A) or d 1, 8, 15 (schedule B) of 21-d cycles. Dose escalation proceeded via a Bayesian continual reassessment method based on DLTs in cycle 1. Adverse events (AEs) were graded using NCI-CTCAE v3.0. Tumor response was assessed by RECIST. Blood samples were collected in cycle 1 for PK/PD analysis. Results: 19 pts have been enrolled to 7 dose levels on schedule A: 50 (n=2), 67 (n=2), 89 (n=2), 118 (n=4), 157 (n=2), 209 (n=5), and 278 (n=2) mg/m2. Median age is 60 yrs (range 34–73); 58% are male. DLTs comprised one episode of grade 3 hypophosphatemia (118 mg/m2) and one of grade 3 acute renal failure (278 mg/m2). The MTD has not been defined. The most common AEs (any grade) include fatigue (58%), diarrhea (47%), nausea (42%), myalgia (37%), and vomiting (37%). Grade ≥3 AEs occurred in 5 pts, including the DLTs, cancer-related pain (n=2), and small bowel obstruction (n=1). One pt with BRAF-wild type tumor, with rapidly progressive disease at entry, achieved a PR at cycle 4 and continues on study. Nine (47%) pts exhibited SD, durable for 4 and 8 cycles in 2 pts. Preliminary PK data suggest no apparent accumulation of MLN4924 concentrations in plasma. Analyses of NAE-regulated transcripts in peripheral blood reveal the expected PD effects of MLN4924-target inhibition. Accrual continues at 209 mg/m2 on schedule A; dose escalation from 157 mg/m2 on schedule B is ongoing. Conclusions: MLN4924 is generally well tolerated at the doses tested on schedule A, with antitumor activity.
In vitro and in vivo activities of KRN330, a fully human monoclonal antibody against colon cancer.
Authors: N. Sawada, E. Taguchi, M. Takahashi
Journal: Journal of Clinical Oncology (2011)

432 Background: KRN330 is a novel recombinant human IgG 1 monoclonal antibody (mAb) targeting A33 surface differentiation antigen that is uniformly expressed on the surface of 95% of colorectal cancer (CRC) cells. In this study, we characterized the activity of KRN330 for its in vitro properties, as well as for its in vivo antitumor activity. Methods: A kinetic analysis of the interaction between KRN330 and recombinant human A33 was conducted using a Biacore 3000. Western blot analysis was conducted using A33 expressing COLO205 lysates under reducing and non-reducing conditions. Binding of KRN330 to human colorectal cancer tissues were investigated using FITC-labeled KRN330. We also developed more conventional staining methods of A33 and investigated A33 expression using human colon cancer tissue microarray (TMA). ADCC and CDC activities of KRN330 were assessed using a standard 51 Cr release assay. A33 expression levels of 14 CRC cell lines were analyzed using flow cytometer. In vivo antitumor activities of KRN330 alone or in combination with chemotherapeutic agents against subcutaneous or intraperiotoneal human CRC (COLO205 and LS174T) models were investigated using mice and rats xenograft model. Results: A kinetic analysis revealed that KRN330 showed a high binding affinity to A33. Western blot analysis also showed that antibody recognized not any protein under reducing condition, but non-reducing condition. A33 staining of TMA with 204 different samples revealed the majority of tumor expressed A33. KRN330 exhibited ADCC activity against A33 expressing human colorectal cancer cell lines which include both K-ras wild and mutated types. KRN330 showed dose-dependent antitumor activities in vivo. KRN330 also significantly prolonged survival of human colon tumor bearing mice. In addition, combination treatment of KRN330 with irinotecan showed increased antitumor activitiy and prolongation of survival, compared to either irinotecan or KRN330 alone. Conclusions: These results suggest that KRN330 is a promising candidate of novel therapy for CRC. The phase I/II study of KRN330 plus irinotecan in patients with second line metastatic CRC is ongoing. [Table: see text]
Pemetrexed monotherapy in patients with advanced non-small cell lung cancer who have had prior chemotherapy: A prospective phase II trial
Authors: H. Lee, M. Ahn, J. Ahn, J. Kwon, S. Lee, S. Bae, B. Kim, H. Kim, D. Hong, K. Park
Journal: Journal of Clinical Oncology (2008)

19137 Background: Pemetrexed (LY231514, MTA) is a novel, multitargeted antifolate chemotherapy agent that has demonstrated clinical activity in non-small cell lung cancer as well as other solid tumors. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Based on these results, treatment with pemetrexed would be considered a standard treatment option for second-line NSCLC. Thus, this prospective, multicenter, phase II study assessed the efficacy and safety of pemetrexed in patients with advanced NSCLC who had prior chemotherapy in Korea. Methods: Patients ≥ 18 years with a histologic/cytologic diagnosis and who have had prior chemotherapy for advanced non-small cell lung cancer received pemetrexed at 500 mg/m2 every 3 weeks with folic acid and Vitamin B12 supplementation. Up to 72 patietns were to be enrolled as a Simin two- stage optimal design. Results: From June 2006 to April 2007, 81 patients with stage IIIB and stage IV disease were enrolled at 12 institutes and 77 patients were evaluable for the analysis. 36 patients had visceral metastasis, and 19 patients had ≥3 organ involved. Partial responses (RECIST criteria) were achieved in 4 patients (overall response rate = 5.2%) and stable disease were in 33 patients (disease control rate = 48.1%). With 8.2 months follow up duration, the median time to disease progression was 2.87 months (95% CI 0.88∼4.86) and median overall survival was 7.77 months (95% CI 5.19∼10.35). CTC hematologic toxicities were grade 3 neutropenia (6.2%) and grade 3 thrombocytopenia(3.7 %) and grade 3/4 anemia(3.7%/1%). No patients had febrile neutropenia. Non-hematologic toxicities were grade 3 nausea(1%) grade 3 constipation(2.5%), and grade 3/4 fatigue(11.1%/1%). Conclusions: Results of this study suggest that pemetrexed monotherapy in patients with advanced non-small cell lung cancer as a second line therapy has promising efficacy, especially in disease control rate, with less hematologic and nonhematologic toxicity. Further biomarker study, correlation of thymidylate synthase expression with clinical outcome in this patients will be updated. No significant financial relationships to disclose.
Acculturation and perceptions of good cancer death among individuals of Japanese ancestry living in the United States.
Authors: M. Mori, Y. Kuwama, H. A. Parsons, T. Ashikaga, S. M. Grunberg, M. Miyashita
Journal: Journal of Clinical Oncology (2011)

e19563 Background: As the American population becomes more diverse, clinicians may face ethical dilemmas due to cultural variation in perception of a “good cancer death.” Of the 1.2 million individuals of Japanese ancestry living in the United States, some identify as Japanese Americans (JA) while others identify as Japanese living in America (J), reflecting different levels of acculturation. To establish appropriate goals for end of life care, it is imperative to understand the impact of such acculturation. Methods: In 2010, an IRB-approved self-administered survey was distributed to JA and J of age ≥ 20 who participated in two social events held in New York and West Virginia or belonged to the New York Japanese American Association. The primary endpoint consisted of ratings on a 7-point Likert scale (1=absolutely unnecessary – 7=absolutely necessary) of 18 components derived from a nationwide quantitative study previously published by our group that identified 18 important domains contributing to a good death in Japanese cancer care. T-tests were used to compare mean ratings between JA and J respondents. Results: 366 of 1132 questionnaires were returned (32%). 69 (19%) subjects identified themselves as JA and 297 (81%) as J. Most were ≥ 60 years old (63%) or female (77%), and have lived in the US for ≥ 21 years (72%). JA rated the following significantly lower compared to J: ‘being able to stay at one’s favorite place’ (6.00 vs 6.27, p=0.0377), ‘trusting physician’ (6.31 vs 6.60, p=0.0089), ‘having some pleasure in daily life’ (6.05 vs 6.30, p=0.0473), ‘feeling that one’s life was completed’ (5.51 vs 6.13, p=0.0002), ‘dying a natural death’ (5.71 vs 6.05, p=0.0424), ‘seeing people whom one wants to see’ (5.33 vs 5.75, p=0.0177), and ‘maintaining one’s role in family or occupational circumstances’ (5.16 vs 5.54, p=0.0397). JA rated ‘having faith’ significantly higher than J (4.89 vs 4.39, p=0.0418). Conclusions: Perceptions of good cancer death differ significantly between JA and J, reflecting prevailing attitudes in American and Japanese society. Appreciation of different levels of acculturation might be an important factor in providing optimal end of life care.
Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction
Authors: Jennifer G. Abelin, Derin B. Keskin, Siranush Sarkizova, Christina R. Hartigan, Wandi Zhang, John Sidney, Jonathan Stevens, William Lane, Guang Lan Zhang, Thomas M. Eisenhaure, Karl R. Clauser, Nir Hacohen, Michael S. Rooney, Steven A. Carr, Catherine J. Wu
Journal: Immunity (2017)
The role of inflammatory monocytes in human metastatic colorectal cancer.
Authors: Julie G. Grossman, Timothy M. Nywening, Brian Belt, Elizabeth Pittman, Andrew Giorgi, Ahlers Michael, William G. Hawkins, Steven M. Strasberg, Peter S. Goedegebuure, Ryan C. Fields, David Linehan
Journal: Journal of Clinical Oncology (2015)

624 Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. 60% of CRC patients are diagnosed with metastatic (m) CRC and the 5-year survival is &lt;20%. Myeloid cells, particularly inflammatory monocytes (IM), are recruited from the bone marrow to the tumor microenvironment where they become tumor associated macrophages and play a crucial role in tumor progression, metastasis, and chemoresistance. While the importance of IM have been shown in other malignancies, little is known about their role in human CRC. Methods: Human tissue was collected under an IRB approved protocol at Washington University. Flow cytometry was performed on PBMCs and single cell suspensions of normal tissue and tumor samples. Qualitative RT-PCR and confocal microscopy were performed for CCL2. T-cell suppression assays were performed using CD14+ IM isolated from patient peripheral blood and tumor samples. Results: Analysis of pre-operative blood revealed that monocyte levels correlate with the extent of disease burden. Monocytes were elevated in CRC patients compared with controls (p&lt;0.0001), additionally patients with liver metastasis had further elevation in monocytes compared with patient’s with primary disease (p=0.01). In metastatic patients, monocyte levels also correlate with survival following resection of hepatic metastasis (p=0.0002). FACS analysis confirmed these findings and demonstrated that the circulating CD11b+/CD14+/CCR2+ subset of IM was responsible for the increase. Both primary CRC and liver mCRC had increased expression of CCL2 compared to uninvolved tissue (p=0.008 and p=0.03, respectively). Production of CCL2 was localized to CRC cells. FACS analysis showed CCR2+ tumor infiltrating macrophages were elevated in CRC liver metastasis compared to adjacent normal liver and a paucity of effector T-cells. CD14+ TAMs isolated from mCRC inhibited T-cell proliferation, illustrating the immune suppressive phenotype of these cells. Conclusions: Inflammatory monocytes correlate to prognosis in mCRC. Therefore, targeting CCR2+ myeloid cells may improve anti-tumor immunity and patient survival in metastatic disease.
DNA-microarrays predicting chemotherapy response of malignant tumors
Authors: M. C. Dietel, C. Denkert, P. Suroviak, H. Lage, B. Györffy
Journal: Journal of Clinical Oncology (2005)

9608 A major obstacle in cytostatic treatment of tumors is the development of resistance to many different antineoplastic drugs, called MDR. Up to date, clinical tests for predicting therapy response are not available. We hypothesized that gene expression patterns specific for chemotherapy resistant cancer cells can predict therapy response. Methods: 30 cancer cell lines were treated with 11 anticancer agents (5-FU, cispl., cyclophosphamide, doxorubicin, etoposide, MTX, mitomycin C, mitoxantrone, paclitaxel, topotecan and vinblastin) at levels achieved in vivo. Resistance index was computed to designate the cells as sensitive or resistant, then for each drug the subset of resistant and sensitive cell lines were compared. Gene signatures were obtained by Affymetrix U133 chips. PAM was applied for feature selection. 46 top features were checked by TaqMan micro fluidic card system. In a preclinical approach the resistance associated gene patterns were checked against ovarian carcinomas, leukemias, malignant melanomas with known clinical follow-up. Results: For the resistance against each cytostatic drug an individual prediction profile was constructed, containing 42 to 516 genes. The overall accuracy of the predictions in a leave-one-out cross validation was 81.7%. A list of the top 67 MDR candidate genes was identified, which were associated with the resistance against at least four anticancer agents. The associations with the resistance were confirmed by TaqMan validation for 76 gene-resistance pairs. Preliminary results on clinical specimens gave a positive predictive value between 80–85%. Conclusion: The study makes in vivo cancer response prediction feasible and provides a strategy to simultaneously predict drug resistance against a set of selected anticancer drugs with an accuracy of up to 85%. This approach will provide a sufficient ratio for the clinical selection of cyostatic drugs with regard to the individual patient and will contribute to personalized medicine No significant financial relationships to disclose.
Pharmacokinetic and pathophysiologic covariates influencing treatment outcomes with T-DM1 in patients with HER2-positive metastatic breast cancer (MBC).
Authors: M. Gupta, P. LoRusso, H. A. Burris, B. Wang, A. Joshi, Y. B. Tong, Y. Chu, S. Girish
Journal: Journal of Clinical Oncology (2011)

633 Background: T-DM1 is a HER2-directed antibody-drug conjugate (ADC) in development for the treatment of HER2-positive MBC. T-DM1 is a unique ADC in that it provides intracellular delivery of the highly potent cytotoxic agent DM1 (derivative of maytansine) in addition to the antitumor properties of trastuzumab. Tumor growth inhibition (TGI) models have been developed for oncology therapies and can be a useful tool for predicting outcomes. We developed a model to predict the effect of T-DM1 exposure and baseline pathophysiologic covariates on TGI. Methods: The TGI model was based on data from one phase I (TDM3569g) and two phase II studies (TDM4258g, TDM4374g) (N=274) of single agent T-DM1 (3.6 mg/kg q3w) in heavily pretreated HER2-positive MBC. Objective response rates (ORR) in clinical studies were according to RECIST; tumor size for the model was based on the Sum of Longest Diameters (SLD) of target lesions. Tumor size is described as a function of time and drug exposure and the model accounts for natural tumor growth rate, antitumor drug effect (cell kill rate) and drug resistance. Baseline patient-specific and pathophysiological characteristics (e.g., time after last trastuzumab dose, total trastuzumab levels, baseline SLD, shed HER2 extracellular domain and albumin level) were evaluated as covariates. Results: The model-predicted TGI rate (SLD reduced by ³30%) with T-DM1 was 38% (90% prediction interval 31%–45%) based on the nominal dosing intensity. ORR ranged from 26% to 44% in the 3 trials. A correlative trend was observed between Week 6 and Week 12 T-DM1 AUC and TGI. Variability in tumor response was high and not explained by variability in exposure. No strong correlation was observed between T-DM1 exposure (AUC, Cmax, and Cmin) and TGI rate. None of the baseline covariates tested appeared to influence TGI. Conclusions: The model-predicted TGI rate appears to correlate with observed ORR. Further work including a drug-disease simulation framework is being developed to predict antitumor response and overall survival with T-DM1 and may be used to simulate untested dosing regimens and support dosing decisions during clinical development.