tbuckley/cabot-search huggingface dataset:
In vitro antitumor activity of catumaxomab on immune effector cells from Caucasian or Asian (Japanese and Korean) healthy subjects.
Authors: K. Hasegawa, J. Atz, K. Fujiwara, K. Dettmar, I. Seitz-Merwald, R. Spannagl, D. Seimetz, H. Martinius
Journal: Journal of Clinical Oncology (2011)

e13031 Background: The anti-tumor activity of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) relies on the activation of immune effector cells against EpCAM+ tumor cells. It has been reported for some antibody-based therapies that ethnic groups may differ with respect to responsiveness of immune effector cells. The present nonclinical study therefore investigated potential inter-ethnic differences (Caucasian vs. Asian Donors) with regard to the potency of catumaxomab in vitro. Methods: Blood samples of healthy subjects of different ethnic backgrounds (25 Caucasian, 25 Korean and 15 Japanese donors) were collected for the comparative analysis. PBMCs of the respective blood sample were purified and used as effector cells evaluating catumaxomab-mediated cytotoxicity towards EpCAM+ tumor target cells (HCT-8; colon) in vitro. Results: The comparative analysis of potency obtained for the individual ethnic subgroups (Caucasian, Korean and Japanese) did not reveal major inter-ethnic differences. Even though a wider variability was observed among Caucasians, the potency range observed with immune effector cells of Asian donor origin (Japanese or Korean) was found to be within the potency range observed for the Caucasian ethnicity. Conclusions: No impact of ethnic background on the immune cell-mediated activity of the trifunctional antibody catumaxomab could be identified in terms of inducing potent pharmacological activity in vitro. Therefore, it is likely that patients of Asian ethnicity may also benefit from catumaxomab therapy as already demonstrated for Caucasian patients.
Distress in gastrointestinal cancer: Distress thermometer (DT, NCCN)—Validation to Brazilian Portuguese.
Authors: A. A. Dettino, L. L. Pontes, T. Pagano, M. F. Fanelli, L. T. Chinen, C. L. Costa
Journal: Journal of Clinical Oncology (2011)

608 Background: Distress is psychological suffering, and DT is its efficient screening scale. Objectives: 1) Translate,culturally adapt,and validate DT to Brazilian Portuguese. 2) Evaluate distress in gastrointestinal cancer patients. Methods: Inclusion: &gt;=200 patients with advanced gastrointestinal cancer, age&gt;=18. Exclusion criteria: uncontrolled psychiatric disorder, not knowing diagnosis, difficulty in understanding informed consent. They answered Brazilian Portuguese translated version of DT, and Hospital Anxiety and Depression Scale (HADS). Obtained data used to calculate validity and reliability of the DT (cutoff &lt;=4 represents significant distress), using HADS as gold-standard evaluation of distress (cutoff &lt;=14, and 7 for subscales). Results: Preliminary relevant results (n=85) shown in the table. Conclusions: Data confirm importance of emotional assistance to patients with oncologic diseases and need of interdisciplinary palliative care. We plan to present updated data in ASCO GI Meeting, and be able to show validation of DT to Brazilian Portuguese. [Table: see text] [Table: see text]
Chemoradiation (CRT) followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant CRT and surgery for locally advanced rectal cancer: Results of the Spanish GCR-3 randomized phase II trial after a median follow-up of 5 years.
Authors: Carlos Fernandez-Martos, Carles Pericay, Jorge Aparicio, Maria Jose Safont, Antonia Salud, Bartomeu Massuti, Vicente Alonso, Ruth Vera, Pilar Escudero, Marta Martin-Richard, Carlos Bosch, Juan Maurel
Journal: Journal of Clinical Oncology (2014)

383 Background: In locally advanced rectal cancer in contrast with the conventional approach the administration of chemotherapy prior to chemoradiation (CRT) and surgery allow most patients receive planned treatment with better toxicity profile without compromising the pCR and complete resection rates, as we previously demonstrated. (J Clin Oncol 28:859-865, 2010). We now report on the 5-year outcomes of this randomized trial. Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by Magnetic Resonance +/- endorectal ultrasound, were randomly assigned to arm A—preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B— four cycles of CAPOX followed by CRT and surgery. The following five-year outcomes were assessed: the cumulative incidence of local-regional (LRF) and distance failure (DF), disease-free (DFS) and overall (OS) using the Kaplan-Meier method. Results: Of 108 patients accrued, 52 were randomly assigned to arm A and 56 to arm B. According to intention-to-treat analysis with a median follow-up time of 69.5 months, the 5-years DFS rates were 64.3% (95% CI, 49% to 76%) in arm A and 60.7% (95 CI, 46% to 72%) in arm B (P=0.73). The 5-year cumulative incidences of local relapse were 1.9 % and 7.1% in A and B arms respectively (P= 0.36). No significant differences were detected for 5-year cumulative incidence of distant metastases (21.1% and 23.2%; P = 0.80) and 5-years overall survival (77.9% and 74.7%; P= 0.64). Conclusions: Both approaches yield similar 5-y outcomes. Because of the associated acute toxicity sparing and better compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy prior to CRT and surgery may well be the next step in phase III testing versus the standard strategy to capture meaningful differences in DFS.
Evaluation of PTEN status in circulating tumor cells (CTCs) and matched tumor tissue from patients with castrate-resistant prostate cancer (CRPC).
Authors: Elizabeth Punnoose, Eric Tucker, Dena Marrinucci, Lukas C. Amler, Hartmut Koeppen, Premal H. Patel, Yibing Yan, Ruth Riisnaes, Gerhardt Attard, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2013)

62 Background: PTEN loss occurs frequently in prostate cancer and may trigger progression to CRPC through activation of the PI3K/AKT pathway. A blood-based assay that determines PTEN status in CRPC patients could enable informed treatment decisions such as the use of a PI3K-targeted therapy. We evaluated PTEN status in archived tissue, metastatic bone biopsies, and CTCs from CRPC patients. Here we report the results of PTEN evaluation in CTCs from 42 CRPC patients and matched tissue from 6 patients with more underway. Methods: Nucleated cells from CRPC patient blood were plated onto glass slides and subjected to IF staining and CTC identification by high-speed fluorescent scanners at Epic Sciences. CTCs were identified as CK+/CD45- cells with intact DAPI nuclei, and samples with ≥5 CTCs per 2 slides (74%) were then tested for PTEN by FISH. Partial loss was defined as a decrease in PTEN copies (PTEN &lt; CEP10) and total loss as zero PTEN copies. PTEN IHC in tissue was stained using CST clone 138G6 and H-scores ≤ 200 counted as loss. Results: Partial or total loss of PTEN by FISH was observed in 15 of 31 patients (48%) by CTC analysis. Changes in ploidy were frequently observed and broad heterogeneity seen both within and between patients. Weighted across patients, the most frequently observed abnormal genotypes in CTCs were 2 CEP10/0 PTEN (total loss, diploid, 5.8%), 3 CEP10/0 PTEN (total loss, triploid, 4.5%), and 3 CEP10/3 PTEN (PTEN-normal, triploid, 4.2%). These genotypes were not observed in over 1,000 white blood cells evaluated evenly across 31 patients, demonstrating that cells identified as CTCs on the Epic platform show malignant features not observed in normal cells. PTEN loss was detected by IHC in 6 of 8 (75%) archived patient samples and 7 of 8 (87%) of matched bone biopsies. Where CTCs were available (6 cases), PTEN status was correctly determined as lost in 4 cases, normal in 1 case and borderline in one case. Conclusions: Our results illustrate the high percentage of PTEN loss in CRPC patients and the potential for using CTCs as a non-invasive, real-time biopsy to determine a patient’s PTEN status. PTEN status will be determined using these assays in an upcoming AKT inhibitor Phase II trial.
Cisplatin plus irinotecan in the treatment of gallbladder or biliary tract cancer: A randomized phase II trial (NCT01859728).
Authors: Lucas Vieira dos Santos, MauriÂcio Wagner Souto Ferraz, Joao Paulo Lima, Kathia Cristina Abdalla
Journal: Journal of Clinical Oncology (2016)

TPS485 Background: Gallbladder and biliary tract cancer (GBTC) have an aggressive behavior and gemcitabine-platinum chemotherapy emerged as the new standard of care for advanced or metastatic GBTC. Despite optimal management, prognosis is still poor. This randomized trial aims to compare irinotecan plus cisplatin versus gembitabine plus cisplatin in advanced or metastatic GBTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic carcinoma of GBTC (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent are stratified by ECOG (0 or 1 vs 2) and hematogenic metastases (yes vs no) and randomized to receive Irinotecan 65mg/m² D1 and D8 q21 days plus Cisplatin 60mg/m² D1 q 21 days (IP) or Gemcitabine 1000mg/m² D1 and D8 every 21 days plus cisplatin 25mg/m² D1 and D8 every 21 days (GC), until disease progression or unacceptable toxicity, with standard hydration and antiemetics. Computed tomography for response evaluation is undertaken every 6 weeks. The primary end-point is overall response rate (ORR). Assuming p0 = 25%, p1 = 50%, alpha = 5% and beta = 20% in an optimal Simon’s two stage design, 24 patients per arm will be recruited (N1 = 9; R1 = 2; Ntot = 24; Rtot = 9). The sample size for each arm was calculated separately. Secondary end-points are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), quality of life and safety. This clinical trial was activated in January 2013 and the accrual period is expected to end by December 2017. This protocol was approved by institutional review board. Clinical trial information: NCT01859728.
VSL#3 and conjugated linoleic acid ameliorate colitis and inflammation-driven colorectal cancer.
Authors: M. Viladomiu, M. Pedragosa, C. De Simone, R. Hontecillas, J. Bassaganya-riera
Journal: Journal of Clinical Oncology (2011)

e14108 Background: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer. Manipulating the gut microbiota has been proposed to decrease inflammation and colorectal cancer. Bacterial species in the VSL#3 mixture are capable of producing conjugated linoleic acid (CLA), a polyunsaturated fatty acid with demonstrated anti-inflammatory and anti-carcinogenic effects. This study aimed to compare the anti-carcinogenic anti-inflammatory efficacies of dietary CLA versus VSL#3 treatment in mouse models of IBD and colon cancer. Methods: Following induction of colitis or inflammation-driven colorectal cancer mice treated with placebo, CLA or VSL#3 for 30 days were monitored for disease activity over time. Colonic specimens were collected for histopathology, gene expression and flow cytometric analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen, blood and colonic lamina propria lymphocytes (LPL) were phenotypically and functionally characterized. Results: VSL#3 and CLA ameliorated disease activity and reduced colonic inflammatory lesions and tumor formation, although VSL#3 was more effective than CLA. Histopathological examination revealed lower epithelial erosion, adenocarcinomas and adenomas in colons of VSL#3-treated mice when compared to the control and CLA groups, although CLA-treated mice had significantly lower tumors and leukocyte infiltration than controls. VSL#3 increased the percentage of interleukin 17 (IL-17) and FoxP3 expressing T cells in the MLN and colonic LPL, VSL#3 also increased the CD4+CD44+CD62L+ memory T cells population in the colonic LPL. Gene expression analyses showed that CLA reduced colonic mRNA expression of cyclooxygenase 2 (COX-2) and VSL#3 upregulated angiostatin expression. Conclusions: Both CLA and VSL#3 improved disease activity and reduced colonic inflammatory lesions and tumor formation in mouse models of IBD and inflammation-induced colorectal cancer, although VSL#3 showed greater anti-carcinogenic and anti-inflammatory activities than CLA. Mechanistically, CLA modulated expression of COX-2 levels in the colonic mucosa, whereas VSL#3 targeted regulatory mucosal CD4+ T cell responses.
Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts).
Authors: Fred Saad, James L. Bailen, Christopher Michael Pieczonka, Daniel R. Saltzstein, Paul R. Sieber, David B. Maclean, Hongliang Shi, Helene M. Faessel, Neal D. Shore
Journal: Journal of Clinical Oncology (2016)

200 Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC 50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T &gt; 150 ng/dL and prostate-specific antigen (PSA) &gt; 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T &lt; 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T &lt; 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over &gt; 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( &lt; 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.
Cost analysis of adjuvant management strategies in early-stage testicular seminoma.
Authors: John A. Cox, Shefali R. Gajjar, Thomas B. Lanni, Todd A. Swanson
Journal: Journal of Clinical Oncology (2013)

320 Background: Acceptable post-orchiectomy management strategies for stage I seminoma include surveillance (SV), para-aortic (PA-RT) radiation therapy, dog-leg (DL-RT) or a single cycle of carboplatin (Carbo). The follow-up recommendations for each option were recently amended by the National Comprehensive Cancer Network (NCCN) in 2012. As such, surveillance imaging after treatment, a contributor to costs, was significantly scaled back. This was driven, in part, by the maturation of data from the MRC TE 19/EORTC 30982 study along with an effort to decrease exposure to frequent CT scans. Methods: NCCN guidelines were used to design treatment plans for each of the acceptable adjuvant treatments strategies: SV, Carbo (AUC=7), PA-RT (20 Gy), DL-RT (20 Gy) and salvage chemotherapy (bleomycin, etoposide, and cisplatin x 3 cycles). NCCN guidelines for growth factor support and anti-emetic use were incorporated into the treatments. Follow-up charges, including weighted costs for salvage for each modality, were generated for 10 years based on both the 2012 and the 2011 NCCN guidelines. According to published literature, the anticipated failure rate for SV, either DL-RT or PA-RT, or Carbo was 18%, 4%, and 5% respectively. 2012 Medicare reimbursement rates (both facility and professional charges) were used to determine the actual reimbursement for each treatment course over a 10-year period. Results: Under the current 2012 NCCN recommendations, the total Medicare reimbursement for SV, PA- RT, DL-RT, and Carbo, when factoring in the cost of salvage, were $10,643, $11,678, $9,662, and $7,870 respectively. This is compared to the reimbursement under the 2011 NCCN guidelines for SV, PA- RT, DL-RT, and Carbo of $20,986, $11,517, $9,394, and $20,365. Conclusions: Reduced imaging during SV or after adjuvant therapy has significantly narrowed the difference in reimbursement between adjuvant management options. This is driven primarily by the integration of results from the MRCTE19/EORTC 30982 outcomes and patterns of failures. We are currently in the process of using Treeage models to fine-tune treatment costs and patient variables to better assess cost-effectiveness between adjuvant treatment modalities.
A model for survivorship care plans (SCP) at a large academic institution.
Authors: Andrew Joseph Ward, John Lawrence Bell, Lindsey Jerkins
Journal: Journal of Clinical Oncology (2016)

35 Background: In 2014, the American College of Surgeons Commission on Cancer mandated in Standard 3.3 that SCP be provided for all patients at the completion of active treatment. Minimum requirements for what SCP should include were provided; however, no standardized model was proposed. We outline how a large academic medical center approached this as an opportunity instead of an obstacle. Methods: A pilot for developing SCP for the University of Tennessee Medical Center Cancer Institute (UTMC, CI), where 2700 new cancer cases per year are seen, was created. Initially approached by the Division of Surgical Oncology, SCPs were established for all patients. This approach allowed the UTMC, CI to determine all best practices for meeting Standard 3.3. This pilot identified all major stake holders including mid-level providers who see follow-up patients, a physician champion, and the survivorship care plan that best fit our organizational challenges and work flow. Results: The described approach allowed us to exceed our goal of providing SCP for 10% of patients seen in 2015 prior to the conclusion of the third-quarter. By keeping the pilot small, we were able to pinpoint the “best practice” for identifying patients, completing the SCP, delivery of the SCP, and providing care in an efficient way. By creating SCP that can be adapted by the entire UTMC, CI, we were able to ensure that we are meeting all of our stakeholder’s needs. Conclusions: Compliance with Standard 3.3 for SCP does not have to be a daunting task. The process can be adapted to be efficient while utilizing already stressed financial and personnel resources. A successful survivorship program can be developed as a pilot prior to being adapted by an entire organization. We recommend identifying the appropriate stake holders, defining a physician champion, and identifying SCP that best serve the mission of each organization while meeting all regulatory requirements.
Actionable targets in patients with cisplatin-resistant advanced germ cell tumors.
Authors: Aditya Bagrodia, Samuel D. Kaffenberger, Byron Lee, William Lee, Eugene K. Cha, John Sfakianos, Sizhi Paul Gao, Emily Craig Zabor, Irina Ostrovnaya, Jana Eng, Michael F. Berger, Dean F. Bajorin, Nikolaus Schultz, Joel Sheinfeld, George J. Bosl, Hikmat Al-Ahmadie, David B. Solit, Darren R. Feldman
Journal: Journal of Clinical Oncology (2016)

473 Background: Approximately 30% of patients with advanced germ cell tumor (aGCT) will progress after first-line chemotherapy. Nearly half of these patients will die of progressive GCT. We describe potentially actionable mutations in a cohort of patients with platinum-resistant aGCT through targeted sequencing. Methods: 76 patients with cisplatin-resistant (CR) disease were sequenced using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay that examines 341 cancer-related genes. Patients were categorized as CR if they met any of the following criteria: 1) incomplete response to first-line cisplatin-based chemotherapy; 2) nonteratomatous tumor progression after standard chemotherapy; 3) nonteratomatous GCT identified at postchemo surgery. We grouped all somatic mutations into core signal transduction pathways or canonical cell functions to identify potential precise targets for therapy. Results: The majority of patients had nonseminoma histology (n = 64, 84%). International Germ Cell Cancer Collaborative Group risk was good, intermediate, and poor in 34%, 13%, and 53% of patients. 17 patients died of disease. In total, 51 potentially actionable alterations were identified in 36/76 (47%) patients. In the TP53 pathway, 7 MDM2 amplifications and 4 MYCN amplifications that may sensitize to nutlin-3 inhibitors were identified. Within the receptor tyrosine kinase pathway, 3 KIT mutations, 1 KDR amplification, and 1 MET amplification were seen that may sensitize to tyrosine kinase inhibitors. Eleven KRAS mutations, 3 NRAS mutations, 3 BRAF mutations, and 2 RAC1 mutations were see among the RAS pathway with preclinical data suggesting efficacy towards respective inhibitors. Actionable targets were also among the PI3-K, WNT, and cell cycle pathways. Potential targets with chromatin modifying or tumor suppressor functions were also seen. Conclusions: We describe actionable alterations that may guide treatment selection in a significant proportion of patients with CR aGCT. Targeted sequencing of these patients may allow us to enrich future clinical trials with patients whose tumors harbor alterations in the drug target of interest.