tbuckley/cabot-search huggingface dataset:
Molecular physiology monitoring of ovarian cancer ex vivo.
Authors: Christina Fotopoulou, Tommy Gorgy, Andrew Paterson, Konstantinos Petkos, Paula Cunnea, Wen Wu, Emmanouil Drakakis, Hani Gabra, Martyn Boutelle
Journal: Journal of Clinical Oncology (2015)

e16567 Background: Epithelial ovarian-cancer (EOC) is a heterogeneous disease which constitutes an area of unmet need. Continuous monitoring of molecular physiology of the disseminated tumour deposits would help to evaluate early tumour response to chemotherapy and profiling of spatial tumour heterogeneity in advanced stage disease. Methods: Surgically removed cancerous and non cancerous omentum is tested ex vivo. The omentum, cut into 1cm3 pieces, is placed in RPMI cell culture media. A liquid junction potential measuring system is used, consisting of a Ag/AgCl reference electrode, and a differential amplifier. After digestion with dispase extracted cells are stained with cell type specific markers and the proportion of cancerous cells are calculated. Statistical significance was calculated with the Mann Whitney U-test. Results: 12 EOC-patients were evaluated. On 12 pairs of cancerous and non-cancerous omentum samples the average biopotential of the non-cancerous and cancerous omentum was 1.43v and 1.07v, respectively, showing a statistically significant difference of 0.36v (p = 0.05). The biopotential of the non-cancerous omentum ranged between 1.20v and 1.73v, versus 0.63v to 1.48v in the cancerous omentum, showing an overlap between 1.20v and 1.48v. In all 12 samples, the biopotential of the non-cancerous omentum was always greater than the cancerous omentum. The biopotential difference between the cancerous and non-cancerous omentum ranged from 0.15v to 0.87v. 10 of the 12 (83.3%) cases had a difference < 0.6v, which correlated with good surgical & clinical patients´outcome in terms of residual disease, and surgical morbidity and 3-mo mortality. Patients with biopotential difference > 0,6v had poor surgical and clinical outcome. Conclusions: The characterisation of EOC parameters that are detectable by electronic sensors will facilitate the development of devices to better monitor the disease and predict treatment outcomes. It appears that the biopotential difference between the cancerous and non-cancerous omentum, above a specific cut-off of 0.6v may be associated with an adverse surgical and clinical outcome. Larger scale measurements are warranted to confirm this hypothesis into a proof of concept.
Abstract 23: Disruption of TRAF2-TAK1-NF-κB Signaling Axis Triggers K-48 Linked Poly-Ubiquitylation of RIP1 and Necrotic Cell Death in Doxorubicin Cardiotoxicity
Authors: Rimpy Dhingra, Victoria Margulets, Floribeth Aguilar, Lorrie A. Kirshenbaum
Journal: Circulation Research (2015)

The anthracycline doxorubicin (Dox) is a highly effective anti-tumour agent, however, its use is limited by its severe cardiotoxic effects that manifests as heart failure. The decline in cardiac performance induced by doxorubicin remains poorly defined. A critical survival role for the canonical IKKβ -mTOR-NF-κB signaling pathway has been demonstrated in ventricular myocytes. In this report, we demonstrate that, Dox impairs IKKβ-mTOR- NF-κB signaling in ventricular myocytes accompanied by mitochondrial perturbations including mPTP, loss of mitochondrial membrane potential and ROS production. IKKβ- NF-κB signaling involves TRAF 2 mediated ligation of K63- ubiquitin chains to RIP1 (Receptor Interacting Protein 1) which serves as scaffold for recruitment of ubiquitylated Tak1 complexes and phosphorylation-dependent activation of IKKβ -NF-kB signaling. Interestingly, ventricular myocytes treated with dox demonstrated reduction in expression levels of TRAF2 and TAK1, in vivo and in vitro. This was accompanied by a decline in K63- and concomitant increase in K-48 linked polyubiquitination on RIP1, impaired NF-kB activation and necrotic cell death of cardiac myocytes. Interestingly, inhibiting the kinase activity of RIP1 with Necrostatin-1, (Nec1) suppressed necrotic cell injury induced by dox but not NF-kB activation. Concordant with these findings was a marked increase in necrotic cell death in cardiac myocytes defective for IKKB signaling or MEF cells deficient for p65 treated with dox. Notably, mitochondrial perturbations, including PT-pore opening , ROS production, calcium uptake, LDH, Tn(T) and HMGB-1 release and necrotic cell injury induced by dox were completely abrogated by restoring NF-kB signaling in cardiac myocytes or Nec-1. Herein, we provide novel evidence that K-48 linked poly ubiquitylation of RIP1 provides a functional switch that impairs NF-kB activation and signals necrosis in cells treated with dox. Interventions that modulate NF-kB activity may prove beneficial in mitigating the cardiotoxic effects of dox.
A prospective pharmacogenetic study of 5FU/LV in high-risk stage II and III colon cancer patients
Authors: K. Mulder, A. G. Scarfe, S. Koski, H. J. Au, C. Butts, A. Fields, H. Razavy, K. Graham, C. E. Cass, M. B. Sawyer
Journal: Journal of Clinical Oncology (2004)

2067 Background: The promoter of thymidylate synthase (TS) has a variable number of tandem repeats (VNTR) polymorphism and a single nucleotide polymorphism (SNP) within the VNTR region. The VNTR have been associated with toxicity of TS inhibitors in retrospective studies. The TS SNP has not been studied with respect to toxicity from TS inhibitors. The TS SNP has been suggested to abolish activity of the USF-1 enhancer located in the 2nd tandem repeat of the VNTR. The combined effect of the VNTR and SNP means that pts will have 2, 3 or 4 USF-1 enhancers in the TS promoter. We hypothesized that the number of enhancers would predict pts at risk for Gr 3/4 mucositis and diarrhea and have undertaken a prospective pharmacogenetic study of TS polymorphisms in colon cancer pts treated with 5-fluoruracil (5FU)/leucovorin (LV). Methods: Pts were treated with 5FU/LV (425mg/m2/20mg/m2) daily for 5 ds every 4 wks. Pts had blood drawn wkly for hematologic toxicity in cycle 1. Pts were assessed for mucositis and diarrhea according NCI CTC 2.0. Blood for genotyping was obtained prior to treatment. Results: Thus far 56 out of 104 pts have been enrolled, 28 pts have been genotyped and 27 are evaluable for toxicity. Patient characteristics: median age 60.5 yrs (range 39–76), 11F/16M, Stage III 23, Stage II 4. The observed toxicities were: diarrhea (37%, Gr 1; 22%, Gr 2; 11%, Gr 3; 4%, Gr 4) and mucositis (59%, Gr 1; 22%, Gr 2; 4%, Gr 3). Frequencies of 2 tandem repeat (TSER*2) and 3 tandem repeat (TSER*3) polymorphisms were respectively 0.38 and 0.62. Patients were genotyped for the C to G SNP at position 12 in the 2ndrepeat of TSER*3, 38% of TSER*3 had a G at position 12 (TSER*3G), and 62% of TSER*3 had a C at position 12 (TSER*3C). The frequency of Gr 3/4 mucositis/diarrhea was 4/12 (33%) in pts with 2 enhancers (TSER*2/TSER*2 or TSER*3G/TSER*3G) vs. 1/15 (7%) in patients with 3 or 4 enhancers (TSER*3C/TSER*3C, TSER*3C/TSER*3G, TSER*3C/TSER*2), (p=0.14, Fisher's exact test). There was no difference in hematologic toxicity between the two groups. Conclusions: Our early results suggest the TS SNP may be a critical determinant of toxicity in pts treated with 5FU/LV. No significant financial relationships to disclose.
<i>BRCA1/2</i> mutation prevalence among triple-negative breast cancer patients from a large commercial testing cohort.
Authors: Kristilyn Dillman Zonno, Rajesh R. Kaldate, Christopher Arnell, Jennifer Saam, Brian Abbott, Anne-Renee Hartman
Journal: Journal of Clinical Oncology (2013)

1544 Background: BRCA1/2 deleterious mutation identification among triple-negative breast cancer (TNBC) patients has gained importance due to cancer-risk management implications for patients and their relatives, and also has an emerging role in guiding treatment selection for therapies such as PARP inhibitors. The National Comprehensive Cancer Network (NCCN) currently recommends BRCA1/2 testing for TNBC patients diagnosed at age &lt;60. Mutation prevalence among TNBC patients has previously been studied only in small regionalized cohorts. A recent study in unselected patients using the updated definitive criteria for TNBC reported mutation prevalence as 10.6%. Methods: Following the 2011 NCCN Hereditary Breast and Ovarian Cancer (HBOC) Testing Criteria update, serial cohorts of &gt; 5,000 Ashkenazi Jewish and &gt; 65,000 non-Ashkenazi Jewish breast cancer patients undergoing commercial BRCA1/2 testing were analyzed. Age at diagnosis, ethnicity, and provider-reported TN status were obtained from test requisition forms completed by ordering providers, and correlated with test results. Neither the accuracy nor definitive criteria used for TN status reported was independently verified. Results: Incidence of TNBC was reported as 9.7% among non-Ashkenazi patients and 16.5% within the subset with African ancestry. Incidence of TNBC was reported as 4.5% among Ashkenazi patients, but this is likely affected by test ordering for this population. The Table displays the BRCA1/2mutation rates classified by ethnicity and age-group. Conclusions: This study provides the most robust estimate to date of BRCA1/2 mutation prevalence among TNBC patients of all ages. The mutation rates seen among TNBC patients diagnosed after age 60 also illustrate the importance of testing such patients who may not meet the current NCCN HBOC testing criteria. [Table: see text]
Do CT features predict the behavior of treatment-naive gastric GIST?
Authors: Ailbhe C. O'Neill, Vikram Kurra, Sree H Tirumani, Jyothi Priya Jagannathan, Akshay Dwarka Baheti, Jason L. Hornick, Suzanne George, Nikhil H. Ramaiya, Atul B. Shinagare
Journal: Journal of Clinical Oncology (2014)

10548 Background: Risk stratification of gastric GIST is currently based on size and mitotic count. Patients with large primary tumors often undergo neoadjuvant treatment with imatinib which limits the assessment of mitotic count in the final resection specimen. Since most patients with gastric GIST undergo pretreatment CT, risk-assessment based on the CT features would be helpful. Therefore, we aimed to assess if pre-treatment CT features can predict the metastatic potential and overall survival (OS) of gastric GIST. Methods: In this IRB approved retrospective study, CT images of 164 patients with pathologically confirmed treatment-naive gastric GIST (88 men; mean age 60 years, SD 13.8) were reviewed in consensus by two radiologists blinded to clinicopathologic features and outcome. The metastatic spread and OS was then recorded using available imaging studies and electronic medical records (median follow up 33 months, IQR 18-56). Predictors of metastatic disease were analyzed using univariate and multivariate (logistic regression) analysis. Effect of the identified predictors on OS was assessed using Log-Rank test. Results: Metastatic disease developed in 51 patients (31%) and 25 (15%) patients died. Tumor size ≥10cm (p=0.02, OR 5.27), irregular/lobulated margin (p=0.009, OR 3.45) and hyperenhancing solid component (p=0.0015, OR 6.68) were independent predictors of metastatic spread. Presence of two or more of these three features predicted a worse OS (p=0.002). Conclusions: Irregular/ lobulated margin, presence of hyperenhancing solid component and tumor size ≥10 cm on pretreatment CT predict worse outcome of gastric GIST. CT feature Patients with metastases (%) Univariate analysis (p value*) Multivariate analysis (p value) Odds ratio (95% CI) Size ≥10 cm 32/41 (78%) <0.0001 0.008 5.27 (1.54-18.05) <10 cm 19/123 (15%) Margin Irregular/lobulated 42/71 (59%) <0.0001 0.02 3.45 (1.21-9.85) Smooth 9/93 (10%) Cystic areas >50% 34/49 (69%) <0.0001 0.11 <50% 17/115 (15%) Exophytic >50% Present 44/102 (43%) <0.0001 Absent 7/62 (11%) Density Homogenous 7/72 (10%) <0.0001 Heterogenous 44/92 (48%) Hyperenhancing solid component^ Present 36/80 (45%) <0.0001 0.0015 6.68 (2.04-21.86) Absent 5/63 (8%) * Fisher’s exact test, ^ Unenhanced CT in 21.
Patterns of recurrence after high-dose chemotherapy with autologous stem cell transplantation for refractory lymphoma
Authors: S. Yano, N. Usui, O. Asai, N. Dobashi, T. Ichiba, Y. Takei, K. Sugiyama, T. Saito, Y. Okawa, M. Kobayashi
Journal: Journal of Clinical Oncology (2004)

6659 Background: High-dose therapy (HDT) with or without total body irradiation followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed or refractory to initial treatment for lymphoma. However, there are relatively few reports regarding outcome following recurrence after HDT therapy. In order to investigate outcome of the HDT, the patterns of recurrence and survival were analyzed. Methods: A total of 61 patients were treated with HDT followed by ASCT between Feb. 1991 and Dec. 2001. In this study, we investigated patterns of relapse and the factor especially bone marrow involvement at time of diagnosis. Results: Fifty-four patients were aggressive lymphoma, 4 were high-grade lymphoma, and 3 were low-grade lymphoma. Involved-field radiotherapy was added to sites of disease, if the sites were indicated after HDT. Median length of follow-up was 70 (24–156) months. Fifty-nine patients were assessable. Forty nine of 59 (83%) patients had complete response or continued CR, and 25 of 49 (51%) patients relapsed at median time of 20.5 (1.4–124.9) months after ASCT. Twelve of 25 patients (48%) relapsed 2 years after HDT. Seventeen of 25 patients (68%) presented with recurrence at previous sites of disease, five patients (20%) at new sites, and three patients (12%) at both previous and new sites. The length of 50% survival of the relapsed patients was 20.7 months. The Kaplan-Meier estimate of patients alive 5 years after recurrence was 13%. We analyzed relapse pattern according to bone marrow involvement. The results were shown in the table. The relapse patterns and survival after HDT followed by ASCT were identical in both groups. Conclusions: The HDT followed by ASCT might be able to save some group of refractory lymphoma patients regardless of bone marrow involvement. No significant financial relationships to disclose.
Prolonged therapy with single-agent bortezomib (btz) in four patients (pts) with relapsed primary systemic AL amyloidosis treated in the CAN2007 phase II study.
Authors: Vishal Kukreti, Lixia Pei, Christopher Enny, Dixie Esseltine, Helgi Van De Velde, Andrew Cakana, Donna E Reece
Journal: Journal of Clinical Oncology (2013)

e19509 Background: CAN2007 was the first prospective study of single-agent btz in relapsed AL. We describe 4 pts in CAN2007 (NCT00298766) who received btz treatment for up to 5.6 yrs. Methods: 70 pts received btz 0.7–1.6 mg/m 2 , d 1, 8, 15, 22, 35-d cycles (QW), or 0.7–1.3 mg/m 2 , d 1, 4, 8, 11, 21-d cycles (BIW), for up to 8 cycles; prolonged treatment was permitted at the discretion of the treating physician for pts showing ongoing clinical benefit. Results: Pt #1 (male, age 53 yrs; IgA lambda AL with cardiac and renal involvement; 16 mos since diagnosis; prior therapy: melphalan plus ASCT) received btz 1.3 mg/m 2 QW for 57 cycles (5.6 yrs). Cumulative dose was 190.5 mg/m 2 . He had a hematologic CR to initial btz therapy and a complete renal response to sustained therapy, without grade 3/4 adverse events (AEs). Pt #2 (male, age 53 yrs; IgG kappa AL with gastrointestinal [GI] involvement; 38 mos since diagnosis; prior therapy: ASCT) received btz 0.7 mg/m 2 BIW for 47 cycles (4.3 yrs; cumulative dose 77.7 mg/m 2 ), had a hematologic response of stable disease, and had a renal response, with no grade 3/4 AEs. The pt progressed and is in remission on alternative therapy. Pt #3 (female, age 55 yrs; IgG lambda AL with GI and other-site involvement; 14 mos since diagnosis; prior therapy: ASCT) received btz 1.6 mg/m 2 QW for 39 cycles (3.7 yrs; cumulative dose 167.7 mg/m 2 ). She had grade 3 paralytic ileus in cycle 8 with dose adjustment to 1.3 then 1.0 mg/m 2 . She had a hematologic PR. Pt #4 (female, age 54 yrs; lambda light-chain AL with cardiac and GI involvement; 44 mos since diagnosis; prior therapy: cardiac allograft followed by ASCT) received 57 cycles (3.5 yrs; cumulative dose 173.7 mg/m 2 ); starting dose was 1.3 mg/m 2 BIW, reduced to 1.0 (cycle 3) and 0.7 mg/m 2 (cycle 16) due to grade 3 AEs of vasculitis and volvulus, respectively. Other grade 3 AEs included pneumonia, hemoptysis, and C. difficile diarrhea. Best hematologic response was PR; a renal response was also achieved. Conclusions: This case series indicates the feasibility and activity of btz for long-term disease control in relapsed AL, particularly in pts who did not achieve a CR to initial btz therapy. Pts 1, 3, 4 remain progression-free and are ongoing on btz. Clinical trial information: NCT00298766.
Multiplexed tissue protein assay as a predictor of response to targeted therapy in advanced renal cell carcinoma.
Authors: Ulka N. Vaishampayan, Alexandrine Derrien-Colemyn, Ye Hong, Seema Sethi, Wei Chen, Brenda Dickow, John Williams Gillespie, Daryn W. Smith, Peter Tunon
Journal: Journal of Clinical Oncology (2013)

4577 Background: A number of prognostic biomarkers have been explored in advanced renal cancer, but to date none have been useful in therapeutic outcome prediction. Methods: Following regulatory approval, formalin-fixed paraffin embedded (FFPE) pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The FFPE tissue was analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Multiplexed panels of protein biomarkers were used to probe tissue sections for proteins along the PI3K/AKT/mTOR and/or the VEGFR/PDGFR signaling pathways. Expression of biomarkers in tumor tissue was scored and predictive scores which correlated with the pt’s clinical outcome status generated. Results: Tissue samples of 51 pts treated with sunitinib (S)were analyzed. A predictive score was generated by combining the scores assigned to VEGFR1 and VEGFR2 and multiplying the sum with the score of VEGFA. A predictive score equal to or above 24, was associated with response or stable disease (SD) at 12 weeks. Patients with a score &lt;24 were predicted to have progression (PD) on S. Using this scoring method, 27 of the 33 responders tested and 15 of the 18 non responders were accurately identified. The accuracy of the test was noted to be 82.6% and sensitivity and specificity were 81.8% and 83.3% respectively. Tissue samples of 33 pts treated with mTOR inhibitor were analyzed using the same technique. Three biomarkers in the mTOR pathway (pmTOR (Ser 2448), p4EBP1 (Ser 65), p4EBP1 (Thr 37-46)) were used to create a predictive score. Eight of 12 OR/SD pts (sensitivity 67%) and 17 of 21 PD pts (specificity 76%) were accurately predicted using a score cut-off of 6 for an accuracy of 71.5%. Statistical modeling, results of ongoing validation testing, and score correlation with time to progression will be presented. Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information to help guide therapy. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by NCI SBIR Contract No. HHSN261201000135C.
A clinical-based risk score for decision making for surgery after induction chemotherapy in malignant pleural mesothelioma patients.
Authors: Isabelle Opitz, Martina Friess, Rolf A. Stahel, Walter Weder
Journal: Journal of Clinical Oncology (2013)

7587 Background: Scoring tools predicting the potential benefit from surgery after induction chemotherapy in mesothelioma patients may influence decision making. Our score is based on 4 clinical variables available before surgery. Methods: 128 patients were uniformly treated with cisplatin based induction chemotherapy followed by extrapleural pneumonectomy between 1999 and 2011. Based on clinical experience and survival influencing factors resulting from uni-and multivariate analysis, we designed a risk score. All 4 variables building up the score were available for 59 patients: pre chemotherapy volumetry above 500 ml, non-epithelioid histotype in the diagnostic biopsy, pre chemotherapy CRP value above 30 mg/l and progressive disease after chemotherapy according to modified RECIST criteria. The 5 resulting groups were analyzed for overall survival (OAS) and progression free survival (PFS) using Kaplan-Meier and Cox regression model. Results: The score strongly stratified patients into high and low risk groups for shorter OAS (Table) (p&lt;0.0005). As to PFS, patients with Score 0 also had significantly longer median PFS (16 months; 95% CI: 12; 20) in comparison to patients with score 3 or higher (6 months; 95% CI: -; -) (p&lt;0.0005). In Cox regression analysis the risk factor for shorter OAS and PFS increased correspondingly to our score. Conclusions: Our new score based on 4 clinical variables available before surgery identifies patients’ subgroups who may benefit from surgery after induction chemotherapy, which will be further assessed prospectively. [Table: see text]
TAX-TORC: A phase I trial of the combination of AZD2014 (dual mTORC1/mTORC2 inhibitor) and weekly paclitaxel in patients with solid tumors.
Authors: Desamparados Roda, Han Hsi Wong, Elena Geuna, Saeed Rafii, Ruth Ruddle, Angela Hayes, Karen E Swales, Sarah Jane Stimpson, Nitharsan Sathiyayogan, Nina Tunariu, Alison Joanne Turner, Emma Hall, Timothy Anthony Yap, Susana N. Banerjee, Mary E.R. O'Brien, L Rhoda Molife, Stan B Kaye, Johann Sebastian De Bono, Bristi Basu, Udai Banerji
Journal: Journal of Clinical Oncology (2014)

2607 Background: AZD2014 (A) is a dual mTORC1/mTORC2 inhibitor and a previous phase I study determined the maximal tolerated dose (MTD) of A to be 50 mg BD 7/7. We have shown high p-P70S6K levels in cancer cells derived from ascites is associated with resistance to subsequent chemotherapy in ovarian cancer. Additive apoptosis was seen when A was added to paclitaxel (P) in preclinical models. We thus set up a multicentre phase I trial to evaluate this combination. Methods: The aims of the study were to determine the MTD, profile safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of the combination of A+P. Dose escalation was performed using a 3+3 design. Patients (pts) with advanced cancers received 6 doses of weekly P (80 mg/m2) and escalating doses of A, BD 3/7, starting on the same day as P in 49-day cycles. Results: 12 pts have been evaluated so far at a fixed dose of P (80 mg/m2) and escalating doses of A; 25 mg (n=3), 50 mg (n=6) and 75 mg (n=3). Two pts had dose-limiting toxicities at 75 mg BD of A (grade 3 fatigue and grade 3 mucositis). The most frequently observed adverse events were fatigue (8/12), diarrhea (6/12), anemia (6/12), mucositis (5/12) and anorexia (4/12). However, of these, only fatigue (2/12) and mucositis (1/12) were grade 3 toxicities and occurred above the MTD. At the dose level of 50 mg BD, the AUC and Cmaxof A was 926.8 ng/mL and 2821.6 ng.hr/mL, respectively. Updated PD data will be presented. Currently, 3/5 pts with taxane pre-treated ovarian cancer have had a GCIG CA125 partial response (PR) (2 of these pts had a RECIST PR). 2/2 pts with squamous non small cell lung cancer (both previously pre-treated with docetaxel) had significant central necrosis of their tumors and one of these pts achieved a RECIST PR. Conclusions: The maximal tolerated dose of P is 80 mg/m2q weekly and for A is 50 mg BD 3/7. This dose/schedule is well tolerated and has shown potentially promising clinical activity. A further intermittent schedule is being tested following which dose expansions in ovarian and lung cancer are planned. This study was supported by AstraZeneca, Cancer Research UK, Experimental Cancer Medicine Centre and Biomedical Research Centre initiatives. Clinical trial information: EudraCT number: 2012-003896-20.