tbuckley/cabot-search huggingface dataset:
Genetic profiling of advanced RAI-resistant differentiated thyroid cancer and correlation with axitinib response.
Authors: Rebecca B. Schechter, Madhavi Nagilla, Loren Joseph, Poluru L. Reddy, Arun Khattri, Sydeaka Watson, Laura D. Locati, Lisa F. Licitra, Angela Greco, Giuseppe Pelosi, Maria Luisa Carcangiu, Tanguy Y. Seiwert, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2013)

6066 Background: The VEGFR inhibitor axitinib has demonstrated compelling antitumor activity in advanced RAI-resistant differentiated thyroid cancer (DTC). Biomarkers predicting which patients may benefit from axitinib are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Methods: Pretreatment FFPE thyroid cancer blocks from patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta Mutation Panel was used to test for 238 mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR. Genomic DNA was analyzed for coding regions of VEGFR1-3 with custom primers. Clinical response to axitinib, including best response (BR) (RECIST) and progression free survival (PFS), was ascertained from corresponding patients. Fisher’s exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. Results: A total of 22 pathology samples (11 primary, 11 metastatic) were identified. In patients with 2 samples (n = 4), results were concordant and only included once for analysis. Of 18 specimens, 4 tumors (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One sample with mutated KRAS also had a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing showed a possibly damaging non-synonymous SNP in VEGFR2 (G539GR) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350VE) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439IT) in 2 samples (11%). No significant relationship was seen between BR or PFS and the presence of molecular defects. Conclusions: While DTC is genetically heterogenous, primary and metastatic lesions showed identical alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but data were limited by small sample size. We did identify molecular changes in VEGFR that should be further explored. This study was supported by Pfizer, Inc.
Final results of the phase I trial of niraparib (MK4827), a poly(ADP)ribose polymerase (PARP) inhibitor incorporating proof of concept biomarker studies and expansion cohorts involving <i>BRCA1/2</i> mutation carriers, sporadic ovarian, and castration resistant prostate cancer (CRPC).
Authors: Caroline Ogilvie Michie, Shahneen Kaur Sandhu, William R. Schelman, L Rhoda Molife, George Wilding, Aurelius Gabriel Omlin, Vikram Kansra, David G. Brooks, Robert E. Martell, Stanley B. Kaye, Johann Sebastian De Bono, Robert Michael Wenham
Journal: Journal of Clinical Oncology (2013)

2513 Background: Niraparib(N) is an oral, potent PARP1/2 inhibitor that induces synthetic lethality in BRCA1/2 deficient tumors. PARP is also implicated in transcription regulated by the androgen receptor (AR) and rearranged ETS genes; key targets in CRPC. Methods: Dose-escalation was enriched for BRCA1/2mutation carriers (BRCA-MCs). Two MTD expansion cohorts were undertaken in patients (pts) with sporadic high grade serous ovarian cancer (HGSOC) and CRPC. In CRPC pts, archival tissue and circulating tumor cells (CTC) were analyzed for PTEN deletion and ETS gene rearrangements. Results: 100 pts [ovary (49), CRPC (23), breast (12) others (16)], received N at 10 dose levels: 30mg to 400mg daily (od), continuously. Grade (G) 4 thrombocytopenia was dose limiting at 400mg od; MTD was established at 300mg od. Drug-related toxicities were G1-2 reversible anemia (48%), fatigue (42%), nausea (42%), thrombocytopenia (35%), anorexia (27%), neutropenia (24%), constipation (23%), and vomiting (20%). PKs were dose proportional with a mean elimination t 1/2 of 40 hours. Peripheral blood mononuclear cells had &gt;50% PARP inhibition from 80 mg od. gH2AX foci formation, a marker of DNA damage, was seen in CTCs. Antitumor activity occurred from 60mg od with RECIST and/or CA125 partial responses (PR) in 9/20 (45%) BRCA-MC ovarian cancer pts and 2/4 (50%) BRCA-MC breast cancer pts. Platinum-sensitive vs resistant BRCA-MC HGSOC response rate was 60% vs 33% with median time for responding pts of 429 and 340 days, respectively. In sporadic HGSOC, there were 2/3 PRs in platinum-sensitive pts, and 3/20 PRs plus 4/20 stable disease (SD) &gt;16 weeks in platinum resistant pts. In CRPC, symptomatic benefit and SD &gt;6 months (median 9 months) was seen in 9/21 (43%) pts treated at MTD. CTC declines of &gt;30% (median 80%; range 36%-92%) were observed in 7/10 (70%) pts with evaluable CTC counts (≥5 cells/ 7.5mL blood). Conclusions: Niraparib was well tolerated and has promising antitumor activity in BRCA-MCs, sporadic HGSOC and CRPC. Clinical trial information: NCT0074902.
Epigenetic loss of the RNA decapping enzyme NUDT16 mediates C-MYC activation in T-cell acute lymphoblastic leukemia
Authors: C Anadón, G van Tetering, H J Ferreira, C Moutinho, A Martínez-Cardús, A Villanueva, M Soler, H Heyn, S Moran, M Castro de Moura, F Setien, A Vidal, E Genescà, J M Ribera, J F Nomdedeu, S Guil, M Esteller
Journal: Leukemia (2017)

Epigenetic loss of the RNA decapping enzyme NUDT16 mediates C-MYC activation in T-cell acute lymphoblastic leukemia
Effect of dose escalation with single opioid, fentanyl matrix, for current cancer pain management: Multicenter, prospective, observational study.
Authors: Sung Ae Koh, Min Kyoung Kim, Kyung Hee Lee, Kyu Taek Lee, Seung Woo Park, Seung-Hyun Nam, Hye-Suk Han, Hun-Mo Ryoo
Journal: Journal of Clinical Oncology (2012)

e19538 Background: It is clinical experience that end-of-dose failure was commonly observed and many cancer patients increase the frequency of opioid administration because of that. Another treatment option could be to increase the dose of the opioid administered. High-dose fentanyl matrix use is known to be effective in controlling pain in cancer patients. To measure effectiveness of increase in single dose of fentanyl matrix in patients whose pain was not controlled sufficiently with the analgesic use in real practice at the investigator’s discretion, we perform the study. Methods: A multi-center, open-label, prospective, observational study was conducted in 30 hospitals in Korea between August and December 2008. Results: 452 patients were enrolled. A total 404 patients completed the study. Mean pain intensity decresed from 5.27 on the second to 3.37 at the end of the trial. There was significant difference in pain intensity (p &lt; 0.001) between first and last visit. The percentage of pain intensity difference was 30.1%. The prevalence of end-of-dose-failure (EOD) at visit 1 was 73% of the enrolled 452 patients. After the use of the fentanyl patch EOD decreased from 73% to 56%. Pain intensity of patients experiencing EOD was 5.64 at baseline compared to 4.27 in patients without EOD. On Visit 2, pain intensity in patienst with and without EOD was 4.02 and 2.54. Of enrolled 404 patients, mean of increasing dose of fentanyl matrix was 55.6mcg/day. Satisfaction rate of investigator’s global assessment was 66.0%, and that of the patients’ global assessment was 63%. The rate of pain improvement was 33.7% by Clinical Global Improvement- Improvement after the use of the fentanyl patch. The observed adverse events were mainly nausea, asthenia, constipation and diarrhea. Conclusions: This study demonstrated that increasing dose of fentanyl patch decreased pain intensity, and decreased the rate of patients experiencing EOD. Also satisfaction rate was increasing after use fentanyl patch. Thus, fentanyl patch may be effective in cancer patients whose pain was previously not controlled sufficiently or who experienced EOD, the side effects were as could be expected with an opioid.
Quantitation of CD11c+ dendritic cells normal breast tissue and benign breast disease.
Authors: Muhammad A Arshad, Daniel W. Visscher, Tanya L. Hoskin, Rushin D Brahmbhatt, Alvaro Pena Jimenez, Marlene H. Frost, Erin E Miller, Melody Stallings-Mann, Linda Murphy, Stacey J Winham, Jodi M Carter, Derek C Radisky, Keith L. Knutson, Amy C. Degnim
Journal: Journal of Clinical Oncology (2015)

e22115 Background: There is a growing interest in the role of inflammatory modulators within the tumor microenvironment in breast carcinogenesis. Here we quantitated the density of dendritic cells in the lobules of breast tissue samples from women with benign breast disease (BBD) and women with no clinical breast disease (normal) from the Komen Tissue Bank (KTB) at Indiana University Methods: Archived breast tissue samples from normal donor women and those with BBD were obtained for this age-matched case-control study. BBD samples included cases [patients who developed Breast Cancer (BC)] and controls (patients who did not develop BC). Following pathologic review of slides, samples were characterized as normal (N) or fibrocystic (FC). Immunohistochemical CD11c staining was performed to identify dendritic cells; lobular CD11c+ cells were digitally quantitated on a per lobule basis by the CD11c+ cell pixel ratio [100 x (positive/total)]. Statistical analysis was performed with mixed effects regression. Results: Among 270 women (median age 53, range 35-79) comprising 90 age-matched triplets, 2492 lobules were evaluated [816 KTB, 824 BBD case, 852 BBD control]. 1429 (57%) lobules were normal and 1063 (43%) were fibrocystic. Almost all lobules contained CD11c+ cells [2486/2492 (99.8%)]; median CD11c+ pixel ratio was 2.8 [Interquartile range (IQR) 1.0-5.6] overall. BBD samples showed significantly higher (p < 0.0001) CD11c+ pixel ratio vs normal subjects overall (see table), but BBD cases and controls did not differ significantly (p=0.17). CD11c+ pixel ratio was also significantly higher in FC vs N lobules (median 3.8 vs 2.1, p<0.0001). Conclusions: CD11c+ dendritic cells are more frequent in breast lobules from women with BBD compared to normal donors. This finding in premalignant breast tissues suggests that dendritic cells may contribute to the chronic inflammatory state associated with benign breast disease and may have implications for breast cancer risk. BBD (180 subjects) KTB (90 subjects) n lobules Median CD11c+ pixel ratio (IQR) n lobules Median CD11c+pixel ratio (IQR) All lobules 1676 4.1 (2.1-7.0) 816 1.0 (0.4-2.2) Normal lobules 768 3.9 (2.0-6.7) 661 0.9 (0.4-2.0) Fibrocystic lobules 908 4.3 (2.3-7.4) 155 1.2 (0.5-2.9)
Cholangiocarcinomas: A study of patient and disease characteristics and the potential use of tumor molecular profiling.
Authors: Petra Prins, Jeff Riskin, Karina Charipova, Michelle Dea, Ben Furlong, Aiwu Ruth He
Journal: Journal of Clinical Oncology (2017)

270 Background: There are approximately 12,000 new cases of cholangiocarcinoma in the US annually and, as for most GI cancers, the incidence is rising each year. Unfortunately treatment options are limited and surgery is only a possible curative option if the disease is diagnosed at an early stage (5 yr. survival, 20-30 %). Molecular profiling may play a crucial role in the discovery of new (early) biomarkers and treatment options for cholangiocarcinoma. Methods: Clinical records 104 cholangiocarcinoma patients (pts) at the Lombardi Comprehensive Cancer Center were reviewed. Only pts that had received surgical therapy were eligible for study. Variables collected included pt demographics, initial disease stage, tumor differentiation, and clinical (pre-existing) conditions. Tumor recurrence and pt survival from time of surgery was evaluated. Molecular profiling data was analyzed when present. Results: In our cohort we identified 41 pts with cholangiocarcinoma who underwent surgery at LCCC. Clinical data was as follows: 20 males and 21 females. Average BMI at diagnosis was 25.8 kg/m 2 . Twelve pts had extrahepatic cancer, 20 intrahepatic, 5 gallbladder, 3 Hilar and 1 combined hepatocellular and bile duct cancer. Most tumors were stage T2 or T3 (61%), and were moderately (71%) to poorly differentiated (22%). Vascular or perineural invasion was identified in 46% of cases. Thirty-four percent and 37% had diabetes and hyperlipidemia, respectively. Tumor recurrence had occurred in 13 cases (32%), and median time to recurrence was 8.5 months (m). Median OS from surgery was 10.5 m (to date, 4 pts &gt; 36 m). Molecular profiles were obtained in 5 cases. Most frequently observed genetic mutations were related to tumor suppression (PTEN, 4 cases) and DNA synthesis, repair, and regulation (TOP2A [3x], TOPO1 [2x], TP53 [2x]). Conclusions: Five-year survival rates for cholangiocarcinomas are low. To improve outcomes, improved early detection methods and better treatment options are urgently needed. Increasing the frequency of molecular profiling can result in new prognostic biomarkers as well as the potential for new treatment ideas.
The underutilization of occupational and physical therapy for older adults with cancer.
Authors: Mackenzi Pergolotti, Allison Mary Deal, Bryce B. Reeve, Hyman Bernard Muss
Journal: Journal of Clinical Oncology (2014)

9548 Background: Older adults are at risk of suffering adverse consequences of cancer and its associated treatments. Occupational and physical therapy (OT/PT) services seek to reduce morbidity, mortality and improve the quality of life of individuals, however little is known about the needs and use of OT/PT for this population. Methods: This study analyzed data from an institution-based registry of older adults 65 + with cancer and linked billing-claims data. Patients completed a geriatric assessment for registry and their clinicians were blind to results. Variables include cancer type and status, functional status (defined by Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), cognition, falls, timed up and go (TUG), and social limitations), social support, demographics linked to billing claims for inpatient and outpatient OT/PT. Logistic regression was used to model predictors of need. Results: 524 patients with cancer, median age of 71, 87% Caucasian, 57 % married, 53% post-secondary education, 81% retired, 63% with breast cancer were included. 65% have at least one functional deficit and 42% have at least two functional deficits potentially requiring OT/PT. Deficits included 40% ADL, 35% IADL and 25% falls. In a multivariable model, less education and older age were significantly associated with the number of deficits (p = 0.05, 0.0001). Odds of having any deficits were higher for patients with no post-secondary education compared to adults with advanced degrees [OR= 1.8] and increased with age [5 year OR= 1.4]. Of patients with functional deficits, 6% (20/339) received OT/PT within the last year and 1.6% (5/319) received OT/PT within 3 months of noted deficit. Conclusions: There is severe underutilization of OT/PT for older adults with cancer. This project is significant because it is the first to outline and define predictors of functional needs and usage of OT/PT in an older population with cancer. These results outline the great need for intervention and referrals to OT/PT in this population. Future policy should be directed towards identifying and breaking down barriers to receipt of rehabilitation services by older cancer patients to decrease morbidity, and improve quality of life.
Noninvasive measurement of prostate-specific membrane antigen (PSMA) expression with radiolabeled J591 imaging: A prognostic tool for metastatic castration-resistant prostate cancer (CRPC).
Authors: Scott T. Tagawa, Naveed Hassan Akhtar, Paul J. Christos, Joseph Osborne, Shankar Vallabhajosula, Shoaib Freedy, Stanley J. Goldsmith, David M. Nanus, Neil Harrison Bander
Journal: Journal of Clinical Oncology (2013)

11081 Background: PSMA is nearly universally expressed by PC, upregulated with increased grade and castration-resistance. Evidence points towards PSMA expression as a downstream cellular biomarker of androgen receptor (AR) activity and non-invasive measurement of PSMA expression has recently been demonstrated to be a novel biomarker of AR activity. Methods: Planar gamma camera images following radiolabeled J591 ( 111 In-J591 or 177 Lu-J591) were semi-quantitatively scored using 2 methods by 2 independent radiologists blinded to outcome.A 5-point visual score (VS) of 0 - 4+ was assigned. Tissue Targeting Index (TTI), a novel metric designed to semi-quantitatively score images was calculated using the ratio of lesion count density (corrected for background) to whole body count density, with maximum (TTI max ) and mean (TTI ave ) scores recorded. Follow up tabulating subsequent therapies and overall survival (OS) was recorded and imaging scores were associated with OS using Cox regression analysis. Results: 130 men with metastatic CRPC underwent radiolabeled J591 imaging. 86.2% had bone metastases, 51.5% lymph node, 16.9% lung, 9.2% liver. 87.7% had accurate targeting of known sites of disease by planar imaging. CALGB (Halabi) nomogram scores were prognostic for the population. As continuous variables, TTI max (p=0.013) and TTI ave (p=0.002) were associated with worse survival. VS demonstrated a trend for worse survival (p=0.09). In multivariate analysis, TTI maintained independent prognostic value when controlling for Halabi score: TTI max HR 1.05 [95% CI 1.01, 1.10; p=0.02], TTI ave HR 1.09 [1.03, 1.16; p=0.004]. Conclusions: Level of PSMA expression measured by planar gamma-camera imaging following radiolabeled J591 is associated with OS in men with metastatic CRPC. High PSMA expression may indicate more aggressive tumor biology with increased AR pathway dysfunction. Improvements in quantitative molecular imaging techniques such as PSMA PET/CT with 89 Zr-J591 may prove to be a valuable prognostic and predictive biomarker, particularly in the setting of AR- and PSMA-targeted therapy. Clinical trial information: NCT00195039, NCT00538668.
Phase II trial evaluating HER2 targeted activated T cells in advanced HER2 low expressing breast cancer patients.
Authors: Deepa Bai Jagtap, Archana Thakur, Abhinav Deol, Zaid Al-Kadhimi, Michael S. Simon, Lawrence E. Flaherty, Anthony Frank Shields, Dana Schalk, Elyse Paul, Vidya Kondadasula, Qin Liu, Lawrence G. Lum
Journal: Journal of Clinical Oncology (2014)

3073 Background: : Despite improvements in the treatment of metastatic breast cancer (MBC), there are no curative treatment options. Anti-CD3 monoclonal antibody (mAb) activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) exhibit anti-HER2 cytotoxicity, proliferate, and secrete immunokines upon tumor engagement. Here we report preliminary results of a phase II immunotherapy trial in which 29 HER2 low expressing(0- 2+) patients (pts) with advanced breast cancer who received infusions of HER2Bi armed ATC (aATC) . Pts were evaluated for time to progression (TTP), overall survival (OS), and immune responses as end points. Methods: Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis were activated with anti-CD3 mAb and expanded with IL-2. aATC were harvested, armed with HER2Bi and cryopreserved in aliquots with a target dose of ≥ 48 billion cells. Pts received oncologist's choice of chemotherapy (4 cycles or 4 months) followed by 3-4 infusions of aATC. A subset of 5 pts received 250 mg/m2cyclophosphamide to create immunologic space prior to aATC infusions. The median age was 53.5 yrs (range 29-75yrs) with 59% of pts over the age of 50yrs. Results: Nineteen pts were ER positive and had received ≥ 2 lines of endocrine therapy and 16 out of 19 ER positive pts had also received at least 2 lines of chemotherapy for MBC . The overall response rate was 31% defined as stable disease . Anti-tumor immune responses were detected in these pts. The K-M curve for all of the pts who received armed ATC reveals a median OS of 16.7 months (from enrollment). In pts who were evaluable (received ≥ 48 billion aATC), 5 of 16 (31%) were stable at 4 months after all aATC infusions. In pts who received < 48 billion aATC, 2 of 8 (25%) pts were stable at 4 months after aATC infusions. Six severe adverse events (grade ≥3), were documented as probably or definitely related to infusions, in 5 different patients. Conclusions: These clinical results suggest that targeting the high risk HER2 low expressing tumors by this approach may provide survival benefit without excessive toxicity. Clinical trial information: NCT01022138.
Inhibition by lenalidomide of growth factor and hypoxia-induced signaling in endothelial and epithelial tumor cells, and effects within the tumor cell microenvironment
Authors: L. Lu, P. Schafer, J. B. Bartlett
Journal: Journal of Clinical Oncology (2009)

e14620 Background: Lenalidomide, an immunomodulatory and anti-angiogenic agent, has activity in many hematological malignancies. It has direct anti-proliferative activity in hematological cells but there is no evidence of direct activity in solid tumor cells. In solid tumors, lenalidomide is being advanced in combination with other agents to take advantage of its immune-enhancing properties in combination with direct anti-tumor agents. Lenalidomide studies in CLL and MM suggest that it may also attenuate pro-survival signals generated by interaction of stroma with the malignant cell itself. Lysophosphatidic acid (LPA) is a key pro-survival factor present at high levels within the ascites of ovarian cancer patients which confers increased tumor invasiveness and reduced survival. Hypoxia-induced factor (HIF)-1α is the key initiator of angiogenesis and tumor invasiveness. Methods: The effect of lenalidomide on growth factor-induced Akt phosphorylation was investigated in endothelial cells, NHL cells, and ovarian cancer cells in vitro. Ovarian cancer cell lines SKOV-3 and OVCAR-3 were treated with LPA and the effect of lenalidomide on invasiveness via enhanced p-Akt was investigated. The effect of lenalidomide on HIF-1α expression by endothelial cells and epithelial cells was also investigated. Results: Lenalidomide inhibited growth factor-induced Akt phosphorylation. Treatment of ovarian tumor cells with LPA increased tumor cell invasiveness via enhanced p-Akt. Lenalidomide strongly inhibited invasion and p-Akt (at S308 but not T473) in a dose-dependent manner. Hypoxic endothelial cells and epithelial tumor cells showed enhanced HIF-1α expression. Lenalidomide inhibited hypoxia-induced HIF-1α expression by endothelial cells and by epithelial tumor cells, including prostate, breast, pancreatic, renal and ovarian tumor cells. Conclusions: Lenalidomide may act within the tumor microenvironment to inhibit key signals of tumor cells survival, growth, and invasiveness. These studies support the potential utility of lenalidomide in combination with other agents in the treatment of patients with solid tumors. [Table: see text]