tbuckley/cabot-search huggingface dataset:
Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice
Authors: D Wang, Y Fløisand, C V Myklebust, S Bürgler, A Parente-Ribes, P O Hofgaard, B Bogen, K Taskén, G E Tjønnfjord, F Schjesvold, J Dalgaard, A Tveita, L A Munthe
Journal: Leukemia (2017)
FDG-PET as a predictive marker for therapy with everolimus in metastatic renal cell cancer (mRCC).
Authors: J. L. Chen, D. E. Appelbaum, M. Kocherginsky, K. Rathmell, D. F. McDermott, W. M. Stadler
Journal: Journal of Clinical Oncology (2011)

e15047 Background: The oral mTOR inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays RCC progression. Yet most patients (pts) will not respond. Preclinical evidence suggests that elevated tumor glucose uptake as quantified by FDG-PET may predict anti-tumor activity. Methods: In this multicenter study, mRCC pts refractory to VEGF inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and at 1 month; serial CT scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, the average SUVmax of all measured lesions and the corresponding one-month relative change were examined for association with 8-week change in tumor size. 60 pts were planned to provide 81% power (α=0.1) to detect a difference between a mean 20% vs. 10% increase in RECIST based tumor burden measurement in pts with low (SUVmax≤4) vs. high (SUVmax>4) FDG uptake. Results: 63 pts were enrolled; 51 were evaluable for primary endpoint of which 48 had both PET scans. Pt characteristics included: 46 (73%) clear cell histology, median age 61 (32 – 80), median number of prior systemic therapies 1.5 (1 – 4). Median pre- and post-treatment average SUVmax were 7 (1 –17.9) and 4.2 (1 – 13.9), respectively. Median relative change in average SUVmax was -21.2% (-59.8% – 0%). RECIST-based measurements demonstrated an average change in tumor burden of 0.3% (-32.0% – 35.9%) at 8 weeks, with 2 patients (4%) experiencing a PR. Among SUV measures considered, relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable p=0.013; clear cell subtype p=0.031), but the overall correlation was modest (ρ = 0.36). Baseline SUV characteristics and low vs. high SUV classification were not associated with tumor response. Evaluation of progression and overall survival is pending. Conclusions: Systemic therapy with everolimus substantially decreased SUVs on follow-up PET scans in mRCC pts, but these changes were only modestly correlated with changes in tumor size. Correlation with survival metrics will be assessed. Clinical use of FDG-PET based biomarkers is challenged by high variability.
ABO blood group and risk of lethal prostate cancer.
Authors: Yuksel Urun, Kathryn M Wilson, Irene M. Shui, Edward L. Giovannucci, Brian M. Wolpin, Paul Linh Nguyen, Lorelei A. Mucci, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2014)

69 Background: An individual’s blood group is defined by variability in glycotransferases expressed on red blood cell surface; these ABO antigens are also highly expressed on epithelial cells. Previous studies have suggested associations between ABO blood group and increased risk of epithelial cancers including gastric, pancreatic, and ovarian; however, its relationship with risk of prostate carcinoma, and its aggressiveness remains unclear. Methods: We prospectively evaluated the association between ABO blood group and risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS) from 1996 to 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with adjustment for other risk factors and prostate-specific antigen testing. Results: During 12 years of follow-up of 26,602 men, 2,703 cases of incident prostate cancer were documented, including 289 lethal cases (prostate cancer death or distant metastases). The frequency of ABO blood type was similar between men who developed prostate cancer (37% A, 7% AB, 13% B, and 43% O) and other participants (37% A, 8% AB, 12% B, and 43% O). On multivariate analysis, blood type was not associated with overall prostate cancer incidence. However, compared to men with blood group O, those with blood group AB were significantly less likely to develop lethal prostate cancer (multivariate-adjusted HR = 0.39 [95% confidence interval {CI} = 0.18-0.85]). There was no association between type B or A compared to O with lethal disease. ABO blood type was not significantly associated with the risk of advanced stage or high-grade cancers (Gleason score 8 to 10). Conclusions: Blood group AB was associated with a lower risk of lethal prostate cancer compared to blood group O. Further studies are needed to replicate these findings and to clarify possible biological mechanisms underlying this association.
Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative
Authors: Tine Cuppens, Daniela Annibali, An Coosemans, Jone Trovik, Natalja ter Haar, Eva Colas, Angel Garcia-Jimenez, Koen Van de Vijver, Roy P.M. Kruitwagen, Mariël Brinkhuis, Michal Zikan, Pavel Dundr, Jutta Huvila, Olli Carpén, Johannes Haybaeck, Farid Moinfar, Helga B. Salvesen, Maciej Stukan, Carole Mestdagh, Ronald P. Zweemer, Leonardus F. Massuger, Michael R. Mallmann, Eva Wardelmann, Miriam Mints, Godelieve Verbist, Debby Thomas, Ellen Gommé, Els Hermans, Philippe Moerman, Tjalling Bosse, Frédéric Amant
Journal: Clinical Cancer Research (2017)

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.
Marker detection in rectal cancer chemoradiation response using an exhaustive combinatorics approach.
Authors: David D. Smith, Karin Avila, Zhenbin Chen, Wenyan Li, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2013)

347 Background: Our objective was to detect a set of markers that predicted tumor response to chemoradiationtherapy (CRT) in a prospective phase II protocol. Our hypothesis was that certain combinations of markers had a synergistic effect on those patients with a complete response (pCR) versus other responses. Methods: 132 rectal cancer patients’ tumors were evaluated for mutations and polymorphisms in 23 genes. The factors were selected prospectively as having the potential to influence CRT outcome. Our selected risk factors were transformed to yes/no values from predetermined cutoffs. We performed a massive computational combinatorics search for those combinations of factors associated with tumor response (3 million possible combinations). Our best sets of candidates were those with the largest association with tumor response to CRT (CR vs other) by Fisher’s Exacttests after adjusting for False Discovery Rate. Results: 33 of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Our results showed that sets of markers may work alone or synergistically. For example, some markers may not be associated with CRT response by themselves, but are highly correlated to outcome in the presence of other markers. Interactions such as we modeled here are often not considered by informatics software due to computational complexity. Conclusions: A combinatorics approach is computationally expensive but is able to detect marker combinations that are more complex (i.e., nonlinear) than those commonly used in popular informatics software. Our methods are readily extensible to any marker detection scenario, given sufficient computational resources. [Table: see text]
Loss of Lysine Histone Methyltransferase Setd2 Disrupts Normal Hematopoiesis, Lineage Commitment and Reveals a Novel Role for H3K36me3 in Immunoglobulin VDJ Recombination
Authors: S. Haihua Chu, Jonathan R Chabon, Janna Minehart, Richard Koche, Katie Li, Matthew Witkin, Andrei Krivtsov, Scott A. Armstrong
Journal: Blood (2016)
Should unknown primary melanomas be excluded from adjuvant therapy trials? Insights from SWOG S0008.
Authors: V. K. Sondak, R. Tuthill, J. Moon, J. A. Thompson, C. D. Lao, B. G. Redman, L. E. Flaherty
Journal: Journal of Clinical Oncology (2010)

8517 Background: Patients (pts) with unknown primary melanoma in regional nodes are widely considered to have a better prognosis, even adjusting for other factors, so many adjuvant trials exclude these pts. Methods: 432 stage IIIB/C pts with known primary (KP) cutaneous and unknown primary (UNK) melanoma went on S0008, a randomized trial of interferon-α2b vs. biochemotherapy. Pooled data blinded to treatment were analyzed for demographics and prognosis of KPC vs UNK. Pts with KP were divided as clinically evident (macromets) versus diagnosed by sentinel node biopsy, and by time from primary diagnosis (dx) to development of nodal metastases (0-6 mos; 6 mos-5 yrs; > 5 yrs). Since UNK pts by definition had macromets, comparative analyses involved only KPC pts with macromets. Results: Of 432 pts entered onto S0008, 33 (7.6%) were UNK, while 222 had KCP macromets. Thus, 13.1% of pts with macromets were UNK. Median age (48) and number of involved nodes (2) was the same for KCP macromets and UNK pts. Overall survival (OS) was not significantly different for the two groups (p = 0.46), but relapse-free survival (RFS) was significantly better for UNK (p = 0.05). When KCP pts were subdivided by time from primary to dx of macromets, RFS was significantly worse for pts whose metastases developed 0-6 mos from dx (p = 0.008), with a trend for worse OS (p = 0.08). RFS and OS for UNK pts were identical to KPC pts where the nodal metastases developed > 6 mos after primary dx. Conclusions: In S0008, unknown primary melanoma pts had significantly better RFS but not OS than pts with macromets from known primaries. However, their outcome was similar to known primaries diagnosed > 6 mos prior to presentation with nodal metastasis. Our data strongly support the inclusion of these pts in adjuvant therapy trials and do not suggest an intrinsically better (e.g., immunologically-mediated) outcome for pts with unknown primaries. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Schering-Plough Novartis, Schering-Plough Schering-Plough
Feasibility and yield of offering genetic counseling to all patients with newly diagnosed high-grade epithelial ovarian cancer.
Authors: A. G. Arnold, J. Bhatia, M. F. Phillips, G. J. Gardner, K. M. Bell-McGuinn, C. Aghajanian, R. R. Barakat, K. Offit, N. D. Kauff
Journal: Journal of Clinical Oncology (2011)

1509 Background: Mutations in BRCA1 and BRCA2 have been reported in 16-21% of patients with high-grade epithelial ovarian cancer (HG-EOC) unselected for family history (Risch 2001; Pal 2005; Press 2008). Given this several professional organizations (NCCN, SGO, ACOG) have stated it is reasonable to offer genetic counseling (GC) to any woman with HG-EOC if it will impact the care of her or her close family members. There has been concern, however, that this approach will not be feasible in high volume settings and that the yield of mutation carriers identified will not justify the resources required. Methods: Beginning July 2008, the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center (MSKCC) began offering GC to any patient with a newly diagnosed non-mucinous HG-EOC. All women who were diagnosed with, or received primary chemotherapy for, a new pathologically confirmed HG-EOC at MSKCC from 07/01/2008 through 09/30/2010 are included in this report. Patients referred for second opinion only, without treatment at MSKCC, were excluded. Results: 325 women with a new diagnosis of HG-EOC were eligible for analysis. 292 (89.8%) of these patients had a serous component in their tumor (S-EOC). 173 of 292 (59.2%) with S-EOC had a GC referral mentioned in the medical record, and 154 (52.7%) have completed (137) or pending (17) GC appointments. Of the 137 patients with completed GC appointments, 130 (94.9%) elected testing for mutations in BRCA1and BRCA2. Of the 126 patients with results available, 38 (30.2%) had a deleterious BRCA mutation detected [28 BRCA1 (22.2%); 10 BRCA2 (7.9%)]. When the cohort was stratified by Ashkenazi Jewish (AJ) heritage, 22 of 54 (40.7%) women with at least one AJ grandparent had a deleterious mutation. Of the patients with no AJ heritage, 16 of 72 (22.2%) had a deleterious mutation identified. Conclusions: Our data demonstrate that it is feasible to offer GC to all patients with HG-EOC and that the yield of mutations identified supports current recommendations that it is reasonable to consider genetic testing in any woman with HG-EOC that has a serous component.
Compliance with NCCN guidelines in the management of extra-abdominal soft tissue sarcoma across the United States.
Authors: Nabil Wasif, Sanjay Prakash Bagaria, Jonathan Ben Ashman, Chritsopher P. Beauchamp, Richard J. Gray
Journal: Journal of Clinical Oncology (2012)

178 Background: Soft tissue sarcoma is a rare disease requiring multidisciplinary care for effective treatment. The National Comprehensive Cancer Network has developed guidelines for surgical resection and adjuvant therapy based on best available evidence. We sought to examine variance from these guidelines in treatment across the United States. Methods: The Surveillance, Epidemiology and End Results cancer registry was queried to identify patients undergoing surgery for extra-abdominal soft tissue sarcoma from 2004-2009. Coded variables signifying radical excision (RE) and the use of radiation therapy (RT) were correlated with stage of the primary tumor. Patients with metastatic disease, unknown size and unknown grade were excluded. Results: A total of 5,600 patients were identified with a median age of 61. Median tumor size was 8cm and most tumors were high grade (57% G3). Stage specific breakdown was as follows; Stage I 24%, Stage II 37% and Stage III 39%. Overall, 54% of patients underwent RE and 50% received RT, mostly in the post-operative setting (83%). The amputation rate was 4%. Although routine radiation therapy is not recommended for Stage IA and IB patients, 24% still underwent RT, whereas only 49% of Stage I patients were noted to have undergone a RE. Even though routine RT is recommended for Stage II and III tumors, 42% of patients did not undergo any RT, and only 58% underwent RE. On multivariate analysis predictors of RE were age &lt;50 (OR 1.3, 95% CI 1.1-1.6), lower extremity tumor (OR 2.2, 95% CI 1.6- 2.8), Stage III, (OR 2.1, 95% CI 1.7- 2.6), and white race (OR 1.4, 95% CI 1.2- 1.8). Variance from guidelines was seen in 64% of patients. Conclusions: Significant heterogeneity and variation in the contemporary treatment for soft tissue sarcoma in the United States exists. Although low rates of RE may be related to coding discrepancies, rates as low as 54% are still a cause for concern. Overuse, and more importantly, underuse of RT is seen for a significant proportion of patients. If these trends are confirmed by further study, more effort will have to be directed towards compliance with appropriate treatment recommendations, perhaps by regionalizing sarcoma care.
Functional imaging of HER2-positive metastatic breast cancer using <sup>64</sup>Cu DOTA-trastuzumab positron emission tomography (PET).
Authors: Joanne E. Mortimer, Peter Conti, Shan Tong, Jose Reyes, Mary I. Carroll, Kofi Poku, David Colcher, Andrew Antony Raubitschek, James R Bading, Joshua Miles
Journal: Journal of Clinical Oncology (2012)

639 Background: We are developing 64 Cu-labeled trastuzumab (tras) as a PET imaging agent for women with HER2+ beast cancer. To maximize image quality and minimize HER2 uptake in normal tissues, we pre-administered 2 different doses of cold tras prior to injection of the imaging agent. Methods: Pts with advanced breast cancer were eligible if they had bx confirmed HER2 + disease, had not received anti-HER therapy for 6 mos. and had &gt; 1 non-hepatic site of metastasis &gt; 2 cm outside the biopsy site. All un-derwent staging FDG/PET and bone scan. Prior to injection of 64 Cu-tras, pts. received 5 or 50 mg (2 and 4 pts) of cold tras. PET-CT was obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 18 F-FDG scans. Uptake in organs and lesions were measured in terms of body wt-normalized SUV. Lesions with intensity &gt; adjacent tissue were considered positive on PET. The number of metastatic sites identified on 64 Cu-tras/PET was compared to the number on FDG/PET. Image quality was assessed according to differences between the 2 pretreatment doses. Results: Six pts have been imaged. Tras dose had a marked effect on liver uptake of 64 Cu [SUV = 23±3 (mean±sd) and 6.3±0.6 for 5 and 50 mg tras, respectively; P &lt; 0.05]. 72 CT+ lesions (32 bone, 28 nodal, 9 liver, 2 breast, 1 lung) were included in D1 and/or D2 scans. Of these, 66 of 72 (92%), 48 of 63 (76%) and 36 of 44 (82%) were detected on FDG, D1 and D2 scans, respectively. Lesion SUV max was 9±5 (n=37, range 3-23) on D1 and 11±6 (n=27, range 1-29) on Day 2. 64 Cu-tras-to-FDG SUV max ratios were 1.0±0.8 (range 0.2-4.3) and 1.3±1.1 (range 0.2-3.5) for D 1 and 2. Lesion 64 Cuuptake trendedliver &gt; bone &gt; nodes. Conclusions: 64 Cu-tras/PET visualizes HER2+ lesions in bone, liver and, to a lesser degree, lymph nodes. Pre-administration of cold tras improves the quality of tras/PET, especially of intrahepatic lesions. In the next phase of study we will perform 64 Cu-tras/PET in pts with HER2 1+ and 2+ disease.
D-dimers as a tumor marker in GIST: Can it reduce the frequency of CT scanning in patients receiving palliative imatinib?
Authors: Jenny F. Seligmann, Peter Hall, Patrick Hamilton, Simon Richard Lord, Paul Baxter, Maria Marples, Daniel P. Stark
Journal: Journal of Clinical Oncology (2012)

119 Background: Treatment with palliative imatinib has improved outcomes in advanced GISTs, with a reported 2 year PFS of 50%. Guidelines suggest monitoring during imatinib by CT scan at 12 week intervals. There are no validated biomarkers to assist in disease evaluation. High d-dimer levels are associated with poor prognosis in several cancers and are predictive of disease progression during chemotherapy. In the diagnosis of venous thromboembolism, low D-dimer levels have a high negative predictive value (npv) for thrombosis. We investigated whether low d-dimers have a clinically useful npv for GIST progression. Methods: We retrospectively identified all patients treated with palliative Imatinib for GIST in a single tertiary referral centre using a systematic search of an electronic clinical database. Every 12 weeks during treatment patients were assessed by clinical evaluation, CT and a d-dimer measurement (HemosIL HS assay). The prognostic value of d-dimers was assessed by Cox regression. The clinical utility of d-dimers as a biomarker for radiological progression (rPD) was evaluated using radio operator curve (ROC) analysis. Results: 50 patients treated between Jan 2002 and June 2011 met criteria for inclusion. D-dimers were prognostic for progression free survival and overall survival, when analysed by level or over time (p &lt;0.05). Over 460 clinical observations with CT and d-dimer were analysed. Scans demonstrating rPD were associated with higher d-dimer levels and a rising trend (p &lt;0.05). D-dimer levels &lt;1000 had a npv for rPD of 85%. An asymptomatic patient with a d-dimer level &lt;1000 and a falling level over time was seen in 32% of observations, and had a npv for rPD of 92%. Conclusions: D-dimers may have a useful role in disease monitoring for GIST patients treated with palliative imatinib, particularly as a negative predictor of progression. This may reduce the burden of CT scanning in a useful percentage of patients but will require further validation.
Potential role of mTOR phosphorylation status as a negative predictor to everolimus plus octreotide in NETs.
Authors: Oriol Casanovas, Jaume Capdevila, Jorge Barriuso, Alex Teule, Daniel E. Castellano, Jose Luis Manzano, Carlos Lopez, Vicente Alonso, Rocio Garcia Carbonero, Emma Dotor, Alba Martinez, Ramon Salazar
Journal: Journal of Clinical Oncology (2014)

484 Background: Everolimus treatment is currently approved for a few tumor types and currently evaluated in several other malignancies, including NETs. Nevertheless, there is an urgent need for histological or molecular factors of prediction of response, as these would help discriminate subgroups of patients more likely to respond. Here we report on a biological sub-study on histological markers to unravel the relationship between the activation of the IGFR-mTOR-S6 signal transduction pathway with treatment response to everolimus plus octreotide combined therapy in patients with GI NETs. Methods: IGFR-1 (Abcam #54274), phospho-mTOR (Ser-2448, Cell Signaling #2976) and phospho-S6 (Ser-235/236, Cell Signaling #4857) were evaluated by immunohistochemistry (according to Choe G. et al, Cancer Research. 2003) from paraffin embedded blocks from patients with progressive locally advanced or metastatic non-functioning GI NETs, included in a national phase II clinical trial (EVERLAR, NCT01567488). Study endpoint was PFS, and 50% of the patients had progressed at the time of analysis. Univariant (Chi square) and multi-variant (COX) statistical analysis were performed. Results: 38 patients were evaluated with a median age of 62.7 years, balanced on gender (57 % vs. 42%), of which 76.3% were metastatic, mostly to liver. IGF1R positivity showed a nonsignificant trend to association to treatment response (50% progression vs. 21% progression, p=0.15). Nevertheless, mTOR activation (phospho-mTOR positivity) was associated with progression (median PFS of 100 days vs. 225 days, p=0.019). Multivariant COX regression analysis showed a Hazard Ratio of 2.96 [0.8-10.2] (p=0.087) for phospho-mTOR activation. Conclusions: Contrarily to expected results, mTOR activation status determined by phospho-mTOR immunohistological positivity seems to be associated to worse outcome in terms of progression to everolimus+somatostatin analogs in GI NETs patients. This could be indicative of a refractoriness or primary resistance to treatment based on a threshold of mTOR activation, possibly due to activation feedback-loops.