tbuckley/cabot-search huggingface dataset:
Effect of anti-GRP78 autoantibodies on prostate cancer progression through tissue factor procoagulant activity.
Authors: Ali Al-Hashimi, Bobby Shayegan, Richard Austin
Journal: Journal of Clinical Oncology (2016)

258 Background: Prostate cancer (PC) is characterized by increased prothrombotic state due to enhanced tissue factor (TF) expression/procoagulant activity (PCA). We and others observed that GRP78, a molecular chaperone, is expressed on the surface of PC cells where it functions as a signaling receptor to promote cell proliferation and survival. Further, exposure of GRP78 on the surface of PC cells stimulates the production of anti-GRP78 autoantibodies in PC patients. We have reported that binding of these autoantibodies to cell surface GRP78 enhances TF PCA. We hypothesize that this autoantibody/cell surface GRP78 complex interaction increase PC progression and that disruption of this complex would represent a viable target for the treatment of advanced PC. Methods: Wild type, TF knockdown DU145 cells, and NOD/SCID mouse model system was used to investigate the effect of anti-GRP78 autoantibodies on tumour growth. Protein expression was determined using western blotting and qRT-PCR. TF activity was determined using the TF PCA continuous assay. Blood samples from patients diagnosed with PC were obtained from the Ontario Tumour Bank and St. Joseph’s Hamilton. Results: Pre-prostatectomy patients demonstrated high levels of anti-GRP78 autoantibodies (60-100µg/ml) vs. healthy individuals (5-10µg/ml). These titres were significantly reduced 24-weeks post prostatectomy. We show here that anti-GRP78 autoantibodies upregulate TF and its PCA through a mechanism involving depletion of ER Ca 2+ stores. This very effect on ER Ca 2+ stores also caused activation of the unfolded protein response, a pro-survival cellular pathway. Furthermore, these autoantibodies were shown to accelerate tumour growth in a NOD/SCID mouse model. Finally, heparin and low molecular weight heparin were shown to interfere with the binding of these antibodies to cancer cells and prevent PC cell activation. Conclusions: We have identified the function of an agent in patients' blood, anti-GRP78 autoantibodies, that correlate with PC stage in patients and increase TF PCA and promote PC progression in mice. The effect of this autoantibody can be reversed using heparin, thus, this acts as a new potential therapeutic target for PC.
Abbreviated 8-week chemotherapy (CT) plus involved node radiotherapy (INRT) for nonbulky stage I-II Hodgkin lymphoma: Preliminary results of the Stanford G5 Study.
Authors: R. Advani, S. J. Horning, E. Jonathan, S. Daadi, J. Allen, S. A. Rosenberg, R. T. Hoppe
Journal: Journal of Clinical Oncology (2011)

8064 Background: Combined modality therapy is the standard of care for non-bulky Stage I-II HL. Currently, brief CT +30 Gy involved field (IF) radiotherapy (RT) is associated with a high cure rate. To further limit treatment risk, we tested brief CT (Stanford V–C x 8 weeks) + 20 Gy INRT (G5 study). Methods: Pts with stage I-IIA supra-diaphragmatic non-bulky disease (mediastinal mass ratio <1/3 and no disease >10 cm) were eligible. Stanford V-C (cyclophosphamide substituted for nitrogen mustard) was administered x 8 weeks. G-CSF was permitted for gr ≥3 neutropenia. Two wks after completion of CT, pts received INRT (20 Gy) to initially involved nodes with 1-1.5 cm margins axially and 2-5 cm cephalo-caudad. All pts were treated and followed at Stanford. Endpoints were toxicity and efficacy (PFS and OS). Results: 43 pts (16% stage I and 84% stage II) were accrued with median age 31 yrs (19-66). 20 pts (47%) were “unfavorable” according to German Hodgkin Study Group (GHSG) criteria: >2 nodal sites (n=20) or elevated ESR (≥ 50 mm/hr) (n=3). G-CSF was required in 60% of pts due to gr 3 (n=10) or 4 (n=16) neutropenia. Other gr 3 toxicities reported: fever (n=1), pain (n=3), acute pulmonary embolism (n=1) and epigastric pain (n=2). At median follow-up of 4.8 yrs (0.8-9.6), the overall PFS and OS are 94.6% and 100%, respectively. For pts with unfavorable risk factors the PFS and OS are 88.5% and 100%, respectively. Therapy failed in 2 pts considered “unfavorable” by GHSG criteria with >2 nodal sites. The mean time to relapse was 23 mths (16-30). One pt failed in RT field and the second in-field and distant. Both were salvaged with secondary therapy and stem cell support. No bleomycin lung toxicity or radiation pneumonitis have been noted and to date there have been no second malignancies, AML or cardiac events. Conclusions: The G5 regimen (8 wks Stanford V-C and 20 Gy INRT) has excellent results with minimal toxicity in pts with non-bulky stage I-II HL, including those defined as “unfavorable” by the GHSG criteria. The outcome is comparable to studies using more intense CT and IFRT. Longer follow up is required to assess the impact of this reduced intensity approach on CT and RT related late effects.
Preoperative sorafenib (Sor) and cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC).
Authors: A. Finelli, A. M. Horgan, A. Evans, T. K. Kim, K. Durrant, S. Yap, C. A. Cassol, W. Dubinski, N. Fleshner, M. A. S. Jewett, A. M. Joshua, S. S. Sridhar, A. Zlotta, J. J. Knox
Journal: Journal of Clinical Oncology (2011)

4668 Background: CN for mRCC in the targeted therapy era is being studied in randomized trials. Pre-op treatment may improve patient (pt) selection for CN and allows for correlative studies. We report our completed phase II trial with pre-op Sor and CN. Methods: Pts with biopsy confirmed clear cell mRCC, suitable for CN, were eligible. Oral Sor (400 mg PO BID), with dose reductions, was given for 12 wks pre-op, with the option to restart post-CN until progression. The primary aim was to determine the relationship between pathological response (pR) and time to progression (RECIST). Feasibility, tolerability, response and paired tissue and radiological correlates were secondary endpoints. Results: 19 men (mean age 57, range 40 - 73) enrolled (6/2007–9/2010). 17/19 pts (89%) had stable disease following pre-op Sor, 13 with overall decrease in disease burden (mean decrease 17%, range 1-62%). 1 pt had partial response (PR); 1 had early progression and did not have CN. Of 18 pts who had CN, there was 1 post-op death, unrelated to protocol. 12 pts continued Sor post-op with ongoing benefit. With median follow-up of 44 wks (15–178), median time to progression is 44 wks (7–170). 6 pts have died. Increased fibrosis was the only notable intraoperative finding. Median post-op stay was 6 days (4-23). Although significant necrosis was seen after Sor, pathology review noted no morphologic differences in viable tumor pre- and post- Sor; 1 pt with PR had near complete pR. Tumors from the first 15 pts, as well as 8 metastases and 5 invasive areas were used for a tissue microarray. Anti-VEGFR1-2, PDGFRα/β and other antibodies were studied. Differences in expression between tumors, metastases and invasive areas were not significant. There was significant (r=0.968; p=0.005) positive correlation between PDGFRβ and VEGFR2 levels. Expression was higher in pts with the greatest response by RECIST (p=0.006 and 0.036 for VEGFR2 and PDGFRβ, resp). Conclusions: Pre-op therapy with Sor in mRCC was well-tolerated, resulted in >70% pts having tumor size reductions and did not impact tolerability to CN. Preliminary correlative studies suggest a relationship between radiologic response and certain receptor subtype expression warranting further review.
Cancer survivorship: Is there a role for cancer survivor clinics?
Authors: Umberto Tirelli, Ernesto Zanet, Michele Spina, Mariagrazia Michieli
Journal: Journal of Clinical Oncology (2016)

e272 Background: The population of survivors of cancer is increasing worldwide. In Italy, 2,243,953 patients (4% of the Italian population) survived after a cancer diagnosis in 2006. The drafting of survivorship care plans (SCPs), consisting of a written treatment summary and a follow-up care plan, is regarded by both the Institute of Medicine and the American Society of Clinical Oncology as an essential step in the care of survivors of cancer. However, Salz et al. in 2013 reported in Cancer that although oncology providers have positive feelings regarding SCPs, only 52% of them ever provided any component of an SCP to their patients. Ultimately, the lack of integration of SCPs into clinical practice is due to the absence of definite guidance regarding what constitutes standards of care for survivors of cancer. Methods: We propose the establishment of cancer survivor clinics (CSCs), which consist of health professionals (i.e., medical oncologists; radiation therapists; psychologists; nurses; and other physicians such as cardiologists, gynecologists, and urologists) dedicated to the care of survivors of cancer who we have previously defined as disease and treatment free for at least 5 years and that is established within our Institution since 2013. Results: The number of these CSCs should be planned in relation to the estimated number of survivors of cancer in each country and designed within the medical oncology departments. Conclusions: CSCs should assess: 1) the occurrence of any known side effects from cancer or its treatment (i.e., neurocognitive problems, premature menopause, infertility, cardiorespiratory system dysfunctions, and chronic fatigue); 2) the concomitant presence of comorbidities and their influence on the patient’s general health status; 3) psychological disturbances (i.e., fear of cancer recurrence, anxiety, depression, and body image perception disorders); and 4) problems regarding social and employment reintegration. Moreover, CSCs should provide screening guidelines for cancer recurrence and second primary tumors, design proper clinical follow-up pathways, promote behavioral changes (i.e., smoking cessation and alcohol intake reduction), and improve screening and prevention programs for the relatives of cancer survivors.
Fractionated irradiation can induce functionally relevant multidrug resistance gene and protein expression in human tumor cell lines
Authors: D. Bottke, U. Keilholz, T. Wiegel, A. M. Asemissen, K. Heufelder, W. Hinkelbein
Journal: Journal of Clinical Oncology (2005)

9573 Background: Radiotherapy (RT) can induce the expression of P-glycoprotein (gene product of the multidrug resistance [MDR] gene 1), which can lead to a broad cytostatic drug resistance. The kinetics and the functional consequences of this expression are unknown, but possibly important for radiochemotherapy (RCT) protocols. We here examined the kinetics of mRNA and protein expression of 3 important MDR-associated molecules MDR1, MRP (multidrug resistance-associated protein) and LRP (lung resistance protein), and the level of drug resistance during RT. Methods: 4 human tumor cell lines (NSCLC [A-427], colon carcinoma [HT-29], breast cancer [MCF-7] and melanoma [SK-MEL-24]) were irradiated with 5 x 1.8 Gy per week up to 59.4 Gy. MRNA expression was measured by quantitative RT-PCR. Protein levels were assessed by flow cytometry. Drug sensitivity to clinically relevant concentrations of cisplatin and doxorubicin (0.1, 1.0 and 10.0 μg) was determined using a novel functional flow-cytometry-based assay. Caspase and propidium iodide were used as markers for apoptosis and necrosis, respectively. Results: During RT, HT-29 and MCF-7 showed persistent overexpression of all 3 MDR molecules at mRNA and at protein level. A-427 showed stable overexpression of LRP at mRNA and at protein level. SK-MEL-24 showed no clear induction of MDR proteins. MCF-7 was completely resistant to cisplatin after 3 weeks of RT and beyond. SK-MEL-24 cells developed resistance only to high concentration of cisplatin. HT-29 cells acquired incomplete resistance to cisplatin and doxorubicin. Conclusions: Expression of MDR-associated genes may be part of a general stress program of cells undergoing irradiation. The functional consequence of significant resistance induction to cytotoxic drugs is of relevance for scheduling of RCT. No significant financial relationships to disclose.
Next-generation sequencing (NGS) in advanced well differentiated pancreatic neuroendocrine tumors (WD pNETs): A study using MSK-IMPACT.
Authors: Nitya Prabhakar Raj, Tara Soumerai, Emily Valentino, Jaclyn Frances Hechtman, Michael F. Berger, Diane Lauren Reidy
Journal: Journal of Clinical Oncology (2016)

246 Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in chromatin modeling genes (MEN1, DAXX, and ATRX), and in the mTOR pathway. NGS brings this technology to the clinic but its relevance in practice has been questioned. In this prospective, IRB-approved study (NCT01775072), we used the MSK-IMPACT assay to perform NGS on WD pNETs in a routine practice setting. MSK-IMPACT, performed in a CLIA-compliant laboratory, is a multiplexed assay (Illumina HiSeq) providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements. Methods: After written consent, tumor and germline DNA were analyzed. Genomic alterations were catalogued. Results: MSK-IMPACT results are available in 39 patients (pts). Actionable alterations were identified in 13/39 pts (33.3%). These actionable alterations included BRAF V600E (2 pts; 5.1%), and mutations in TSC1 (1 pt; 2.6%), TSC2 (5 pts; 12.8%), PTEN (4 pts; 10.3%), CDKN1B (2 pts; 5.1%), CDKN2A (2 pts; 5.1%), CDKN2B (2 pts; 5.1%), CDKN2C (1 pt; 2.6%), and ARID1A (5 pts; 12.8%). Other recurrently altered genes included MEN1 (23 pts, 59.0%), DAXX (13 pts, 33.3%), and ATRX (10 pts, 25.6%). Notably, 7 pts (17.9%) had alterations in the histone methyltransferase SETD2. All 7 pts presented with metastatic liver disease. No tumors were low grade; 6/7 (85.7%) were intermediate grade and 1/7 (14.3%) were high grade. All 7 pts received capecitabine/temozolomide (cape/tem); 6 pts (85.7%) had disease shrinkage and 1 pt (14.3%) had stable disease. Conclusions: The mutational landscape in our study was in line with prior work in pNET whole exome sequencing. In one-third of our cohort, potentially actionable alterations were identified through NGS but have not yet been shown to be therapeutically relevant. An exploratory analysis to identify responses to different therapies is ongoing. In addition, we report a novel finding of SETD2 alterations in pNETs. All pts with SETD2 alterations had intermediate to high grade tumors that responded to cape/tem. The clinical significance of SETD2 in pNETs is unknown, and evaluation using tissue microarrays is ongoing.
First-in-human phase I study of the antiangiogenic vaccine (OTS11101) targeting VEGFR-1 in patients with solid tumors.
Authors: H. Hayashi, T. Kurata, Y. Fujisaka, T. Satoh, M. Takeda, M. Miyazaki, T. Okabe, H. Kiyota, K. Tanaka, T. Tsunoda, K. Nakagawa
Journal: Journal of Clinical Oncology (2011)

2568 Background: OTS11101 is a novel peptide vaccine which acts as an angiogenesis inhibitors by specifically targeting vascular endothelial cells with vascular endothelial growth factor receptor (VEGFR)-1 expressing target by inducing cytotoxic T cell lymphocyte (CTL). The objectives of this phase I study is to evaluate the safety, tolerability, maximum tolerated dose (MTD), and pharmacodynamics of this agent. Methods: Nine patients with advanced solid tumors received OTS11101 1.0 mg/ml, 2.0 mg/ml, or 3.0 mg/ml subcutaneously once a week of a 28-day cycle. Also, we explored the induction of specific activated CTL, and the alternation of the serum concentration of VEGFR-1 and VEGFR-2, and various kinds of cytokines. Results: Three patients were enrolled in each dose level, respectively. A total of three patients experienced the reaction of injection site of grade 1, which was the most frequent adverse event in this study. As the other toxicities were also generally mild, MTD was not reached. No objective response was observed, but five had stable disease. According to the biomarker analysis, induction of specific CTL was observed in both levels of 2.0 mg/ml and 3.0 mg/ml, respectively. Conclusions: OTS11101 was well tolerated in patients with advanced tumors up to 3.0 mg/ml once a week. Further investigations are recommended to confirm efficacy of the vaccine.
A polymorphism in a transporter of testosterone as a determinant of androgen independence in prostate cancer
Authors: N. Sharifi, A. Hamada, T. Sissung, R. Danesi, D. Venzon, C. Baum, J. L. Gulley, D. K. Price, W. L. Dahut, W. D. Figg
Journal: Journal of Clinical Oncology (2008)

5066 Background: Metastatic prostate cancer is first treated with androgen deprivation therapy (ADT), however, the majority of patients will eventually progress to androgen independence. In addition, many patients commence ADT prior to radiographic evidence of metastasis. Determining which patients will acquire androgen independent disease quickly and which patients will have durable responses to ADT would help guide treatment. Methods: We had previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those individuals who have at least one wild-type T allele at the 334 T>G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to PSA nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure without metastatic disease (D0). Results: When examined separately, patients in the individual stages had a trend toward a shorter time to androgen independence with the T allele in the D0 (p=0.11) and D2 (p=0.18) cohorts. Combining these groups and stratifying by stage yields a statistically significant shorter time to androgen independence with the T allele (p=0.048). Conclusions: A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in prostate cancer patients treated with ADT. No significant financial relationships to disclose.
A population-based study of factors associated with post-prostatectomy radiation therapy utilization.
Authors: Matthew J. Maurice, Hui Zhu, Robert Abouassaly
Journal: Journal of Clinical Oncology (2014)

182 Background: Based on level one evidence, adjuvant radiation therapy (aRT) improves cancer control in post-prostatectomy patients with adverse pathologic features. We sought to evaluate its utilization and to identify factors affecting of its use. Methods: Using the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, we identified men diagnosed with prostate cancer between 2004 and 2011 who were found to have pT3 disease or pT2 disease with positive margins following prostatectomy. We defined aRT as radiation to the prostate and/or pelvis 6 months or less after prostatectomy. We then used univariate and multivariate logistic regression models to assess potential patient and provider predictors of aRT use. Results: We evaluated 103,092 men who had either pT3 disease (81%) or pT2 with positive margins (19%). Of these, we identified 10,043 men (9.7%) who received aRT. Since 2004, there has been a steady decline in aRT usage with time (range, 11.5% to 7.8%). Compared to 2004, patients diagnosed in 2011 were significantly less likely to receive aRT (odds ratio [OR] 0.78, confidence interval [CI] 0.71-0.85, p&lt;0.0001). Higher Gleason score and T stage were strongly associated with positive aRT utilization (p&lt;0.0001), while increasing age was associated with decreased use (p&lt;0.0001). Another strong predictor of aRT uptake was hospital type. Compared to patients treated at community hospitals, patients treated at comprehensive cancer centers or teaching hospitals were significantly less likely to receive aRT (OR 0.63, 0.58-0.68, p&lt;0.0001 or OR 0.42, CI 0.39-0.46, p&lt;0.0001, respectively). Charlson score and hospital location were significantly but weakly associated with aRT. Other demographic variables were not predictive of aRT. Conclusions: Post-prostatectomy aRT use is declining despite clear proof of its benefit. Consistent with the evidence, patients with risk factors for biochemical relapse (i.e. high Gleason score or T3 disease) and younger patients, who are more likely to benefit, are receiving aRT. Surprisingly, aRT use is lower at teaching hospitals, which may reflect higher usage of salvage radiation.
Phosphorylated ERK (pERK) as biomarker in patients with advanced pancreatic cancer treated with erlotinib within a randomized phase III trial (AIO-PK0104).
Authors: Stefan Hubert Boeck, Steffen Ormanns, Ruediger Paul Laubender, Andreas Jung, Jens T Siveke, Michael Haas, Jens Neumann, Ursula Vehling-Kaiser, Cornelia Winkelmann, Ludwig Fischer von Weikersthal, Michael R. Clemens, Thomas C. Gauler, Angela Marten, Stefan Klein, Georgi Kojouharoff, Michael Geissler, Tim F Greten, Thomas Kirchner, Volker Heinemann
Journal: Journal of Clinical Oncology (2013)

189 Background: Validated biomarkers for patients (pts) with advanced pancreatic cancer (APC) treated with anti-EGFR drugs have not yet been defined. pERK represents the downstream target of the RAS-RAF-MEK cascade. Methods: Within AIO-PK0104 281 pts with APC were randomized between gemcitabine/erlotinib followed by capecitabine and capecitabine/erlotinib followed by gemcitabine. Archival formalin fixed paraffin embedded (FFPE) tumor tissue for central pERK analysis by immunohistochemistry (IHC) was available from 153 pts. Within a retrospective subgroup analysis, pERK data (either as dichotomous or continuous variable) were correlated with AIO-PK0104 biomarker results on KRAS mutation status and EGFR expression and with efficacy study endpoints using a Cox regression model. Results: A semi-quantitative immunohistochemistry scoring system considering cytoplasmic and nuclear pERK expression (staining intensity &amp; % of positive cells) was developed (score 0-12). FFPE samples with a score of 6-12 were defined a pERK high . 98/153 pts were classified as pERK high and 55/153 pts as pERK low , respectively. The median pERK score was 7 (range 0-12). No significant correlation of pERK with baseline characteristics like stage of disease, gender, age, KPS or CA 19-9 was detected. Median OS in pERK high pts was estimated with 5.7 months and with 6.2 months in pERK low pts (HR 1.29, 95% CI 0.90-1.83, p=0.16). However, when analysing pERK as continuous variable, a significant association between the pERK score and OS was found (HR 1.06, 95% CI 1.0-1.12, p [log rank]=0.050, p [likelihood ratio]=0.047), indicating an increase in the hazard for death by a factor of 1.06 for each score level of pERK expression. There was no correlation of pERK expression with the objective disease control rate (OR 0.99, p=0.91) or the occurrence of skin rash (OR 0.93, p=0.41). Pts with a KRAS mutation had a similar rate of pERK high expression compared to patients with KRAS wildtype (61% vs 71%, p=0.32). Conclusions: pERK expression may have an impact on OS of APC pts treated with the anti-EGFR agent erlotinib. Prospective validation of these results is recommended. Clinical trial information: NCT00440167.
Analysis of Clonal T-Cell Receptor Gamma Gene Rearrangements, NOTCH1, FBW7 and PTEN Mutations in Paired Pediatric T-Cell Acute Lymphoblastic Leukemia Samples at Diagnosis and Relapse Reveals Evidence of Relapse in New Leukemic Clones.
Authors: Qing Chen, Amanda Larson Gedman, Larry H. Matherly, Jeffrey W. Taub
Journal: Blood (2008)