tbuckley/cabot-search huggingface dataset:
Psychological status and pain outcome evaluation in patients with painful bone metastases from castration resistant prostate cancer treated with 223Radium.
Authors: Viviana Frantellizzi, Flavia Longo, Giovanni Schinzari, Mauro Liberatore, Massimiliano Pacilio, Vincenzo Bianco, Giulia Anna Follacchio, Giuseppe De Vincentis
Journal: Journal of Clinical Oncology (2016)

e16512 Background: Radium 223 Dichloride (223Ra) has been shown to improve overall survival in men with metastatic Castration-Resistant Prostate Cancer (mCRPC) with symptomatic bone metastases. Pain is the most common symptom developed by patients (pts) with bone metastases with psychological status impairment. Our aim was to evaluate the psychological distress, (such as functional status, social support, anxiety and depression), and trend of pain response during 223Ra treatment. Methods: Our current clinical experience accounts for 39 pts affected by mCRPC and bone metastases. A total of 118 cycles were administred with 50 KBq/Kg i.v. q4w of 223Ra. Mean age was 75,2±6,07. Gleason Score average value was 8 and ECOG Performance Status mean value was 1,48. Pts were evaluated with Brief Pain Inventory (BPI 0-10 Scale) and data were collected. To examine quality of life (QoL) endpoints, pts were asked to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the bone metastasis module, QLQ-BM22. Both were submitted at baseline and after every cycle of therapy. Edmonton Symptom Assessment Scale (ESAS) was used with the same timing to evaluate response to treatment. Results: 39 pts underwent 1 cycle of therapy with 223Ra. Of these 43% had psychological distress, with an average value of 7,6 in BPI Scale for pain outcome. Second cycle was administered to 33 pts. Pain mean value of these pts was 7,13 and psychological distress was present in 35%. The evaluation of functional scales after third cycle showed that of 29 pts, 32% had psychological distress with a pain average value of 6,4. Analyzing pts that underwent 6 cycles showed that 27% present psychological distress and the mean value of BPI was 5,6. Conclusions: 223Ra therapy shows a multidimensional impact on quality of life, in particular as regards psychosocial aspects. In patients with painful bone metastases from CRPC there is a strong direct relationship between pain reduction and improvement of the subjective psychological distress.
Engagement in cardiovascular disease preventive and cardiac outcomes in colon cancer survivors.
Authors: Sally C Lau, Richard M. Lee-Ying, Davis Sam, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

e18700 Background: There is an increasing number of long-term CCS, but continued focus on the follow-up of the primary cancer may shift significant attention away from other important health conditions, such as CVD. We aim to characterize the quality of CVD prevention in CCS and their outcomes. Methods: CCS seen between 2000 and 2012 at any one of six cancer centers in a large Canadian province were identified. An age and gender matched non-cancer control (NCC) cohort was also constructed for comparison. All patients with non-metastatic disease were examined for primary CVD prevention. A subgroup of patients with known CVD were reviewed for secondary prevention. Multivariate logistic regression models were used to adjust for potential confounding factors. Results: We identified 9,381 CCS and 94,174 NCC. Among CCS, median age at diagnosis was 68 years and 58% were men. At the time of analysis, 46% of the colon cancer cohort had died. Of these, 45% died from colon cancer and 7% from CVD. CCS were just as likely as NCC to have a cardiac-related hospitalization (OR 0.90 p = 0.07). However, they were less likely to undergo screening for high cholesterol (OR 0.89), diabetes (OR 0.88), or their general health (OR 0.86) (all p < 0.01). In the subgroup of CCS (n = 3,489) and NCC (34,874) with known CVD, median survival was worse in CCS than in NCC (9 vs 11 months, p < 0.01). Compliance with secondary preventive drugs, such as beta blockers, ACE inhibitors, and statins, were similar in CCS and NCC (OR 1.0, 0.8, and 0.8, respectively, all p > 0.05). However, CCS with CVD were more likely to have a cardiac-related hospitalization and receive critical care and intervention for their CVD (OR 1.3, 1.5, and 1.3, respectively, all p < 0.05). Conclusions: Although CCS have a significant risk of CVD morbidity and mortality, they were less likely to engage in primary CVD prevention than NCC. Among CCS with known CVD, there were no differences in their compliance with secondary preventive medications, but they were more likely to use health services related to their CVD than NCC. Cardio-oncology and cancer survivorship care planning should extend their focus beyond cardiac toxicities from cancer therapies to include an emphasis on primary and secondary CVD prevention.
Accrual of older adults to Canadian Cancer Trials Group (CCTG) led trials: A retrospective analysis from 1990 to 2015.
Authors: Catalina Hernandez Torres, Winson Y. Cheung, Christopher J. O'Callaghan, Tina Hsu
Journal: Journal of Clinical Oncology (2017)

10031 Background: Older adults (OA) age 65+ make up to 60% of all newly diagnosed cancers. However, only 22-32% of patients accrued in cooperative group studies in the 1990s were age 65+. In 2003, several studies suggested that clinical trial design, in particular the presence of strict exclusion criteria, was a major barrier to accrual of OA. The objective of this study was to determine: 1) whether there has been an improvement in accrual of OA to clinical trials led by the Canadian Cancer Trials Group (CCTG) over time; 2) clinical trial features associated with accrual of OA to clinical trials 3) whether exclusion criteria in trials initiated 2003 or after have been relaxed. Methods: All completed randomized Phase II and III CCTG-led clinical trials initiated between 1990 or later were included. Trial characteristics including tumor type, stage, treatment type, and exclusion/inclusion criteria, as well as percentage of OA age 65+ accrued were recorded. Association between percentage of OA accrued and trial characteristics were compared using the Wilcoxin rank sum test. Assessment of exclusion criteria before and after 2003 was compared using the Chi Square test or Fisher exact test. Results: A total of 68 trials were included. Most trials were phase III (73%), chemotherapy trials (48%), opened before 2003 (70.6%), advanced disease (73%) and lung cancer was the most common tumour site (17.6%). OA accrual remains low compared to OA diagnosed with cancer in Canada (41% vs. 56%, p &lt; 0.001). There was an improvement in accrual of OA after 2003 (47.1% vs. 34.9%, p = 0.02). Tumour site, early stage disease, more restrictive performance status, requiring a new biopsy, and having a longer consent form, were associated with lower accrual of OA (p &lt; 0.05). There was no significant loosening of exclusion with time though patients with pulmonary comorbidities were more likely to be excluded in studies initiated in 2003 or later (p = 0.006). Conclusions: OA remain under-represented in clinical trials. There has been no relaxing of exclusion criteria; however, exclusion based on comorbidities was not significantly associated with under accrual of OA in our study.
Affinity histochemical evaluation of hyaluronan accumulation in solid malignancies of the digestive system.
Authors: Darin Taverna, Sheryl Garrovillo, Barbara Blouw
Journal: Journal of Clinical Oncology (2018)

e24270 Background: Hyaluronan (HA), a primary component of the extracellular matrix (ECM), can accumulate in a variety of solid malignancies. Analyses of patient tumor tissues demonstrated that increased HA accumulation in the tumor microenvironment (TME) can be associated with poor prognosis. Preclinical studies in animal models have shown that elevated HA content in the TME increases tumor interstitial pressure, reduces tumor blood flow, and results in poor penetration of anti-cancer agents. Halozyme Therapeutics developed a PEGylated recombinant human hyaluronidase, pegvorhyaluronidase alfa (PEGPH20), which depolymerizes HA, leading to increases in tumor vascular perfusion and access of lymphocytes to the tumor. PEGPH20 may act additively or synergistically with anti-cancer agents, such as chemotherapies and/or immune-oncology agents. PEGPH20’s pan-tumor potential is currently being evaluated in clinical studies for a variety of tumors, including malignancies of the gastrointestinal tract, with promising results in a metastatic pancreatic cancer study (HALO-109-202). Methods: HA levels in tissue micro-arrays and biopsies of 7 different tumor types of the digestive system were evaluated by affinity histochemistry. Slides were stained with a proprietary HA-specific probe, HTI-601. HA-staining was assessed using an image analysis software (HALO, Indica Labs), which provided HA levels of different tumor compartments (stromal, tumor cells, or immune infiltrates) and an HA-scoring algorithm developed by Ventana Medical Systems, Inc., for pancreatic ductal adenocarcinoma (PDA). Results: The overall findings using both scoring systems suggested an average higher level of HA in the ECM in PDA compared to hepatocellular carcinoma, gastric, colon, gallbladder, cholangiocarcinoma, and esophagus cancers. Conclusions: Understanding the prevalence and accumulation of HA in solid tumors may identify malignancies that could benefit from the combination of PEGPH20 with other therapies when targeting HA.
Neoadjuvant androgen deprivation therapy and enzalutamide: Imaging and pathological responses.
Authors: David James VanderWeele, Baris Turkbey, Fatima Karzai, Stephanie Harmon, Adam G. Sowalsky, Huihui Ye, Scott Wilkinson, Guinevere Chun, Samuel A Gold, Peter A. Pinto, Peter L. Choyke, William L. Dahut
Journal: Journal of Clinical Oncology (2018)

5082 Background: Neoadjuvant androgen deprivation therapy (nADT) with abiraterone and prednisone for localized disease leads to pathological complete response (pCR) rates of up to 10%. In this study we tested the efficacy of nADT with enzalutamide for patients with high risk, localized disease. We also tested the ability of post-treatment multiparametric MRI (mpMRI) to evaluate response. Methods: A single institution trial (NCT02430480) evaluated nADT (goserelin) and enzalutamide 160 mg daily in patients with high risk non-metastatic prostate cancer. Patients underwent MRI-TRUS-guided fusion biopsy at screening and repeat mpMRI followed by radical prostatectomy (RP) after completing six months of therapy. Results: Twenty-two patients have completed therapy and undergone radical prostatectomy. Baseline clinical characteristics were typical of those with high risk disease: median PSA 10.3 ng/ml (range 2.1-985.9) and clinical stage by mpMRI cT2-cT4. Following 6 months of therapy, median pre-RP PSA was 0.02 ng/ml (range < 0.02 – 0.35). On final pathology, 0 patients were upstaged, 5 (23%) were unchanged, and 15 (77%) were downstaged, including 4 (18%) with pCR or near pCR (Residual Cancer Burden < 0.001 cc). Five of 9 patients with bulky nodes at baseline were downstaged to pN0. Of 9 patients with pT3 disease at prostatectomy, 6 were cT3 on post-treatment mpMRI. Of 4 patients with pCR or near pCR, 1 was cT0, 1 was cT2, and 2 were cT3 on post-treatment mpMRI. One additional patient had radiographic complete response but was pT3a on pathological review. Conclusions: Six months of nADT with enzalutamide has activity in high risk, localized prostate cancer, with a small number of patients having exceptional responses. Standard analysis of mpMRI identifies most patients with persistent T3 disease but does not reliably identify exceptional responses. Evaluation of molecular characteristics that predict exceptional response or intrinsic resistance is on-going. Clinical trial information: NCT02430480.
HORMAD1 Is a Negative Prognostic Indicator in Lung Adenocarcinoma and Specifies Resistance to Oxidative and Genotoxic Stress
Authors: Brandt A. Nichols, Nathaniel W. Oswald, Elizabeth A. McMillan, Kathleen McGlynn, Jingsheng Yan, Min S. Kim, Janapriya Saha, Prema L. Mallipeddi, Sydnie A. LaDuke, Pamela A. Villalobos, Jaime Rodriguez-Canales, Ignacio I. Wistuba, Bruce A. Posner, Anthony J. Davis, John D. Minna, John B. MacMillan, Angelique W. Whitehurst
Journal: Cancer Research (2018)

Abstract Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non–small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to γ-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth in vivo. These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA-damaging agents or as an immunotherapeutic target in patients. Significance: This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC. Cancer Res; 78(21); 6196–208. ©2018 AACR.
Lack of a US Food and Drug Administration indication should not limit access to appropriate treatment
Authors: Joerg Albrecht, Adewole S. Adamson, John S. Barbieri, Daniel D. Bennett, Elizabeth A. Kiracofe, A. Shadi Kourosh, Kieron S. Leslie, Joseph F. Merola, Josephine Nguyen, Elaine Siegfried, Nicole Strickland, Suzanne Olbricht, Maryam M. Asgari
Journal: Journal of the American Academy of Dermatology (2018)
Phase Ib study of rapid alternation of sunitinib (SU) and regorafenib (RE) in patients (pts) with advanced gastrointestinal stromal tumor (GIST).
Authors: Cesar Serrano, Alessandro Leal, Jillian Phallen, Adrian Marino-Enriquez, Yanan Kuang, Olivia Triplett, Jeffrey A. Morgan, Constance Barysauskas, Andrew J. Wagner, George D. Demetri, Victor E. Velculescu, Cloud Paweletz, Jonathan A. Fletcher, Suzanne George
Journal: Journal of Clinical Oncology (2018)

11510 Background: Polyclonal emergence of KIT secondary mutations (muts) is the main mechanism of imatinib (IM) progression in GIST. Although approved KIT inhibitors SU and RE each suppress only a subset of these muts, they have shown complementary activity in GIST models and clinical trial correlates. Preclinical evidence suggests that rapid alternation of SU and RE broadens the spectrum of IM-resistant subclones targeted, compared to either agent as monotherapy. Methods: This phase Ib study of rapid alternation of SU and RE was performed in pts with IM-resistant advanced GIST. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Pts received continuous treatment with cycles of 3 days of SU followed by 4 days of RE. Plasma samples for pharmacokinetics and ctDNA studies (deep next generation sequencing and ddPCR) were collected at several timepoints. Results: Fourteen pts were enrolled, and 13 received treatment. Median age 64 (range 42-78), 43% female, median prior therapy 4 (range 3-7, all pts had ≥ 3 prior therapies). SU 37.5mg daily 3 days followed by RE 120mg daily 4 days was established as the RP2D. Two dose limiting toxicities (DLTs) occurred at DL2 (asymptomatic G3 hypophosphatemia). Non-DLT G3/4 toxicities were hypertension (1/13 pts) and hand-food syndrome (2/13 pts). 8/13 patients experienced dose modification, delay, or both. No unexpected toxicities were observed. Of the 13 pts with evaluable CT scans, stable disease (SD) was the best response observed in 4 pts by RECIST. Median progression free survival was 8.4 weeks (95% CI of 6.0-15.7). SU and RE did not reach the steady state, although pts with SD had higher median drug concentration than progressing pts. ctDNA studies show that GIST has low ctDNA shedding and remains KIT-driven even at late stages of disease, with a predominance for activation-loop secondary mutations. Conclusions: Rapid alternation of drugs with complementary activity is a well-tolerated treatment strategy. Drug exposure is critical to target effectively specific subpopulations. Although GIST sheds low ctDNA in this heavily pretreated population, identifying KIT muts in plasma is feasible. Clinical trial information: NCT02164240.
CARAMEL study: Clinical prognostic biomarkers for ipilimumab-related outcome in metastatic melanoma patients.
Authors: Laura Orgiano, Francesca Bruder, Clelia Madeddu, Riccardo Marconcini, Elisabetta Gambale, Eva Galizia, Stefania Stucci, Francesco Spagnolo, Lorenza Di Guardo, Loi Carla, Fabiana Pani, Daniela Massa, Elena Massa, Giorgio Astara, Michele Del Vecchio, Francesco Silvestris, Clara Natoli, Alfredo Falcone, Paola Queirolo, Mario Scartozzi
Journal: Journal of Clinical Oncology (2016)

e21009 Background: Ipilimumab is an inhibitor of CTLA4 receptor of T lymphocytes that has been approved by FDA both as first and second line treatment for patients with metastatic melanoma. Despite the efficacy reported in literature is very promising, it still remain a therapy with a considerable outlay, both from an economic and safety point of view. Therefore, it is relevant to identify in advance which patients could benefit from treatment: the aim of our study is validate predictive biomarkers of treatment efficacy among hematological parameters normally used in clinical practice. Methods: This is a retrospective multicenter study which enrolled 120 patients with hystologically confirmed metastatic melanoma treated with ipilimumab between January 2013 and January 2016. To date 70 patients are completely evaluable (mean age 62.2±14.58). They received Ipilimumab as first line (35 patients, 50%), as second line (31 patients, 44.3%) or as third line treatment (4 patients, 5.7%). We assessed before and regularly every 3 weeks the full blood count with absolute WBC (aWBC), neutrophil count, neutrophil/lymphocyte ratio (NLR) and LDH serum levels. We evaluated the mutational BRAF status and the number of metastatic sites involved before and after treatment. The cut-off value for aWBC and LDH were determined with time-dependent receiver operating characteristic (ROC) analysis. To identify prognostic and predictive biomarkers the above parameters have been correlated with Progression Free Survival (PFS) and Overall Survival (OS). Results: After a median follow up of 21 months the median PFS was 6 months and the median OS was 9 months. We found a significant inverse correlation between PFS and LDH (p = 0.018) and aWBC values (p = 0.0062). As for survival analysis high LDH (HR 8.390; 95% CI 5.865 - 118.3; p < 0.001) and high NLR (HR 2.972; 95% CI 1.035 - 8.530; p = 0.043) were related to worse PFS. Conclusions: The OS analysis in still in progress, but these data are very promising and, if confirmed, they really could help us to better manage the correct therapeutic sequence for treatment of metastatic melanoma patients.
TCT-868 Drug-eluting stents and short duration of DAPT in elderly patients with coronary artery disease. Results of the SENIOR randomized clinical trial at 2 years
Authors: Olivier Varenne, None Stephane Cook, Georgios Sideris, Sasko Kedev, Didier Carrie, Thomas Hovasse, Philippe Garot, Gerard Helft, Salvatore Brugaletta, Eduardo Pinar Bermudez, Josepa Mauri, Philippe Commeau, Emmanuel Teiger, Kris Bogaerts, Manel Sabate, Marie-Claude Morice, Peter Sinnaeve
Journal: Journal of the American College of Cardiology (2018)
Pharmacological targeting of the Aurora A and histone 3 lysine 9 methyltransferase pathways in pancreatic cancer.
Authors: Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Thiago de Assuncao, Jennifer Bintz, Juan Iovanna, Robert Huebert, Gwen Alyce Lomberk
Journal: Journal of Clinical Oncology (2016)

e15715 Background: Aurora kinase A (AurkA) is a key mitotic regulator, which has been targeted for the treatment of pancreatic cancer (PDAC), though the efficacy of this approach needs improvements. We have shown that the methyl lysine 9 (K9) histone 3 (H3) binding protein, HP1, is phosphorylated by AurkA to support mitotic progression. The methyl K9H3 histone mark to which HP1 binds is established by the histone methyltransferases (HMTs) G9a, GLP, SUV39H1 and SUV39H2, which are emerging drug targets. In this work, we investigate the effects of inhibiting both the AurkA and methyl K9H3 pathways on PDAC growth. Methods: MTS, beta-galactosidase, and clonogenic assays were utilized to monitor the effects of drug treatments. Mitotic defects were studied by confocal and electron microscopy, FASC analyses, and western blots. Subcutaneous and orthotopic xenografts were treated with vehicle, individual drugs, or their combination and tumor growth evaluated by bioluminescence. Results: In vitro treatment of PDAC cells with individual drugs inhibited cell growth by inducing senescence, a cytostatic response. However, their combination had a synergistic effect for reducing cell growth, bypassing senescence to achieve a cytotoxic effect. At the cellular level, the combination induced mitotic aberrations, including spindle abnormalities and lagging chromosomes, ultimately leading to mitotic cell death. At the molecular level, AurkA inhibition triggered a Chk1-Cdc25c-Cdk1-dependent G2/M arrest. However, the combination of AurkA with K9H3 HMT inhibition regulated checkpoint proteins, bypassing G2/M arrest with downregulation of the Chk1-p53 pathway to culminate in mitotic catastrophe. In vivotreatment of PDAC subcutaneous and orthotopic xenografts with the K9H3 HMT inhibitor alone demonstrated reduced PDAC growth, but increased efficacy was observed in combination with the AurkA inhibitor over either individual treatment. Conclusions: This study demonstrates that the combined targeting of AurkA and the K9H3 HMT pathway transforms cytostatic effects of these drugs into cytotoxicity via a mechanism that involves mitotic catastrophe, a more desirable therapeutic outcome.
Activation of dopamine receptor D2 to inhibit non-small cell lung cancer growth in vivo.
Authors: Xiaoyuan Wu, Chenxi Zhang, Wei Zhao
Journal: Journal of Clinical Oncology (2016)

e23197 Background: Lung cancer ranks the first cancer related mortality worldwide. Dysregulation of dopamine-related pathways have been implicated in tumor development/angiogenesis. Methods: In this study, dopamine receptor D2 (DRD2) agonist, quinpirole, was utilized to treat nude mice which burden A549 xenograft. The tumor size and mice body weight were measured in 3 days. In the end point, tumor/heart/liver/spleen weight was measured. IHC analyzed Ki-67 and p65 in control and quinpirole group to identify the difference of tumor growth and NF-κB signal pathway. Results: DRD2 agonist, quinpirole inhibits NSCLC tumor growth (P < 0.0001). In addition, the usage of quinpirole has no side effect to mice heart/liver/spleen. This chemical not only decreases the tumor proliferation, but also inhibits NF-κB signal pathway in tumor cells. Conclusions: Our data indicates that the activation of DRD2 decreases NSCLC tumors growth through abrogation of NF-κB signal pathway ,and the axis might be a novel therapeutic strategy in NSCLC patients.