tbuckley/cabot-search huggingface dataset:
P01.030 Combination of Tumor Treating Fields (TTFields) and radiochemotherapy in patients with newly diagnosed glioblastoma
Authors: M Avgoustidou, U Mahlknecht
Journal: Neuro-Oncology (2018)

In a multi-center phase 3 trial in patients with newly diagnosed glioblastoma (GBM), the combination of Tumor Treating Fields (TTFields) at 200 kHz with adjuvant chemotherapy after surgery and radiochemotherapy showed significantly increased overall survival (OS) and progression-free survival (PFS). Preclinical data demonstrated synergistic effects when TTFields were combined with radiotherapy. We report on two newly diagnosed glioblastoma (GBM) patients at our hospital who received TTFields therapy concomitant to radiochemotherapy; TTFields treatment was initiated at the start of radiochemotherapy. Patient #1 was an eighty-two year old female with newly diagnosed GBM, underwent a biopsy followed by combination treatment of TTFields, radiotherapy and chemotherapy with temozolomide (TMZ). Patient #2 was a fifty-three year old male treated with a combination of TTFields and radiochemotherapy with TMZ after surgery. In both patients, transducer arrays through which TTFields therapy is applied, were removed before radiotherapy and replaced immediately afterwards. The combination of TTFields was feasible and safe in these two patients. No additional adverse effects associated with the addition of TTFields to radiochemotherapy were observed. Compliance rate with TTFields therapy in both patients was 79% during the time of radiochemotherapy. This is well above the 75% recommended threshold for compliance and underlines the feasibility of this concept. In addition, these case studies show that TTFields can be applied in and is feasible in patients over 80 years. We present two patients with newly diagnosed GBM who received TTFields therapy in combination with radiochemotherapy. In these two patients, the combined therapy was feasible and safe. The combination of TTFields therapy with radiochemotherapy is a promising approach and should be investigated in future trials.
Short-term change in comprehensive geriatric assessment (CGA) scores following treatment of primary breast cancer in older women.
Authors: Ruth M. Parks, Penny Howard, Karen Cox, Kwok-Leung Cheung
Journal: Journal of Clinical Oncology (2016)

10060 Background: Treatment decision making in older women with primary breast cancer can be challenging. Evidence is growing for the use of a comprehensive geriatric assessment (CGA) tool to help identify patients who may be suitable for surgery or non-surgery. Methods: A prospective, two-centre, pilot study was conducted evaluating a previously validated, cancer-specific CGA tool [1] in older women with primary (stage I/II) breast cancer. CGA was conducted within 6 weeks and again at 6 months post-diagnosis. The decision of primary treatment followed consultation with the clinical team and was not guided by CGA. CGA used included assessment of these domains: activities of daily living, independent activities of daily living, performance status, comorbidity, mood, social activity and social support. Results: At the time of analysis, 60 patients had completed CGA at both 6 weeks and 6 months post-diagnosis. 42 of these underwent surgery and 18 non-surgery (primary endocrine therapy). Average age was 80 years (range 68-92). Average mood score for all participants, where a greater score indicates better overall mood (maximum score 102) was 83 at 6 weeks and 85 at 6 months. For the patients who had surgical treatment average score was 85 at 6 weeks and 86 at 6 months. Non-surgical patients had an average mood score of 77 at 6 weeks and 84 at 6 months. There was a significant (p = 0.045) improvement in mood score for non-surgical patients between 6 weeks and 6 months following diagnosis. When comparing surgery versus non-surgery, there were no significant differences between scores at 6 weeks and 6 months for all the other CGA domains mentioned above. Conclusions: In this small pilot study, a short-term (at 6 months) improvement in mood has been observed in patients undergoing non-surgery (primary endocrine therapy). This may be related to the effects of treatments (endocrine therapy and/or a ‘lack of’ surgery). It is worth noting that this group of patients appear to have a lower baseline mood score. Further work is required to investigate this. The study is ongoing and is expanding into a multi-centre one.
Abstract 19846: Development of a Murine Pacemaker System for Mechanistic Studies of Dyssynchrony and Resynchronization in Heart Failure
Authors: Marcus Stahlberg, Ryo Nakagawa, Djahida Bedja, David A Kass
Journal: Circulation (2016)

Background: The cellular and molecular effects of dyssynchrony and resynchronization in heart failure (HF) have so far been studied in canines where genetic manipulation is not possible. Therefore,...
Relationship of Interleukin-1β Blockade With Incident Gout and Serum Uric Acid Levels
Authors: Daniel H. Solomon, Robert J. Glynn, Jean G. MacFadyen, Peter Libby, Tom Thuren, Brendan M. Everett, Paul M Ridker
Journal: Annals of Internal Medicine (2018)

Background: Although studies have shown that interleukin-1β (IL-1β) inhibitors can shorten gout attacks, whether they can prevent gout attacks is unclear. Objective: To examine the relationship among canakinumab, a monoclonal antibody targeting IL-1β; serum uric acid levels; and the incidence of gout attacks. Design: Secondary exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846) Setting: Many clinical sites in 39 countries. Participants: 10 059 patients with a prior myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of at least 19.1 nmol/L. Intervention: Random allocation to canakinumab (50 mg, 150 mg, or 300 mg) versus placebo, administered subcutaneously every 3 months. Measurements: Rates of gout attacks were compared across patients with different baseline concentrations of serum uric acid (≤404.5 µmol/L, 404.6 to 535.3 µmol/L, and ≥535.4 µmol/L) and in different intervention groups in Cox proportional hazards regression models. Results: The median baseline concentration of serum uric acid was 362.9 µmol/L (interquartile range, 309.3 to 428.3 µmol/L), and median follow-up was 3.7 years. Among participants receiving placebo, incidence rates of gout attacks for serum uric acid concentrations of 404.5 µmol/L or lower, 404.6 to 535.3 µmol/L, and 535.4 µmol/L or higher were 0.28, 1.36, and 5.94, respectively, per 100 person-years. Canakinumab did not affect serum uric acid levels over time yet significantly reduced rates of gout attacks at all baseline concentrations of serum uric acid: Hazard ratios were 0.40 (95% CI, 0.22 to 0.73) for concentrations of 404.5 µmol/L or lower, 0.48 (CI, 0.31 to 0.74) for those between 404.6 and 535.3 µmol/L, and 0.45 (CI, 0.28 to 0.72) for those of 535.4 µmol/L or higher. Limitation: No adjudication of gout attacks. Conclusion: Quarterly canakinumab administration was associated with significantly reduced risk for gout attacks without any change in serum uric acid levels. These data have relevance for the development of agents for gout that target the IL-1β pathway of innate immunity. Primary Funding Source: Novartis.
Evaluating immune checkpoint inhibition in solid tumor patients with homologous recombination repair deficiency.
Authors: Fernando Manuel Vargas Madueno, Wenrui Duan, Zuanel Diaz, John Paul Diaz, Federico Albrecht, Siddharta Venkatappa, Eric Douglas Schroeder, Santiago Aparo, Vanessa Yanek, Gail Walker, Miguel Villalona
Journal: Journal of Clinical Oncology (2018)

TPS3108 Background: Recent studies have shown that patients with mismatch repair deficiency have an increased response rate to immune checkpoint inhibitors (ICI). This led to the tissue-agnostic FDA approval of pembrolizumab (PEM). Stemming from this, we are investigating the interplay between homologous recombination (HR) repair deficiency, another mechanism of DNA repair, and solid tumor response to ICI using an all-inclusive functional immunofluorescence assay of the Fanconi Anemia pathway (FATSI) that we developed and which can be performed in paraffin embedded tumors. Methods: This is a phase 2 open-label single center trial evaluating the role of PEM in patients with metastatic solid tumors who have progressed on first-line standard of care chemotherapy and for whom PEM does not have an FDA approved indication. FATSI will be performed in all patients, as well as stool analyses for microbiome composition evaluation. We hypothesize that FATSI negative tumors will be associated with improved responses. Other eligibility criteria include measurable disease by imaging, 18 years of age or older and no previous exposure to ICI. Patients with known microsatellite instability (MSI) high tumors are not eligible. The primary objective is to evaluate the immune-related objective response rate (iORR) achieved in patients with FA Repair Pathway functionally competent and functionally deficient tumors. Secondary objectives include 20-week progression free survival and overall survival. Other exploratory objectives include evaluation of the mutation load, markers of neo-antigenicity, T cell receptor clonotype analyses (before and after treatment) and alterations in HR repair genes. We will utilize a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%, representing a response by chance alone, or other infrequent unknown mechanism. An interim analysis requires that at least 2 of the first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 19 additional patients for a total of 39. Enrollment is ongoing and seven patients are currently on treatment. Clinical trial information: NCT03274661.
The impact of cetuximab plus AKT- or mTOR- inhibitor in patient-derived colon cancer cell model with RAS wild type and PIK3CA mutation.
Authors: Seung Tae Kim, Su Jin Lee, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Jeeyun Lee
Journal: Journal of Clinical Oncology (2016)

e15153 Background: Anti-EGFR therapies have recommended to the advanced CRC with RAS wild type and PIK3CA mutation. However, PIK3CA mutation has been reported to be not only poor prognostic factor but also negative predictive marker to anti-EGFR therapies in RAS wild type CRC. Thus, for a step forward in the personalized medicine of CRC patients, the advance for new treatment strategies are needed in subgroup of RAS wild type and PIK3CA mutation. Methods: Patient derived tumor cells were collected from ascites of refractory colon cancer patient with RAS wild type and PIK3CA mutation. We performed a cell viability assay for drugs such as cetuximab, AZD5363 (AKT inhibitor), and everolimus (mTOR inhibitor) using PDCs. Combinations of cetuximab plus AZD5363 or everolimus were also evaluated in a cell viability assay. Results: Based on the cellular proliferation by MTT assay, tumor cells were significantly inhibited by 1uM cetuximab (control vs cetuximab, mean growth = 100.0% vs 58.07%, difference = 41.81%, 95% CI = 13.52% to 70.1%, P = 0.), 1uM AZD5363 (control vs AZD5363, mean growth = 100.0% vs 58.22%, difference = 41.67%, 95% CI = 15.00% to 68.34%, P = 0.0123), and 1uM everolimus (control vs everolimus, mean growth = 100.0% vs 52.17%, difference = 23.57%, 95% CI = 15.84% to 31.30%, P = 0.0011) as compared with the control. The growth of tumor cells was more profoundly reduced by combinations of cetuximab plus AZD5363 (control vs cetuximab plus AZD5363, mean growth = 100.0% vs 25.00%, difference = 74.88%, 95% CI = 66.26% to 83.51%, P < 0.0001) or everolimus (control vs cetuximab+Everolimus, mean growth = 100.0% vs 28.24%, difference = 71.65%, 95% CI = 63.07% to 80.22%, P < 0.0001). Conclusions: Taken together, the RAS wild and PIK3CA mutant PDCs originated from CRC was considerably inhibited by the treatment with cetuximab plus AZD5363 or everolimus with downregulation of AKT and ERK pathway. These combinations may be considered as new option for advanced CRC patient with RAS wild-type and PIK3CA mutation in the context of clinical trials.
Validation of the JCOG prognostic index in advanced gastric cancer of the SPIRITS and G-SOX trials, using individual patient data.
Authors: Daisuke Takahari, Junki Mizusawa, Wasaburo Koizumi, Ichinosuke Hyodo, Narikazu Boku
Journal: Journal of Clinical Oncology (2016)

4026 Background: While the Royal Marsden Hospital (RMH) prognostic model had been established in Western patients with advanced gastric cancer(AGC) (Chau, JCO, 2004), we identified four risk factors; performance status (PS) ≥ 1, number of metastatic sites ≥ 2, no prior gastrectomy, and serum alkaline phosphatase (ALP) > normal range, and proposed Japan Clinical Oncology Group (JCOG) prognostic index based on the number of these factors (good risk 0,1; moderate risk 2,3; poor risk 4) in the JCOG9912 trial (Takahari, Oncologist, 2014). Methods: To validate our JCOG prognostic index, it was applied to the combined cohort of other two Japanese phase III trials for AGC; SPIRITS trial comparing between S-1 and S-1 + Cisplatin (SP) (Koizumi, Lancet Oncol., 2008) and G-SOX trial comparing between SP and S-1 + Oxaliplatin (SOX) (Yamada, Ann. Oncol., 2015). Results: 936 (94.5%) out of the totally 990 patients randomized in these trials, whose complete data were available for multivariate analyses, were included in the present study (S-1 n=150, SP n=470, SOX n=316). The median survival time (MST) for all patients was 13.2 months, and each risk factor of the JCOG index remained a significant prognostic factor (Table). Three risk groups categorized by the JCOG prognostic index identified highly significant survival differences (compared with good risk group [n=338]; HR, [95%CI];1.71[1.46-2.01], p<0.001 in moderate risk group [n=537] and 3.32[2.47-4.46], p<0.001 in poor risk group [n=61]), associated with MST of 17.2, 12.0 and 7.8 months, respectively. Good and moderate risk groups categorized by RMH index showed no significant survival differences (compared with good [n=314]; HR, [95%CI];1.10[0.94-1.28], P =0.23 in moderate [n=598] and 1.98[1.27-3.10], P =0.003 in poor [n=24]), associated with MST of 14.9, 13.0 and 6.9 months, respectively. Conclusions: JCOG prognostic index was validated and can be used for patient stratification in the future clinical trials. Factor Hazard Ratio 95% CI P value PS ≥ 1 (vs. 0) 1.44 1.23-1.67 <0.0001 No. of metastatic sites >2 (vs. <2) 1.45 1.24-1.71 <0.0001 Prior gastrectomy(-) (vs. (+)) 1.55 1.31-1.84 <0.0001 ALP >(vs. < normal range) 1.19 1.02-1.38 0.03
A phase 2 biomarker trial of combination cediranib and olaparib in relapsed platinum (plat) sensitive and plat resistant ovarian cancer (ovca).
Authors: Joyce F. Liu, William Thomas Barry, Robert Michael Wenham, Andrea Elisabeth Wahner Hendrickson, Deborah Kay Armstrong, Nancy Chan, David E. Cohn, Jung-min Lee, Richard T. Penson, Mihaela C. Cristea, James L. Abbruzzese, KOJI MATSUO, Alexander Olawaiye, Sarah Farooq, Elizabeth M. Swisher, Eliezer Mendel Van Allen, Geoffrey Shapiro, Elise C. Kohn, S. Percy Ivy, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2018)

5519 Background: The combination of cediranib (ced) and olaparib (olap) improves progression-free survival and overall response rates (ORR) in women with recurrent plat sensitive high-grade serous (HGS) ovca compared to olap alone. However, the activity of this combination in plat resistant disease has not been characterized and biomarkers of response are poorly understood. We conducted a Phase 2 study to assess the activity of ced/olap in plat resistant ovca and to identify biomarkers of response (NCT02345265). Methods: Patients (pts) across 11 centers were enrolled to two cohorts (plat sensitive or resistant ovca). All pts received ced 30mg daily and olap tablets 200mg BID. Eligibility included pts with recurrent HGS or BRCA-related ovca. Pts had measurable disease by RECIST 1.1, the ability to take POs, available archival tissue, and biopsiable disease. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. All pts underwent mandatory pre-treatment and on-treatment biopsies and had the option of undergoing a post-progression biopsy. Results: 72 pts were enrolled, with 70 pts receiving treatment (35 plat sensitive and 35 plat resistant). The ORR in plat sensitive pts was 77% (90%CI 63-88%), with 3 confirmed CRs and 24 confirmed PRs. 22 of 27 responders remain progression free with a median follow-up of 7 months. Ten of the plat sensitive responders had a germline BRCA mutation, 8 were wild type, and 9 had not been tested. Disease control rate (DCR; SD at 16wks + CR + PR) was 91%. The ORR in plat resistant pts was 20% (90% CI 11-38%) with 7 confirmed PRs. Median duration of response was 6 months and DCR 43% in plat resistant patients. Among the 7 pts with confirmed response in the plat resistant cohort, 3 had germline BRCA mutation, 3 were wild type, and 1 had not been tested. Conclusions: Ced/olap demonstrated clinical activity in women with recurrent plat sensitive and plat resistant ovarian cancer. While the presence of germline BRCA mutation was correlated with increased likelihood of response, confirmed responses were observed in BRCA wild type pts with plat resistant disease. Molecular studies are ongoing to investigate additional predictive biomarkers. Clinical trial information: NCT02345265.
OS6.1 Glioma anatomic location and clinical phenotype relate to regional healthy brain network signature
Authors: T Numan, J Derks, P C de Witt Hamer, E R Gerstner, S M Stufflebeam, B Alexander, K R A van Dijk, D N Cagney, J C Reijneveld, L Douw
Journal: Neuro-Oncology (2018)

In network neuroscience, patterns of communication between brain regions are investigated. Particularly high connectivity (‘hubness’) may predispose certain regions to pathology and may impact clinical symptoms. For example, Alzheimer’s pathology and cognitive decline are related to hubness. The relation between hubness, glioma location and clinical phenotypes is currently unknown. We explored whether (1) glioma location associates with regional hubness of the healthy brain, and (2) whether Lesional hEalthy Network SignaturE (LENSE), which describes the regional healthy hubness of the tumor location of an individual patient, relates to tumor volume, overall survival (OS) and performance status. Glioma patients (LGG n=46, HGG n=37), n=21 IDH mutant, 1p19q codeleted (type I), n=30 IDH mutant, non-codeleted (type II), and n=15 IDH wildtype (type III), n=17 molecular subtyping not available) were included at VU University Medical Center. Tumor masks were manually drawn on 3DT1-weighted MRI and concatenated into a cohort tumor occurrence map, which was parcellated into 210 cortical regions (Brainnetome atlas). Healthy regional hubness was obtained from 96 healthy controls using preprocessed fMRI. Pearson’s correlations between time series from all 210 regions defined connectivity strength. Regional hubness (the sum of all connections per region) was non-parametrically correlated to regional tumor occurrence. This analysis was repeated in a second cohort of 121 glioma patients (collected at Massachusetts General Hospital) and a cohort of brain metastases (n=17, collected at Dana-Farber Cancer Institute). LENSE was quantified by averaging the healthy hubness of the regions within the tumor mask of each individual patient. Locations with high glioma occurrence had low hubness in healthy controls and vice versa (R=-0.45, p=1.9e-10), which was replicated in the second glioma cohort (R=-0.43, p=2.0e-09), but not in metastases patients (R=0.06, p=0.40). Higher healthy hubness of the tumor location related to larger tumor volume (R=0.54, p=1.8e-07). Within type I patients, higher healthy hubness of the tumor location related to lower KPS (p=0.071) and shorter OS (HR=1.36 (95% confidence interval 1.02–1.82), p=0.04). Glioma locations are generally marked by lower healthy regional hubness, suggesting (1) ‘beneficial glioma-outgrow’ properties in low hubness regions, (2) protective properties in high hubness regions, or (3) both. However, when gliomas do occur in high hubness regions, they represent a poorer clinical phenotype, particularly within type I gliomas. Our results suggest that LENSE may convey additional prognostic value in (subpopulations of) glioma patients.
P01.056 Tumor Treating Fields therapy in a newly diagnosed glioblastoma patient with multiple sclerosis
Authors: R Kassubek, A C Ludolph
Journal: Neuro-Oncology (2018)

BackgroundTumor Treating Fields (TTFields) are low intensity (1–3 V/cm) alternating electric fields with an intermediate frequency of 100–300 kHz. TTFields in addition to adjuvant chemotherapy demonstrated significant benefits for glioblastoma (GBM) patients in the EF-14 trial. However, patients with additional severe neurological disease have not been included in this trial.
Retrospective review of clear cell and non-clear cell renal carcinomas: Characteristics and course in the pre-TKI (tyrosine kinase inhibitor) and post-TKI era.
Authors: Kanika Gupta, Amanda Nizam, Kristen Millado, Jiaqi Liu, Hiwot Guebre-Xabiher, Hong Nguyen, Robert S. Siegel, Jeanny B. Aragon-Ching
Journal: Journal of Clinical Oncology (2017)

e16052 Background: Renal cell carcinoma (RCC) confers a lifetime risk of 1.6% of developing cancers. Early, localized cancers have high cure rates after surgical treatment, but locally advanced/distant metastatic disease remains a devastating disease. The use of TKIs has been considered a mainstay of treatment for clear cell pathology, but other histologic subtypes such as papillary, chromophobe, and mixed subtypes, which is considered non-clear cell RCC, also make up a heterogeneous pattern and course of disease. This retrospective study characterizes renal cell carcinomas and their treatments. Methods: A retrospective chart review of the last 15 years was performed using data from a single-institution center at the George Washington University Cancer Center Tumor Registry Data. Statistical analysis was performed using the Fisher’s test, Chi-squared test, T-test, and Kaplan-Meier survival curves. Results: 1043 patients with RCC were identified. Preliminary data analysis was performed on 92 of these patients. 48 had pure clear cell renal cell carcinoma (CCRCC) and 44 had non-clear cell carcinoma (NCC). Mean age of diagnosis was similar for both groups (58.25 years for CCRCC vs 62.14 years for NCC, p = 0.0977). However, hemoglobin levels at diagnosis were statistically significantly lower for CCRCC (p = 0.0261), as were calcium levels (p = 0.0187). All patients underwent surgical or local treatment. Only 2 patients received chemotherapy and 5 patients received molecularly targeted therapy. While not statistically significant, patients with CCRCC had surgery sooner after diagnosis than NCC (71 days vs 92 days), had longer time to metastatic disease (1033 days vs 820 days), and improved overall survival (1955 days vs 1446 days). Conclusions: NCC was a less favorable pathology than CCRCC with apparent later institution of surgical intervention as well as shorter time to metastatic disease and worse overall survival. Identifying patients with more aggressive disease earlier allows for the potential role for more aggressive therapies that may result in improved outcomes.