tbuckley/cabot-search huggingface dataset:
Peptide receptor radionuclide therapy (PRRT) transcriptomic signature in blood for prediction of <sup>177</sup>lu-octreotate efficacy.
Authors: Lisa Bodei, Mark S. Kidd, Aviral Singh, Wouter A van der Zwan, Stefano Severi, Ignat Drozdov, Jaroslaw B Cwikla, Richard P. Baum, Dik J. Kwekkeboom, Giovanni Paganelli, Eric Krenning, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2018)

4101 Background: PRRT uses somatostatin receptor (SSR) expression on neuroendocrine tumors (NET) to deliver radiotherapy. Pretreatment patient stratification for response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ). This study validates the clinical utility for PRRT. Methods: Development and validation was undertaken in 3 independent 177Lu-PRRT-cohorts. Specificity and prognostic value was tested in two somatostatin analog-treated and untreated patients. Developmental cohort: lung and gastroenteropancreatic [GEP] NETs (n= 72). The majority were GEP (71%), low grade (86% G1-G2). Prospective validation cohorts (n= 42-44) were well differentiated, low grade (86-95%) lung and GEP-NETs. SSA Cohort I n= 28 (100% low grade, 100% GEP-NET); SSA Cohort II n= 51 (98% low grade; 76% GEP-NET) and an untreated cohort n= 44 (64% low grade; 91% GEP-NET). NET blood gene transcripts (n= 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model with a binary output: “predicted responder” (PPQ+); “predicted non-responder” (PPQ-). Response was evaluated using RECIST criteria [Responder (stable, partial/complete response) vs Non-Responder)]. All measurements and analyses were blinded. Statistics included Kaplan-Meier survival and test evaluation analyses. Results: Developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In two validation cohorts (response: 64-79%), PPQ was 95% accurate (PPQ+ = 94-97%, PPQ- = 93-100%). Overall, median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p< 0.0001). In comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months). Conclusions: The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.
A phase I/II study of MLN-8237 (alisertib), an oral aurora kinase inhibitor, in combination with erlotinib in patients with recurrent or metastatic EGFR wild-type non-small cell lung cancer.
Authors: James Luke Godwin, Ranee Mehra, Samuel Litwin, Anthony J. Olszanski, Jessica Ruth Bauman, Hossein Borghaei
Journal: Journal of Clinical Oncology (2016)

e20588 Background: Erlotinib (E) is an oral reversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), known to have efficacy in NSCLC. The aurora kinases are necessary for cell cycle regulation and may have altered function in certain cancers; MLN-8237 (A) is an oral selective aurora kinase A inhibitor. Preclinical data suggested that the combination of an EGFR inhibitor and an aurora kinase inhibitor may have synergistic effects in wild-type EGFR NSCLC, leading to this phase I/II trial. Methods: Using a 3 + 3 dose escalation design, A was increased over four dose levels from 30 mg - 50 mg; it was given twice daily on days 1-7 of a 21 day cycle. E was given daily at 100 mg in DL1 and 150 mg in DL2-4. Key eligibility criteria: age > 18, histologically confirmed NSCLC, ECOG PS 0-1, prior appropriate first line therapy, acceptable organ function. Key exclusion criteria: EGFR mutation, prior treatment with an EGFR pathway inhibitor or aurora kinase inhibitors. Results: We report our experience with the phase I portion of this study. Eighteen patients were treated on four dose levels. Patient characteristics: Median age 61, M/F (8/10), 10/18 had received RT in addition to systemic therapy. 14/18 patients completed at least 2 cycles. Median number of cycles completed was 4.6. Common drug-related AEs of any grade were fatigue (89%), anemia (83%), leukopenia (78%), dyspnea (78%), diarrhea and anorexia (61% respectively). Drug-related Grade 3/4 AEs included neutropenia and leukopenia (33% each), febrile neutropenia, lymphopenia and anemia (11% each). Two DLTs occurred at DL4 (febrile neutropenia, neutropenia delaying a cycle by > 7 days, both in cycle 1). Disease responses were noted, including one patient with a PR who completed 10 cycles, and 5 patients who achieved SD. Conclusions: In patients with recurrent or metastatic EGFR wild-type NSCLC, the combination of A and E was tolerable. MTD was declared at DL3 (E 150 mg daily plus A 40 mg BID); anti-tumor activity is noted. The recommended phase II dosing is now being studied. Clinical trial information: NCT01471964.
Is there a role for older-patient-specific cancer clinical trials? A pooled analysis of 2277 older patients in adjuvant breast cancer trials (Alliance A151715).
Authors: Dyda Dao, Tyler Zemla, Aminah Jatoi, Rachel A. Freedman, Arti Hurria, Hyman Muss, Harvey Jay Cohen, Lawrence N. Shulman, Marc L. Citron, Daniel Budman, Ryan McMurray, Ann Partridge, Lisa A. Carey, Jacqueline M. Lafky, Jennifer Le-Rademacher
Journal: Journal of Clinical Oncology (2018)

10034 Background: Breast cancer incidence increases with age, but older patients tend to be underrepresented in clinical trials. To address this underrepresentation, this study examined the role of older-patient-specific trials – defined as those designed explicitly for older cancer patients. Methods: This study focused on patients 65 years of age or older (younger patients in age-unspecified trials were excluded). It included all Alliance phase III adjuvant breast cancer trials conducted from 1985-2012, encompassing older-patient-specific trials (CALGB 49907 and NCCTG 89-30-52; the latter was the only hormonal trial) and age-unspecified trials (CALGB 40101, NCCTG 9831, CALGB 9741, CALGB 9344, and CALGB 8541). Comparisons were based on trial type (older-patient-specific versus age-unspecified). Results: 2277 older patients were included (1014 from older-patient-specific trials; 1263 from age-unspecified trials). The cohort of older-patient-specific trials compared to the cohort of age-unspecified trials comprised a greater percentage of patients 75 year of age or older: 26% versus 6% (p < 0.0001) with a median age (range) of 72 years (65, 89) and 68 years (65, 84), respectively, (p < 0.0001). Median overall survival (OS) was comparable: 12.8 years (95% confidence interval (CI): 11.9-13.7 years) and 13.5 years (95% CI: 12.9-14.1 years) in older-patient-specific trials and age-unspecified trials, respectively. After adjusting for age, estrogen receptor status, tumor size, and positive lymph nodes, OS remained comparable (hazard ratio 0.9; 95% CI: 0.8-1.0; (referent: older-patient-specific trials; performance score excluded from the model due to missing data)). Similar conclusions were reached for recurrence-free survival. Older-patient-specific trials had lower grade 2-5 adverse event rates (68% versus 73%; p = 0.03). Sensitivity analyses with only chemotherapy trials (NCCTG 89-30-52 excluded) yielded similar findings. Conclusions: Older-patient-specific trials appear to help address the underrepresentation of older patients in cancer clinical trials. Support: UG1CA189823, U10CA180821, U10CA180882
Detection and treatment of colorectal cancer (CRC) recurrence during routine surveillance: A nationwide cohort study.
Authors: Rebecca A Snyder, Chung-Yuan Hu, Amanda Cuddy, Amanda B. Francescatti, Jessica R. Schumacher, Y. Nancy You, Daniel McKellar, David P Winchester, George J. Chang
Journal: Journal of Clinical Oncology (2016)

e18137 Background: A primary goal of surveillance after treatment of CRC is identification of recurrent disease for curative treatment, but there is limited data regarding rates of treatable recurrence to inform optimal surveillance in everyday practice. The purpose of this study was to evaluate rates of CRC recurrence and its management in routine practice. Methods: Primary medical records of a random sample of 10,885 patients with Stage I-III CRC treated at Commission on Cancer accredited hospitals (2006-2007) were individually abstracted; detailed results of surveillance testing were reviewed, and detection and treatment of recurrence was assessed. Data was merged with corresponding records in the National Cancer Database (NCDB). Results: CRC recurrence at 3-years was strongly associated with Stage; among stage I, II and III: locoregional recurrence (LR) 0.8%, 3.8%, and 7.3% (colon) and 3.8%, 5.4%, and 7.3% (rectum); and distant recurrence (DR) 2.6%, 8.5%, and 20.6% (colon) and 4.4%, 12.4%, and 21.3% (rectum). The majority (82%) of recurrent disease was detected within 3 years of initial resection. 18.2% of patients with DR underwent surgical resection, and 8.8% received both surgery and chemotherapy (Table). Notably, 30.8% and 32.1% of patients with LR or DR, respectively, received no additional treatment. Conclusions: This is the first study to date to describe the effectiveness of CRC post-treatment surveillance for detection of recurrence and its treatment within a US nationwide cohort. Notably, fewer than 1 in 11 patients were treated with both surgery and chemotherapy for distant metastasis, and one-third received no additional treatment. Further study to identify optimal surveillance strategies and factors associated with treatment of disease recurrence is ongoing. Local (%) Distant (%) Surgery ± XRT 18.6 9.4 Surgery + Chemo ± XRT 13.3 8.8 Chemo ± XRT 33.7 45.5 XRT Only 3.6 4.3 No Treatment 30.8 32.1
Change in metabolic tumor activity on <sup>18</sup>F-FDG PET after a single dose of cetuximab to predict for treatment benefit, PFS, and OS in patients with advanced colorectal cancer.
Authors: Erik Jacobus Van Helden, Catharina Wilhelmina Menke, Eline Boon, Suzanne van Es, Marc C. Huisman, Derk Jan De Groot, Ronald Boellaard, Carla M.L.- Van Herpen, Elisabeth De Vries, Otto S. Hoekstra, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2017)

11519 Background: Despite RAS selection, one third of patients with metastatic RAS wild-type colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Therefore, an additional or more accurate predictive biomarker is needed to identify patients with primary resistant mCRC. Methods: In the IMPACT-CRC trial (NCT02117466) patients with chemotherapy refractory mCRC received 500 mg/m 2 cetuximab every 2 weeks. Before the first dose and just before the second dose, patients underwent a 18 F-FDG PET/CT (FDG PET). PET scans were quantitatively assessed by manual tumor delineation of ≤ 5 lesions, 2 per organ. Outcome is reported in total lesion glycolysis (TLG), defined as metabolic tumor volume times mean standard uptake value of the tumor. An optimal threshold to assess metabolic response was defined as decrease in TLG ≥15%. Quantitative data were correlated with CT evaluation after 8 weeks of treatment according to RECIST v1.1. Results: Out of 35 patients, 1 was excluded due to an infusion reaction. Median age was 64 years, 74% was male, 4 patients had a BRAF mutated tumor and 9 patients had right-sided primary tumors. 62% of patients had stable disease or partial response on CT after 8 weeks. At the time of this analysis, 88% of patients had progressive disease and 71% had died. Of the patients with right-sided tumors 11% had treatment benefit, compared to 80% in the left-sided group (p = 0.001). None of the 9 metabolic non-responders had treatment benefit, whereas 83% of the metabolic responders had treatment benefit according to RECIST v1.1. After adjustment for age, WHO score, BRAF mutation, sex and primary tumor site, FDG PET response remained correlated with PFS and OS (p = 0.002 and p = 0.014). Conclusions: Early evaluation of metabolic response after 1 dose of cetuximab is highly and independently predictive for treatment benefit with a 100% negative predictive value. Implementation of early FDG-PET evaluation in daily clinical practice can prevent unnecessary toxicity, costs of ineffective treatment and allows timely treatment adjustment for patients with mCRC undergoing anti-EGFR treatment. Clinical trial information: NCT02117466.
A phase 1b study of durvalumab (MEDI4736) alone or in combination with pomalidomide (POM) with or without low dose-dexamethasone (LoDEX) in patients (pts) with relapsed and refractory multiple myeloma (RRMM).
Authors: David Samuel DiCapua Siegel, Niels van de Donk, Pieter Sonneveld, Craig C. Hofmeister, Nizar J. Bahlis, Ruben Niesvizky, Lars Axel Sternas, Teresa Peluso, Sheetal Shah, Ana Slaughter, Mohamed H. Zaki, Jianming Wang, Jesus San Miguel
Journal: Journal of Clinical Oncology (2016)

TPS8072 Background: Multiple myeloma (MM) plasma cells express programmed cell death ligand 1 (PD-L1). In preclinical studies, monoclonal antibodies (mAbs) directed against PD-L1 demonstrated antimyeloma immune responses that were synergistic when combined with an IMiD immunomodulatory agent (Görgün, Clin Cancer Res 2015). Furthermore, blockade of the programmed cell death protein 1 (PD-1)/PD-L1 pathway in combination with lenalidomide or POM and LoDEX has shown clinical activity (Badros, ASH 2015; San Miguel, ASH 2015). Here, we evaluate durvalumab, a selective, high-affinity human IgG1 mAb that blocks PD-L1 binding to PD-1 (IC50 , 0.1 nM) and CD80 (B7.1; IC50 , 0.04 nM), alone or with POM ± LoDEX. Methods: Up to 138 pts from sites in the US, Canada, and Europe will be enrolled into this open-label study with the primary endpoint of determining the recommended dose and regimen of durvalumab alone or with POM ± LoDEX for the treatment of RRMM. Secondary endpoints include safety, overall response rate, time to response, duration of response, and pharmacokinetics. Pts must have documented MM, received ≥ 2 lines of prior therapy including LEN and a proteasome inhibitor (≥ 2 cycles each), progressive disease (PD) on or within 60 days after the last therapy, and an Eastern Cooperative Oncology Group status of ≤ 2. Exclusion criteria include creatinine clearance < 45 mL/min, peripheral neuropathy grade ≥ 2, and prior treatment with POM without achieving at least a stable disease (SD). Pts will be randomized in a 1:1:2 ratio to escalating doses of durvalumab alone or with POM ± LoDEX (Table) using a modified rolling 6 design (Skolnik, J Clin Oncol2008) and treated until PD or unacceptable toxicity. Pts will then be randomized to the dose-expansion phase. Enrollment is currently ongoing. Clinical trial information: NCT02616640.Study Drug Treatment (28-day cycle) Cohort A Cohort B Cohort C Durvalumaba 750, 1500, 2250, or 3000 mg on day 1 Yes POMa 4 mg on days 1-21 Nob Yes LoDEXa 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, 22 Nob Yes aYes/No refers to whether drug is administered at start of study treatment. bMay be added upon PD or SD ≥ 4 cycles.
TCT-457 Short- and long-term changes in left ventricular mass and geometry post TAVR
Authors: Mohammad Thawabi, Amer Hawatmeh, Nawar Al Obaidi, Sarah Studyvin, Alexis Okoh, Gautam Visveswaran, Mark Russo, Chen Chunguang, Marc Cohen
Journal: Journal of the American College of Cardiology (2018)
Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol‐Induced Liver Damage, Steatosis, and Inflammation in Mice
Authors: Aditya Ambade, Patrick Lowe, Karen Kodys, Donna Catalano, Benedek Gyongyosi, Yeonhee Cho, Arvin Iracheta‐Vellve, Adeyinka Adejumo, Banishree Saha, Charles Calenda, Jeeval Mehta, Eric Lefebvre, Pamela Vig, Gyongyi Szabo
Journal: Hepatology (2018)

Kupffer cell and macrophage (MØ) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells, and expression of C-C chemokine receptor type 2 (Ccr2) and C-C chemokine receptor type 5 (Ccr5) in the livers of patients with ALD, and increased circulating chemokines, C-C chemokine ligand types 2 (CCL2), and C-C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as "prevention" throughout the alcohol feeding or as "treatment" started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen-1) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol-related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and CCL2. CVC administration regimens prevented the increase in infiltrating MØ (F4/80lo CD11bhi ) and reduced proinflammatory Ly6Chi MØ in livers of alcohol-fed mice. CVC increased liver T-cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T-cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte fatty acid synthase (Fasn) and adipose differentiation-related protein (Adrp), whereas it augmented acyl-coenzyme A oxidase 1 (Acox-1), proliferator-activated receptor gamma co-activator alpha (Pgc1α) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide-induced liver injury (TNF-α, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP-ribose polymerase [PARP] and caspase-3 [CASP-3] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. Conclusion: Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.
A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked, advanced endometrial carcinoma.
Authors: Daniela Matei, Virginia L. Filiaci, Marcus Randall, Margaret Steinhoff, Paul DiSilvestro, Katherine M. Moxley, Byoung Kim, Matthew A. Powell, David M. O'Malley, Nicola M. Spirtos, Krishnansu Sujata Tewari, Wm Edward Richards, John Nakayama, David Gardner Mutch, David S. Miller
Journal: Journal of Clinical Oncology (2017)

5505 Background: Patients with stage III/IVA uterine cancer (UC) carry high risk of systemic and local recurrence. Chemotherapy was shown to reduce systemic recurrence, however the risk of local failure remains high. Methods: The primary endpoint of this open label, randomized phase III trial was to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (C-RT, experimental arm) reduces the rate of recurrence or death (i.e., increases recurrence-free survival, RFS) when compared to carboplatin and paclitaxel for 6 cycles (CT, control arm) in patients with stages III-IVA (&lt;2 cm residual disease) or FIGO 2009 stage I/II serous or clear cell UC and positive cytology. Secondary objectives were assessment of overall survival (OS), acute and late toxicities, and quality of life. A 28.5% reduction in the rate of recurrence or death was considered significant. Treatment randomization and analysis were stratified by gross residual tumor and age. Results: Between 6/2009 and 7/2014, 813 patients were enrolled and randomized (407 C-RT and 406-CT). Of those, 733 were eligible (344 C-RT and 360 CT), and 680 received the trial intervention (333 C-RT and 347 CT). Median follow up is 47 months. Patients characteristics were balanced between arms. There were 201 (58%) &gt; grd 3 toxicity events in the C-RT arm and 227 (63%) in the CT arm. The most common &gt; grd 3 events were myelosupression (40% vs. 52%), gastrointestinal (13% vs. 4%), metabolic (15% vs. 19%), neurological (7% vs. 6%), infectious (4% vs. 5%). Treatment hazard ratio for RFS was 0.9 (C-RT vs. CT; CI 0.74 to 1.10). C-RT reduced the incidence of vaginal (3% vs. 7%, HR = 0.36, CI 0.16 to 0.82), pelvic and paraaortic recurrences (10% vs. 21%, HR=0.43, CI 02.8 to 0.66) compared to CT, but distant recurrences were more common with C-RT vs. CT (28% vs. 21%, HR 1.36, CI 1 to 1.86). The analysis is premature for OS comparison. Conclusions: Although C-RT reduced the rate of local recurrence compared to CT; the combined modality regimen did not increase RFS in optimally debulked, stage III/IVA UC. Clinical trial information: NCT00942357.
The stability and variations in the reporting of the CAGE-AID screening questionnaire among patients with advanced cancer.
Authors: Tonya Edwards, Joseph Anthony Arthur, Leela Kuriakose, Neeraj Joshi, Manju P Joy, Seyedeh Dibaj, Donna S. Zhukovsky
Journal: Journal of Clinical Oncology (2018)

e22198 Background: The CAGE-AID questionnaire (CA) is a 4-item patient reported validated screening tool has been used to assess risk of aberrant drug related behaviors in cancer patients receiving opioids. Consistency of responses to the CA between settings is lacking. We evaluated the frequency of CA positivity in each setting and change in score (+ or -) between the first inpatient supportive care consultation and the first outpatient follow up visit within 3 months. Methods: A retrospective chart review was conducted to ascertain CA scores and clinical and demographic characteristics of consecutive adult patients who were initially seen during inpatient consultation (T1) and had an outpatient follow up within 3 months (T2). CA positivity was defined as a score of ≥2 in males or ≥1 in females, with score at T2 considered the gold standard. Results: 333 patients were seen over 11 months. Median age was 58 years (18-87); 53% were female. The most common cancers were GI (23%) and GU (15%). Mean morphine equivalent daily dose (±SD) was 122 mg (150) at T2. CA was completed for 87% of T1 patients and 94% at T2. Scores are noted below. Hispanics (23%) were more likely to be CA positive as compared with Caucasians (15%) and African Americans (11%), p = 0.02. Between T1 and T2, CA score changed from negative to positive in 4% and positive to negative in 1% of patients. The Kappa coefficient for agreement of CA between T1 and T2 was 0.74 (0.62, 0.86), p = 0.02. Conclusions: The rate of completion and consistency of patient responses to the CA was high irrespective of clinical setting. Between 10-13% of patients with advanced cancer are at increased risk for aberrant opioid use. Further studies are needed to evaluate the reasons for a change in CA scores between T1 to T2 in some patients so as not to miss those at higher risk for aberrant behaviors in need of additional monitoring and support. T1 (Inpatient) CA Score T2 (Outpatient) Negative Positive Total Negative 243 85.9% 12 4.2% 255 90.1% Positive 3 1.1% 25 8.8% 28 9.9% Total 246 86.9% 37 13.1% 283 100.0%