tbuckley/cabot-search huggingface dataset:
Heat-Activation Concentrates Chemotherapy in Liver Tumors
Authors: Jennifer Abbasi
Journal: JAMA (2018)

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Final results of the phase II, single arm trial of irinotecan and cisplatin in children with high-risk glial tumors.
Authors: Ofelia Cruz, Jaume Mora, Mariona Suñol, Joan Vinent, Eva Rodriguez, Jordi Muchart, Carlos Trampal, Victoria Caloretti, Antonio Guillen, Carmen de Torres
Journal: Journal of Clinical Oncology (2018)

10549 Background: We conducted an open label, single arm phase II clinical trial with irinotecan and cisplatin (I/C) for pediatric patients with glial tumors (EudraCT:2009-010742-59). Methods: Patients diagnosed with high-risk (HR) gliomas at diagnosis (HGG, Ependymomas, DIPG, or HR-LGG) received sixteen weekly outpatient iv cycles of Cisplatin (30mg/m2) and Irinotecan (65mg/m2). Malignant gliomas received radiation upon progression. Objective response was evaluated by MRI volumetric analysis. Clinical and neurological changes were assessed. Results: From November 2009 until December 2012 39 patients aged 7m to 17y (mean 84 months) diagnosed with DIPG (n = 7); HGG (n = 5); Ependymoma (n = 6); atypical neurocytoma (n = 1); LGG (n = 22); pilocytic (n = 7) or pilomyxoid Astrocytoma (n = 1); Astrocytoma NOS (n = 5); Ganglioglioma (n = 2); and NF1 related LGG (n = 3) were included. Most frequent events were nausea/vomiting (5/39 grade > 2); 17 patients (43.6%) with grade-1 diarrhea. Three of 31 (9.7%) evaluable patients developed hypoacusia, all grade 1. Five (45.5%) patients with HGG, 1 relapsed HGG (100%), 7 DIPG (100%) and 3 LGG (15%) progressed during treatment. Objective response rate (ORR) at the end of therapy (week 21) is 54.4% for HGG; 0% for DIPG; and 85% for HR-LGG. After a median follow-up of 67.5 months OS/EFS for relapsed HGG and DIPG is 0%/0%; for high-grade glial tumors 62%/23%; and 95%/43% for HR-LGG. Radiation was avoided in 19 of 20 HR-LGG patients. Conclusions: The I/C regimen was well tolerated and showed anti-tumor activity and clinical benefit for children with HR-LGG. Clinical trial information: NCT01574092.
The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy.
Authors: Shenying Jin, Bo Xu, Lixia Yu, Yao Fu, Hongyan Wu, Xiangshan Fan, Baorui Liu, Jia Wei
Journal: Journal of Clinical Oncology (2017)

e15609 Background: Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in SRCC patients. Methods: SRCC samples from 89 patients were stained by immunohistochemistry to evaluate PD-L1, PD-1, CD3+ T cells, and MSI. EBV was detected by DNA in-situ hybridization. Results: All 89 patients had advanced gastric SRCC (89.9% were stage III, 10.1% were stage IV). All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r = 0.363, p &lt; 0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. However, there was no association between the expression of PD-L1, PD-1 or MSI status to overall survival (OS). Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r = 0.256, p = 0.012) and MSI status (r = 0.208, p = 0.05). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p = 0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR = 0.68, 95% CI: 0.42-1.10, p = 0.116). Conclusions: CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer characteristics and immunotherapy markers of the gastric SRCC immune microenvironment may highlight targets for immunotherapy.
Effect on health-related quality of life (HRQOL) of adjuvant treatment (tx) with dabrafenib plus trametinib (D + T) in patients (pts) with resected stage III <i>BRAF</i>-mutant melanoma.
Authors: Dirk Schadendorf, Axel Hauschild, Mario Santinami, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James M. G. Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Laurent Mortier, Caroline Robert, Jacob Schachter, Ran Ji, Paola Aimone, Stephanie Manson, Richard Kefford, Reinhard Dummer, John M. Kirkwood, Georgina V. Long
Journal: Journal of Clinical Oncology (2018)

9590 Background: Adjuvant tx of resected stage III BRAF-mutant melanoma with D + T significantly reduced risk of recurrence vs placebo (pbo). In the COMBI-AD study, 1-y tx with D + T resulted in improvements in relapse-free survival, distant metastasis–free survival, freedom from relapse, and overall survival. The effect of D + T on HRQOL in the adjuvant setting is reported here. Methods: COMBI-AD (NCT01682083) was a randomized, double-blind, phase 3 study evaluating pts with resected stage III BRAF V600E/K–mutant melanoma. Pts were randomized 1:1 to receive D 150 mg twice daily plus T 2 mg once daily or matching pbo for 12 mo. HRQOL assessment using the EuroQol-5D (EQ-5D-3L) questionnaire and visual analogue scale (VAS) was an exploratory endpoint. A mixed-model, repeated-measures analysis was used to assess differences in mean scores. Results: A total of 870 pts were randomized (D + T, n = 438; pbo, n = 432). Although pts available for assessment declined during study primarily due to consent withdrawal, missed scheduled visits, and deaths, completion rates among available pts were high (98% at baseline [BL], ≥ 90% throughout the 12-mo tx period, and ≥ 75% at assessments after 12 mo). Pts in both arms had similar BL VAS values (D + T, 79.0; Pbo, 80.4 [0-100 scale]). During tx (3- to 12-mo assessments), VAS scores remained similar to BL, with no clinically meaningful differences observed between arms (adjusted mean change from BL at 12 mo: D + T, 0.14; pbo, −0.02). In the D + T arm, no clinically meaningful or statistically significant difference in VAS was reported between pts who did and did not experience pyrexia (P > .1). During follow-up (15-48 mo), VAS scores were similar between arms, with no significant or clinically meaningful differences reported. At relapse, a statistically significant reduction in VAS score was observed in both arms (mean difference [pre- vs postrecurrence], D + T, −6.02, P = .003; pbo, −6.84, P < .001). Conclusions: In the absence of disease-related symptoms in the adjuvant setting, these results demonstrate that D + T do not negatively impact HRQOL during tx or in long-term follow-up and further emphasize the importance to pt HRQOL of preventing relapse. Clinical trial information: NCT01682083.
In silico validation of a prostate cancer recurrence prognostic signature based on pathways related to stem cells.
Authors: Miguel Arturo Espinoza-Portocarrero, Jhajaira M. Araujo, Joseph A. Pinto, Fanny Lys Casado
Journal: Journal of Clinical Oncology (2017)

e23205 Background: Prostate cancer has the highest incidence in Peruvian male population with mortality close to 50% as opposed to countries with strong preventative programs were mortality is between 10-15%. Early detection and close follow up to avoid or detect recurrence as soon as possible is considered to be the best strategy to reduce this high mortality. However, this is not always the case due to limitations in prevention programs and cultural characteristics of male behavior. Therefore, there is a need to develop better biomarkers and targets. We hypothesize that recurrence occur due to the existence of cells that have acquired stem cell behavior that we denominate prostate cancer stem cell, which are not affected by first-line therapies. Methods: We curated a list of stem-cell genes meshing the WNT Signaling Pathway (KEGG entry: hsa04310) and the Signaling Pathways Regulating Pluripotency of Stem Cells (KEGG entry: hsa04550). We used data from 497 samples of primary tumors whose expression for 231 genes was quantified with NanoString from a public genomic information database (TCGA, provisional). The validation set (GSE21032) consisted of 131 primary tumors cases of prostate cancer. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected FZD3, PLCB2, PLCB3 and TP53 as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a four-genes signature using the regression coefficients for each gene. Results: The signature was: -0.363 × FZD3 + 0.432 × PLCB2 + 1.313 × PLCB3 - 0.237 × TP53. The percentile seventy-five score in the discovery set (0.6734) identified two subgroups with different DFRS (P &lt; 0.05). The same score we used in the validation set and was also able to discriminate patients with different DRFS (P = 0.000003). Conclusions: Our in silico validation of a prostate cancer recurrence prognostic signature supports the involvement of stem cell-related pathways in prostate cancer genomics.
The role of atypical chemokine receptor-1 in breast cancer immune response.
Authors: Rachel Martini, Petros Nikolinakos, Jamie Hodgson, Brittany Jenkins, Melissa Davis
Journal: Journal of Clinical Oncology (2017)

e23072 Background: Interactions between chemokines and their receptors can regulate anti-tumor response by influencing the migration of immune cells. Atypical Chemokine Receptor 1 (ACKR1/DARC), a genetically diverse transmembrane GPCR, acts as a decoy receptor for a variety of CXC and CC chemokines, including those with pro-malignant and pro-inflammatory effects, such as CCL2 and CXCL8 . The purpose of this study is to determine if the migration of tumor-associated immune cells is unique based on epithelial ACKR1 expression on breast cancer cells, and if this association is correlated to an increase in pro-malignant chemokines, survival, or race. Methods: Immunohistochemistry techniques were used to determine expression of ACKR1 on primary breast tumors, along with T-cells, B-cells, dendritic cells, and macrophages. Concentrations of pro-inflammatory chemokines in circulation were determined using a Luminex-based immunoassay. In silco analyses were performed to determine associations between ACKR1 tumor status, race, and survival. Finally, using human breast cancer cell lines and immunofluorescence techniques, co-localization between ACKR1 and pro-inflammatory chemokines was investigated. Results: Results from these tests indicate that there is differential infiltration of immune cell types in tumors expressing ACKR1, , which were not detected in ACKR1 negative tumors. Significantly increased circulating CCL2 and CXCL8 chemokine levels we also determined to be positively correlated with ACKR1 expression in primary breast tumors. Survival analyses showed a significantly increased relapse free survival in patients having tumors with high ACKR1 expression, while investigations into racial differences revealed a significant race effect, with Caucasians having higher ACKR1 levels on their tumors than African-Americans. Finally, co-localization between ACKR1 with CCL2 and CXCL8 is observed in cultured human breast cancer cells. Conclusions: tumors positively expressing ACKR1 to have a more favorable prognosis suggest that a role of ACKR1 on breast tumor cells is to sequester pro-inflammatory chemokines in the tumor microenvironment, recruiting a distinct subset of tumor-associated immune cells.
Epidemiology of neuroendocrine tumors: Initaial results of independent national register of Russia.
Authors: Vera Gorbunova, Ayrat R. Kaldarov, Irina Laricheva, Michail Chernikov, Andrey Kriger, Lyubov Komarova, Larisa Gurevich, Oxana Paklina
Journal: Journal of Clinical Oncology (2018)

e13606 Background: neuroendocrine tumors (NETs) – are relatively rare tumors with the different malignant potential. National databases are created in different countries for adequate treatment control and investigation in occurrence factors. The most well-known of them are SEER database from the USA and NRS from the Norway. We decided to create independent Russian Epidemiology Neuroendocrine tumors Database – the “REND” – register to collaborate information about patients with NETs Methods: the REND was created in 2016 in Moscow, Russia and based on the “MOLNEO” society for treatment of neuroendocrine tumors. Official start was done at the September 5, 2016. Information about patients carried out with official software “регистр МОЛНЭО” version 1.0.29. Results: 13 centers in different regions of Russia took part in the REND project. After 13 month of work there were 1596 cases of NETs registered. Major cohort became young patients (45-65 years old) – in 43% cases. Most of them were gut NETs – 61%, less there were bronchopulmonary NETs – 27%, other locations – 9.5%. In 2,5% cases there were not revealed primary tumor. Surgical treatment was performed in 58% cases. Interestingly that cohort of 319 (20%) patients didn’t receive any type of treatment. Conclusions: at the present time there are a lot of discuss about policy in treatment and observation for patients with NETs. Initial results of the Russian register show the different approaches for treatment these tumors depending of position of each doctor. This register will not only mark the epidemiology of NETs in Russia, but will help in review and change the line of treatment this cohort of patients.
Two prognostic populations of ovarian cancer patients defined by CA125 modeled kinetic parameter KELIM (AGO-OVAR 7 &amp; 9; ICON 7 AGO/GINECO/ MRC CTU/GCIG trials).
Authors: Benoit You, Olivier Colomban, Gilles Freyer, Alexandra Leary, Isabelle Laure Ray-Coquard, Alain Lortholary, Anne Claire Hardy Bessard, Jacobus Pfisterer, Andreas Du Bois, Christian Kurzeder, Alexander Burges, Michel Tod
Journal: Journal of Clinical Oncology (2017)

5554 Background: Longitudinal CA125 kinetics during treatment can be assessed by mathematical models. The modeled CA125 elimination parameter KELIM (with 3-4 timepoints) was an early prognostic factor in CALYPSO (Gynecol Oncol 2013). Validating the prognostic value of KELIM in phase 3 trial datasets with different 1 st line treatments was warranted. Methods: Data from AGO-OVAR 9 (training set: carboplatin-paclitaxel (CP) +/- gemcitabine; n=1742); AGO-OVAR 7 (validation set: CP +/- topotecan; n=1308); and ICON 7 trials (validation set: CP +/- bevacizumab; n=1528) were analyzed. CA125 profiles were fit to nonlinear mixed effect equations, and KELIM estimated in all patients at 100 days. KELIM prognostic value was tested regarding PFS and OS against other prognostic factors (stage; pathology; grade; arms; GCIG CA125 criteria; Oza groups in ICON 7) using univariate/multivariate tests. Results: KELIM (≤ or &gt; median 0.0598) had reproducible independent prognostic value for PFS (AGO 9: HR = 0.60 [0.53-0.69]; AGO 7: HR = 0.58 [0.40-0.83]; ICON-7: HR=0.65 [0.44-0.96]) and for OS (AGO 9: HR = 0.55 [0.47-0.64]; AGO 7: HR = 0.55 [0.35-0.86]; ICON-7: HR=0.49 [0.41-0.57]) by multivariate tests. Other significant factors for PFS &amp; OS: stage IV in AGO7 &amp; 9 (HR=6.0 to 8.3) and ICON 7 poor progn group (PFS HR=2.24 PFS; OS HR=2.22 [1.9-2.6]). KELIM prognostic value was independent on regimen arms (Table), maintained within ICON7 progn groups (best OS gain with bevac if poor progn &amp; unfav KELIM), and better than GCIG CA125 (inconsistent progn value). Conclusions: The reproducible &amp; independent early prognostic value of KELIM regarding PFS and OS is validated. Easily calculable online, it early discriminates 2 ovarian cancer populations for PFS &amp; OS whatever treatments, and is a new reference prognostic factor. [Table: see text]
Comparative efficacy and safety of immunotherapies targeting PD-1/PD-L1 pathway for previously treated advanced non-small cell lung cancer: Bayesian network meta-analysis.
Authors: Abdulaali Almutairi, Nimer Alsaid, Jennifer Martin, Hani M. Babiker, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2018)

e21012 Background: Two PD-1 (pembrolizumab, nivolumab) and one PDL-1 (atezolizumab) inhibitors are FDA approved for previously treated advanced non-small cell lung cancer. In the absence of head-to-head trials we conducted a Bayesian network meta-analysis to compare these agents on efficacy and safety. Methods: Eligible randomized controlled trials were identified by searching PubMed, Embase, and Cochrane and the websites of the FDA and the European Medicines Agency (EMA). A fixed-effect Bayesian network meta-analysis was conducted on overall (OS) and progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), with subgroup analyses for OS and PFS. Results: Five trials, all with docetaxel as the common comparator, met the inclusion/exclusion criteria. There were no differences in OS and PFS when comparing the PD-1/PDL-1 inhibitors to each other. The probability of being first rank therapy was 53% for pembrolizumab in OS and 59% for nivolumab in PFS. Pembrolizumab and nivolumab had higher ORRs vs. atezolizumab (odds ratio(OR) = 2.22, 95%CrI 1.28-3.70 and OR = 1.92, 95%CrI 1.15-3.23, resp.). Pembrolizumab was ranked first for ORR with a probability of 68%. For AEs, nausea was lower in nivolumab vs. pembrolizumab (OR = 0.56,95%CrI 0.32-0.97) and atezolizumab (OR = 0.56, 95%CrI0.35-0.89). Diarrhea was 43% lower in nivolumab vs. atezolizumab (OR = 0.57,95%CrI 0.34-0.94). There were no significant differences in OS and PFS between PD-1/PDL-1 inhbitors in subgroup analyses. However, pembrolizumab ranked first in OS subgroups by adenocarcinoma, EGFR-mutant, ECOG-1, male, and younger patients ( < 65 years) while nivolumab ranked first in squamous, EGFR-wild-type, and ECOG-0. Conclusions: Pembrolizumab may be preferred for OS and ORR as well as OS subgroups of adenocarcinoma, EGFR-mutant, ECOG-1, male, patient age < 65 years. Nivolumab may be preferred for OS subgroups of squamous cell, EGFR-wild-type, and ECOG-0.
All-trans retinoic acid + arsenic trioxide versus other regimens for the treatment of acute promyelocytic leukemia: A single institution experience.
Authors: Pritam Tayshetye, Prashant Mukesh Jani, Daniel Jung Lee, Santhosh K. Sadashiv, Salman Fazal, Cyrus Khan, Prerna Mewawalla, Anna Koget, Gina Berteotti, Amy Tang, John Lister
Journal: Journal of Clinical Oncology (2018)

e19010 Background: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APML). Anthracycline is added at induction for high risk patients. Adding maintenance therapy after induction and consolidation with ATRA + ATO has not been rigorously tested. In early 2007, we standardized our institutional practice to use ATRA + ATO alone for low risk patients, adding idarubicin to the combination for high risk patients. Maintenance therapy was not given. Methods: We reviewed 36 patients with APML diagnosed between 2000 and 2016. We compared the overall survival (OS) and event-free survival (EFS) of patients treated with the combination of ATRA + ATO (Cohort_AA) with patients treated on other regimens (Cohort_OT) at our institution. 7 patients in Cohort_OT were treated on CALGB 9710. Cohort_AA received induction with ATRA 45 mg/m2 and ATO 0.15 mg/kg IV both daily until hematological remission. High-risk patients received idarubicin on days 2, 4, 6 ± 8. Consolidation consisted of ATO for 5 days/week for 4 weeks every 8 weeks for 4 cycles and ATRA for 14 days every 4 weeks for 7 cycles. Results: Median follow-up was 30 months (range: 6-208 months) for the entire group. OS of Cohort_AA (n = 20) was 100% with a median follow-up of 22 months (range: 6-130) and 75% in Cohort_OT (n = 16) with a median follow-up of 84 months (range 8-208) (p = 0.0462). EFS was 100% (Cohort_AA) and 68% (Cohort_OT) (p = 0.0458). There were four relapses and three deaths (2 within one year) in Cohort_OT. There are no relapses or deaths in Cohort_AA. Patients in both groups were stratified according to high or low risk. There was no difference in terms of risk stratification between the two groups (p = 0.36). Conclusions: ATRA + ATO with idarubicin for high-risk disease and without maintenance is a feasible and superior treatment when compared to other regimens used at our institution. It is unlikely that maintenance therapy would improve survival. With the advent of molecular testing, clinical trials designed to test tailored therapy based upon risk and molecular response would seem to be a logical next step.