tbuckley/cabot-search huggingface dataset:
Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.
Authors: Tara Elisabeth Seery, Mira Kistler, Leonard S. Sender, John H. Lee, Arvind Manohar Shinde, Anand Annamalai, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2019)

e15787 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that sustained response against pancreatic cancer requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low-dose chemotherapy, SBRT, cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with recurrent metastatic pancreatic cancer was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral CEA vaccine, yeast Ras vaccine, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 12 subjects with 3rd-line or greater metastatic pancreatic cancer were treated. All treatment was administered in an outpatient setting. AEs were primarily hematologic and managed by planned chemo dose reduction. Grade ≥3 TRAEs were observed in 9 out of 12 subjects, predominately chemotherapy-related neutropenia. 9 out of 12 subjects (75%) had a best response of stable disease (≥ 8 weeks). Median PFS is 7.1 months (4.4 – 8.8) and median OS is 8.2 months (5.7 – 9.7) with 1 subject continuing treatment. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary OS of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869.
Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction cancers: A provincial population-based analysis.
Authors: Irene S. Yu, Shiru Lucy Liu, Yizhou Zhao, Sally CM Lau, Devin Schellenberg, Sharlene Gill, Howard John Lim
Journal: Journal of Clinical Oncology (2019)

e15506 Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responders (R, ≥ 35% decrease in max SUV) or PET non-responders (NR, &lt; 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts with locally advanced DE/GEJ cancers, 232 pts were eligible for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p&gt;0.05). Median time from end of treatment to PETs was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response rates (14% vs 13%, p=0.079) were similar for PET-R vs PET-NR, respectively. Discordance rate was 34% between PET vs pathologic response (Table). Aborted surgery rate was higher in the PET-NR group (8% vs 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the groups (PET-R 31.5 mo vs PET-NR 36.1 mo, p=0.616). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility. PET-NR were more likely to have their surgeries aborted. The predictive ability of PET in determining surgical resectability should be further investigated to avoid unnecessary high morbidity surgeries.[Table: see text]
Factors affecting sleep quality and its association to quality of life in adult Filipinos with cancer.
Authors: Amabelle Trina Borgonia Gerona, Ryelene Baquilod, Deborah A. Bernardo, Roselle B. De Guzman
Journal: Journal of Clinical Oncology (2019)

e23100 Background: Sleep disturbances are highly prevalent in cancer patients and may be attributable to factors including pain, treatment side effects and psychological factors. However, the relationship between sleep and cancer is bidirectional. There is substantial evidence that sleep disturbance is associated with many aspects of cancer treatment, morbidity, mortality and quality of life. This study evaluated sleep quality in adult Filipinos with cancer and determined the association of demographic characteristics and clinical features to sleep quality. Methods: This was a cross-sectional surveillance study conducted among adult Filipinos with cancer seen at the Ambulatory Care Unit of a tertiary hospital. Questionnaires were answered to assess subjective sleep quality, pain score and quality of life. Frequency and percentages were determined. Determination of factors affecting sleep quality was analyzed using univariate and multivariate statistics. Results: Of the 406 cancer patients studied, 80% were women and the mean age was 53 years old. Majority (62%) had breast cancer. Seventy-nine percent (79%) of the patients had a PSQI score of 5 or greater, indicating poor sleep quality. Sleep among participants was characterized by prolonged time to fall asleep and shortened sleep duration. Majority reported some degree of daytime dysfunction due to poor sleep. Age, gender and marital status did not appear to affect the quality of sleep. Among disease-related factors, presence of more advanced disease, increasing pain severity and treatment with chemotherapy and/or radiotherapy were demonstrated to lead to poorer sleep quality. Surprisingly, even patients who were not receiving any active therapies (on-going surveillance) complained of sleep disturbance. Upon further investigation, poor sleep quality was shown to predict a worse quality of life among the study participants. Conclusions: Overall, the quality of sleep among adult Filipinos with cancer is significantly impaired. In particular, presence of more advanced disease, treatment with chemotherapy and radiotherapy and moderate to severe pain significantly increase the risk of having poor sleep. In turn, disturbed sleep predicted a poorer quality of life. These findings support the need to include assessment of sleep quality for a more holistic approach to cancer care.
Prognostic value of PAM50 in residual breast cancer following neoadjuvant endocrine therapy (NET): A retrospective analysis with long follow-up.
Authors: Miguel J. Gil Gil, Francisco Javier Perez, Teresa Soler Monso, Tomas Pascual, Patricia Galván, Laia Pare, Anna Petit, Catalina Falo, Agostina Stradella, María Jesús Pla, Ramon Salazar, Aleix Prat
Journal: Journal of Clinical Oncology (2019)

575 Background: NET is gaining more acceptances for the management of hormonal receptors (HR)-positive breast cancer (BC). To date, the decrease of Ki-67 and PEPI score are the only prognostic factors associated with relapse-free survival after NET. PAM50 is a validated prognostic test in newly diagnosed BC; however, its value in residual tumors after NET is currently unknown. Methods: We took tumor tissues from patients of a retrospective study of 119 postmenopausal women with HR-positive stage II-III BC. Patients were diagnosed from 1997 to 2009 and were treated with NET for a median duration of 8.5 months . Median age was 74 (63-88). After NET all patients underwent surgery (73% conservative). Adjuvant treatment were endocrine therapy in 100%, radiotherapy in 76.5% and chemotherapy 7%. Median follow-up from surgery was 112 months. Median follow-up from surgery was 112 months. We observed 26 (24%) of distant relapses and 75 deaths (44 without cancer). Median overall survival was 134.8 months. RNA was extracted from FFPE tumor tissues of surgical specimens. A panel of 55 BC-related genes, including the research-based PAM50 assay (subtypes, ROR-S and ROR-P pre-defined cutpoints), androgen receptor (AR), immune genes (CD8A, CD4, PDL1 and PD1). Uni- and multi-variable Cox models were used to evaluate the association of each variable with distance recurrence free interval (DRFI). Results: PAM50 subtype distribution: Luminal A 54.3%, Normal-like 24.3%; HER2-enriched 16,5%, Luminal B 1% and basal 1%. Distribution of ROR-S groups was Low 64%, medium 30%and high 6%. Distribution of PEPI score was: 0 in 43%, 3 in 37% and 6 in 20%. Among the different variables explored, PEPI score 0 (HR 0.27 [95%IC 0.09-0.79] p=0.001), low ROR-S (HR 0.39 [95%CI 0.17-0.91] p=0.001) and high AR expression (HR 0.71 [95CI 0.53-0.96] p=0.007) were significantly associated with lower DRFI in univariate analyses. After adjusting for PEPI (with or without Normal-like tumors), ROR-S and AR remained significantly associated with outcome. Conclusions: PAM50 ROR-S and AR expression in residual tumors after NET provide independent prognostic information beyond PEPI. With further validation, these biomarkers could help clinicians in the decision-making of adjuvant chemotherapy.
Randomized, optimal dose-finding, phase II study of tri-weekly nab-paclitaxel in patients with metastatic breast cancer (ABROAD).
Authors: Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa, Hiroaki Kato, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara, Hirofumi Mukai
Journal: Journal of Clinical Oncology (2019)

1070 Background: Although nab-paclitaxel (nab-PTX) has shown superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m 2 ) every 3 weeks (q3w) demonstrated a good objective response rate (39.5%) without grade 3 or higher CIPN. Herein, we conducted multicenter randomized controlled study to evaluate optimal dose of nab-PTX comparing lower dose (LD or MD) to standard dose (SD). Methods: This study compared three different doses of q3w nab-PTX (SD: 260 mg/m 2 vs. MD: 220 mg/m 2 vs. LD: 180 mg/m 2) in patients with HER2 negative metastatic breast cancer. Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses are estimated by the logistic regression. Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 or more than 1.33, the inferior dose was dropped. Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%, that dose was also dropped. This trial is registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). Results: In this study, 141 patients were randomly assigned to SD (n = 47), MD (n = 46) or LD (n = 48). Median PFS was 6.66 vs 7.34 vs 6.82 months, respectively. HR was 0.73 (95% confidence interval (CI): 0.42-1.28) in MD vs SD. SD was dropped due to inferiority to MD. HR was 0.77 (95%CI 0.47-1.28) in LD vs SD, and 0.96 (95%CI 0.56-1.66) in LD vs MD. LD and MD were carried over to next step due to equivalence. Overall survival was not different among all dose arms. Rate of dose reduction by treatment course was significantly higher in SD arm. Estimated incidence of grade 3/4 neurotoxicity rate was 29.5% in SD, 14.0% in MD and 5.9% in LD. Final selected dose was LD 180mg/m 2 . HR-QOL results will be presented. Conclusions: Low dose nab-PTX at 180 mg/m 2 /3 weeks could be an optimal dose with good clinical efficacy and tolerability for patients with MBC. Clinical trial information: C000012429.
Follow-up evaluation of outliers with elevated spermine-spermidine acetyltransferase-1 activity.
Authors: Andrew W. Maksymiuk, Paramjit S. Tappia, Bram Ramjiawan, Nazrina Khatun, Rahnuma Parveen, Rashiduzzaman Ahmed, Gina Huang, Rashid Bux Ahmed, Parveen S. Akhtar, Horacio Bach, Daniel Sitar
Journal: Journal of Clinical Oncology (2019)

e14536 Background: In the evolving role of biomarkers, proteinomic signatures related to up-regulation of polyamine synthesis including spermine/spermidine acetyltransferase-1 (SSAT-1) appear to be promising markers of malignancy. Acetylamantadine (AA) excretion, a measure of SSAT-1 up-regulation, has been shown to be a marker for malignant proliferation. In preliminary analyses of ostensibly normal individuals from Canada (Winnipeg) and Bangladesh (Dhaka), a proportion were identified to have evidence of SSAT-1 up-regulation above the expected non-malignant range (outliers). These outliers were assessed and followed for development of identifiable medical conditions. Methods: SSAT-1 up regulation was assessed in 60 ostensibly normal individuals by analysis of urinary excretion of AA after ingestion of amantadine 200 mg x 1 dose. AA was assayed using HPLC-mass spec techniques as previously described. Outliers who consented were followed-up by clinical examinations, routine biochemical and hematological tests and radiographs, where indicated. Results: Total AA average (median) excretion at 6 hrs in the Winnipeg cohort was 579+/-252 vs 1699+/-633 ng in the Dhaka cohort. Average urinary concentration at 6 hrs was 3.75+/-0.75 vs 21+/-20 ng/ml. In outliers consenting to follow-up, 1 case of invasive malignancy was identified, 6 cases of pre-malignant neoplastic change, chronic liver disease in 7 cases and chronic inflammation in 2 cases. In others, no malignant or inflammatory conditions have yet been identified. The range of SSAT-1 activity in individuals living in Bangladesh was significantly higher than in the Canadian cohort. Bangladesh volunteers live in an area of known to have high natural contamination with arsenic, a recognized carcinogen and they are exposed to high levels of air pollution. Conclusions: By this assay, high SSAT-1 activity has been confirmed in patients harbouring malignancy; however, pre-malignant and inflammatory conditions may result in a positive test. Follow-up of individuals with elevated SSAT-1 activity may reveal unrecognized malignancies, pre-malignant neoplasms, liver disease, inflammatory conditions and possibly false-positivity in individuals exposed to carcinogens such as arsenic. In further work, SSAT-1 up-regulation is being correlated with 5 other putative polyamine metabolite markers for accurate diagnosis of lung cancer.
NEONAX trial: Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer, a phase II study of the AIO pancreatic cancer group (AIO-PAK-0313)—Safety interim analysis.
Authors: Waldemar Uhl, Thomas Jens Ettrich, Anke C. Reinacher-Schick, Hana Algül, Helmut Friess, Marko Kornmann, Alexander Koenig, Michael Ghadimi, Uwe A Wittel, Eike Gallmeier, Kai Wille, Michael Geissler, Carl Christoph Schimanski, Nicole Prasnikar, Andrea Tannapfel, Lukas Perkhofer, Andreas W. Berger, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2019)

4128 Background: Survival in pancreatic cancer (PDAC) is still poor even after curatively intended resection. Perioperative treatment approaches improve outcome in various tumor entities. Data on perioperative treatment in resectable PDAC are limited and there is a debate whether neoadjuvant treatment might impair subsequent surgery by adding perioperative morbidity or mortality. Methods: NEONAX is a randomized phase II study (planned 166 patients) of perioperative gemcitabine/nab-paclitaxel (Arm A: 2 pre- and 4 post-operative cycles, Arm B: 6 cycles adjuvant) for patients with primarily resectable PDAC. Primary objective is DFS at 18 months after randomization. Secondary objectives are 3-year OS-rate and DFS-rate, progression during neoadjuvant therapy, R0/R1 resection rate and QoL. Results: NEONAX was initiated in March 2015 in 26 centers for PDAC surgery in Germany. The data represent the safety interim analysis (IA) of the first 48 patients. 25 patients were randomized to Arm A and 23 to Arm B. Patients’ median age was 65.3 years (56.3% males, 43.8% females, 85.4% ECOG 0). Out of 25 patients in Arm A 20 patients (80%) underwent surgery, compared to 21 of 23 patients (91.3%) in Arm B with upfront surgery. Reasons for no resection were intraoperatively determined small liver metastases (2 cases, Arm A), withdrawal of informed consent (2 cases in each arm) and 1 patient with uncontrolled cholestasis (arm A). Postoperative complications occurred in 45% of arm A and 42.8% of arm B. (pancreatic fistula: 15% in arm A and 9.5% in arm B, infections: 10% in arm A and 9.5% in arm B) All resected patients were alive 60 days after surgery. At least 1 adverse event (AE) NCI-CTCAE ≥ grade 3 occurred in 60% of the perioperative and 39.1% of adjuvant treatment arm. Most common AEs were neutropenia (16.7%), fatigue (10.4%) and infections (10.4%). Conclusions: There was an increase in NCI-CTCAE ≥ grade 3 events in the perioperative arm, but this was manageable and did not result in increased peri- or postoperative mortality. 8% of patients in the perioperative arm did not get resected due metastases detectable during surgery, but not on preoperative imaging immediately prior to surgery. Therefore, it cannot be determined whether these metastases were preexistent or developed during neoadjuvant treatment. In conclusion, the first interim analysis of the NEONAX trial shows that this protocol can be safely applied to patients with resectable PDAC in a perioperative setting. Clinical trial information: NCT02047513.
A regulatory program that promotes metastasis in colorectal cancer (CRC) through modulation of mRNA stability.
Authors: Hani Goodarzi, Robert S. Warren, Johnny Yu, Lisa Fish
Journal: Journal of Clinical Oncology (2019)

3523 Background: CRC progression accompanies dysregulations in pathways of gene expression control. Regulatory pathways that govern RNA decay have emerged as key mechanisms coopted by cancer cells. Here, we have described a novel regulatory program that acts as a suppressor of metastasis in CRC. Methods: We have developed a computational approach called PRADA that identifies master regulators of aberrant mRNA stability. By applying this tool to a compendium of gene expression data collected from patient samples and colon cancer cell lines, we have identified a novel regulatory program involved in CRC metastasis. We have used xenograft models and genomic technologies to functionally dissect this pathway. We have also performed multivariate analysis in public datasets, as well as qPCR-based measurements in tumor samples to establish its clinical relevance. Results: PRADA identified the RNA-binding protein RBMS1 as a key factor in CRC metastasis. RBMS1, which is silenced in highly metastatic cells, binds and stabilizes a large regulon of mRNAs. Silencing RBMS1 in established lines resulted in increased liver colonization in xenograft models and its over-expression reduced metastasis. We also identified the set of genes that are directly bound and regulated by RBMS1 and function downstream. Loss of RBMS1 and its regulon provide a signature predictive of RFS in localized CRC (n = 574, HR = 0.48, p = 0.038) even when controlled for known prognostic factors in a multivariate analysis (Table). We also observed a 4-fold reduction (P&lt;1e-3) in the expression of RBMS1 in stage IV tumors relative to earlier stage disease. Conclusions: In sum, we have discovered a previously unknown regulatory pathway of RNA stability that acts as a suppressor of metastasis in CRC which may inform new therapeutic targets among the RBMS1 regulon for adjuvant therapy.[Table: see text]
Multicentric prospettive study of validation of angiogenesis-related gene polymorphisms in hepatocellular carcinoma patients treated with sorafenib: Interim analysis of INNOVATE study.
Authors: Andrea Casadei Gardini, Giorgia Marisi, Vincenzo Dadduzio, Luca Faloppi, Luca Ielasi, Caterina Vivaldi, Mario Domenico Rizzato, Lorenzo Fornaro, Sara Lonardi, Laura Gramantieri, Irene Pecora, Giuseppe Francesco Foschi, Nicola Silvestris, Francesca Fornari, Giulia Orsi, Giulia Rovesti, Daniele Santini, Vittorina Zagonel, Stefano Cascinu, Mario Scartozzi
Journal: Journal of Clinical Oncology (2019)

4075 Background: In the ePHAS study we analyzed three eNOSpolymorphisms and at univariate analysis, patients with eNOS-786 -TTgenotype had significantly shorter median Progression Free Survival (PFS) and Overall Survival (OS) compared to those with other genotypes. On the basis of these preliminary results, our aim is to validate in a prospective study this data in patients with HCC treated with sorafenib. Methods: This is a prospective Italian multicenter study, that includes 141 HCC patients receiving sorafenib. We analyzed eNOS-786and itwas analyzed by Real Time PCR in relation to the primary end point (OS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. Results: 141 HCC patients (122 males and 19 females), prospectively treated with sorafenib from May 2015 to September 2018 were included. Median age was 69 years (range 28-88 years). 120 patients had Child-Pugh A and 21 had Child-Pugh B7. 43 had BCLC-B and 98 patients had BCLC-C. Atunivariate analysis, we confirmed that eNOS-786 TT genotype were significantly associated with a lower median OS than the other genotypes (8.8 vs 15.7 months, HR 1.69, 95% CI 1.02-2.83 p=0.0424). Following adjustment for clinical covariates (age, gender, etiology, BCLC stage, serum α-FP level, MELD score), multivariate analysis confirmed eNOS- 786 and BCLC stage as the independentsprognostic factors predicting OS (TTvsTC+CC; HR: 2.39, 95% CI 1.14-5.03 p=0.0211; C vs B;2.23, 95% CI 1.44-4.77 p=0.039). Conclusions: Our prospective study confirms the prognostic role of eNOS-786 in advanced HCC patients treated with sorafenib. Clinical trial information: NCT02786342.
Hepatitis C virus network dynamics among people who inject drugs in Vancouver, Canada
Authors: B Jacka, A Poon, T L Applegate, M Krajden, A Olmstead, R Harrigan, B D Marshall, K DeBeck, Milloy M-J., F Lamoury, O Pybus, V Lima, G Magiorkinis, V Montoya, J Montaner, J Joy, G J Dore, T Kerr, E Wood, J Grebely
Journal: Hepatology (2014)