tbuckley/cabot-search huggingface dataset:
Stage-based variation in the impact of colon cancer surveillance.
Authors: Lucy Gately, Christine Semira, Azim Jalali, Ian Faragher, Sumitra Ananda, Suzanne Kosmider, Kathryn M. Field, Sheau Wen Lok, Malcolm Steel, Margaret Lee, Rachel Wong, Hui-Li Wong, Peter Gibbs
Journal: Journal of Clinical Oncology (2019)

3609 Background: Multiple meta-analyses have demonstrated that routine surveillance following curative intent colorectal cancer surgery improves overall survival. This benefit is largely driven by early detection and curative intent resection of oligometastatic disease. Intuitively, any surveillance benefit should be proportional to recurrence risk, leading some to question the value of surveillance for stage I patients where recurrence rates are low. However, the survival benefit of surveillance has not previously been reported by stage. Methods: We explored data from a multi-site cohort of colorectal cancer patients (pts) diagnosed from 1 January 2001 to 31 December 2016. Pts were followed according to standard protocols with a standardized comprehensive outcome data captured prospectively. Pts with a rectal primary or metastatic disease at presentation were excluded from the analysis. We examined the correlation of stage at diagnosis with tumor recurrence and subsequent outcomes. Results: Of 3608 colon cancer pts, 690 (19%) had stage 1, 1580 (44%) had stage 2, and 1338 (37%) had stage 3 disease. Median follow-up was 7.8 years. Stage at diagnosis impacted recurrence rate (4% stage I vs 12% stage II vs 28% stage III, p &lt; .0001) but not median time to recurrence. Recurrence patterns varied with stage (e.g. distant nodal disease 5% vs 7% vs 16%, p = .003; liver metastases 90% vs 53% vs 42%, p = 0.001). In pts with recurrence, resection of oligometastatic disease varied significantly by stage (58% vs 42% vs 30%, p &lt; .0001) as did post-resection 5 year survival (91% vs 66% vs 43%, p &lt; 0.001). In pts with recurrence treated with palliative intent, stage at diagnosis also impacted post-recurrence 5 year survival (11% vs 7% vs 5%, p &lt; 0.03). Conclusions: Colon cancer stage at diagnosis substantially impacts the proportion of pts able to undergo curative intent surgery for surveillance detected recurrent disease, potentially driven by stage specific metastatic patterns. Stage at diagnosis also has a significant impact on post-resection survival outcomes potentially driven by stage specific biology. Our data indicate a far greater survival impact of surveillance for stage I colon cancer than would be anticipated based on recurrence rate alone.
Enhanced CD138 peptide-specific cytotoxic T lymphocyte activities against breast, colon and pancreatic cancers in combination with pembrolizumab (anti-PD1).
Authors: Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Nikhil C. Munshi, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2019)

e14302 Background: We investigated the ability of CD138 antigen-specific CD8 + cytotoxic T lymphocytes (CD138-CTL), generated using a novel HLA-A2-specific CD138 260-268 (GLVGLIFAV) peptide, in combination with various immune checkpoint inhibitors, to target breast, colon, and pancreatic cancer. Methods: This study was designed to evaluate anti-tumor activities of CD138-CTL, alone or in combination with Pembrolizumab (anti-PD1), against solid tumors. Results: Upregulation of CD138 protein expression was detected on breast, colon, and pancreatic cancer cells. CD138-CTL induced ex vivo by repeated stimulations with HLA-A2-specific CD138 260-268 (GLVGLIFAV) peptide were enriched for CD45RO + memory CTL and demonstrated antigen-specific and HLA-A2-restricted anti-tumor activities. Treatment of CD138-CTL with anti-PD1, anti-TIM3, or anti-LAG3 or tumor cells with anti-PDL1, anti-Gal9 or anti-LAG3 resulted in an increased proliferation of CD138-specific CD8 + CTL, which express costimulatory and activation markers (CD28, CD40L, 41BB, CD69, CD38). However, expression of immune checkpoints (PD1, LAG3, CTLA4) was also induced on these CD138-CTL upon stimulation. Importantly, anti-tumor activities of CD138 peptide-CTL was significantly enhanced in combination with Pembrolizumab, especially within the antigen-specific memory CD8 + T cell subsets (central memory &gt; effector memory), directed against HLA-A2 + breast cancer, colon cancer and pancreatic cancer. Conclusions: These data provide the framework for an immunotherapeutic strategy encompassing a CD138 260-268 (GLVGLIFAV) peptide-based cancer vaccine in combination with Pembrolizumab to enhance antigen-specific central memory cells with more potent and long-lasting CD8 + CTL immune responses in patients with solid tumors. Based on these result, clinical trials evaluating CD138 260-268 (GLVGLIFAV) in multi-peptide cancer vaccine are on-going in patients with triple negative breast cancer in combination with anti-PD1 (Pembrolizumab) in metastatic setting (NCT 03362060) or anti-PD-L1 (Durvalumab) in stage II/III, adjuvant setting (NCT 02826434).
AB1001 ARE ANY DIFFERENCES IN THE LOCATION OF BONE LESIONS BETWEEN BONE MALIGNANT TUMORS AND INFLAMMATORY OSTEOPATHIES?
Authors: Vyacheslav Silkov, Nikita Suvorov, Mikhail Kostik, Olga Kopchak, Alexei Maletin, Vyacheslav Zorin, Alexander Mushkin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Different pediatric bone destructive diseases may have similar radiological findings but have their typical localizations [1]. <h3>Objectives</h3> The aim of our study was to differences in the bone lesions location in various pediatric bone destructive diseases. <h3>Methods</h3> Our cohort (n=204) consists of four main subtypes: i) chronic non-bacterial osteomyelitis (CNO, n=91), ii) hematogenous osteomyelitis (HO, n=47); iii) tuberculosis osteomyelitis (TBO, n=33), and iv) malignant bone tumors (MBT, n=33) - osteosarcoma and Ewing's sarcoma. <h3>Results</h3> Al bone destructive diseases have the similar frequency of femur and humerus involvement. MBT patients compare to others had the highest onset age, and higher frequency of pelvic involvent, and comparatively rare the involvement of spine, tibia, foot bones, sternum, the bones of forearm and hand (table). <h3>Conclusion</h3> Patients with bone destructive process with femur, humerus and pelvic involvement have to be under high level of consideration about all type of osteopathy, especially MBT. This work supported by the Russian Foundation for Basic Research (grant ? 18-515-57001). <h3>References</h3> [1] McCarville MB. The child with bone pain: malignancies and mimickers. Cancer Imaging. 2009;9 Spec No A:S115-21. <h3>Disclosure of Interests</h3> None declared
Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).
Authors: Timothy Iveson, Alberto F. Sobrero, Takayuki Yoshino, Ioannis Sougklakos, Fang-Shu Ou, Jeffery P. Meyers, Qian Shi, Mark P. Saunders, Roberto Labianca, Takeharu Yamanaka, Ioannis Boukovinas, Niels Henrik Hollander, Valter Torri, Kentaro Yamazaki, Vassilis Georgoulias, Sara Lonardi, Andrea Harkin, Gerardo Rosati, James Paul
Journal: Journal of Clinical Oncology (2019)

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p &lt; .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.
Defining cardiotoxicity of doxorubicin and trastuzumab.
Authors: Abir Khan, Omid Amidi, Kenneth R. Hess, Michael S. Ewer, Wamique Yusuf, Jose Banchs, Nicolas Palaskas
Journal: Journal of Clinical Oncology (2019)

e23097 Background: Doxorubicin and trastuzumab have been described to cause clinical heart failure and asymptomatic declines in left ventricular ejection fraction (LVEF). Initial studies of doxorubicin in the 1970’s defined cardiotoxicity by the clinical syndrome of heart failure without imaging for LVEF determination. Trials with adjuvant trastuzumab used various LVEF cut-offs that were arbitrarily determined. This study aims to compare the predictive value of commonly used definitions of cardiotoxicity associated with chemotherapy for the development of clinical heart failure. Methods: A retrospective chart review was performed on an IRB approved cohort of 638 patients with breast cancer who received doxorubicin, trastuzumab, or both and who had baseline and follow up echocardiograms, collecting LVEF values for each echocardiogram. Clinical heart failure was determined by formal cardiology evaluations denoting clinical heart failure in patients. Four different definitions of cardiotoxicity were compared; American Society of Echocardiography (ASE), Cardiac Review and Evaluation Committee (CREC), Alexander et al, and Schwartz et al (Table). Results: Only 8 patients (1.25%) developed clinical heart failure. The sensitivity, specificity, positive predictive value, and negative predictive value of each definition of cardiotoxicity are listed in the table. Conclusions: Overall there is a low threshold for detection of clinical heart failure in breast cancer therapy. While the ASE definition has the highest combination of sensitivity, specificity, and positive predictive value, it has a sensitivity of only 62.5%. Thus, cardiologists and oncologists should collaborate to develop a definition of cardiotoxicity better correlated to clinical outcomes. [Table: see text]
SLAMF8, a novel biomarker for personalized immune checkpoint blockade therapy in gastrointestinal cancer.
Authors: Qun Zhang, Lei Cheng, Jing Hu, Li Li, Mi Yang, Linghui Kong, Lixia Yu, Jia Wei, Baorui Liu, Xiaoping Qian
Journal: Journal of Clinical Oncology (2019)

e14078 Background: Immune checkpoint inhibitors have brought great breakthroughs in cancer therapy. Activated immune response is known to be the prerequisite for exerting immunotherapy efficacy. Epstein-Barr virus (EBV) infection is associated with longer survival in gastric cancer (GC) patients due to enhanced anti-tumor immune response, and therefore it was reportedly played an important role in modulating immune checkpoint blockade therapy efficacy. However, molecular dimensions underlying the good response to immune checkpoint inhibitors in presence of EBV infection are still unclear. The aim of this study is to identify a gene signature related to EBV induced anti-tumor immune response, and select a tag gene from this signature to predict which patients are most likely to benefit from immune checkpoint blockade therapy. Methods: Two large transcriptome datasets from Gene Expression Omnibus(GEO) database (GSE51575 and GSE62254) were used to screen gene signature for EBV infected gastric cancer tissues. We further selected genes that showed a trend towards differential co-expression independent of EBV infection status. The tag gene of this differential co-expression signature was finally identified by bioinformatics analysis. To make an external validation, we performed RNA sequencing in 20 colorectal caner (CRC) tissues and 20 GC tissues, respectively. Meanwhile, tissue microarrays of CRC cohort (36 paired tumor and normal tissues) and GC cohort (75 paired tumor and normal tissues) were used to analyze the association of SLAMF8 with CD8 protein expression by immunohistochemistry (IHC). Results: Analysis of GEO datasets indicated 788 genes as feature gene cluster for EBV-positive gastric cancer, from which 290 genes were selected to be characterized by differential co-expression in either EBV-positive or EBV-negative gastric cancers. SLAMF8 was identified as the tag gene for this differential co-expression signature. This signature, tagged by SLAMF8, was successfully validated by our RNA sequencing data in presence of its good performance in dividing CRC and GC patients into two subsets. Moreover, we observed a significant association between SLAMF8 and CD8 expression in our CRC and GC tissue samples, in terms of either mRNA or protein level. Conclusions: SLAMF8, a potential indicator for T cell‐mediated immune response induced by EBV infection, may be served as a biomarker for individualized immune checkpoint blockade therapy in gastrointestinal cancer. Further SLAMF8 guided drug sensitivity tests are warranted to validate our results.
Effects of online education on the identification and management of immune-related adverse events over time.
Authors: Lori Keys Pender, Haleh Kadkhoda, Katie S. Lucero, Patti Repetto, Charlotte Warren, Jacqueline Gearhart, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2019)

e18224 Background: Immune checkpoint inhibitors (ICIs) are increasingly used in oncology care and produce a wide variety of immune-related adverse events (irAEs) that differ from toxicities of other systemic therapies. The objective of this study was to assess trends over time in oncologists’ knowledge, competence, and confidence managing irAEs. Methods: A series of online continuing medical education (CME) activities addressing irAEs was launched beginning in April 2014; 39 included multiple-choice knowledge/competence questions and a confidence question assessed on a 5-point Likert-type scale before and immediately after the activity. Activities that had at least 30 oncologists participate pre/post are included in this analysis. A pre-/post-assessment study design was used, and educational effect was assessed with chi-square tests. Analyses were conducted to examine trends in knowledge, competence, and confidence recognizing, identifying, and managing irAEs over four years on a quarterly basis. Weighted averages in each of the outcomes were calculated by quarter. Results: A total of 187,800 learners participated from April 2014-March 2018, including 96,177 physicians, of whom 25,127 were oncologists. The average increase pre- to post-test for 22 activities that asked a knowledge-based question was 18% (P &lt; 0.001). The absolute increase from pre-test in 2014 (67%) to post-test in 2018 (87%) was 20 percentage points. For 16 activities with competence questions, the average increase from pre- to post-test was 8% (P &lt; 0.001), and the absolute increase from pre-test in 2014 (39%) to post-test in 2017 (87%) was 48 percentage points. For 5 activities with a confidence question, the average increase from pre- to post-test was 8% (P &lt; 0.05), and the mean rating pre-test in 2016 was 2.85 versus 3.53 post-test in 2018. Conclusions: Online CME is effective to improve oncologists’ knowledge, competence, and confidence managing irAEs; however, pre-test outcomes in 2018 demonstrate ongoing knowledge and competence gaps that should be addressed, and post-test confidence data indicate a persistent lack of confidence among oncologists even after participating in online CME.
Biomarkers involved in the neoadjuvant therapy response in triple-negative and Her2+ subtypes breast cancer.
Authors: Salvador Bofill, Marta Benavent, Ana Gil, Antonia Pineda, Sonia Molina-Pinelo, Rosario Gonzalez, Alvaro Montaño, Manuel Ruiz Borrego, Alejandro Falcon, Carmen Garrigos
Journal: Journal of Clinical Oncology (2019)

e12098 Background: Neoadjuvant systemic therapy for breast cancer is used increasingly for patients with breast cancer. One of the more compelling theoretical arguments for primary systemic therapy is its value as an in vivo test for drug sensitivity. The oncogenesis of breast cancer, progression and development of metastasis is influenced by the deregulation of a multitude of processes. Several long non-coding RNAs (LncRNAs) and genes are important regulators of gene expression, acting at almost all regulatory levels: transcriptional, posttranscriptional, epigenetic, and protein translation. Our main objective was to identify the differential expression of genes and LncRNAs in paraffin-embedded breast cancer samples Her2+ and triple negative (TN) subtypes in responders (R) and non-responders (NR) patients (pts) to neoadjuvant therapy. Methods: The expression RNAs was analyzed by ClariomD Asssay (ThermoFisher). Results were analyzed with Transcriptome Analysis Console and with in-house scripts in R (version 3.5.1). Data were corrected and normalized using Robust Multichip Average method from the oligo package. Expression was summarized at gene level using the corresponding annotation for ClariomD array BrainArray. Expression analyses were performed with limma package. We defined R (RCB 0; n = 29) and NR (RCB III; n = 11) pts. Results: The differential expression (p &lt; 0.01) of two LncRNAs (RP1-213J1P_B.1 and AC053503.12), one miscellaneous RNA (miscRNA) (Metazoa_SRP) and five genes (STMND1, C8orf33, RP11-144G6.12, ZNF555, RGS2) were found between R and NR. Among others, we highlighted one of these LncRNAs (AC053503.12) and one gene (Metazoa_SRP) that were also identified in TN R (n = 11) vs NR (n = 6). In the Her2+subtype, STMND1 gene also showed a differential expression in R (n = 18) vs NR (n = 5). Conclusions: We found these LncRNAs, miscRNA and genes were involved in different cancer pathways and the their differential expression in R vs NR pts suggest that they could be involved in the response to neoadjuvant therapy in TN and Her2+ subtypes breast cancer. LncRNAs, miscRNA and genes differentially expressed are being independently analyzed by individual qPCR assays in the study cohort.
Early non-invasive detection of stage Ia lung cancer using circulating tumor DNA methylation haplotypes (ctmDNA) in plasma.
Authors: Kun Zhang, Zhoufeng Wang, Zhe Li, Jingyi Lu, Jun Min, Athurva Jayavant Gore, Jeffrey Gole, Rui Liu, Yuan Gao, Weimin Li
Journal: Journal of Clinical Oncology (2019)

e13159 Background: Lung cancer is one of the most common forms of cancer and is responsible for approximately 1.8 million deaths per year worldwide. The current 5-year survival rate for lung cancer is only 18%; however, this improves to 56% if the cancer is detected early. While low-dose CT scans have shown promise as an early detection method, only 16% of lung cancer is currently detected at an early stage. We therefore set out to develop a non-invasive blood-based screening assay to identify lung cancer at an early stage using ctmDNA (circulating tumor methylated DNA haplotypes). Methods: Blood samples were prospectively collected from two partner hospitals from 325 healthy individuals and 116 individuals diagnosed with lung nodules by low-dose CT scan in EDTA or Streck BCT tubes and immediately separated into plasma. Patients with lung nodules that appeared cancerous then underwent surgical resection, and cancer diagnosis was confirmed via pathology. Patients were matched between healthy and cancer groups by age, sex, and smoking status. Plasma samples were processed using the Singlera Genomics LUNA assay, a targeted bisulfite sequencing method which identifies methylation haplotype patterns related to early-stage lung cancer. 241 samples were used to train a classification model based on pathology results, and 200 samples were used as a test set to validate the model. Results: In the independent test set, the LUNA assay was able to show a sensitivity of 91.9% to detect early-stage lung cancer with a specificity of 93.3% in healthy patients. Even patients with stage Ia lung cancer were readily detected by the LUNA assay (sensitivity of 91.7%). Conclusions: We have shown that ctmDNA can be utilized to non-invasively screen for early-stage lung cancer with high sensitivity and specificity, paving the way for a blood-based lung cancer early screening assay.
Continuous intravenous infusion Rh-endostatin in combination with dacarbazine and cisplatin as the first-line therapy for metastatic melanoma.
Authors: Chuanliang Cui, BIN LIAN, Xuan Wang, Zhihong Chi, Lu Si, Xinan Sheng, Yan Kong, Lili Mao, Xieqiao Yan, Bixia Tang, LI Zhou, Jun Guo
Journal: Journal of Clinical Oncology (2019)

e21007 Background: Immunotherapy and targeted therapy have dramatically improved the survival of advanced melanoma patients (pts), but they show relative lower efficacy in Asian pts especially in acral and mucosal subtypes. Rh-Endostatin (endostar) is a potent endogenous inhibitor of angiogenesis. Previous studies have indicated that endostar combined with dacarbazine (DTIC) was effective in the treatment of metastatic melanoma. To further improve the effectiveness, this study was designed to observe the efficacy and safety of continuous infusion (CIV) of endostar combined with DTIC and cisplatin as the first line therapy for advanced melanoma pts. Methods: Pts with treatment naive, ECOG 0/1, and unresectable stage IIIC or IV melanoma were enrolled. DTIC (250 mg/m 2 , intravenous infusion, day 1-5), cisplatin (75 mg/m 2 , intravenous infusion, separated in 3 days) and endostar (15 mg/m 2 , CIV, day 1-14) were administered in a 28-day cycle until disease progression or intolerable toxicity. The primary endpoint was progression free survival (PFS). Secondary endpoints included disease control rate (DCR) and safety. Results: From January 2016 to May 2018, 64 pts were enrolled and 50 pts were evaluable. 26 pts were female. The median age was 50 years (range 28-71 years) old. 10/64 (15.6%) were primary mucosal and 21/64 (32.8%) were primary acral, 40 pts were at stage IV and 32% pts got BRAF mutation. At the last follow up of Dec 2018, 5 pts achieved partial response and 27 pts got stable disease. The objective response rate was 10%. The DCR was 64%. The median PFS was 6.0 months (95% CI 1.7-10.3 months). The median overall survival was not reached. The most common adverse events were nausea (56.25%), vomiting (31.25%) and leucopenia (29.7%). Grade 3-4 toxicity was few, one got intermittent palpitation and one got atrial fibrillation, which caused drug discontinuation and recovered to normal. Conclusions: Continuous infusion of endostar plus DTIC and cisplatin improved median PFS as the first line therapy for advanced melanoma. This combination therapy was well tolerated and might be recommended as the first line therapy for advanced melanoma. Clinical trial information: NCT03095079.