tbuckley/cabot-search huggingface dataset:
Who should undergo lateral pelvic node dissection after neoadjuvant chemoradiation for rectal cancer?
Authors: Songphol Malakorn, Tarik Sammour, Brian K. Bednarski, Y. Nancy You, John Michael Skibber, Miguel A. Rodriguez-Bigas, George J. Chang
Journal: Journal of Clinical Oncology (2018)

3606 Background: The optimal surgical strategy for rectal cancer patients with suspected lateral pelvic lymphadenopathy (LPN) in unknown. Despite the use of neoadjuvant chemoradiation (CRT), lateral compartment treatment failure has emerged as an important clinical problem. The purpose of this study was to evaluate association between preoperative LPN size on imaging and disease diagnosed at pathology in order to determine the indication for lateral pelvic lymph node dissection (LPND). Methods: Rectal cancer patients with lateral pelvic node metastasis who underwent TME with LPND between 2006 and 2017 were identified from the institutional database of a tertiary cancer center and their medical records were retrospectively reviewed for information regarding patient, tumor, and treatment. Indication for LPND was suspected LPN based on CT or MRI. Patients with locally recurrent cancers at presentation were excluded. Primary outcome was rate of pathologic LPN positivity. Associations between LPN size on post-neoadjuvant CRT imaging and pathologic lateral pelvic lymph node positivity were evaluated. Results: A total of 70 patients who underwent TME & LPND met criteria and were analyzed. The median number of LPN evaluated was 3 (IQR 1 – 5) per patient. The mean LPN size before and after CRT was 15.7 ± 12.7 mm and 11.0 ± 10.0 mm, respectively and the minimum size of positive LPN was 6 mm on post-treatment imaging. Overall, a total of 56 of 256 LPN were positive (22%). Twenty patients (28.6%) had only ≤ 5 mm LPN after CRT; none were positive at pathology. Among 50 (71.4%) patients who had > 5 mm LPN after CRT; 34 patients (68%) were positive at pathology. 3 year OS was higher among patients who had ≤ 5 mm LPN vs > 5 mm LPN after CRT (OS 90.9% vs 70.4%, P = 0.05) but the difference in DFS was not statistically significant (77.9% vs 56.7%, P = 0.12). After a median 43 months of follow-up, one patient developed local recurrence (≤ 5 mm group). Conclusions: Post-CRT LPN size > 5 mm was strongly associated with pathologically positive LPN but no patients with size ≤ 5 mm had positive LPN at pathology. Following LPND no patients with positive LPN developed local recurrence. Therefore, patients with LPN > 5 mm on post-CRT MRI should undergo TME with LPND.
Clinical experience with dermatofibrosarcoma protuberans (DFSP) in a diverse ethnic population.
Authors: Ah-Reum Jeong, James Hu, Shauna Higgins, Ashley Wysong, Gino Kim In
Journal: Journal of Clinical Oncology (2018)

e23531 Background: Dermatofibrosarcoma Protuberans (DFSP) is a low/intermediate grade cutaneous sarcoma that arises from the dermis. DFSP may be surgically challenging, and local recurrences are common. While it is reported that DFSP occurs with equal frequency among all ethnic groups, it is unclear whether ethnicity may have an impact on clinical outcomes. Methods: We retrospectively reviewed medical records from 23 patients with DFSP who were treated at the USC Medical Center. Progression free survival was estimated using Kaplan-Meier curve analysis. The median follow-up period was 3.6 years. Results: Among 23 patients diagnosed with DFSP, 34.9% were Hispanic, 30.4% non-Hispanic white (NHW), 13% Asian and 8.7% African American. The median age was 41 (range 34-74). Primary tumors were located most often on the trunk (39.1%), head/neck (34.8%), and extremity (13% each, upper and lower extremity). When analyzed by ethnicity, 50% of Hispanics had primary tumor on the trunk, while 57.1% of NHW had primary tumor on the head/neck. Treatment modalities included Mohs micrographic surgery (MMS) (34.8%), wide excision (34.8%), adjuvant radiation (13%), and imatinib (8.7%). Local recurrences occurred in 5 of 23 patients (21.7%), with 3 of 5 (60%) occurring on the head and neck. Recurrent disease was less likely with MMS (12.5%), compared to wide excision (25.0%). None of the 5 patients with recurrent disease received adjuvant radiation or imatinib following resection. Three of 5 patients (60%) with recurrent disease had 2 or more recurrences, including one patient with metastasis to the lung. Conclusions: Anatomic distribution of DFSP primary tumor location varies by ethnicity, with NHW having higher incidence of head/neck primary location. Given the increased risk of local recurrences on the head / neck, patients with this primary tumor location may benefit from surgery with complete margin assessment, increased surveillance strategies, and multi-modality treatment including adjuvant radiation and/or imatinib.
Spleen to liver ratio (SLR): Novel PET imaging biomarker for prediction of overall survival after ipilimumab and anti-PD1 in patients with metastatic melanoma.
Authors: Annie Ngai Man Wong, Jason Callahan, Jenny Beresford, Alan Herschtal, Sonia Fullerton, Donna Milne, Rodney J Hicks, Grant A. McArthur
Journal: Journal of Clinical Oncology (2016)

9523 Background: Immunotherapy has resulted in unprecedented improvements in survival for patients with metastatic melanoma. Despite a response rate of 10% and 40% respectively for Ipilimumab (ipi) and antiPD1, the majority of patients do not respond. Biomarkers that can predict clinical outcome are urgently needed. We analysed baseline parameters on 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) and its association with clinical outcome to identify novel PET imaging biomarkers. Methods: Patients with advanced melanoma who received at least one dose of ipi or anti-PD1 at Peter MacCallum Cancer Centre (1st July 2010-30thJune 2015) were included. Baseline PET scans were assessed for maximum standardised uptake value (SUV max), whole body metabolic tumour volume (MTV), tumoral percentage of injected dose (%ID) and spleen to liver ratio (SLR). PFS and OS were analysed by univariate Cox proportional hazards regression, controlled for treatment line and stage. Multivariate analyses considered LDH, stage, MTV, Absolute Lymphocyte Count (ALC) and SLR. Results: 90 evaluable patients (pts) were included: 51 pts had ipi, 20 pts had antiPD1 and 20 pts had ipi followed by antiPD1. 48 pts (68%) had M1c disease and 48 pts (68%) had LDH > ULN. Baseline parameters for this cohort are as follows: mean SUVmax 20.3 (2.2-78.2), mean MTV 197.6mL (0.03-2693.7mL), mean %ID 1.8 (0.002-22.2), and mean SLR 0.9 (0.7-1.4). For ipi, association with PFS was found for SLR > 1.1 with HR 3.14 (p = 0.008). No significant associations between PET parameters and PFS were found for antiPD1. Considering all patients from date of first immunotherapy (71 ipi and 20 antiPD1), SLR > 1.1 was associated with OS with HR 3.92 (p = 0.003). Multivariate analyses for ipi cohort showed SLR and ALC to be independently prognostic for PFS; SLR and stage to be independently prognostic for OS. Conclusions: Spleen to liver ratio (SLR) > 1.1 is a predictor of clinical outcome in this patient cohort. SLR may represent a novel PET biomarker to evaluate patients' baseline immune state prior to immunotherapy. OS analysis was limited by patients' subsequent treatments. Further validation is warranted.
Clinical outcomes of DLBCL, follicular lymphoma (FL) and Richter transformation (RT) patients treated with ibrutinib: A real-world experience of off-label ibrutinib use.
Authors: Krista Isaac, Kaitlin Kennard, Daniel Jeffrey Landsburg, Mitchell E. Hughes, Jakub Svoboda, Sunita Nasta, Tanya Latorre, William Surkis, Molly J Fanning, Elizabeth Chatburn, Colleen Dorsey, Catherine Daniel, Colleen Timlin, Jennifer Gill, Stephen J. Schuster, Anthony R. Mato
Journal: Journal of Clinical Oncology (2017)

e19043 Background: Ibrutinib (IBR), a BTK inhibitor, is FDA approved for CLL, Waldenstrom macroglobulinemia, marginal zone lymphoma and mantle cell lymphoma. Despite limited data, IBR is being utilized as a therapy for patients (pts) with relapsed/refractory (RR) DLBCL and FL. In an effort to further characterize the efficacy of IBR in these settings, we conducted a retrospective cohort study of IBR-treated pts with DLBCL, RT or FL. Methods: A retrospective cohort study of DLBCL, RT and FL pts treated with IBR was completed. Data collected included demographics, stage, IPI, prior treatments, IBR dose/duration, reasons for discontinuation, and response. PFS and OS were estimated using the Kaplan Meier method. Results: 44 pts were identified (DLBCL: n = 24, 55%; FL: n = 12, 27%; RT: n = 8, 18%). Baseline characteristics: age (range 19 – 80), 61% male, 95% ECOG 0 - 1, 71% stage IV, 62% elevated LDH, 48% R-IPI ≥ 4. DLBCL subtypes (Hans criteria) were 46% non-GC (n = 11), 29% GC (n = 7), 25% unclassifiable (n = 6). In FL, 8% were grade 1, 59% grade 2, and 33% grade 3a. Med number of prior therapies was 5 (range 1-11). Most common reasons for IBR discontinuation were progression (35%), toxicity (20%), bridge to CAR-T (10%). PFS and OS data are shown in the table below. In DLBCL, cell of origin (Hans) did not impact outcomes (p = .97, LR test). PFS was superior in RT as compared to DLBCL (p = .03, LR test). Conclusions: In the largest single-center, real-world experience of IBR use in DLBCL, RT and FL, we validate findings reported in clinical trials. In FL, responses appear to be durable (median PFS &gt; 10 months). Outcomes are poor in DLBCL and use of IBR as monotherapy is not recommended. Perhaps IBR is best used as a short-term bridge to more definitive therapies. Cell of origin (Hans) may not predict PFS and should not be used to select pts for IBR. Pts with RT appear to have more durable responses (vs. DLBCL) suggesting differing dependence on BTK signaling. [Table: see text]
PD-L1 expression correlation with TP53 gene mutation status in lung cancer but not in colorectal cancer.
Authors: Sally Agersborg, Shiping Jiang, Wayne Chen, Wanlong Ma, Maher Albitar
Journal: Journal of Clinical Oncology (2016)

11557 Background: Expression of PD-L1 is, in general, associated with response to immunotherapy. However, it is believed that additional intrinsic factors play a role in determining the potential of response to immunotherapy. Toward this goal we investigated the relationship between mutation profile and PD-L1 expression in lung and colorectal cancers. Methods: Molecular profiling using a panel of gene 24 genes was performed by next generation sequencing (NGS) on 158 non-small cell lung cancer (NSCLC) and 42 colorectal cancers. The genes studied included ERBB2, FGFR1, FGFR2, FGFR3, SRC, JAK3, ERBB4, ERBB2, and SMAD4. In addition, these tumors were studied for the expression of PD-L1 using immunohistochemistry (IHC). PD-L1 expression was performed using standard IHC approach using SP142 clone (Spring Biosciences). Results: The level of PD-L1 expression was significantly (P = 0.0005) lower in colorectal cancer as compared with NSCLC. The NSCLC cohort had significantly (P = < 0.0001) more cases with 3 or more genes mutated as compared with colorectal cancer. However, there was no significant difference in TP53 mutation frequency between the two tumor types. There was no correlation between PD-L1 expression and the presence or absence of 3 or more gene mutations in either NSCLC or colorectal cancer. However, PD-L1 expression was significantly (P = 0.01) higher in tumors with TP53 mutation in the NSCLC cohort, but not in the colorectal carcinoma cohort (P = 0.5). This was true whether PD-L1 level was used as a continuous variable or if it was dichotomized at 20% (P = 0.02) or 40% (P = 0.03) cutoffs. Conclusions: There is significant difference between NSCLC and colorectal cancers in PD-L1 expression levels. More importantly, TP53 mutation in NSCLC correlates with the expression of PD-L1 protein, but not in colorectal cancer despite similar rate of mutation of the TP53 between the two tumor types. This suggests a possible difference in the mechanism of regulating PD-L1 expression between the two tumor types.
Correlation of genomic copy number variation with survival outcomes in high-grade glioma patients.
Authors: Zachary Buchwald, Michael R. Rossi, Geoff Smith, Jeffrey M. Switchenko, Jen Hauenstein, Jim Zhong, Robert H. Press, Sibo Tian, Debra Saxe, Stuart Neill, Jeffrey J. Olson, Kirtesh R. Patel, Ian R. Crocker, Walter John Curran, Hui-Kuo George Shu
Journal: Journal of Clinical Oncology (2018)

e14091 Background: Allele-specific copy number analysis of tumors (ASCAT) is a quantitative method of assessing copy number variations that accounts for non-aberrant cell contributions and tumor ploidy. The purpose of this study is to determine if ASCAT-assessed genomic complexity or overall gene copy number variations are associated with survival outcomes in patients with WHO grade IV gliomas. Methods: Tumor samples from 55 patients with WHO grade IV gliomas who underwent surgical resection from 2009-2015 were analyzed using the Affymetrix OncoScan FFPE Assay for gene copy number variations. Ploidy and aberrant cell fraction (ACF) were derived from these data via ASCAT. Genomic complexity was quantified using the number of segments in the log R and B-allele frequency (BAF) signals after processing by the ASCAT segmentation function, which approximates number of inflection points in copy number. 85% of patients received adjuvant treatment including involved volume radiation therapy and temozolomide. Actuarial overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method and subgroups compared by the log-rank test. Results: Of 55 patients in the cohort 33 were male. Median age was 60.7 years (range: 34.9-86.3). Median KPS was 80 (range: 40-100). 23 (43.4%) tumors were MGMT hyper-methylated and 3 (6.3%) were IDH1 mutated. The median follow-up length was 15.8 months. Median PFS and OS were 8 and 12.5 months, respectively. PFS was longer in those with higher log R (hazard ratio (HR) of 0.47, p = 0.016), as well as tumors with higher BAF segment counts (HR 0.5, p = 0.024), using a median cut point. Patients with higher ACF had superior survival, 1-yr OS was 73.5% vs 23.8% (p < 0.0001), and 1-yr PFS of 32.2% vs 11.8% (p = 0.0133). The HR for death for higher ACF was 0.35 (p = 0.007). Conclusions: OS was associated with overall gene copy number variation when evaluated using our quantitative approach with ASCAT. This hypothesis-generating result warrants validation with a larger independent dataset. Increased ACF correlated with improved PFS and OS suggesting that increased non-aberrant immunosuppressive tumor infiltrate may predict for poor survival.
TCT-203 Incidence and Clinical Impact of Device Related Thrombus after Percutaneous Left Atrial Appendage Occlusion; A Meta-Analysis
Authors: Mohamad Adnan Alkhouli, Tatiana Busu, Kuldeep Shah, Mohammed Osman, Fahad Alqahtani, Chalak Berzingi, Bryan Raybuck
Journal: Journal of the American College of Cardiology (2018)
Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy
Authors: Guozhu Xie, Tan Cheng, Jie Lin, Lanfang Zhang, Jieling Zheng, Ying Liu, Guobo Xie, Baiyao Wang, Yawei Yuan
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Current checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microenvironment is an important factor mediating the original resistance of tumors to immunotherapy. A previous report by our group has demonstrated that local angiotensin II (AngII) predominantly exists in a tumor hypoxic microenvironment where hypoxic tumour cells produced AngII by a hypoxia-lactate-chymase-dependent mechanism. <h3>Results</h3> Here, using 4T1 and CT26 syngeneic mouse tumor models, we found that local AngII in the tumor microenvironment was involved in immune escape of tumour cells and an AngII signaling blockage sensitized tumours to checkpoint immunotherapy. Furthermore, an AngII signaling blockage reversed the tumor immunosuppressive microenvironment, and inhibition of angiotensinogen (AGT, a precursor of AngII) expression strongly triggered an immune-activating cytokine profile in hypoxic mouse cancer cells. More importantly, AGT silencing combined with a checkpoint blockage generated an abscopal effect in resistant tumors. <h3>Conclusion</h3> Our study demonstrated an important role of local AngII in the formation of a tumor immunosuppressive microenvironment and its blockage may enhance tumor sensitivity to checkpoint immunotherapy. The combination of an AngII signaling blocker and an immune-checkpoint blockage could be a promising strategy to improve tumors responses to current checkpoint immunotherapy.
Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study
Authors: Josep Tabernero, Paulo M Hoff, Lin Shen, Atsushi Ohtsu, Manish A Shah, Karen Cheng, Chunyan Song, Haiyan Wu, Jennifer Eng-Wong, Katherine Kim, Yoon-Koo Kang
Journal: The Lancet Oncology (2018)
Comparison of characteristics and outcomes of follicular lymphoma cohort between a cancer center and the SEER registry.
Authors: Mateo Mejia, Aditi Shastri, Adam Binder
Journal: Journal of Clinical Oncology (2018)

e19558 Background: Follicular lymphoma (FL) is the most common indolent lymphomas in the US. Prior studies have assessed the effect of race on the outcomes of patients with FL, identifying disparities in treatment and survival across different socio-demographic populations. Minorities are a small percentage of this studies, potentially misrepresenting this population outcomes. Montefiore Medical Center (MMC) is a designated cancer center that serve a minority enriched population, with heterogenous characteristics when compared to national data. Methods: Retrospective analysis of patients diagnosed with FL between 1/1/2000 and 12/31/2010. The primary outcome was survival. Patient demographic, stage, socioeconomic characteristics were evaluated as potential independent variables. SEER data for the same period was used as a control. A cox proportional hazard ratio was used control for covariates known to impact this outcome. Baseline variables were compared using parametric or nonparametric test according to variable characteristics and distribution. Results: 251 and 35,583 cases of FL were found in the MMC and SEER cohort, respectively. The mean age of diagnosis (60 vs 63 years), race (white 39.9% vs 90%, Afroamerican 17.1% vs 4.5%, other 33.5% vs 4.49%,) were different between groups. Patients in the MMC cohort presented at higher histologic grade (all P < 0.001). Mean survival was 158 and 164 months in the MMC and SEER cohort. In a cox proportional hazard ratio model, there was no correlation of group allocation with the outcome. However, age, diagnosis year, and sex were noted to affect outcome. Subgroup analysis of socioeconomic status and clinical variables in the MMC group did not impact survival Conclusions: While one often sees disparate outcomes in minority, underserved populations, our retrospective analysis did not reveal a survival difference between our patient population and that of the SEER database. The demographic and observed survival are in line with prior published data. We observed higher histologic grade and age at presentation in the MMC cohort. Although our study involved a large control sample, lack of clinical data or treatment used limit our study.
Trial of topotecan with VX970, an ATR kinase inhibitor, in relapsed or refractory small cell lung cancer (NCT02487095).
Authors: Anish Thomas, Linda Sciuto, Emerson Padiernos, Yves Pommier
Journal: Journal of Clinical Oncology (2016)

TPS8581 Background: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. Despite exceptional initial responsiveness to DNA damaging chemotherapy, SCLC usually relapses quickly. Ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) is activated by single stranded DNA and by DNA replication stress. ATR is an attractive target in SCLC because: 1) loss of compensatory repair mediated by ATM signaling is frequent, either through loss of expression of ATM itself, or through defects in upstream regulators and downstream effectors such as p53; 2) expression of oncogenes that drive replication stress (for e.g. RB1 inactivation, MYC activation) is exceedingly common in SCLC. A combination of high replication stress and a defective ATM-p53 signaling provides a strong reliance on ATR for survival under replicative damage DNA damage in SCLC. VX970 is a potent, selective ATP competitive inhibitor of ATR (Fokas et al. 2012; Hall et al. 2014) with over 100-fold selectivity for ATR over other kinases (including ATM). Combination of VX970 + topoisomerase I (Top1) inhibitors including camptothecins and the indenoisoquinoline derivative LMP-400 sensitize cancer cells and inhibit phosphorylation of ATR/ Chk1 (Josse et al. 2014; Hall et al 2014). VX970 also enhances the in vivo tumor response to irinotecan with no impact on body weight loss compared with irinotecan alone. Combination of VX970 plus DNA damaging chemotherapy is therefore an attractive therapeutic option for SCLC. Methods: Patients with advanced cancer with no standard treatments are eligible for phase I. Primary endpoint is to determine the maximum tolerated dose of VX970 + topotecan using the traditional 3+3 design. SCLC patients with progressive disease after one prior chemotherapy are eligible for phase II. Primary endpoint is to determine the objective response rate (ORR) to VX970 + topotecan using a Simon two-stage Minimax design [rule out 10% ORR and target 30% ORR (alpha = 0.10 and beta = 0.10)]. Circulating tumor cell analyses and tumor whole exome and transcriptome sequencing will be performed to identify predictors of response to synthetic lethal inhibition of ATR in SCLC. Phase I enrolment is ongoing. Clinical trial information: NCT02487095.