tbuckley/cabot-search huggingface dataset:
An examination of the use of CD19 CAR NK-92 cells to induce complete remission and vaccine effect against rechallenge in a highly aggressive murine leukemia.
Authors: Nathan Thomas Schomer, Laurent Boissel, John H. Lee, Hans Klingemann, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2018)

e15034 Background: The L1210 malignant lymphoma cell line, derived from DBA/2 mice, is notable both for its short doubling time of 8-10 hours and for its long history of successful use by the NCI in the identification of effective clinical treatments for hematological malignancies. In previous studies we have demonstrated the effectiveness of intra-tumor injection using NK-92 cells expressing a CAR against the murine CD19 positive A20 lymphoma cell line. Here we examine if a durable vaccine like effect can be elicited even against this aggressive lymphoma and without the aid of additional checkpoint inhibitors. Methods: 60 DBA/2 mice were injected sc. (flank) with 2x105 L1210-Luciferase (L1210 Luc) cells. After 8 days, tumors were measured and the 30 animals clustering closest to the median tumor size(~90mm3) were randomized into three treatment cohorts of 10 animals each: vehicle, unmodified clinical grade NK-92 (aNK) and aNK modified with mCD19 CAR (mCD19-taNK). Each treatment was administered by intra-tumor injection on days 0, 2, and 4 post randomization. Tumor growth was traced both by caliper measurements and IVIS imaging. Complete and partial responders were re-challenged with L1210 Luc injected into the contralateral flank 30 days after initial treatment, with continued observation until either lethal outgrowth or complete clearance of the re-challenge tumor cells. Results: A Kaplan-Meier survival comparison of naïve and treated cohorts reached significance by both Mantel-Cox test (p = .0081) and Gehan-Breslow-Wilcoxon test (P = .0089), with significant inhibition of tumor growth at day 6 (P = .018) in the treatment cohorts and three durable responses (2 complete with taNK, 1 partial in the aNK cohort). Conclusions: Of the responders, all three showed a vaccine-like effect in their capacity to completely clear a re-challenge dosing of L1210 into the contralateral flank, as compared to 5 naïve controls which all displayed rapid tumor take and lethal outgrowth. To our knowledge, no similar vaccine effect has been described for CAR-T based therapies.
TCT-522 Long-Term Outcomes with Saphenous Vein Graft versus Native Coronary Artery Intervention in Patients with Coronary Artery Bypass Grafting: Evidence From Meta-analysis and Meta-regression
Authors: Marwan Saad, Ramez Nairooz, Ayman Elbadawi, Fuad Habash, J. Dawn Abbott, Neal Kleiman, Emmanouil Brilakis, Ashwat Dhillon, Lena Awar, Leonardo Clavijo, Ray Matthews, David Shavelle
Journal: Journal of the American College of Cardiology (2018)
Independent prognostic value of inflammation in metastatic pancreatic cancer.
Authors: Berna Oksuzoglu, Ece Esin, Elif Berna Koksoy, Nebi Serkan Demirci, Mehmet Ali Nahit Sendur, Isa Dede, Ahmet Sezer, Ebru Karcı, Nuriye Yildirim, Bulent Yalcin, Gungor Utkan, Yuksel Urun
Journal: Journal of Clinical Oncology (2018)

e16212 Background: The aim of this study is to investigate whether Prognostic Nutritional Index (PNI), which is an inflammation based prognostic index, is associated with survival in metastatic pancreatic cancer patients. Methods: A total of 221 metastatic pancreatic adenocarcinoma patients were recruited between 01/ 2010 and 01/ 2013. PNI was calculated as (10 x serum albumin [g/dL]) + (0.005 x peripheral lymphocyte count [per mm3]). Independent prognosticators were tested on Cox regression analysis. Results: Median age was 61(31-85) with male predominance (2,4/1). Median OS was 6.3 months (%95 CI 4.9-7.6). PNI was not associated with gender, age, weight loss and the localization of metastasis and the number of metastatic sites. Kaplan-Meier analyses revealed that patients low PNI ( < 50) is correlated with shorter OS (5.4 vs 9.7 months, log-rank = 9.47, p = 0.002). Weight loss, the choice of first line regimen, higher than normal CEA and Ca 19-9 levels were not to be found to be significant. However, ECOG performance status at diagnosis (HR:0.5. 95%CI:0.36-0.72, p < 0.001) and PNI score (HR:0.66. 95%CI:0.47-0.93, p = 0.01) were found to be significantly prognostic. Of note, the prognostic significance remained after stratification according to ECOG PS, first line chemotherapy choice, weight loss and localization of metastasis (p < 0.05). Conclusions: According to the results of this analysis, the determination of PNI score is independently prognostic for metastatic pancreatic cancer. The importance might be related to its inflammatory prognostic value rather than being a nutritional index which remains to be elucidated by further studies. The clinicopathologic characteristic of patient population n = 221 Primary Metastatic sites (n) Liver 166 Peritoneum 32 Lymph Nodes 49 Soft Tissue 4 Lung 42 CEA (median, range) 6,1 (0.4-2627.1) CA 19-9 (median, range) 543.1 (0.3-53519.1) Tumor Location (n/%) Head 97 / 43.9 Body 56 / 25.3 Tail 27 / 11.8 Weight loss at diagnosis ( > 10%) Yes n (%) 121 (42.4) No n (%) 89 (57.6) ECOG PS 0-1 (%) 151 (78.4) > 2 (%) 69 (31.3) First line palliative chemotherapy choice of regimen (n/%) Gemcitabine/Cisplatin 113 / 51.1 Gemcitabine only 75 / 33.9 Folfirinox 19 / 8.6 Folfox/xelox 1 / 0.5 Nab-paclitaxel 9 / 4.1 Capecitabine 4 / 1.8
Mutation tracking of circulating tumor DNA during neoadjuvant period predicts relapse in stage II-III breast cancer patients.
Authors: Po-Han Lin, Li-Wei Tsai, Chiao Lo, Sung Hsin Kuo, Chiun-Sheng Huang
Journal: Journal of Clinical Oncology (2018)

e24101 Background: Patients with stage II-III breast cancer have a higher relapse rate, but no effective marker can early predict relapse. Analysis of circulating tumor DNA (ctDNA) have been proved as an early marker to detect disease progression in metastatic breast cancer and predict early relapse in patients after resection of breast cancer. However, the prognostic value of mutation status in ctDNA during neoadjuvant period was not understood. Methods: CtDNA was collected before the neoadjuvant chemotherapy (T0), after two cycles (T1) and the end of chemotherapy (T2). Mutation of ctDNA was assessed by ultra-deep targeted next-generation sequencing. Results: A total of 72 patients were enrolled and 42 patients were found somatic mutation in the targeted sequencing. There were 7 patients with luminal A, 8 with luminal B/non-Her2, 7 with luminal B/Her2, 7 with Her2 and 13 with TNBC. The overall 3-year disease-free survival (DFS) was 59.4% (95% CI 75.8-42.9%). 18 patients had undetected mutation ( < 0.05%) at T1 and T2; 6 had undetected status at T2 and 18 had detectable mutation at T1 and/or T2. The 3-year DFS of the 18 patients without mutation at T1/2 was 80.9%, 6 without mutation at T2 was 62.5% and the 18 with mutation was 42.3% (p = 0.043). 3 patients had new mutations (2 TP53 and 1 PTEN) at T2, and all of them had relapse. One patient had complete pathologic response and was found persisted mutation at T0, T1 and T2; she had hepatic metastases 6 months after mastectomy. Conclusions: This study suggested that dynamic change of ctDNA during the neoadjuvant period could be an early marker to predict relapse in stage II-III breast cancer patients.
NGS for cancer testing: A clinical laboratory’s perspective.
Authors: Yassmine Akkari
Journal: Journal of Clinical Oncology (2018)

e24158 Background: In the last few years, molecular cancer diagnostics using next generation sequencing (NGS) has become an integral part of disease detection, management and treatment. As an inherently complex process, NGS still requires extensive quality management and technical qualifications in clinical practice, both at the wet bench and bioinformatics levels. To address these challenges while meeting the goal of providing best-in-class patient care, we sought an integrated workflow, and implemented tumor NGS testing utilizing the GeneReader NGS System and a “necessary and sufficient” targeted panel. Methods: Our validation algorithm was initiated by determining appropriate referred specimen types to be tested, and diagnostic/prognostic information to be evaluated and reported. Following discussions with our pathologists and oncologists, we opted to focus on a small set of core genes deemed necessary and sufficient to maximize clinical utility of our NGS testing service. We then validated each step of the workflow by testing commercially available reference samples, conducting inter-laboratory comparisons and analyzing precision, reproducibility and limit of detection. Results: We set up a workflow in our CLIA-licensed laboratory, tested 100+ samples of various tissue sources and disease characteristics, and validated all components of this NGS testing. The integration of this workflow from a single vendor allowed rapid integration, increased efficiency, accurate reporting and effective troubleshooting. The availability of an integrated bioinformatics pipeline enabled us to provide analysis and interpretation of variant findings with up-to-date and clinically relevant information to guide individualized cancer care. Conclusions: As a regionally-based, seven-hospital system providing cancer care to surrounding communities, we successfully implemented an NGS workflow with direct impact to improve cancer care. As other healthcare systems in the US adopt similar models, we can collectively drive towards personalized medicine with molecular testing that is local, timely and cost-effective.
Safety and efficacy of olaratumab added to doxorubicin-based combination chemotherapy in the treatment of advanced soft-tissue sarcoma (STS).
Authors: Andrea P. Espejo Freire, Vaia Florou, Ty Subhawong, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2018)

e23542 Background: Patients with advanced STS face a median overall survival of 12-16 months. Olaratumab (olara) in addition to doxorubicin (dox) showed survival advantage over single agent dox without adding significant toxicity. Dox and ifosfamide versus dox alone has higher response rates and progression free survival, with a trend for overall survival benefit. Whether the use of olara with dox-based doublet regimen would be beneficial is unknown. Methods: We conducted a case-control study identifying 10 consecutive patients treated with olara plus a dox-based doublet regimen and 20 consecutive patients treated with a dox-based doublet regimen alone, matched for age and race. Odds ratios (OR) and the 95% confidence interval (CI) for adverse events (AE) and initial responses were calculated using logistic regression. Results: All patients had ECOG score 0-1, and stage III or IV high grade STS. There were no statistically significant different AE. The use of olara had a trend towards fewer AE. OR for all AE 0.8 (95% CI 0.5632-1.1616, p .2507); grade 1-2 AE 0.9811 (95% CI 0.63-1.52, p .9325); grade 3-4 AE 0.62 (95% CI 0.37-1.04, p .0726; clinical AE 0.8 (95% CI 0.50-1.30, p .37990); hematologic AE 0.53 (95% CI 0.21-1.36, p .1861). Interestingly, olara was associated with lower grade hematologic AE: OR for grade 1-2 hematologic AE 7.5 (2.62-21.58, p .0002). Contrary, OR for hematologic grade 3-4 AE was 0.33 (0.15-0.73, p .0059). Responses after 3 cycles were similar in both groups. By RECIST, 60% of cases had stable disease (SD) vs. 65% of controls; 20% of cases had partial response (PR) vs. 10% of controls; 1 patient had progression of disease (PD) in each group. By CHOI, 40% of cases had SD vs. 10% of controls; 40% of cases had PR vs. 50% of controls; 10% of cases PD vs 20% of controls. One case and 4 controls had non-measurable disease for assessment. Conclusions: In this study, the addition of olara to a dox-based doublet was safe and effective. Olara was associated with fewer grade 3-4 hematologic AE. These data support feasibility of adding olara to dox-based combination regimens in patients with advanced STS. Prospective trials will determine whether this translates into better outcomes.
P01.027 Pseudoprogression in glioblastoma: how sure are radiologists in location of “high-dose RT region”
Authors: R Belanova, A Sprlakova-Pukova, M Standara, E Janu, R Koukalova, P Burkon, P Pospisil, R Jancalek, P Slampa, T Kazda
Journal: Neuro-Oncology (2018)

In the glioblastoma follow up evaluation, the differentiation between the pseudoprogression and true tumor progression remains challenging. According to the original RANO criteria from 2010, the progression within the first 12 weeks of completion of radiotherapy (RT) can only be determined if the majority of the new enhancement is outside of the high-dose radiation region. However, radiation oncologists do not always report 3 dimensional RT izodoses while ordering follow up imaging, even for patients treated within clinical trials. Thus, we questioned the general awareness of radiologists about the spatial location of high-dose RT region, which is needed for valid differential diagnostics. Four radiologists worked with MR images which were used for RT planning for 8 glioblastoma patients. Radiologists were blinded to RT target volumes which were defined by radiation oncologists according to Radiation Therapy Oncology Group contouring approach (sequential boost, clinical target volume for high dose is defined as the sum of contrast enhancing T1 abnormality and the surgical cavity plus a margin of 2 cm). The aim was to draw target volume for high dose RT fields (that is the region, where they would consider that there may be a psudoprogression in the future MRI scans). Percentage overlap, conformality index (Dice index ranging from 0-no overlap to 1-identical) and median (and maximal - so called Hausdorff distance) distance measurement (of the point on one surface to the nearest point on the second structure′s surface) was analyzed in comparison with original RT target volumes which were used in clinical practice. Eight patients, median age 57, four men, four patients after gross total resection, four after subtotal resection. Median volume for RT high dose filed was 277 ccm as defined by radiation oncologist and 87 ccm (range 32 - 338) as defined by radiologists (median 31%, range 15 - 112%). Median Dice index 0.46 (range 0.14 - 0.78), median distance (mean 11 mm ±6mm) with median Hausdorff distance 25 mm. Large inaccuracy in the awareness of region where pseudoprogression would be considered based on RANO criteria was observed with almost one-third size of estimated volume of target volume. Close collaboration between radiation oncologists and radiologists is needed to correctly evaluate follow up MRI after treatment of glioblastoma patients in daily routine practice as well as in clinical trials.
FRI0323 Apremilast therapy in refractory skin lupus lesions
Authors: J.L. Martín-Varillas, J. Loricera, S. Armesto, E. Cuende, V. Calvo-Río, C. González-Vela, B. Atienza-Mateo, J.L. Hernández, M.A. González-Gay, R. Blanco
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Skin lesions of lupus may be refractory to standard therapy. Apremilast is an orally small molecule which inhibits phosphodiesterase-4 (PDE-4) that modulates some inflammatory pathways. <h3>Objectives</h3> Our aim was to assess the efficacy of apremilast in lupus rashes refractory to conventional treatment. <h3>Methods</h3> Retrospective study on 5 lupus patients treated with apremilast at standard dose of 30 mg twice daily. The outcome was improvement of lupus rashes. <h3>Results</h3> We described 5 patients (4 women and 1 male) with a mean age of 44.2±8.5 years with extensive skin lesions due to lupus. Three patients had a discoid lupus and 2 patients had systemic lupus erythematosus (SLE) (one with panniculitis and the other with polycyclic ring lupus). The cutaneous lupus was confirmed in all patients by skin biopsy. Prior to apremilast all patients had received conventional treatment: topical corticosteroids (n=5), antimalarials (n=5), topical tacrolimus (n=2), oral corticosteroids (n=2), thalidomide (n=1), belimumab (n=1) and rituximab (n=1). After a mean follow-up of 6.2±2.9 months, all the patients experienced improvement of the skin lesions (in two patients was complete). In one patient it was necessary to reduce the dose of apremilast to 30 mg/day because of digestive symptoms. <h3>Conclusions</h3> Apremilast can be useful in the treatment of refractory skin lesions of lupus. <h3>Disclosure of Interest</h3> None declared
Atypical negative <i>ALK</i> FISH accompanied by immunohistochemistry positivity and <i>ALK</i> rearrangements in NSCLC patients and response to targeted therapy.
Authors: Jürgen C. Becker, Ivelina Spassova, Robert Walter, Mathias Stiller, Selma Ugurel, Sine Reker Hadrup, Cathrin Ritter
Journal: Journal of Clinical Oncology (2016)

e21050 Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Its explicit immunogenicity led to the discovery of the Merkel cell polyomavirus (MCPyV), which is clonally integrated in approximately 80% of MCCs. Moreover, in most MCC cell lines there is a clear oncogene addiction to the MCPyV-encoded early genes. Cellular immune responses to the MCPyV early genes are readily detectable in MCC patients. However, we detected CD8+ T-cell responses to the T-antigens not only in patients with MCPyV+ MCCs, but also in patients whose tumors were MCPyV-. Notably, a loss of oncogene addiction in MCPyV+ MCC cells to the MCPyV early genes, i.e. supporting a ‘hit-and-run’ viral carcinogenesis. Methods: Multimer TCR staining, immunohistochemistry, PCR, next generation sequencing Results: Here we provide evidence that loss of MCPyV addiction and T-antigen expression in MCC occurs in patients mounting MCPyV T-antigen specific T-cell responses. Loss of MCPyV is associated with an impaired prognosis. Notably, patients with T-antigen specific T-cell responses and MCPyV+ tumors have a favorable clinical course than patients without such responses. Likewise, both the extent of T-cell infiltration as well as the expression of PD-L1 in MCC in patients with a MCPyV T-antigen specific T-cell response correlated with the presence of MCPyV. Conspicuously, in a few patients in which we did not detect a MCPyV T-antigen specific T-cell response in circulating blood and whose tumors were MCPyV-, we still observed a strong T-cell infiltrate. Scrutinizing for possible driver mutations in MCPyV- MCC allowing for loss of oncogene addictions using targeted amplicon sequencing revealed distinct differences between MCPyV- MCCs in patients with and without MCPyV T-antigen specific T-cell responses, i.e. in patients with MCPyV-specific responses the number of mutations is much lower and predominately affecting the RB pathway. Conclusions: MCPyV- MCC can be subdivided into tumors without an obvious viral carcinogenesis and into tumors with a hit-and-run viral carcinogenesis. The latter appear to be particular aggressive as they neither express immunogenic viral antigens nor mutational neoantigens.
TCT-229 Outcomes with Drug-coated Balloons versus Drug-eluting Stents in Percutaneous Coronary Intervention in Diabetic Patients.
Authors: Michael Megaly, Abdelrahman Ali, Bishoy Abraham, Magdi Zordok, Marco Shaker, Mariam Tawadros, Bassam Hennawy, Ayman Elbadawi, Mohamed Omer, Marwan Saad
Journal: Journal of the American College of Cardiology (2018)
Clinicopathologic characteristics and molecular features of BRG1-deficient non-small cell lung cancer (NSCLC).
Authors: Ibiayi Dagogo-Jack, Alexa Betzig Schrock, Marina Kem, Nicholas Jessop, Jeffrey S. Ross, Vincent A. Miller, Siraj Mahamed Ali, Alice Tsang Shaw, Mari Mino-Kenudson
Journal: Journal of Clinical Oncology (2018)

12083 Background: Genomic alterations (GA) in SMARCA4, the gene encoding the SWI/SNF complex subunit BRG1, have been observed in 10% of NSCLC. RNA-based analyses suggest that loss of BRG1 expression is frequently associated with frameshift/nonsense (F/N) SMARCA4 GA. In preclinical studies, BRG1 deficiency sensitizes to enhancer zeste homolog 2 (EZH2) inhibition combined with chemotherapy (PMID: 25629630). To characterize the subset with SMARCA4 GA, we reviewed 2 independent NSCLC datasets and analyzed BRG1 protein expression in cases with available tissue. Methods: To identify cases with SMARCA4 GA, we examined the molecular profiles of 27,281 NSCLCs sequenced at Foundation Medicine (FM) and a separate cohort of 820 consecutive NSCLCs sequenced at Massachusetts General Hospital (MGH). We performed immunohistochemistry (IHC) using the Abcam rabbit BRG1 antibody (EPR3912) to assess BRG1 expression in NSCLCs with SMARCA4 GA. Results: We detected SMARCA4 GA in 73 (9%) and 3,188 (11%) patients (pts) in the MGH and FM datasets, respectively. SMARCA4 GA were distributed throughout all protein domains. F/N GA comprised approximately one-third of SMARCA4 GA in both groups (MGH: 32% and FM:36%). 40 pts (15 with F/N GA) in the MGH group had available tissue for IHC. Thirteen specimens—all from smokers with F/N SMARCA4 GA— had loss of BRG1 expression. Median age of pts with absent BRG1 expression was 69.2 years. Loss of BRG1 expression was observed in 9 adenocarcinomas as well as 2 poorly-differentiated,1 sarcomatoid, and 1 neuroendocrine carcinoma(s). Ten of the 13 pts with BRG1-deficient NSCLC underwent PD-L1 testing. Eight tumors had no PD-L1 expression and one had ≥50% expression. With the exception of 5 (38%) pts with concurrent KRAS GA, we did not find driver GA in the BRG1-deficient specimens. As BRG1 loss was limited to F/N GA, we queried the FM dataset to identify genes frequently co-altered with F/N SMARCA4 GA. F/N SMARCA4 GA commonly co-occurred with TP53 (74%), CDKN2A (38%), STK11 (34%), and KRAS (26%) GA. Conclusions: SMARCA4 GA are present in approximately 10% of NSCLC, but our data suggest that F/N GA may disproportionately lead to BRG1 loss. F/N SMARCA4 GA occur in 3-4% of NSCLC and overlap with KRAS GA.
Association of multimodality treatment (MT) with improved overall survival (OS) in patients (pts) with advanced/metastastic soft tissue sarcoma (a/m STS).
Authors: Philipp Ivanyi, Katharina Stange, Hendik Eggers, Christoph W. Reuter, Martin Panzica, Patrick Zardo, Florain Länger, Hans Christiansen, Arnold Ganser, Viktor GrÃ¼nwald
Journal: Journal of Clinical Oncology (2018)

e23566 Background: MT applies to a selected group of pts with a/m STS. The impact of MT on prognosis remains undefined. We report results on palliative medical treatment (Rx) with MT(+) or without MT(-) in a/mSTS pts. Methods: Within the observation period 12/1998–05/2016 a/mSTS pts were identified from medical records, retrospectively. All pts received Rx. MT(+) pts received in addition surgery (Sx) with or without radiotherapy (RTx) throughout the course of treatment. Overall survival (OS) was defined as time from first palliative treatment until death. Descriptive statistics Kaplan-Meier and Log-rank analysis, as well as Cox-regression and Land-mark analyses were applied. Results: 111/181 a/mSTS pts (61.3%) received MT(+). Number of lines of Rx where similar among both groups. MT(+) pts received a median of 1 Sx (range (r):0-7) and 1 RTx (r: 0-8). The median OS of all pts was 18 (95%CI:14.1-21.9) months (mo), while MT(+) patients showed a superior OS of 22 (95%CI: 15.2-28.8) mo vs. MT(-) of 15 (95%CI:8.8-21.2) mo p = .029). Among MT(+) pts, OS improvement was associated with the use of Rx+Sx±RTx (p≤.001), which remained significant at 3- (p = .001) and 6-mo land-marks (p = .004). While Rx+RTx was not identified as independently associated with risk of death, Rx+Sx±RTx showed a independent association with decreased risk of death (HR:0.45 (95%CI: 0.4-0.8); p = .004). Conclusions: MT in a/mSTS within the palliative treatment sequence was performed in a relevant proportion of pts at our center. MT was associated with superior OS, mainly in pts receiving Rx+Sx ±RTx within 6 months upon first palliative treatment, rendering additive surgery the preferred approach within the multimodal strategy.