tbuckley/cabot-search huggingface dataset:
Relationship of anaplastic thyroid cancer high tumor mutation burden and MSI-H status with response to anti-PD1 monotherapy.
Authors: Saad A. Khan, Pamela Kurian, Bianca Mobley, Tam Burks, Muhammad Shaalan Beg, Jeffrey S. Ross, Siraj Mahamed Ali, Daniel W. Bowles
Journal: Journal of Clinical Oncology (2018)

e18114 Background: Anaplastic thyroid cancer (ATC) is a rare aggressive malignancy with no treatment options that prolong survival. ATC tumor mutation burden (TMB) is rarely high, possibly suggesting that there is a limited role for immune checkpoint inhibitor (ICI) monotherapy. Methods: We conducted IRB-approved review of ATC patients who had received pembrolizumab. Comprehensive genomic sequencing of 4 ATC patient samples was performed prior to treatment with pembrolizumab. No responder showed a concurrent differentiated thyroid cancer in their surgical specimen, only ATC. Results: No patients had high TMB or high microsatellite instability (MSI); responders were either low (≤5 Muts/Mb) or Intermediate (6-Muts/Mb) and had neither BRAF nor RAS mutations. A patient with rapid progression had BRAF V600E. None had altered TERT or CD274. Responses were seen in therapeutic radiation-naïve patients. Conclusions: Pembrolizumab monotherapy is a promising option for patients with metastatic ATC, regardless of TMB/MSI. ICI trials should evaluate patient BRAF and RAS status to determine if there is differential response in these patients. Prior radiation, TMB-high, MSI-H or CD274/TERT/TP53 mutations were not required for response to pembrolizumab and may not be useful predictive biomarkers for anti-PD1 agents in ATC. While better biomarkers are sought, these should not be required for ATC patients to be treated with ICI. Patient Age Local therapy given and (duration from radiation [RT] completion to starting ICI) Mutation status BRAF/NRAS Best response to ICI TMB (muts/Mb) MSI status Notable mutations 58F Carboplatin+ paclitaxel+ RT (2 months) -/- Partial Response (PR) sustained 5 months, taken off for irAE toxicity Low (0.8 ) Stable CDKN2aNF1 53F Carboplatin+ paclitaxel+ RT (12 months) -/- Stable disease (12 weeks) Low (4.8) Stable TP53 E287D, R280K ATRX E1446del NF1 Q236Ã, NF2 loss 46F Carboplatin+ paclitaxel+ RT (5 months) BRAF V600E/- Rapid progression 6 weeks N/A N/A TP53 Q331 86F No RT. Surgery only -/- PR-Ongoing 8 weeks Intermediate (10.8) MSI-low TSC2TP53 G245S JAK 1
Association of regulatory- and helper-T- cells with inferior survival of neuroblastoma patients treated with long-term infusion of ch14.18/CHO combined with interleukin-2.
Authors: Holger N. Lode, Sascha Troschke-Meurer, Madlen Marx, Maxi Zumpe, Karoline Ehlert, Hans Loibner, Ruth Lydia Ladenstein, Nikolai Siebert
Journal: Journal of Clinical Oncology (2018)

10530 Background: Long-term infusion (LTI) of the anti-GD2 antibody (Ab) ch14.18/CHO in combination with interleukin-2 (IL-2) prolongs survival in patients (pts) with high-risk neuroblastoma compared to historical controls. We investigated a correlation between lymphocyte subsets, functional immune-parameters and survival in treated patients. Methods: 53 pts received 5 cycles (35 days (d)) of 6x106 IU/m2 subcutaneous IL-2 (d1-5; 8-12), LTI of 100 mg/m2 ch14.18/CHO (d8-18) and 160 mg/m2/d oral 13-cis RA (d22-35) in a closed single center program (APN311-303). The counts of cytotoxic NK cells (CD16++/CD56dim), helper T cells (CD3+/CD4+), cytotoxic T cells (CD3+/CD8+), regulatory T cells (Treg; CD4+/CD25+/CD127-) and granulocytes (CD64+) were determined by flow cytometry (cycle 1; d1, 8 and 15). Ab-dependent cellular cytotoxicity (ADCC) was determined and correlation between cell counts and progression-free survival (PFS) was analyzed. Results: IL-2 treatment resulted in a strong increase of cytotoxic NK cells, cytotoxic- and helper T cells and Treg on d8 compared to baseline (d1) (2.4-, 3.9-, 2.6- and 15.0-fold increase, respectively). Subsequent combined treatment with IL-2 and ch14.18/CHO did not further increase lymphocyte counts on d15. In contrast, elevation of granulocytes occurred during the combined treatment. We did not observe any correlation between cell counts and ADCC on d15 as well as between cytotoxic NK and cytotoxic T cells and PFS. Similar observations were made for granulocytes. In contrast, pts with low Treg (≤ 138 cells/µl) on d15 (n = 11) showed a better PFS compared to high Treg pts (n = 31) (P = 0.072). The 5-year PFS was 44% (95% CI [0.13, 0.74]) and 19% (95% CI [0.05, 0.33]) for low and high Treg counts, respectively. On d15, pts with low helper T cells (n = 11, ≤ 365 cells/µl) also showed an improved PFS compared to those who had high helper T cells (n = 31; P = 0.013). The 5-year PFS was 53% (95% CI [0.23, 0.83]) and 16% (95% CI [0.03, 0.29]) for low and high helper T cell count, respectively. Conclusions: IL-2-dependent elevation of helper T- and Treg-cells may negatively affect efficacy of ch14.18/CHO combined with IL-2.
BMI differences for clinical outcome in patients with advanced or metastatic gastric cancer treated with apatinib: Data from a post-marketing phase IV study (Ahead-G201).
Authors: Yu-Xian Bai, Shukui Qin, Jin Li, Lu Wen, Junsheng Wang, Wenying Deng, Guifang Zhang, Tongfu Jia, Yi Ba, Jianwei Yang, Xiaoyan Lin, Yifu He, Zhong Xie, Tienan Yi, Xiangyuan Wu, Feng Ye, Likun Liu, Yong Huang, Mei Wang, Haijun Zhong
Journal: Journal of Clinical Oncology (2018)

e16027 Background: Studies have shown BMI could affect long-term survival in advanced gastric cancer. In this analysis, based on a large population, we further investigated the effects of BMI on the safety and efficacy of apatinib in patients (pts) with advanced or metastatic gastric cancer. Methods: The data was from a phase IV clinical trial of Ahead-G201. At the cut-off date of Dec 21, 2017, 1394 pts had been enrolled for this analysis. The lower, normal and higher BMI were defined as BMI < 18.5, 18.5≤BMI < 24 and BMI≥24. Results: There were 404 pts with lower BMI, 798 pts with normal BMI, and 192 pts with higher BMI. The mean daily medication dosage were respectively 500.1±90.12 mg, 513.3±95.12 mg, and 523.1±115.5 mg. There was no statistical difference among groups (p= 0.095). The data of toxicity and efficacy are listed in Table. The incidence of grade ≥3 drug related adverse events (DRAEs) were 29.5%, 29.5% and 33.3% in pts with lower, normal and higher BMI. No significant difference was found among groups (p= 0.555). The objective response rate and disease control rate were also similar among groups. For survival outcome, pts with lower BMI got the shortest median progression-free survival (mPFS, 3.0 mos) and overall survival (mOS, 4.8 mos). Pts with higher BMI achieved the longest mPFS (4.7 mos) and mOS (7.7 mos). Multivariate Cox regression analysis showed that BMI was an independent prognostic factor for PFS and OS. Compared with lower BMI, pts with normal BMI was associated with longer PFS (HR 1.35; 95%CI, 1.06-1.73) and OS (HR 1.91; 95%CI, 1.47-2.48). Conclusions: For gastric cancer pts receiving apatinib, the adverse events were tolerable for all pts with different BMI. Pts with normal BMI might benefit more in survival outcome. Clinical trial information: NCT02426034.Table BMI-related safety and efficacy BMI < 18.5 (n = 404) 18.5≤BMI < 24 (n = 798) BMI≥24 (n = 192) p DRAEs (%) 275 (68.1%) 504 (63.2%) 121 (63.0%) 0.216 DRAEs≥3 (%) 119 (29.5%) 235 (29.5%) 64 (33.3%) 0.555 ORR 9.6% 9.5% 15.3% 0.266 DCR 69.2% 68.7% 71.8% 0.859 PFS (mos, 95%CI) 3.0 (95%CI, 2.7-4.1) 4.5 (95%CI, 3.2-4.7) 4.7 (95%CI, 3.1-6.5) 0.009 OS (mos ,95%CI) 4.8 (95%CI, 4.1-5.6) 7.0 (95%CI, 6.4-8.3) 7.7 (95%CI, 6.3-8.6) < 0.001
Infrared spectroscopy as a novel tool to diagnose onychomycosis
Authors: S. De Bruyne, R. Speeckaert, J. Boelens, M.‐P. Hayette, M. Speeckaert, J. Delanghe
Journal: British Journal of Dermatology (2018)

The determination of causative organisms of onychomycosis is still not optimal. There remains a need for a cheap, fast and easy-to-perform diagnostic tool with a high capacity to distinguish between organisms.To determine whether attenuated total-reflectance Fourier transform infrared (ATR-FTIR) spectroscopy can detect and differentiate causative agents in culture-based, ex vivo nail and in vivo nail models.A methodological study was conducted. Both the ex vivo nail model and in vivo pilot study were carried out in an academic university hospital.Analysis of cultured fungi revealed spectral differences for dermatophytes (1692-1606 and 1044-1004 cm-1 ) and nondermatophytes and yeasts (973-937 cm-1 ), confirmed by dendrograms showing an excellent separation between samples from different genera or species. Exploration of dermatophytes, nondermatophytes and yeasts growing on ex vivo nails exposed prominent differences from 1200 to 900 cm-1 . Prediction models resulted in a 96·9% accurate classification of uninfected nails and nails infected with dermatophytes, nondermatophytes and yeasts. Overall correct classification rates of 91·0%, 97·7% and 98·6% were obtained for discrimination between dermatophyte, nondermatophyte and yeast genera or species, respectively. Spectra of in vivo infected and uninfected nails also revealed distinct spectral differences (3000-2811 cm-1 , 1043-950 cm-1 and 1676-1553 cm-1 ), illustrated by two main clusters (uninfected vs. infected) on a dendrogram.Our data suggest that ATR-FTIR spectroscopy may be a promising, fast and accurate method to determine onychomycosis, including identification of the causative organism, bypassing the need for lengthy fungal cultures.
A retrospective study of the treatment-associated mortality of the patients with primary ocular adnexal mucosa-associated lymphoid tissue lymphoma after the molecular and immunological diagnosis.
Authors: Yuya Masuda, Kazuto Takeuchi, Toshio Kodama, Tomoaki Fujisaki, Yoshitaka Imaizumi, Eiichi Otsuka, Shuji Ozaki, Shinji Hasebe, Yoshihiro Yakushijin
Journal: Journal of Clinical Oncology (2018)

e19534 Background: Differentiation between primary ocular adnexal mucosa-associated lymphoid tissue (POA-MALT) lymphoma and reactive lymphoid hyperplasias sometimes may be difficult. We have examined the treatment-associated mortality of POA-MALT lymphoma after accurate diagnosis. Methods: From 1991 through 2016, cases of POA-MALT lymphoma were retrospectively analyzed based on their pathological and molecular/immunological diagnoses, and their prognoses were evaluated. Results: 78 cases of POA-MALT lymphoma were analyzed over a median observation of 6.4 years. 44 patients were diagnosed with IgH gene clonality in addition to the pathological decision, and 10 patients were diagnosed with FACS analysis in addition to the pathological decision. The rest of the 24 patients were diagnosed employing pathological decision of hemato-pathologists and clinical decision. All patients, except cases of watchful waiting, achieved complete remission. Two patients died after a recurrence. 68 patients presented disease-free after initial treatment during their observation. As treatments, radiotherapy-based strategy (over 30 Gy) was administered with 15 patients (group A). Immuno-chemotherapy was administered to 24 patients (group B). Surgical extraction only was selected for 36 patients (group C). Watchful waiting was selected with 3 patients. Recurrence after the initial treatment was found in one out of group A, in 3 out of group B, and in 6 including 2 patients' experiencing mortality out of group C, respectively. Progression-free survivals at 5 years and 10 years were 100% and 100% in group A, 95% and 75% in group B, and 88% and 81% in group C, respectively. Interestingly, none out of 24 patients who diagnosed with only pathological decision died in this study, suggesting that benign diseases might be included in the cases diagnosed as the POA-MALT lymphoma after the pathological decision only. Conclusions: Radiotherapy-based treatment for POA-MALT lymphoma as an initial therapy shows a low rate of recurrence. Clear diagnosis and initial radiotherapy-based strategies should improve the prognosis of POA-MALT.
Is mild asymptomatic left ventricular systolic dysfunction always predictive of adverse events in high-risk populations? Insights from the DAVID-Berg study
Authors: Mauro Gori, Margaret M. Redfield, Alice Calabrese, Paolo Canova, Giovanni Cioffi, Renata De Maria, Aurelia Grosu, Alessandra Fontana, Attilio Iacovoni, Paola Ferrari, Gianfranco Parati, Antonello Gavazzi, Michele Senni
Journal: European Journal of Heart Failure (2018)
Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency
Authors: Donald B. Kohn, Michael S. Hershfield, Jennifer M. Puck, Alessandro Aiuti, Annaliesse Blincoe, H. Bobby Gaspar, Luigi D. Notarangelo, Eyal Grunebaum
Journal: Journal of Allergy and Clinical Immunology (2018)
Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (<i>EGFR</i>) mutations.
Authors: Satoshi Oizumi, Shunichi Sugawara, Koichi Minato, Toshiyuki Harada, Akira Inoue, Yuka Fujita, Makoto Maemondo, Satoshi Watanabe, Kazuhiko Ito, Akihiko Gemma, Yoshiki Demura, Masao Harada, Hiroshi Isobe, Ichiro Kinoshita, Satoshi Morita, Kunihiko Kobayashi, Koichi Hagiwara, Minoru Kurihara, Toshihiro Nukiwa
Journal: Journal of Clinical Oncology (2017)

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.
A priori filtering of post-operative (post-op) circulating tumor DNA (ctDNA) to predict recurrence in post-metastasectomy colorectal cancer patients (CRC pts) without knowledge of tumor genotype.
Authors: Michael J. Overman, Ariel Jaimovich, Drew Kennedy, Michelle Tan, Danielle Gavino, Stefanie Mortimer, Darya Chudova, AmirAli Talasaz, Justin Odegaard, Scott Kopetz
Journal: Journal of Clinical Oncology (2018)

12044 Background: ctDNA in post-op CRC pts correlates with molecular residual disease and may be useful to guide adjuvant therapy. However, initial studies employed clinically impractical assays indexed to individual pt-specific tumor tissue-defined mutations or were confounded by non-tumor-associated somatic alterations, including variants related to clonal hematopoiesis. Methods: 51 CRC pts undergoing curative intent metastasectomy were prospectively recruited at a single institution. Pre and post-op (1-17 days) plasma was sequenced to high depth using a 23-gene NGS panel with 96% theoretical sensitivity for CRC. Tumor tissue was sequenced using this panel or local testing. ctDNA profiles from 4000 CRC pts (Guardant Health) were used to train a variant classifier to predict truncal CRC mutations. Results: At median follow up of 10 months (range 1.2-57.7), 37 of 51 pts recurred (median 7.8 months, range 1.2-34.5). Based on post-op mutation detection alone, ctDNA was identified in 31 of 36 recurrent (sensitivity 86% [71-96%]) and 9 of 15 non-recurrent pts (specificity 60% [32-84%]). When restricted to variants detected in tumor tissue, ctDNA was identified in 14 of 31 recurrent (sensitivity 38% [27-64%]) and 0 of 10 non-recurrent pts (specificity 100% [69-100%]). When filtered by the variant classifier, post-op ctDNA was found in 18 of 36 (sensitivity 50% [33-67%]) recurrent pts and 0 of 15 non-recurrent pts (specificity 100% [78-100%]). Median somatic allelic fraction was similar after tumor tissue- and classifier-based filtering (median 0.48% vs. 0.65%, range 0.02-20.0%). Conclusions: Recurrence prediction using post-op somatic variant detection alone is fraught by a high clinical false positive rate. Filtering using tumor tissue is effective but reduces sensitivity substantially and is clinically impractical. However, filtering using a variant classifier without knowledge of tumor genotype eliminated false positives and maintained clinical sensitivity in this cohort. A priori variant classification may enable clinically feasible ctDNA diagnostics for adjuvant decision making in early-stage disease.
A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor.
Authors: Jinhyun Cho, Myung-Ju Ahn, Kwai Han Yoo, Hansang Lee, Hee Kyung Kim, Mi Hwa Heo, Joo Hyun Hong, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park
Journal: Journal of Clinical Oncology (2017)

8521 Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. Clinical trial information: NCT02607631.
P04.25 Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas
Authors: A M Knudsen, I Eilertsen, S Kielland, M W Pedersen, M D Sørensen, R H Dahlrot, H B Boldt, C S Mellegaard, S Munthe, F R Poulsen, B W Kristensen
Journal: Neuro-Oncology (2018)

Gliomas are the most frequent primary brain tumors. For the most malignant glioma - the glioblastoma - the median survival is only 15 months. Few prognostic biomarkers are useful in daily practice, and new markers are urgently needed. EGR1 and EGR3 are transcription factors involved in the regulation of mitogenesis, cell differentiation, and EGR3 has also been suggested to be involved in cell migration. Both proteins have shown prognostic potential in other cancers. The aim of this study was to investigate the expression of EGR1 and EGR3, and investigate their prognostic value in gliomas. A total of 207 gliomas including 190 glioblastomas were stained with antibodies against EGR1 and EGR3 and assessed with a software-based classifier and semi-quantitative scoring system. A cohort consisting of tissue from 21 gliomas with high expression of mutated P53 in the tumor cells was established. For all cases, tissue with central tumor region, infiltrating tumor region and peripheral region was available. The cohort was used to investigate and quantitate protein expression in migrating tumor cells by double immunofluorescence with mutated P53 and EGR1/EGR3 respectively. In silico data analysis was performed using the Ivy GAP database. Kaplan-Meier estimates and Log-rank tests were used for survival comparison. Cox-regression was performed to identify independent variables. Both EGR1 and EGR3 protein expression was found in all investigated tumors but with considerable inter-tumor variation. EGR1 expression was declining from the central tumor area towards the tumor periphery which had the lowest expression - consistent with Ivy GAP mRNA data. EGR3 mRNA data showed that EGR3 expression increased in peripheral areas, and EGR3 immunofluorescence stainings are currently in progress to validate these findings. In univariate survival analysis, high EGR1 levels, as well as the combination of high EGR1 levels and simultaneous low EGR3 levels, were associated with improved survival in glioblastomas, but the results were non-significant when adjusted for relevant confounders. EGR1 and EGR3 expression was found in all investigated gliomas but with considerable inter- and intra-tumor variation. EGR1/EGR3 expression did not have independent prognostic potential.