tbuckley/cabot-search huggingface dataset:
The Nationwide Cancer Genome Screening Project for Gastrointestinal Cancer in Japan (GI-SCREEN): MSI-status and cancer-related genome alterations in advanced colorectal cancer (CRC)—GI-SCREEN 2013-01-CRC sub-study.
Authors: Takeshi Kajiwara, Kohei Shitara, Tadamichi Denda, Satoshi Yuki, Takao Tamura, Kenta Kawasaki, Eiji Shinozaki, Takako Eguchi Nakajima, Ken Kato, Kiwamu Akagi, Taito Esaki, Naohiro Okano, Toshihiro Kudo, Shigenori Kadowaki, Hiromichi Ebi, Yoshiyuki Yamamoto, Satoshi Fujii, Toshihiko Doi, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2016)

3573 Background: We initiated a nationwide screening project in Japan to detect rare cancer-related genome alterations in CRC (GI-SCREEN 2013-01-CRC) or non-CRC GI cancer and to facilitate the enrollment of patients (pts) in clinical trials for targeted therapies (Shitara Ket, al ASCO 2015 TPS4134). In this sub-study, we evaluated relationship between MSI status and oncogenic genome alterations as well as clinicopathological features. Methods: Pts with advanced CRC who are or will be treated with systemic chemotherapy were eligible. A total of 36 mutations of KRAS, NRAS, BRAF, PIK3CA in genomic DNA from FFPE tumor specimens were simultaneously analyzed by Luminex (xMAP) technology. Using the MSI Analysis System (Promega) composed of 5 mononucleotide markers, MSI status was analyzed with or without paired DNA from FFPE normal tissue. Results: Among 853 pts enrolled from Feb. 2014 to Jan. 2015, 839 tumor samples have been analyzed for both oncogenic genome alterations and MSI. Mutations in KRAS exon 2, other KRAS or NRAS, BRAF and PIK3CA were detected in 34.0%, 8.0%, 4.6%, and 8.6%, respectively. MSI status was evaluable in 805 pts, of which MSI-H was detected in 15 pts (1.9%). These MSI-H were also detected without normal tissue in this study. Among MSI-H pts, 6 were associated with BRAF V600E mutation, 3 with KRAS exon 2 mutation, and 2 with PIK3CA mutation (overlapping with KRAS exon2). BRAF+MSI-H was associated with older age at presentation and worse OS than non-BRAF+MSI-H (median age, 71.5 vs. 47yrs; median OS, 6.9 vs. 18.1 months).We also found rare germline variants in microsatellite of NR21 and BAT25, and these allele frequencies were 0.33% and 0.25%, respectively. Conclusions: The frequency of MSI-H advanced CRC was 1.9% in Japan. BRAF+MSI-H was associated with worse prognosis. MSI test and multi-oncogenes mutation analysis were feasible without normal tissue, although rare variant of microsatellite markers may affect the decision of MSI status.
Speech efficacy, safety and factors affecting lifetime of voice prostheses in patients with laryngeal cancer: A systematic review and network meta-analysis of randomized controlled trials.
Authors: Gehad Mohamed Tawfik, Thuan Minh Tieu, Sherief Ghozy, Omar Mohamed Makram, Peter Samuel, Abdelaziz Abdelaal, Mona Hanafy, Heba Hussien Eltanany, To Kim Sang, Amira Farghaly Ali, Seif Mahmoud Abdelghany, Osama Gamal Sweiny, Võ Thị Trâm Anh, Khaled Essam Elsherbiny, Ahmad Morad, Nusaiba Adam Yahia, Amr G. Shafik, Nguyen Tien Huy
Journal: Journal of Clinical Oncology (2018)

e18031 Background: Prognosis of total laryngectomy following laryngeal tumors mostly SCC, reaches a five-year survival rate of 65-75%, making it treatment of choice. Total laryngectomy is accompanied with loss of voice with a mandatory. An early rehabilitative measure better done; tracheoesophageal puncture with voice prostheses (VPs) is the gold standard approach. Aim: To compare different VPs and find best device & factors affecting VPs in term of patient preferences and for better quality of life. Methods: On 14 September 2017, we have searched 15 electronic database searches. We have included all RCTs comparing different types of VPs and measuring factors that influence VPs; lifetime, voice quality, patient preference, and replacement frequency after surgery. Network meta-analysis was used to compare available treatment strategies. Results: Seven studies were eligible for final NMA. Regarding patients’ preferences, Provox devices were significantly the most preferred device (ORs 2.55, 95%CI [0.67,4.44]), followed by Groningen and Blom-singer (BS), respectively. In term of devices’ lifetime, Provox devices had significantly the highest mean lifetimes (MD -1.5, 95%CI [-2,-1]), followed by Groningen and Nijdam, respectively. For devices’ replacements, BS devices are the best with lowest replacement rates (OR -0.75, 95%CI [-3.72,2.21]), followed by Nijdam, Provox, and Groningen, respectively. Maximum phonation time indicated that Provox devices have the highest mean phonation times (MD 2.37, 95%CI [-0.29,5.03]), followed by BS, Groningen, and Panje, respectively. Regarding leakage rates, Nijdam devices were the best with the lowest leakage rates (OR -0.96, 95%CI [-1.39,-0.52]), followed by Groningen, BS, and Provox, respectively. Lastly, airflow resistance indicated that Groningen devices had significantly the lowest airflow resistance rates (OR 0.95 95%CI [0.57,1.32]), followed by Nijdam and Provox, respectively. Conclusions: Provox was significantly superior in most of the factors assessed in our network including maximum phonation time, device lifetime, and most importantly patients' preference.
Treg infiltration and the expression of immune checkpoints associated with T cell exhaustion in AML.
Authors: Patrick Williams, Sreyashi Basu, Guillermo Garcia-Manero, Jorge E. Cortes, Farhad Ravandi, Elias Jabbour, Zainab Al-Hamal, Marina Konopleva, Jing Ning, Lianchun Xiao, Juliana Hidalgo Lopez, Steven Kornblau, Michael Andreeff, Carlos E. Bueso-Ramos, Jorge M Blando, Gheath Alatrash, James Patrick Allison, Hagop M. Kantarjian, Padmanee Sharma, Naval Guastad Daver
Journal: Journal of Clinical Oncology (2018)

7016 Background: Better defining the immune checkpoint landscape of Acute Myeloid Leukemia will facilitate the rational selection of immune checkpoint targets and combination approaches for future clinical trials. Methods: Flow cytometry was performed on bone marrow aspirates (BMA) from 107 patients with AML treated at the MD Anderson Cancer Center. We evaluated the expression of inhibitory (PD1, CTLA4, LAG3, TIM3) and stimulatory receptors (GITR, OX40, 41BB, ICOS) on T cell subsets and the expression of their ligands (41BBL, B7-1, B7-2, ICOSL, PDL1, PDL2 and OX40L) on AML blasts. We correlated the expression of these markers with age, karyotype, a baseline next generation sequencing for 28 myeloid-associated genes including P53, DNA methylation proteins (DNMT3a, IDH1, IDH2, TET2) and FLT3, as well as prior treatment history. Results: When gating on CD45+ cells, compared to healthy donors, patients with new and relapsed AML had an increased frequency for CD3+ T cells (60.3% vs 78.0% vs 81.1%, P = 0.02), Tregs (1.7% vs 2.02 vs 3.02, P = 0.02), PD1+ CD8+ T cells (12.1% vs 27.3% vs 30.3%, P = 0.02) and OX40+ CD8+ T cells (0.62% vs 0.85% vs 2.26%, P = 0.03), PD1+ CD4+ T effector cells (13.2% vs 13.4% vs 25.5%, %, P < 0.01) and OX40+ CD4+ T effector cells (0.79% vs 4.81% vs 5.86%, P = 0.04). Compared to healthy donors, patients with new and relapsed AML had a higher incidence of exhausted PD1+ TIM3+ CD8+ T cells (0.75% vs 1.36% vs 1.72%, P = 0.09), PD1+ TIM3+ CD4+ T effector cells (0.75% vs 2.2% vs 2.8%, P = 0.16), PD1+ LAG3+ CD8+ T cells (2.71% vs 4.69% vs 8.98%, P < 0.01) and PD1+ LAG3+ CD4+ T effector cells (2.71% vs 14.3% vs 13.5%, P = 0.05), with bimodal distributions. The Treg to CD8+ T cells correlated with increased frequencies of PD1+TIM3+ and PD1+LAG3+ CD8+ T cells (P = 0.01). Blasts in BMAs from patients with TP53 mutated AML were more frequently positive for PD-L1 (6.95% vs 12.5%, P = 0.05). Conclusions: The increased Treg and exhausted T cell frequency in AML BMAs point to worsening exhaustion of the immune response. The dual contributions from Tregs and checkpoint ligand expression by blasts to immune suppression indicate that these pathways may play an important role in AML survival and therefore patients may benefit from checkpoint antibody therapy.
Conjoined hyperactivation of the RAS and PI3K pathways in advanced GIST.
Authors: Bin Li, Cesar Serrano Garcia, Adrian Marino-Enriquez, Susanne Grunewald, Yuexiang Wang, Nacef Bahri, Alexandra Lauria, Chandrajit P. Raut, Suzanne George, George D. Demetri, Jason L. Hornick, Javier Martin Broto, Michael C. Heinrich, Sebastian Bauer, Christopher L. Corless, Jonathan A. Fletcher
Journal: Journal of Clinical Oncology (2016)

e22520 Background: KIT/PDGFRA-mutant GISTs feature oncogenic signaling via both the PI3K/mTOR and RAS/MAPK pathways. However, in GISTs that lose KIT/PDGFRA-dependence, the biologic and clinical relevance of these pathways is unclear. Methods: The study group included pts with high-risk or metastatic GIST that were either KIT/PDGFRA/SDH-wildtype (N = 7) or KIT-mutant with progression on TKI but no 2nd KIT mutation (N = 10). Genomic alterations were screened by NGS (Ion Torrent/Haloplex hybrid-capture), and protein alterations by IHC and immunoblotting. GIST cell lines were developed by drug-selection and shRNA or CRISPR to assess the biologic roles and clinical implications of PI3K and/or RAS pathway oncogenic activation. Results: 8 GIST had mutations activating PI3K and/or RAS pathways. 7 had concurrent PI3K and RAS pathway alterations (Table). Sublines of KIT-mutant GIST882 with concurrent PTEN and NF1 inactivation, or with NF1 inactivation alone, were IM-resistant (IC50 750nM and 500nM, respectively), whereas parental GIST882 and a subline with PTEN inactivation alone remained IM-sensitive (IC50 175nM and 125nM). Likewise, a novel GIST line, NS72, with NF1 inactivation and both PIK3CA and PTEN mutations was IM-resistant (IC50 > 2000nM). A genome-wide functional screen of 11,000 genes showed that NF1 inactivation ranked in the top 0.5% of events for IM-rescue in GIST, whereas PTEN inactivation did not. Conclusions: Coactivation of the RAS and PI3K pathways in GIST fosters KIT-independence and contributes to TKI-resistance. GIST models with RAS pathway activation are IM-resistant, whereas those with PI3K pathway activation alone are not. However, the clinical association of RAS and PI3K pathway mutations in high-risk or metastatic GIST highlights essential functions for both pathways in supplanting the broad oncogenic roles of KIT/PDGFRA in advanced GIST. These findings support continued efforts to develop co-targeting strategies for the RAS and PI3K pathways in GIST. Case Clinical KIT Status RAS-PI3K Mutations 1 Untreated WT NF1 + PTEN 2 Untreated WT NF1 + PTEN 3 Untreated WT HRAS + PIK3CA 4 Untreated WT NF1 + PIK3CA + PTEN 5 TKI-resistant Ex 11 KRAS + PTEN 6 TKI-resistant Ex 11 NF1 + PIK3CA 7 TKI-resistant Ex 11 TSC1 + PTEN 8 TKI-resistant Ex 11 NF1
Genetic variants including microsatellite instability in metastatic Hürthle cell carcinoma of the thyroid.
Authors: Natalie Hale-Wallace, Hari Anant Deshpande, Elizabeth H Holt, Glenda G Callender, Courtney Gibson, Grace Lee, Tobias Carling, Alan Loh Ho, Joseph Paul Eder, Karin E Finberg
Journal: Journal of Clinical Oncology (2018)

e18110 Background: Hürthle cell carcinoma is a rare type of thyroid cancer. We report the results of tumor profiling from patients seen at Yale Cancer Center / Smilow Cancer Hospital including a tumor with microsatellite instability (MSI) and a somatic MSH2 mutation. Methods: 5 patients with metastatic Hürthle cell carcinomas were identified between 2014-2017. Tumor profiling was performed by targeted DNA sequencing assays (Oncomine Comprehensive Assay at the Yale-New Haven Hospital Tumor Profiling Laboratory, FoundationOne at Foundation Medicine, or MSK-IMPACT at Memorial Sloan Kettering Cancer Center). Microsatellite instability testing by PCR was performed by the Yale Pathology Molecular Diagnostics Laboratory. Results: Tumor profiling results are shown in Table 1. Some of the patients were offered mutation – directed treatments. One tumor harbored a somatic MSH2 frameshift mutation and was found to exhibit a high level of microsatellite instability; this patient had an ongoing partial response when treated with pembrolizumab. Conclusions: Hürthle cell carcinoma may have mutations that are amenable to directed therapy. The finding of MSI has been reported in thyroid cancer but in one series was not seen in Hürthle cell carcinomas[i]. The response of Case 4 to pembrolizumab confirms the activity seen in other MSI high tumors treated with immune checkpoint inhibitors. Other potentially targetable mutations identified include NF1, BARD1 and PTEN. [i] Lazzereschi D, Palmirotta R, Ranien A, Ottini L, Veri MC, Carna A, Cetta F, Nardi F, Colletta G, Mariani-Costantini R. Microsatellite instability in thyroid tumours and tumour-like lesions. British Journal of Cancer (1999) 79 (2), 340-345 Table 1. Patient characteristics Genes harboring DNA variants Mutation - directed treatment given Status Case 1 None identified None Alive Case 2 TP53, ARID2, ATRX, LATS1, NF1, RB1, TERT None Transformed to anaplastic thyroid cancer (ATC) Died of disease Case 3 BARD1, CDKN2C, DAXX Being evaluated for Phase 1 trials Alive Case 4 NOTCH1, MSH2, NF1, ATM, PTEN, DNMT3A Pembrolizumab Ongoing partial response Case 5 None identified None Transformed to ATC. Died of disease
Nomogram for lymph node metastasis prediction with early gastric cancer patients: To decide additional gastrectomy after endoscopic dissection.
Authors: Su Mi Kim, Byung-Hoon Min, Ji Yeong An, Min-Gew Choi, Keun Won Ryu, Young Woo Kim, Sin-Ho Jung, Tae Sung Sohn, Jae-Moon Bae, Sung Kim, Jae J. Kim, Jun Ho Lee
Journal: Journal of Clinical Oncology (2017)

4045 Background: Accurate prediction of metastatic lymph node is critical to avoid unnecessary gastrectomy and improve quality of life for patients with early gastric cancer. The aim of this study was to develop and validate a nomogram for prediction of lymph node metastasis in early gastric cancer patients. Methods: We reviewed the clinicopathological data of 10595 patients who underwent curative resection for early gastric cancer from 2001 to 2015 at Samsung Medical Center. This model was externally validated by 2100 patients who underwent curative resection for gastric cancer in National Cancer Center. Multivariate analysis using the Cox proportional hazard regression model was performed to develop the nomogram, and discrimination and calibration were evaluated by external validation. Overall survival, disease free survival, and recurrence free survival were compared between gastrectomy groups of 6641 patients and endoscopic dissection group of 999 patients who was performed the treatment in Samsung Medical Center for early gastric cancer by risk on nomogram to demonstrate the efficacy of nomogram. Results: Multivariate analyses revealed that age, tumor size, lymphatic invasion, depth of invasion, and histologic differentiation were significant prognostic factors for lymph node metastasis. The nomogram had good discrimination with a concordance index of 0.845 [95% confidence interval 0.832-0.858], supported by an external validation point of 0.813[95% confidence interval 0.786-0.84]. In low risk on nomogram, endoscopic dissection group had similar overall survival (P = 0.319), disease free survival (P = 0.469) and recurrence free survival (P = 0.091) compared to gastrectomy group. Conclusions: We developed and validated a nomogram predicting lymph node metastasis for early gastric cancer based on a large database. This personalized nomogram is useful to avoid unnecessary gastrectomy after endoscopic dissection resulting in improved quality of life for early gastric cancer patients.
Implementation of a model for training and career development in the emerging academic field of global oncology.
Authors: Rebecca Deboer, Dharma N Bhatta, Geoffrey Buckle, Melody Ju Xu, Stephanie Kennell-Heiling, Michael Mwatsuma Mwachiro, Alan Paciorek, Li Zhang, Katherine Van Loon
Journal: Journal of Clinical Oncology (2018)

11008 Background: As interest in global oncology increases, the need to support early career investigators is a priority, as advocated by the ASCO Global Oncology Leadership Task Force. The Global Cancer Program (GCP) at UCSF strives to implement a novel multifaceted strategy to support trainees from UCSF and our partner institutions in low and middle-income countries in pursuing careers focused on global cancer research and capacity-building. Methods: In 2017, the GCP launched a Global Cancer Fellowship (GCF) for post-doctoral trainees, Future Global Cancer Leaders (FGCL) monthly seminar, and quarterly Global Cancer Lecture Series. GCF protects research time, provides mentorship, and lends credibility to an unprecedented career track in this emerging field. FGCL is a multi-disciplinary group of students, residents, fellows, and others who convene to share experiences, present works-in-progress (WIPs), and interact with faculty mentors and visiting experts. After one year GCP evaluated the feasibility and adoption of this strategy and measured early indicators of effectiveness with an anonymous survey administered to FGCL members. Results: Post-doctoral trainees in public health (DB; Nepal), medical oncology (RJD; U.S.), and surgery (MM; Kenya) were selected as inaugural GCF recipients in 2017-18. Monthly FGCL seminars were regularly attended; 21 trainees responded to the survey. Despite variable training levels and disciplines, 19 (90%) reported that the meetings were “just right” for their level. All meeting formats were rated as very or extremely valuable to career development (4-5 on a 5-point Likert Scale) by a majority of respondents. The most preferred formats were “town halls” with visiting experts (89% Likert 4 or 5), faculty lectures (85%), presenting a WIP (74%), and reviewing a WIP presented by a peer (70%). Conclusions: A multifaceted strategy to support trainees in pursuing global oncology careers is feasible, adopted with high fidelity, and effective by early measures. In 2018, the GCP aims to expand support for trainees at partner institutions; for example, providing funding and mentorship for pilot research projects submitted by trainees at our partner institution in Tanzania.
CXCR4 blockade at the end of irradiation to improve local control of glioblastoma (GBM).
Authors: Reena Parada Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Sophie Bertrand, Judith Shanika Pelpola, Jaden Yang, Robyn L. Ball, Martin Brown, Lawrence David Recht
Journal: Journal of Clinical Oncology (2018)

2019 Background: Based on preclinical work identifying an important role for the CXCL12 (SDF1)/CXCR4 chemokine axis in reestablishing vascularity after irradiation of GBM, we launched a Phase I/II study assessing the impact of CXCR4 blockade with a continuous infusion of Plerixafor (AMD3100, Mozobil), an established CXCR4 small molecule antagonist, already in clinical use for bone marrow stem cell mobilization. Methods: Open label Phase I/II study for newly diagnosed adult GBM patients, ages 75 or younger, with KPS of at least 60 were administered a 4-week continuous intravenous infusion starting one week prior to the completion of standard irradiation. Results: 29 patients (median age: 60 years) were enrolled and completed the infusion course. The Phase I study established that 16.6 µg/kg/hr was well tolerated (no Gr III drug associated toxicity) with achievable Plerixafor serum values above the threshold level for CXCR4 blockade. A total of 19 patients underwent DSC-MRI for quantification of relative cerebral blood volume (rCBV) at their 1-month and 6-month follow up scans. Compared to a group of 11 contemporaneous patients treated with standard chemo-radiation, there was a significant reduction of mean rCBV within the 95% isodose radiation field at 1-month (0.76 vs 0.88, p = 0.04) and 6-months (0.67 vs 0.87, p = 0.001), as observed in our preclinical studies. In association with this, was an out of field (i.e., beyond the 95% isodose field or within leptomeninges) first recurrence rate of 58.8% compared to 10% in the control group (p = 0.018, Fisher exact test). The Kaplan-Meier estimated median overall survival in months was 20.7, 95% CI (17.3, NA) and was not correlated with surgical extent, age, or MGMT status. Conclusions: GBM recurrences using standard treatment are generally local in 80% of patients. The high out of field first recurrence rate in this series, in conjunction with a marked decrease in rCBV, is therefore extremely notable. When viewed with the favorable survival data, it suggests improved local control and enhancement of the therapeutic response to radiation. We therefore conclude that blockade of the SDF1/CXCR4 axis represents a novel, clinically impactful strategy worthy of further investigation in GBM.
OS5.5 Surveillance data demonstrates the tolerability of tumor treating fields in pediatric glioma patients
Authors: A Kinzel, S Perez, J Stindl, J Grewal, E Kirson
Journal: Neuro-Oncology (2018)

There are few treatment options for pediatric patients with high grade gliomas Adult patients with newly diagnosed or recurrent glioblastoma multiforme have the option of treatment with tumor treating fields (TTFields), which have shown efficacy and safety in Phase 3 randomized trials. TTFields are a noninvasive anti-mitotic therapy administered via transducer arrays strategically arranged on the shaved scalp. TTFields are not approved for the treatment of high grade glioma in pediatric patients. Post-marketing surveillance data were collected for pediatric glioma patients receiving TTFields. Compiled safety data are presented for patients <18 years receiving TTFields for the treatment of glioma. A review of the clinical information for pediatric patients (<18 years of age) treated with TTFields in the United States and Europe identified 30 patients. The safety data obtained from post-market surveillance in all 30 patients were analyzed to identify adverse events (AEs) based on the MedDRA body system (system organ class) preferred terms. Sixteen (53%) pediatric patients experienced at least 1 AE while receiving TTFields treatment. Patients reported general AEs include: electric sensations in 10% (3/30); fatigue in 10% (3/30), heat sensation in 10% (3/30) and 17% reported pain (5/30) in any location. Nervous system AEs included headache (10%), seizure (7%) and balance disorder (7%). The most common AE were skin reactions that were reported by 7 patients (23%). One patient reported hyperhidrosis (3%). There were no unexpected AEs associated with TTFields in pediatric patients. The most frequently reported AEs were skin reactions likely related to the placement of TTFields transducers on the scalp; incidence was comparable to the rate of skin reactions reported in adult GBM patients. The tolerability of TTFields in pediatric patients from this post-marketing surveillance data support further investigations to assess efficacy and safety of TTFields in pediatric glioma patients.
Aging as a Biological Target for Prevention and Therapy
Authors: Nir Barzilai, Ana Maria Cuervo, Steve Austad
Journal: JAMA (2018)

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