tbuckley/cabot-search huggingface dataset:
Pilot study combining PD-L1 antibody durvalumab (D) with CTLA-4 antibody tremelimumab (T) and stereotactic body radiotherapy (SBRT) to treat metastatic anaplastic thyroid cancer (ATC).
Authors: Eric Jeffrey Sherman, C. Jillian Tsai, Wanqing Iris Zhi, James Vincent Fetten, Vanessa Wu, Alan Loh Ho, Nadeem Riaz, David G. Pfister, Nancy Y. Lee
Journal: Journal of Clinical Oncology (2019)

6088 Background: ATC is a rare and aggressive cancer with very limited treatment options. The thyroid is one of the most immunogenic organs in the body and PD-L1 is commonly expressed on ATC tumor cells and PD-1 in the inflammatory cells in the ATC microenvironment. However, antibodies to PD-1 as single agents have a poor record in this disease. Methods: This study evaluated the addition of T (75 mg every 4 weeks up to 4 doses) to D (1500 mg every 4 weeks). SBRT 9Gy x 3 fractions was given within the first 2 weeks of treatment to produce an “abscopal” effect. Major inclusion criteria: Metastatic ATC; ECOG PS 0-2; No prior immunotherapy; Last anti-cancer treatment &gt; 7 days prior to starting study. Primary objective 1-year overall survival with target of ≥ 2 out of 12 patients. Results: 12 patients were accrued. Male – 50%; Median PS 1; Median Age – 71 (49-82); Prior radiation to neck (75%); Prior chemotherapy (75%). MSI-High was noted in 2/11 subjects. BRAFV600E mutation in 3/12 subjects. There were 0 confirmed responses and only 1 subject with SD for 4 cycles or longer. Median time on treatment was 11 weeks (1-28+ weeks). MSI status did not affect treatment response. MSI-High patients were on treatment before progression for 8-14 weeks. Median overall survival was 14.5 weeks with only one person alive past 1 year. Neither the presence of a BRAF or p53 mutation appeared to affect either outcome. Conclusions: T/D with SBRT was not active in metastatic ATC. Future studies looking at other novel immunotherapy combinations in ATC should be evaluated. Biopsies done on study are being analyzed. Clinical trial information: NCT03122496.
Germline mutation status and therapy response in high-risk early breast cancer: Results of the GeparOcto study (NCT02125344).
Authors: Esther Pohl-Rescigno, Jan Hauke, Kerstin Rhiem, Volker Möbus, Jenny Furlanetto, Carsten Denkert, Peter A. Fasching, Claus Hanusch, Hans Tesch, Nana Weber-Lassalle, Volkmar Müller, Michael Untch, Kristina Luebbe, Bianca Lederer, Christian Jackisch, Valentina Nekljudova, Rita K. Schmutzler, Sibylle Loibl, Andreas Schneeweiss, Eric Hahnen
Journal: Journal of Clinical Oncology (2019)

573 Background: GeparOcto compared the efficacy of two neoadjuvant treatment (NAT) regimens in high-risk early breast cancer (BC): Sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly paclitaxel plus non-pegylated liposomal doxorubicin (PM), plus carboplatin (PMCb) in triple-negative BC (TNBC). There was no difference in pathologic complete response (pCR) rates (Schneeweiss et al. Eur J Cancer 2019). Here, we stratified pCR rates according to germline mutation status. Methods: Germline (g) mutation analysis of BRCA1/2 and 16 further BC predisposition genes in 914 patients (pts) enrolled (393 pts with TNBC, iddEPC n = 194, PMCb n = 199; 156 pts with HER2-/HR+ BC, iddEPC n = 75, PM n = 81; and 365 pts with HER2+ BC, iddEPC n = 182, PM n = 183). Results: The gBRCA1/2 mutation prevalence was 17.6% in TNBC, 14.1% in HER2-/HR+ BC and 1.4% in HER2+ BC. Overall, pts with gBRCA1/2 mutations achieved higher pCR rates than gBRCA1/2 wildtype pts (60.4% vs 46.7%, OR 1.74, P = 0.012), with more pronounced effects in the PM(Cb) arm (68.1% vs 45.7%, OR 2.53, P = 0.005). Among gBRCA1/2 wildtype pts, 76 carried mutations in non- BRCA1/2 predisposition genes. pCR rates were similar to those observed in pts without any mutation. Conclusions: Pts with gBRCA1/2 mutations benefitted most from NAT with highest pCR rates achieved in the gBRCA1/2 TNBC / PMCb group. The role of Cb for NAT of gBRCA1/2 TNBC should be further explored. Clinical trial information: NCT02125344. [Table: see text]
Clinical efficacy of tumor-treating fields for newly diagnosed glioblastoma.
Authors: Yang Liu, Margie Richardson, Kwanza Warren, Myla S. Strawderman, Nimish Mohile, Michael T. Milano, Kevin Walter
Journal: Journal of Clinical Oncology (2019)

2046 Background: Recent clinical trials have shown that adding tumor treating fields (TTF) to the Stupp protocol (SP) has increased survival after glioblastoma (GBM) diagnosis. However, whether this regimen improves population-based survival for patients with GBM remains unknown. Methods: We retrospectively identified adult patients with newly diagnosed GBM treated at our institution from January 2000 to July 2017 (n = 438, median age: 63 years).We grouped patients into three time periods for comparison: 2000-2004 (group 1, prior to SP), 2005-2013 (group 2, SP) and 2014-2017 (group 3, adding TTF to SP). The Kaplan-Meier method was used to estimate survival. Statistical analysis included unadjusted group comparisons by Chi-square and Log-rank tests and adjusted group comparisons using logistic and Cox models. Results: Thirty-seven percent (43/117) of patients with GBM in group 3 received TTF with SP therapy; when compared to those who received SP only, these patients had significant improvements in 6-month and 1-year overall survival (OS) rates (100.0% vs. 82.4%, p &lt; 0.01; 86.0% vs. 66.2%, p &lt; 0.05, respectively) (unadjusted for prognostic factors including sex, age, KPS and extent of resection) and an increased trend of median OS (479.0 vs. 448 days, p = 0.269). However, after adjusting for those prognostic factors, we didn’t find a statistically better survival for patients treated with TTF (OR: 6.156, p = 0.097, OR: 2.102, p = 0.185, respectively). Furthermore, multivariate Cox proportion hazards model after adjusting for those prognostic factors showed no significant survival benefits for patients treated with TTF and SP compared to those treated with SP only (HR = 0.797, p = 0.648). In addition, we didn’t find significant increases of 6-month, 1-year survival rates and median OS for patients in group 3 when compared to those in group 2 who had seen increased trends of survival trends when compared to those in group 1. Conclusions: Although adding TTF to SP appeared to benefit patients with GBM, this effect might be due to selection bias, e.g., TTF was offered to those patients with better prognostic factors. Ascertaining the long-term benefits of TTF requires further investigation.
Molecular stratification of endometrioid ovarian carcinomas.
Authors: Barbara Stanley, John P Thomson, Robert L Hollis, Alison Meynert, Tzyvia Rye, Yasushi Iida, Fiona Nussey, Melanie J Mackean, Michael Churchman, Colin Semple, Aikou Okamoto, Charlie Gourley, C Simon Herrington
Journal: Journal of Clinical Oncology (2019)

5553 Background: Endometrioid ovarian carcinomas (EC) have been historically under-investigated. We sought to determine the molecular landscape of contemporarily defined EC using whole exome sequencing (WES). Methods: Tumours diagnosed as EC between May 1980 and December 2013 were identified through the Edinburgh Ovarian Cancer Database. Pathology review was performed according to WHO 2014. Other pathologies including WT1 positive HGSOC were excluded. A selected cohort underwent WES and were analysed for single nucleotide and copy number variants across a panel of genes previously reported as mutated in endometrial, ovarian or pan cancer studies. Tissue microarrays were stained for ER, PR and AR. Multivariable analysis for disease specific survival (DSS) was performed. Results: 125 tumours were included. 61 tumours of all grades underwent WES. 5 molecular groups were identified based on the presence of TP53 mutations (45.9%); or an EC like profile (one or more mutations in ARID1A (41.0%); CTNNB1 (31.1%), PTEN (24.6%) or PIK3CA (23.0%)). Tumours with no mutations in EC like genes were termed EC null . Each group demonstrated differential DSS (table). Some EC null : TP53 mut tumours also displayed mutations in KRAS, APC and mismatch repair genes. Unsupervised clustering analysis based on the top 100 differentially mutated genes across the dataset validated these groups. Somatic copy number alterations were significantly higher in the TP53 mu t groups than the TP53 wt groups (P&lt;0.0001), and were identified across EC like genes in the EC null groups. A PR histoscore of &gt;150, but not ER or AR, was more frequent in the TP53 wt group compared to the TP53 mut groups (P=0.003). TP53 mut status (P=0.0182) and PR histoscore ≤150 (P=0.0115) were independently associated with DSS. Conclusions: EC is a heterogeneous disease comprising 5 molecular subgroups each demonstrating differential clinical outcome. TP53 mutations and PR histoscore ≤150 are independently associated with poor prognosis. [Table: see text]
A versatile supramolecular nanoadjuvant that activates NF-κB for cancer immunotherapy
Authors: Yan Xu, Youzhi Wang, Quanli Yang, Zhijia Liu, Zhiqiang Xiao, Zhicheng Le, Zhimou Yang, Chengbiao Yang
Journal: Theranostics (2019)

Although powerful adjuvants hold promise of vaccines for cancer immunotherapy, cumbersome preparation processes, elusive mechanisms and failure to induce T cell responses have largely limited their clinical translation. Due to their ease of synthesis, good biocompatibility and designable bioactivity, peptide derivatives-based supramolecular nanomaterials have attracted increasing interest in improving the immunogenicity of cancer vaccines. Methods: Herein, we synthesized an NF-κB-activating supramolecular nanoadjuvant (3DSNA) that is prepared by pH-triggering self-assembly of a positively charged D-configurational peptide derivative. The immunostimulatory activity of 3DNSA was explored in vitro and in vivo. Results: 3DSNA can strongly absorb the model antigen (ovalbumin, OVA) through electrostatic interaction. Then, 3DSNA promotes ingestion and cross-presentation of OVA, upregulation of costimulatory factors (CD80 and CD86) and secretion of proinflammatory cytokines (IL-6 and IL-12) by dendritic cells (DCs), accompanied by activation of the innate immune response (NF-κB signaling), resulting in long-term antigen-specific memory and effector CD8+ T cells response. When compared with conventional aluminum hydroxide adjuvant and the corresponding L-configurational supramolecular nanoadjuvant (3LSNA), 3DSNA-adjuvanted OVA (3DSNA+OVA) significantly prevents oncogenesis in naïve mice with a complete response rate of 60 %, restrains the tumor growth and prolongs the survival of melanoma-bearing mice. Conclusion: These findings demonstrate that 3DSNA is a promising neo-adjuvant that enables various vaccines to be therapeutic for many important diseases including cancer.
Electron microscopy in the diagnosis of Ehlers–Danlos syndromes: correlation with clinical and genetic investigations
Authors: C. Angwin, N. Ghali, D. Baker, A.F. Brady, F.M. Pope, A. Vandersteen, B. Wagner, D.J.P. Ferguson, F.S Dijk
Journal: British Journal of Dermatology (2019)

Background  The Ehlers-Danlos syndromes (EDS) consist of 13 subtypes with overlapping features including joint hypermobility, skin and vascular fragility and generalized connective tissue friability. As DNA analysis has become the gold standard for investigation of EDS, transmission electron microscopy (TEM) in clinical practice is decreasing. However, owing to the use of next-generation sequencing, the frequency of variants of uncertain significance (VUS) identified using DNA analysis is increasing. We hypothesized that TEM can provide evidence for or against pathogenicity of VUS.  Objectives  The aim of this study was to evaluate the role of TEM in the diagnosis of EDS subtypes.  Methods  Data were collected from patients who underwent a skin biopsy between October 2012 and March 2017 at the London EDS National Diagnostic Service. TEM biopsies were categorized as 'normal' or 'abnormal' according to the description and conclusion in the TEM reports. Definitive diagnoses were reached via a combination of clinical features, structural and functional studies and DNA investigations.  Results  The analysis included 177 patients, comprising 30 abnormal and 147 normal TEM reports. A definitive diagnosis of monogenic EDS subtypes was made in 24 patients. Overall, 17 of these 24 patients (71%) had an abnormal biopsy report and seven (29%) had a normal biopsy report. No TEM findings were specifically associated with any EDS subtype, although collagen flowers were present in most patients with a genetically confirmed diagnosis of classical EDS.  Conclusions  TEM analysis of collagen structure may have the potential to provide evidence for or against the pathogenicity of a VUS, but more work is needed to establish a clear role for TEM in this process. What's already known about this topic? Collagen fibril abnormalities can be seen in several Ehlers-Danlos syndrome (EDS) subtypes. What does this study add? This study provides clinical data, transmission electron microscopy (TEM) data and molecular data of one of the largest groups of patients suspected to have a monogenetic EDS subtype. No TEM findings were specifically associated with an EDS subtype. There was a higher percentage (71%) of abnormal biopsy findings in patients with a definitive diagnosis of a monogenetic EDS subtype and where a class 4/5 genetic variant was present.
Circulating bacterial DNA as a tool towards noninvasive biomarkers for colorectal adenocarcinoma and adenoma.
Authors: Ke-Feng Ding, Qian Xiao, Xiangxing Kong, Yeting Hu, Wei Lu, Ao Wang, Kaihua Liu, Hua Bao, Ying Yuan, Jiaqi Chen, Da Wang, Xiaonan Wang, Xue Wu, Yang Shao
Journal: Journal of Clinical Oncology (2019)

3045 Background: The gut microbiota is closely associated with the progression of colorectal neoplasia. While most metagenomics studies utilized fecal samples, circulating bacteria DNA in colorectal adenocarcinoma (ADC) or adenoma (ADM) patients remain unexplored. This study aimed to characterize microbiota DNA in plasma samples and build a machine-learning model for ADC and ADM early detection. Methods: In this proof-of-concept study, we performed whole genome sequencing (~30X) of plasma samples from 25 ADC patients, 10 ADM patients, and 22 healthy controls (HC). Significant biomarkers were identified in the discovery cohort (12 ADC and 11 HC) and built into a random-forest model which was tested in the validation cohort (13 ADC and 11 HC). These biomarkers were further examined in ADM and tested for abundance difference with ADC and HP. Results: In the discovery cohort, 111 species had increased relative abundance in ADC compared to HC and 165 species had decreased relative abundance. Alteration in several species such as Flavobacterium and Ruminococcus torques were consistent with previously published results in faecal and gut microbiome samples. The random forest-recursive feature elimination model selected 28 significant species from the discovery cohort (mean AUC = 0.98, repeated 2-fold cross-validation) and yielded an AUC of 1 in the validation cohort. Interestingly, most biomarker species in ADM patients, with abundance intermediate between ADC and HC, were distinguished from HC. To further test the clinical utility of this model, sequencing data were randomly down-sampled to 1X and the model performance remained robust (AUC = 1) at distinguishing ADC and ADM from HC. Conclusions: This study is the first effort to characterize circulating bacteria DNA in patients with ADC and ADM. Our findings revealed significant difference in relative abundance of several bacterial species between ADC, ADM and HC. A predictive model constructed with selected microbial features accurately distinguished ADC and ADM from HC. Circulating bacteria biomarkers represent potential non-invasive tools for early diagnosis of colorectal neoplasia.
EGFR extracellular domain mutation in patients with lung cancer.
Authors: Renhua Guo, Dejian Gu, Jun Zhao, Lingjun Zhu, Mingjiu Chen, Shuoyan Liu, Bo Tang, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e20532 Background: Missense mutations in the EGFR extracellular (EC) domain are found in 10% to 15% of glioblastomas(GBM). However, little is known about EGFR EC domain mutations in lung cancer. In this study, we retrospectively analyzed distribution of EGFR EC domain mutation in lung cancer. Methods: A total of 10100 lung cancer patients were analyzed in this study. EGFR mutations were detected by hybridization capture-based NGS panel sequencing with tumor biopsy, ctDNA or pleural effusion samples. Results: We identified gain-of-function mutations in the EC domain of EGFR in 36 (0.36%, 36/10100) patients with 23 patients carrying EGFR A289D/V/T/Y mutation, 10 patients harboring EGFR R108K/S mutation, 2 patients having EGFR T263P mutation, and 1 patient with EGFR G598R mutation. The EGFR EC domain mutation was detected in 23 patients with lung adenocarcinoma and 13 patients with other types of lung cancer (P = 0.018). Notably, 29 (80.56%) patients were detected with EGFR EC domain mutation and EGFR intracellular kinase domain (KD) mutation (P = 2.15×10 -7 ). The incidence of L858R concomitant EC domain mutation was significantly higher compared with 19del (72.41% vs 17.24%, p = 28.64×10 -5 ) or other EGFR KD mutations (72.41% vs 10.34%, p = 6.79×10 -6 ). To further study whether L858R concomitant with EC domain mutation affected the efficiency of targeted therapy, we analyzed 6 patients who were treated with EGFR-TKIs. Among them, disease control rate of 2 months was 83.33% (5/6). Two patients had 10 months PFS. Three patients have been treated for 2, 5 and 12 months respectively, and are still on treatment. Conclusions: Our study reveals the distribution of EGFR EC domain mutation in lung cancer. EGFR EC domain mutation are more likely to occur concomitantly EGFR KD mutation, especial L858R. Meanwhile, our study shows that concomitant EC domain mutation and L858R may not affect the efficiency of targeted therapy.
Platypnoea–orthodeoxia syndrome: beware of investigations undertaken supine
Authors: Felicity Liew, Fatma Gargoum, Robert Potter, Stuart D Rosen, Simon Ward, Matthew Hind, Michael I Polkey
Journal: Thorax (2019)

Platypnoea–orthodeoxia syndrome (POS) is a rare disorder, manifesting as deoxygenation occurring when the patient is in the upright position. Four broad mechanisms for the condition have been described: intracardiac shunts, intrapulmonary shunts, hepatopulmonary syndrome and pulmonary ventilation–perfusion mismatch. Here, we present the first case of POS in a patient with a proven right to left intracardiac shunt occurring in the context of postural hypotension and normal right heart pressures. We highlight the need to carry out investigations in the upright position before discounting intracardiac shunting as a cause for the syndrome. Short-term improvement of the syndrome was obtained with medical management of the patient’s orthostatic hypotension and as such suggests a conservative management strategy for similar patients, which may delay the need for invasive procedures to close the anatomical defect.
Medication-related osteonecrosis of the jaw: Evidence for infection versus oversuppression.
Authors: Kenneth Evan Fleisher, Franco Muggia, Robert S Glickman
Journal: Journal of Clinical Oncology (2019)

e18268 Background: Antiresorptive medications are important in maintaining bone health for patients with osteoporosis, metastatic cancer and multiple myeloma. Medication-related osteonecrosis of the jaw (MRONJ) may compromise quality of life and treatment of the underlying disease. There are many controversies regarding the pathogenesis, risk and management of MRONJ. Evidence-based data that suggest osteonecrosis of the jaw (ONJ) is triggered by infection and reports of ONJ unrelated to antiresorptive therapy (ART) have confounded previous hypotheses that pathogenesis is directly attributed to ART by oversuppression of bone remodeling. The aim of this study is to determine the outcome for management of MRONJ based on eradication of infection. Methods: The investigators designed a retrospective cohort study for patients who underwent surgical management of MRONJ. Identification of infected and necrotic bone was achieved via nuclear imaging (i.e., technetium bone scan, positron emission tomography), computed tomography and/or cone beam computed tomography. Surgical techniques included bone resection (i.e., marginal, segmental), local flap, reconstruction with microvascular free flap, and/or autogenous platelet graft. Perioperative modalities included hyperbaric oxygen therapy and culture-guided antibiotic administration. We recorded medical history, location of the MRONJ lesion, type of antiresorptive therapy and duration of perioperative antiresorptive therapy. The outcome variable was postoperative healing defined by mucosal closure without signs of infection or exposed bone at the time of follow-up including cases with complications related to subsequent dental infection or treatment. Descriptive statistics were calculated for successful management, medical history and duration of perioperative antiresorptive therapy. We excluded cases treated by palliative intent, when surgery was limited or contraindicated, and/or inadequate follow-up. Results: A total of 54 patients with 59 MRONJ lesions were evaluated (40 with cancer and 14 with osteoporosis). All patients were successfully treated with 13 patients continuing ART after surgery (average follow-up 10 months) and 8 patients requiring more than 1 surgery for lesions associated with osteosclerosis. Conclusions: This study suggests that MRONJ is an infection-driven process that can be managed with various modalities to control diseased bone and facilitate healing. Patients may resume ART following successful management of MRONJ.
Cell-free junctional DNA fragment from hepatitis B virus integration in HCC for monitoring postresection recurrence and clonality.
Authors: Ya-Chun Wang, Chiao-Ling Li, Ming-Chih Ho, You-Yu Lin, Sheng-Tai Tzeng, Yun-Ju Chen, Hsin-Yung Pai, Shiou-Hwei Yeh, Pei-Jer Chen
Journal: Journal of Clinical Oncology (2019)

4090 Background: About one-third of patients suffer tumor recurrence within the first year after surgical resection of HCC. Early recurrence compromised their overall survival. Timing detection of HCC recurrence and its clonality is required to implement therapeutic trials appropriately. This study examined the virus-host chimera DNA (vh-chimera DNA), generated from junctions of HBV integration in HCC chromosome and released into blood, as a potential circulating biomarker for this clinical setting. Methods: We established a capture-next generation sequencing (NGS) platform to identify the HBV integrations in 50 resected HBV-related HCC. For individual HCC, the major clonal HBV integration sites were chosen to design specific primers for droplet digital PCR (ddPCR) to detect and quantify the vh-chimera DNA in plasma samples, collected either just before surgery or two months after surgery. Levels of vh-chimera DNA were then correlated with baseline HCC size or recurrence in one-year follow up. Results: We succeeded in detecting HBV integrations in the HCC from 44 out of 50 HBV-related HCC patients (88%). The copy number of vh-chimera DNA in plasma at surgery from 42 patients correlated with tumor sizes, with the detection limit at 1.5-2 cm. Among the plasma collected 2 months after surgery, 26.2% of samples contained the same HCC signature vh-chimera DNA as baseline plasma, indicating a possible residual tumor. Consistently, 81.8% of them suffered HCC recurrence within one year. The signature vh-DNA in the plasma suggested the majority of recurrences coming from the original HCC clones, whereas 2 from de novo ones. Conclusions: This study supported vh-chimera DNA as a new circulation marker for detecting the existence of most HBV-related HCC. This new biomarker may complement AFP to help detect residual or recurrent HCC and their clonality after curative therapies.