tbuckley/cabot-search huggingface dataset:
Effect of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy on nutritional status in locoregionally advanced nasopharyngeal carcinoma patients: A prospective observational study.
Authors: Jingjing Miao, Chaosu Hu, Shaojun Lin, Xiaozhong Chen, Yuan yuan Chen, Yahua Zhong, Feng Jin, Qin Lin, Xuefeng Hu, Ning Zhang, Rensheng Wang, Lin Wang, Cong Wang, Manyi Zhu, Haijun Wu, Muping Di, Yuqing Huang, Conghua Xie, Chong Zhao
Journal: Journal of Clinical Oncology (2018)

e18002 Background: To investigate the influence of neoadjuvant chemotherapy (NACT) plus concurrent chemoradiotherapy (CCRT) on nutritional status in locoregionally advanced nasopharyngeal carcinoma (LANPC) patients. Methods: Patients were recruited from ten hospitals. All patients received NACT plus CCRT. Nutrition related parameters including weight loss (WL), body mass index (BMI), Nutrition Risk Screening 2002 (NRS2002), Patient-Generated Subjective Global Assessment (PG-SGA), and Quality of life (QoL) score (EORTC QLQ-C30) as well as toxicity were recorded before, during, and after treatment. Statistical analyses are using SPSS 22.0. The study was registered on ClinicalTrials.gov, No. NCT02575547. Results: From Jun 2015 to Nov 2016, 186 patients enrolled, of whom 171 were eligible for analysis. The overall incidence of mild and severe malnutrition was 68.5% and 37.4%, as shown in Table 1. Patients with ≥ 2 grade mucositis have higher risks of WL ≥ 10% (P = 0.037), NRS2002 ≥ 3 points (P = 0.002) and PG-SGA ≥ 9 points (P < 0.001). 97.7%, 87.7% and 99.4% patients finished NACT, CCRT and radiotherapy, respectively. Patients with PG-SGA ≥ 9 points and C30-QoL < 50 points had poor chemotherapy compliance (P = 0.014, P < 0.001), and BMI < 18.5 had poor radiotherapy compliance (P = 0.036). Conclusions: Malnutrition was prevalent in LANPC patients treated with NACT plus CCRT, especially during CCRT, even lasted until 1 year after treatment. Its impact on clinical outcomes need long-term follow-up. Table 1 Incidence of nutrition related parameters on each observation points Clinical trial information: NCT02575547. prior NACT after 1 cycle NACT prior RT 4th week of RT end of RT 3 months after RT 1 year after RT WL ≥ 5% (mild malnutrition) 5.3% 6.0% 5.4% 38.7% 68.5% 64.1% 54.1% WL ≥ 10% (severe malnutrition) 0 1.8% 1.8% 7.7% 33.3% 37.4% 28.4% BMI < 18.5 5.8% 7.1% 6.5% 12.5% 19.4% 16.8% 13.5% NRS2002 ≥ 3 points (high risk of malnutrition) 8.2% - 6.9% 54.4% 79.4% 10.9% 6.7% PG-SGA ≥ 4 points (need nutrition treatment) 16.8% - 23.6% 96.7% 96.6% 38.3% 12.2% PG-SGA ≥ 9 points (need nutrition treatment urgently) 3.0% - 3.9% 72.0% 76.6% 6.3% 0 C30-QoL score 73.65 - 71.82 50.76 48.49 71.03 76.64
Therapy in Multiple Sclerosis — Coming of Age
Authors: Jack Antel
Journal: New England Journal of Medicine (2018)

In this issue of the Journal, Chitnis and colleagues report a phase 3 clinical trial of two drugs to treat pediatric multiple sclerosis, defined as occurring in persons younger than 18 years of age.1 Although the peak age at clinical presentation of multiple sclerosis is in the third and fourth decades of life, 3 to 5% of patients present before adulthood1 (most are teenagers rather than prepubertal children). The current trial raises issues for the pediatric age group regarding how to use the increasing number of immune-directed therapies that are available for relapsing multiple sclerosis in adults. These issues include . . .
P02.17 CHMP4B is upregulated in meningiomas
Authors: D T D Dinh, S Kuhl, G Röhn, R Goldbrunner, M Timmer
Journal: Neuro-Oncology (2018)

The endosomal sorting complexes required for transport (ESCRT), take part in various cellular processes. ESCRT-III a subunit of the complex, is especially involved in the final stage of cytokinesis, the abscission. An essential constituent of ESCRT-III is the charged multivesicular body protein 4B (CHMP4B), promoting the scission of membranes during cytokinesis. The dysfunction of ESCRT is associated with the progression of different tumors like hepatocellular carcinoma, prostate cancer and breast cancer. However, the exact role of CHMP4B in tumor genesis or development is not clear yet. The intent of this study is to explore whether CHMP4B is higher expressed in meningioma and whether the protein level differentiate dependent on their malignancy. The expression of CHMP4B was measured through qPCR and Western Blots. The meningioma samples were divided in grade I, grade II and grade III. Non-tumorous brain tissues were used as control group. The samples were shock frozen (-80°C) after surgery. All qPCRs were done in triplicates. SYBR-Green was used as fluorescent, ß-Actin and MRLP19 as reference genes. For all samples undergoing Western Blot, Rabbit polyclonal anti-CHMP4B was used as primary antibody and HPR-linked anti-rabbit as secondary antibody. ß-Actin was also measured for reference. The qPCR data showed higher protein CHMP4B expression in grade III samples than grade I (0.879 ± 0.62 vs. 0.431 ± 0.290) and higher than grade II (0.451 ± 0.229). Western Blot data indicate an upregulation of CHMP4B in meningiomas compared to non-tumorous brain tissue (0.779 ± 0.303 vs. 0.486 ± 0.2457). Meningiomas have higher expression of CHMP4B than non-tumorous brain tissues. On posttranscriptional level the protein concentration even correlates with their malignancy. This data implies, that CHMP4B might be relevant for meningiomas and could have an influence on their malignancy.
Demonstration of anti-tumor immunity via intratumoral regulated platform ad-RTS-hIL-12 in advanced breast cancer and recurrent glioblastoma patients.
Authors: Francois M. Lebel, John A Barrett, Heather L. McArthur, Jill Y. Buck, Nathan Demars, Rich Mackenna, Laurence JN Cooper, E. Antonio Chiocca
Journal: Journal of Clinical Oncology (2018)

3038 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate expressing IL-12 under the control of an orally administered activator ligand, veledimex (V), through a proprietary RheoSwitch Therapeutic System (RTS) gene switch. This platform reduces systemic toxicity and stimulates anti-cancer T cell immune response. Methods: Two open label trials evaluated the tolerability of local inducible IL-12 expression in heavily pretreated patients with metastatic breast cancer (mBC) or recurrent glioblastoma (rGBM). Ad was administered as a single intratumoral injection with V 80 mg PO Qdx7 in mBC and 10-40 mg Qdx15 PO in rGBM. Results: We observed local expression of IL-12 and downstream IFNg demonstrating biological activity with a mean increase in tumor cytotoxic T cells (CD3+CD8+) baseline: 0.4 ± 0.2 to biopsy:1.9±0.8% cells with a mean reduction in Treg (CD4+FOXP3+) baseline: 0.8 ± 0.4 to biopsy: 0.6±0.3% cells. Sustained increases in tumor IFNg were documented in both mBC (by biopsy at Day 42 post injection) and rGBM (biopsy range:130 - 175 days post injection) while tumor IL-12 returned to baseline and systemic levels of IFNg and IL-12 were undetectable. In mBC, injected and non-injected lesions (abscopal effect) showed a reduction in lesion diameter. In the mBC study, 9 iRECIST evaluable subjects showed PR/stable disease in 5 subjects, for a disease control rate of 44% at Week 6 and 22% at Week 12. In the ongoing rGBM study we observe a mOS of 12.5 months with 5 of 15 subjects alive in the 20 mg V cohort with survival follow up ongoing. Across studies, the adverse event profile of Ad+ V, was predictable, controllable, and fully reversible upon stopping V including a dose response to frequency and severity of cytokine release syndrome. Conclusions: Local regulated controlled IL-12 expression using the Ad + V platform in advanced mBC and rGBM patients is promising, eliciting sustained increases in cytotoxic T cells, reduces Treg, including in non-injected lesions (abscopal effect) turning cold tumors hot, with a good safety profile. This platform warrants further evaluation in multiple tumor types in monotherapy and in combination with immune checkpoint inhibitors. Clinical trial information: NCT02026271; NCT02423902.
TCT-715 EVALUATION OF THE IMPACT OF PERCUTANEOUS CORONARY INTERVENTION OF CHRONIC TOTAL OCCLUSION ON REGIONAL MYOCARDIAL FUNCTION USING STRAIN ECHOCARDIOGRAPHY
Authors: Mohamed El Gowelly, None Abdel Fattah Kholeif, Mohamed Elsayed, None Eman Elsharkawy
Journal: Journal of the American College of Cardiology (2018)
Can bortezomib combined chemotherapy be helpful for even elderly unfit patients with newly diagnosed multiple myeloma.
Authors: Ho Sup Lee, Da Jung Kim, Lee Chun Park, Je-Jung Lee, Sung-Hoon Jung, Jae-Cheol Jo, Ji Hyun Lee, Su-Hee Cho, Young Kwang Chae
Journal: Journal of Clinical Oncology (2018)

e20020 Background: Patients with frail, accounting for one third of the elderly multiple myeloma (MM) can not be included in clinical studies for the presence of comorbidities, abnormal laboratory test results, and physical disability. So far, there have been few studies on patients with unfit or frail. Therefore, this study was planned to compare the response and survival rates of patients with fit and unfit who treated with bortezomib combined chemotherapy as an initial treatment. Methods: Data from patients at twenty five university hospitals in South Korea between December 2012 and Oct 2017 were collected retrospectively. Clinical and laboratory data were collected retrospectively by review of medical records. The criteria for classifying all patients as fit and unfit patients were based on the revised Myeloma Comorbidity Index (R-MCI) criteria. The R-MCI is consisted of impaired lung and kidney function, the Karnofsky Performance Status, frailty, age and unfavorable cytogenetics. The parameters are used as weighted factors within the R-MCI. Classification of risk groups were 0-3 points of low risk, 4-6 points of intermediate risk and 7-9 points of high risk. Results: The median age of the 399 patients was 70 years (range, 47-90 years). Most of the patients treated with VMP (93.2%). The 253 (63.4%) patients were low risk, 115 (28.8%) were intermediate risk and 31 (7.8%) were high risk by R-MCI criteria. The response rates according to R-MCI risk groups were following: 134 (55.8%), 66 (58.9%) and 18 (60.0%) of patients were achieved VGPR or more than VGPR in low, intermediate, and high risk group, respectively. The differences of survival rates according to R-MCI risk groups, the 2-year PFS were 49.2%, 46.3% and 29.6% in low, intermediate and high risk groups, respectively (p = 0.744). The 2-year OS were 84.0%, 84.8% and 50.7% in these groups, respectively (p = 0.002). Conclusions: In our study, unfit patients showed a significant decrease in OS compared to fit patients. But there is no difference between unfit patients and fit patients in terms of response rate or disease progression in patients with elderly MM. So, unfit patients should be treated with appropriate doses of chemotherapy in order to reduce toxicity.
P04.01 Synergistic antitumor effects of a combined therapy consisting of immune checkpoint inhibitors and tumor-targeting nanoparticles in glioblastoma
Authors: M Shevtsov, S Stangl, B Nikolaev, S Edmond, L Yakovleva, Y Marchenko, V Ryzhov, B Margulis, E Pitkin, G Multhoff
Journal: Neuro-Oncology (2018)

Immune checkpoint inhibitors are reshaping therapeutic strategies in neuro-oncology. We hypothesize that the anti-cancer activity of immune checkpoint inhibitors could be further enhanced by tumor-targeting theranostic nanoparticles. The 70-kDa heat shock protein (Hsp70) is known to be overexpressed on the membrane of tumor cells, but not on normal cells. Granzyme B specifically targets Hsp70 membrane-positive tumor cells and thereby causes apoptotic cell death. Superparamagnetic iron oxide nanoparticles conjugated with granzyme B (GrB-SPIONs) were characterized using dynamic light scattering, zeta potential analyzer, magnetometry, nonlinear magnetic response measurements (NLR-M2), and transmission electron microscopy techniques. The cytotoxicity of SPIONs was assessed using MTT assay and flow cytometry (annexin V, caspase-3). Targeting of tumor cells was analyzed using confocal and electron microscopy and flow cytometry. Retention of the particles in the tumor was assessed using high-field (11 T) magnetic resonance imaging (MRI) and by biodistribution of fluorescently labeled conjugates with granzyme B. In vivo therapeutic potential of GrB-SPIONs was tested in different orthotopic glioblastoma models. Therapeutic efficacy of the combined therapeutic approach consisting of GrB-SPIONs and anti-PDL-1 immune checkpoint inhibitors was explored by 3D volumetric MR-imaging. Synthesized GrB-SPION conjugates (ζ-potential -13.2 mV, average size 46 nm) were shown to specifically target Hsp70 membrane-positive tumor cells, in vitro. After internalization of the nanoparticles apoptotic cell death was initiated in a dose-dependent manner (as shown by flow cytometry). Biodistribution studies (employing ultramicroscopy) of fluorescently labeled granzyme B (CdSe quantum dots (QDs)) showed specific accumulation of the protein inside tumor cells. Due to the MR contrast enhancement properties tumor retention of intravenously injected GrB-SPIONs provided tumor imaging of orthotopic gliomas. Monotherapy with GrB-SPIONs in animal models resulted in a significant delay in tumor progression (MRI volumetry) and an increased overall survival. Combining anti-PDL-1 antibodies with GrB-SPIONs elicited a synergistic anticancer activity in mice that was accompanied by an intratumoral infiltration of cytotoxic CD8+ T cells and NK1.1 cells. These findings for the first time reveal that a combined therapy consisting of targeting theranostic GrB-SPIONs with immune checkpoint inhibitors synergistically enhances anti-tumor immunity in glioblastoma. The study was supported by Alexander von Humboldt Fellowship, DFG grant SFB824/2, and grant of the Russian Science Foundation 14-50-00068 and by the Federal Agency of Scientific Organizations, Russia, State Grant of the Ministry of Health of the Russian Federation №32.
[<sup>18</sup>F]FET-βAG-TOCA versus [<sup>68</sup>Ga]DOTATATE PET/CT in functional imaging of neuroendocrine tumours.
Authors: Suraiya Rahim Dubash, Tara Barwick, Francesco A Mauri, Kasia Kozlowski, Andreja Frilling, Juan W. Valle, Angela Lamarca, Rohini Sharma, Eric Aboagye
Journal: Journal of Clinical Oncology (2018)

e24193 Background: Radiolabelled somatostatin analogs are invaluable in diagnosis and therapy of neuroendocrine tumours (NETs). [68Ga] DOTA-peptides have limitations in accessibility and low throughput. The development of a novel [18F]octreotate analog with high SSTR2 receptor affinity and ability of transport to multicentre sites would overcome these difficulties faced in clinical practice. We report the first in human phase 1 study comparing [18F]FET-βAG-TOCA and [68Ga]DOTATATE PET/CT in NETs. Methods: All 32 patients recruited were diagnosed with NETs as per ENETS criteria. All patients had a [68Ga]DOTATATE scan within 6 months ([68Ga]DOTANOC PET/CT in 3 patients). Patient-by-patient and lesion-by-lesion analysis were performed. Seven regions were identified and in any organ up to 5 target lesions were chosen. SUV measurements were performed side-by-side on corresponding lesions. Normal background tissue, were outlined. SSTR2 receptor expression on diagnostic tissue were obtained. Results: All 7 regions had positive uptake in 31 patients. 223 lesions were detected on PET and cross-sectional imaging. 209 lesions were detected on [18F]FET-βAG-TOCA and 197 on [68Ga]DOTATATE PET. Additional 13 lesions in 3 patients (bone and lymph node) were detected on [18F]FET-βAG-TOCA. [68Ga]DOTANOC PET/CT detected an additional liver lesion in 1 patient. The overall sensitivity (per lesion) of [18F]FET-βAG-TOCA PET was 92.8% (95%, CI 89.3%-96.3%), compared with 87.5% (95%, CI 82.9%-92.1%) for [68Ga]DOTATATE PET. Specificity could not be determined as all patients recruited to this study had a histological diagnosis of NET. Conclusions: [18F]FET-βAG-TOCA ,the first GMP compliant SSTR-2 targeting fluorine-18 radioligand has been shown to be safe and well tolerated. This direct comparative study, has demonstrated [18F]FET-βAG-TOCA to be superior compared to [68Ga]DOTATATE in the detection of NET lesions. With recent FDA approval of [177Lu]DOTATATE, [18F]FET-βAG-TOCA is a potential radiotracer with high SSTR2 receptor affinity, and further developments could lead to its use as a potential theranostic agent in locally advanced and metastatic NETs. Clinical trial information: EudraCT Number: 2013-003152-20.
Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial.
Authors: Kenneth Stephen Thress, Aleksandra Markovets, J Carl Barrett, Juliann Chmielecki, Sarah B. Goldberg, Frances A. Shepherd, Sarah Vowler, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2017)

9018 Background: Osimertinib, an EGFR T790M-selective tyrosine kinase inhibitor (TKI), provides high and durable response rates in patients (pts) with T790M positive advanced NSCLC whose disease has progressed following EGFR-TKI therapy. We investigated whether changes in the levels of plasma EGFRmutations post-osimertinib treatment are associated with clinical outcome. Methods: We studied pts from the AURA Phase I study (NCT01802632) with acquired resistance to EGFR-TKIs, T790M positive baseline genotyping (in tumor or plasma), and plasma samples collected at baseline and 6 weeks (wks) post- osimertinib (20–240 mg daily) treatment. Plasma samples were analyzed for the presence of detectable EGFR mutations (Ex19del, L858R and T790M) using BEAMing digital PCR (Sysmex/Inostics). In pts with detectable plasma EGFR mutations at baseline, clinical outcomes (by investigator, per RECIST 1.1) were compared for pts with or without detectable plasma EGFRmutations at 6 wks. Results: Evaluable baseline and 6 wk plasma samples were collected from 160 pts with T790M positive genotyping, of whom 143 had detectable EGFR mutations at baseline (median allelic fraction for Ex19del: 7.09%; L858R: 3.81%; T790M: 2.12%). In this cohort, the overall median progression-free survival (mPFS) was 9.3 months (m; 95% CI 8.2, 9.7). Clearance of plasma EGFRmutations at 6 wks was seen in 92/143 (64%) pts. mPFS was longer in pts with plasma clearance (10.9 m; 95% CI 9.5, 15.2) compared with pts without (5.5 m; 95% CI 3.9, 6.7), as was objective response rate (ORR; 70%; 95% CI 59%, 79% vs. 35%; 95% CI 22%, 50%). Conclusions: Clearance of plasma EGFR mutations after 6 wks of osimertinib therapy appears to be associated with improved ORR and mPFS in pts with T790M positive NSCLC. Evidence or lack of such a “plasma response” measured at 6 wks could, potentially, be used to predict subsequent outcomes on therapy. Further research is needed to better understand whether continued detection of plasma EGFR mutations at 6 wks may indicate the presence of heterogeneous resistance mechanisms, which could, potentially, be targeted by combination therapies. Validation of these results in an independent cohort of pts is ongoing. Clinical trial information: NCT02228369.
The impact of clonal size on the revised international prognostic scoring system (R-IPSS) in myelodysplastic syndromes (MDS) with a single cytogenetic abnormality.
Authors: Omar Alkharabsheh, Salwa Shihadeh Saadeh, Mrinal Mahesh Patnaik, Hassan Alkhateeb, Naseema Gangat, Kebede Begna, William J. Hogan, Patricia T. Greipp, Rong He, Phuong L. Nguyen, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2018)

7068 Background: Cytogenetics is the backbone of the R-IPSS for MDS, contributing the most points (0 to 4) to the total scoring system. The current R-IPSS cytogenetics does not factor in the clone size or the number of abnormal metaphases. The International System for Human Cytogenetic Nomenclature (ISCN) in 2016 defined the clone by the presence of a structural rearrangement in at least 2 metaphases or 3 metaphases in case of monosomies. Methods: This is a retrospective study from the Mayo Clinic records for patients with confirmed MDS by a hematopathology review. Analysis included patients with adequate karyotyping of 20 metaphases only. Patients were divided into 3 groups (grp) based on their R-IPSS cytogenetics category (Intermediate, Poor and Very Poor). Patients with a single abnormal clone only were included. The size of the abnormal clone was calculated by dividing the number of abnormal metaphases by 20. The overall survival (OS) of each R-IPSS grp with different clonal percentage was compared to the diploid cytogenetics (DC) group. The Good and Very good R-IPSS cytogenetics were excluded. Survival estimates were calculated by Kaplan-Meier curves and log-rank testing using JMP v.13. Results: Of 1301 patients, 36.5% (n = 475) had a DC, 49% (n = 637) had an abnormal karyotype and 15% (n = 189) had no available cytogenetic results. Of those with abnormal karyotype, 58% (n = 372) had a single clone. Of those with a single clone, 70% (n = 260) had a single chromosomal abnormality. The OS of the 3 groups was statistically different and consistent with their R-IPSS score. OS was higher in the DC group (OS = 54 months, n = 474) compared to the Intermediate (OS = 30.5 months, n = 121), Poor (OS = 21.1 months, n = 49), and Very poor (OS = 8.7 months, n = 75), p < 0.005 for all grps. The clone size had no impact on overall survival above 5% when combining the 3 grps, the lowest threshold to make statistical conclusions was 10% (p = 0.01). Conclusions: The clonal percentage of any abnormality detected by conventional karyotype did not affect OS in patients with MDS that have an R-IPSS risk of intermediate or above. Therefore, any chromosomal abnormality should be included in the R-IPSS cytogenetics.
The prognostic significance of cancerous inhibitor of PP2A (CIP2A) expression in cervical cancer (CC).
Authors: Sareena Singh, Analisa DiFeo, Hadi Shojaei, Raymond Redline, Kimberly Erin Resnick
Journal: Journal of Clinical Oncology (2016)

e17019 Background: CIP2A is a newly elucidated oncogene that demonstrates high expression in many human cancers. CIP2A may not only serve as a drug target, but may play a role as a biomarker, predicting tumor response to therapy. While the pathways involving CIP2A are complex, it acts as an inhibitor of Protein Phosphatase 2A (PP2A) through dephosphorylation of the transcription factor c-Myc. We previously reported on PP2A overexpression and correlation with improved PFS and OS in CC. Our objective is to describe CIP2A expression in a cohort of CC patients using tissue microarray (TMA). Methods: Immunohistochemical staining of a CC TMA was performed on specimens from patients with locally-advanced disease who underwent definitive radiation (± sensitizing chemotherapy). Stained slides were reviewed by 2 independent investigators to determine cytoplasmic H-Scores (HS). Samples were then divided into 2 groups: HS < 9 and HS ≥ 9 (CIP2A Overexpression). The association between HS and survival was evaluated. Results: A total of 65 patient samples were stained and analyzed. Stage breakdown was as follows: Stage IB-21, stage II-25, stage III-17 and stage IV-3. Thirty-nine samples had HS ≥ 9 and 26 had HS < 9. Median follow-up time was 33 (1 – 82) months (mos). PFS was shorter for the HS ≥ 9 group (37.7 mos, 95% CI 26.9 – 48.4) than the HS < 9 group (55.6 mos, 95% CI 42.7 – 68.5), although not statistically significant (p = 0.083). OS was significantly shorter for the HS ≥ 9 group (47.4 mos, 95% CI 37.2 – 57.7) than for the HS < 9 group (68.8 mos, 95% CI 58.6 – 79.0) (p = 0.026). Conclusions: CIP2A overexpression is correlated with significantly shorter OS and a trend towards shorter PFS in CC. This preliminary data provides that rationale for therapeutically targeting the interactions between PP2A and CIP2A with investigational agents for the treatment of CC.