tbuckley/cabot-search huggingface dataset:
Vorolanib, everolimus, and the combination in patients with pretreated metastatic renal cell carcinoma (CONCEPT study): A randomized, phase 3, double-blind, multicenter trial.
Authors: Xinan Sheng, Dingwei Ye, Ai-Ping Zhou, Xin Yao, Hong Luo, Zhisong He, Zengjun Wang, Yingchao Zhao, Zhigang Ji, Qing Zou, Chaohong He, Jianming Guo, Xinhua Tu, Ziling Liu, Benkang Shi, Ben Liu, Peng Chen, Qiang Wei, Fang-Jian Zhou, Jun Guo
Journal: Journal of Clinical Oncology (2021)

4512 Background: The combination of agents targeting both VEGF- and mTOR-mediated pathways has been investigated in renal cell carcinoma (RCC). We conducted the CONCEPT study to assess vorolanib, everolimus, or their combination as second-line treatment in Chinese patients (pts) with metastatic RCC. Methods: Pts with cytologically or histologically confirmed RCC who had disease progression after one prior VEGFR-TKI were eligible for participation in the study. They will be randomized by 1:1:1 ratio to receive matching placebo plus vorolanib or everolimus, or the combination. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between November 2016 and June 2019, 399 pts (133 pts in each group) were enrolled. At the data cutoff (October 23, 2020), the median PFS in combination group was significantly longer than that in single-agent everolimus group (10.0 months [95% CI, 8.2-10.4] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.70 [95% CI, 0.52-0.94]; P = 0.0171), while the median PFS was similar between single-agent vorolanib group and single-agent everolimus group (6.4 months [95% CI, 4.6-8.3] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.94 [95% CI, 0.69-1.24]; P = 0.6856). An objective response was achieved by 33 (24.8%) of 133 pts allocated vorolanib plus everolimus compared with 11 (8.3%) of 133 who received single-agent everolimus and 14 (10.5%) of 133 pts assigned single-agent vorolanib. OS was immature with no significant difference between pts assigned vorolanib plus everolimus (30.4 months [95% CI, 16.5-NE]) and those allocated single-agent everolimus (25.4 months [95% CI 19.4-NE]) or single-agent vorolanib (30.5 months [95% CI, 22.8-NE]). Treatment-related adverse event (TRAE) occurred in 132 (99%) of 133 pts with vorolanib plus everolimus, 127 (96%) of 133 pts with single-agent vorolanib and 131 (99%) of 133 pts with single-agent everolimus, respectively. Grade 3 or higher TRAEs occurred in fewer patients who received single-agent vorolanib (52 [39%]) than in those who received single-agent everolimus (71 [53%]) or vorolanib plus everolimus (96 [72%]). Safety profiles of both agents were consistent with previous studies. Conclusions: This is the first phase 3 study of combination of mTOR- and VEGF-targeted agents in second-line treatments. Vorolanib plus everolimus showed a PFS benefit for patients with metastatic RCC who have progressed after one previous VEGF-targeted therapy with a safe tolerance profile. Clinical trial information: NCT03095040.
P01.146 Neurocognitive changes after awake surgery for diffuse glioma; a retrospective cohort study
Authors: E van Kessel, T J Snijders, A E Baumfalk, C Ruis, K M van Baarsen, M L Broekman, M J E van Zandvoort, P A Robe
Journal: Neuro-Oncology (2018)

Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients. Both treatment and the tumor itself contribute to these deficits. In order to minimize the harmful effects of surgery, it is becoming more common that patients are operated under awake conditions. To investigate if we can indeed preserve cognitive functioning after state-of-the art awake surgery and to identify factors determining the course of NCF after awake surgery, we performed a retrospective cohort study. From our consecutive cohort of patients with a diffuse glioma (WHO grade II-IV), we included patients with a clinical indication for awake craniotomy and sufficient data from neuropsychological testing, both pre-operatively and 3–6 months postoperatively. Evaluation covered five neurocognitive domains. We compared pre- and postoperative NCF data for mean scores per domain, and for the percentage of patients that deteriorated after surgery (individual level). We evaluated the value of patient-, tumor- and treatment characteristics for predicting change in NCF, using linear and logistic regression analyses. A total of 163 patients met our inclusion criteria. Mean NCF-scores of psychomotor speed and visuospatial functioning significantly deteriorated after surgery. The percentage of serious neurocognitive impairments (-2SD or worse) increased postoperatively for psychomotor speed, but not for other domains. Extension of the glioma in the left thalamus predicted a decline in the domains of overall-NCF, executive functioning and psychomotor speed. Absence of an IDH-mutation also predicted cognitive decline, for overall-NCF and executive functioning. In the majority of cognitive domains, cognitive functioning is preserved after surgery. Psychomotor speed seems to be most vulnerable to the effects of surgery. The predictive value of thalamic involvements and IDH-status for cognitive changes after awake surgery support the idea that a combination of locoregional (“mechanical”) and biomolecular effects of the tumor determine cognitive performance.
UK women living shorter lives than most European counterparts
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Women in the UK are faring worse than their European counterparts on major health indicators, a major new analysis has found.1

Public Health England’s annual health profile report notes that UK women ranked 18th out of 28 European Union member states for premature death. UK men are doing better by comparison and are ranked 10th.

And while UK male life expectancy was above the EU average in 2016 (ranked 10th), it was below average for females (ranked 17th).

While PHE’s report focuses on England, data on some indicators such as premature death and life expectancy is collected for the UK as a whole.

Life expectancy of both …
Comprehensive genomic profiling of advanced Merkel cell carcinoma to reveal insights into immunotherapy response.
Authors: Todd Cory Knepper, Jeffery Scott Russell, Meagan Montesion, Ethan Sokol, Garrett Michael Frampton, Phil Stephens, Lee A. Albacker, Michael J. Schell, James A DeCaprio, Kenneth Yee Tsai, Andrew Scott Brohl
Journal: Journal of Clinical Oncology (2018)

9523 Background: Merkel Cell Carcinoma (MCC) is a rare and aggressive neuroendocrine skin malignancy. Recently, high response rates to immune checkpoint inhibitor therapy (ICT) have been demonstrated, but predictive factors for response are lacking. We therefore performed immunogenomic analyses on a cohort of MCC patients (pts) with concurrent review of clinical outcomes. Methods: A retrospective chart review was performed to collect demographic, clinical, disease, treatment, and outcomes variables on 57 pts with advanced MCC whose tumors underwent comprehensive genomic profiling by FoundationOne testing. Genomic data were analyzed for recurrent alterations, tumor mutational burden (TMB, calculated as the number of non-driver somatic, coding mutations per megabase of genome sequenced), and mutational signatures. Presence of Merkel Cell Polyomavirus (MCPyV) was evaluated by de novo assembly of non-human sequencing reads. Results: MCC TMB demonstrated a striking bimodal distribution between TMB high (≥20 mutations/mb) and TMB low ( < 6 muts/mb) with only 4 pts having an intermediate TMB. Overall, 21/57 (36.8%) MCC samples were TMB high (median 63 muts/mb) and all carried mutations in TP53, RB1, or NOTCH1. 21/21 (100%) TMB high pts had a mutational signature consistent with UV damage. 21/32 (65.6%) TMB low (median 1 mut/mb) pts were positive for MCPyV integration as opposed to 0/25 (0%) TMB high or intermediate pts (P = 1.03e-07, Fisher's exact). 34/57 (59.6%) pts were treated with at least one ICT. Within this group, response to ICT dramatically impacted overall survival with 15/15 (100%) responders vs. 3/19 (15.8%) non-responders alive at date of last contact and significantly prolonged survival (p < 0.0001, Kaplan-Meier). 7/11 (64%) pts classified as TMB high responded to ICT compared with 8/23 (35%) low/intermediate TMB pts (p = 0.13). Viral status in the TMB low group had no significant impact on response rates, with MCPyV integration detected in 6/8 (75.0%) responders and 9/13 (69.2%) non-responders. Conclusions: Response to ICT leads to high rates of durable overall survival in advanced MCC. High TMB and prolonged UV exposure, but not viral status, are associated with higher responsiveness to ICT.
FGFR3 correlation with mutant p53 and its prognostic value in oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Zhuo Georgia Chen, Sreevinas Nannapaneni, Christopher C Griffith, Dongsheng Wang, Chao Zhang, Kelly R. Magliocca, Xu Wang, Zhengjia Chen, Mihir Patel, Conor Ernst Steuer, Dong Moon Shin, Nabil F. Saba
Journal: Journal of Clinical Oncology (2017)

6057 Background: Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. Information on its prognostic value and its correlation with other relevant cancer related proteins is limited. Methods: We performed immunohistochemistry (IHC) analyses of p16, mutant p53 (mp53), and FGFR3 on 221 retrospectively collected OPSCC tissue samples. mp53, and FGFR3 were semi-quantified as weighted index [WI = % positive x intensity (0. 1+, 2+, and 3+)]. Correlations of FGFR3 WI with p16 status, and mp53 WI were analyzed. Association of FGFR3 with disease-free survival (DFS) or overall survival (OS) was assessed. Results: A total of 144/221 (65%) were p16 +, 93/172 (54%) had mp53, and 140/221 (63%) expressed FGFR3. FGFR3 was highly correlated with mp53 (p &lt; 0.001), which was true in both p16 + and – OPSCC (p &lt; 0.0001 and p = 0.0006, respectively).mp53 level was significantly lower in p16 positive versus p16 negative group (p &lt; 0.0001). Univariate analysis revealed an association of p16 negative and high mp53 with worse OS (p &lt; 0.001 and p &lt; 0.001, respectively) and DFS (p &lt; 0.001 and p = 0.004, respectively). FGFR3 was associated with worse OS and DFS (p = 0.014 and p = 0.047, respectively). On multivariable analysis FGFR3 was associated with worse DFS (p = 0.005), but not OS. Kaplan-Meier plot using medians of both FGFR3 and mp53 as the cut-off values showed that higher FGFR3 and mp53 correlated to worst DFS (p = 0.025) and OS (p = 0.009). Conclusions: Our results suggest that FGFR3 is associated with mp53 and p16 – OPSCC and correlates with worse clinical outcome. The biologic relation of FGFR3 and mp53 in OPSCC deserves further investigation. (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).
Evaluation of liquid biopsies for molecular profiling in patients (pts) with advanced non-small cell lung cancer (NSCLC): What happens after panel testing by next generation sequencing (NGS)?
Authors: Jing Zhao, Jiqiao Shen, Xuefei Li, ChunXia Su, Caicun Zhou
Journal: Journal of Clinical Oncology (2018)

e21210 Background: Molecular profiling is limited by tumor heterogeneity and access to sufficient tissue for comprehensive analysis. ctDNA is promising as a minimally-invasive liquid biopsy for testing gene alterations and monitoring personalised treatment strategies. Because of its high expense, translation of the sensitive and accurate next generation sequencing (NGS) into routine cancer care has been slow. Methods: We retrospectively reviewed 60 advanced NSCLC pts who were performed gene test prior to treatment using tissue by ARMS. Blood collections were performed after disease progression and analysed by NGS using a 10-gene panel (EGFR, KRAS, BRAF, HER2, PIK3CA, ALK, ROS1, RET, MET and TP53). We evaluated the significance of the outcome of panel testing by NGS in guiding the subsequent treatment in clinical practice. Results: ctDNA profiling detected alterations in 50 pts (83%). TP53 (53%), EGFR (48%) and KRAS (15%) were the most common abnormalities detected. Additionally, MET (8%), ALK (3%), HER2 (3%) and PIK3CA (2%) mutations were detected, respectively. Sensitizing mutations were detected in 22 pts (37%) prior to treatment using tissue by the method of ARMS, including 20 EGFR mutations and 2 ALK fusions, and all pts received tyrosine kinase inhibitor (TKI) as first-line therapy. Among 20 EGFR mutant pts, T790M mutation was detected in 9 pts (45%), KRAS mutation was detected in 4 pts (20%), and TP53 mutation was detected in 12 pts (60%), while MET amplification was found in 1 pt (5%). 1 KRAS mutation and 1 TP53 mutation were detected in 2 ALK –TKI resistant pts, respectively. 28 pts (47%) reported as tissue negative had a positive liquid biopsy, including 4 MET 14 exon skipping mutations, 2 EGFR 19 DEL, 4 EGFR L858R and 1 EGFR L861Q, and 2 EGFR T790M mutations. The mutation abundance is all below 1%, except 2 EGFR 19 DEL and 4 L858R. Ten pts received TKIs; 2 got parcial responses, 5 stable diseases and 3 progressive disease. Conclusions: ctDNA can be used as a ‘liquid biopsy’ for NSCLC pts, and NGS, as a highly sensitive method to detect mutations with low mutation abundance, can provide more chances to pts to receive precise treatment.
Targeting the cell cycle for cancer therapy in rhabdomyosarcoma.
Authors: Elizabeth Stewart, Victoria Honnell, Monica Ocarz, Kaley Blankenship, Jason Dapper, Burgess Freeman, Anang Shelat, Alberto S. Pappo, Michael A. Dyer
Journal: Journal of Clinical Oncology (2017)

10535 Background: Rhabdomyosarcoma (RMS) is an aggressive malignancy of childhood with a poor prognosis in patients with metastatic or recurrent disease. Inhibitors of Wee1 kinase and heat shock protein 90 (HSP90) have in vitro activity in RMS and have emerged as potential novel treatment strategies. We performed a comprehensive preclinical phase III study to compare the Wee1 inhibitor AZD1775 and HSP90 inhibitor ganetespib (GANET) in combination with irinotecan (IRN) and vincristine (VCR). Methods: Orthotopic xenografts (O-PDXs) were created by injecting luciferase labeled RMS cells into the hind-leg muscle of CD-1 nude mice. Pharmacokinetic studies on RMS O-PDXs were performed to determine matched human AUC-guided dosing. A total of 540 O-PDXs derived from 4 high risk RMS patients, 2 alveolar and 2 embryonal, were randomly enrolled into 14 treatment groups. Six courses of blinded placebo-controlled therapy were given on a clinically relevant schedule. Mice were classified as having progressive disease if tumor approached 20% body weight at any time in the study. For mice completing all 6 courses, bioluminescence was used to determine complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Results: The addition of AZD1775 to IRN and VCR demonstrated the most significant response for all 4 O-PDX lines tested; 70% of mice achieved a CR or PR. GANET combined with IRN and VCR had a 54% response (CR + PR) which was not significantly better than IRN plus VCR for most O-PDXs tested. Overall response data for select treatment groups is shown in the table below. Conclusions: Comprehensive preclinical testing using multiple O-PDX models of RMS that represent the clinical spectrum of disease is feasible. Comparison of novel treatment regimens to standard of care at clinically relevant doses is warranted as justification for future clinical trials. Observation to assess durable response following completion of therapy is ongoing to determine if AZD1775 remains a promising treatment strategy. [Table: see text]
Validation of a population pharmacokinetic (PPK) model for onapristone (ONA) in patients (pts) with cancer: Analysis of 2 clinical trials.
Authors: Keyvan Rezai, Samuel Huguet, Fanny Bret, Paul H. Cottu, Gerhardt Attard, Antoine Italiano, Andrea Varga, Jacques Bonneterre, Mario Campone, Anuradha Jayaram, Alice Susannah Bexon, Erard M. Gilles, Stefan Proniuk, Charles Barranco, Alexander Zukiwski, Francois Marc Lokiec
Journal: Journal of Clinical Oncology (2016)

e14099 Background: A type I progesterone receptor (PR) antagonist that prevents PR-induced DNA transcription, ONA is being developed to target PR-expressing tumors. It has shown anti-cancer activity in preclinical models and pts with endometrial, breast, and ovarian cancer. We evaluated a population model for ONA clearance using an external validation technique in women with PRpos tumors and men with castrate-resistant prostate cancer (CRPC). Methods: PPK modeling used data from a multi-center, open-label, randomized, parallel-group, phase 1 study (NCT02052128). 52 female pts with PRpos tumors received ONA extended release (ER) or immediate release (IR) tablets. External validation assessed the ability of the PPK model to predict concentrations and clearances in 21 male pts with CRPC who received ONA ER in another study (NCT02049190). Real-time PK and PPK modeling were 2ndary endpoints of both trials. PK blood samples were collected at 4-8 time points for 12 h post-ONA on Day 1. PPK used nonlinear mixed-effect modeling to calculate: absorption constant (Ka ), apparent distribution volume (V/F), and apparent clearance (CL/F). Results: a PPK model was constructed with 488 plasma concentrations from 42 ONA ER pts and external validation used 125 concentrations in 21 CRPC pts. A 2-compartment open model adequately described the total ONA time-concentration curve with linear elimination. The main PK parameters (RSE%) were Ka = 0.34 (16) h-1, CL/F = 0.78 (23) L/h, Q = 8.1 (13) L/h, V1/F = 14.7 (23) L, V2 = 78.8 (18) L. Mean AUC0-24h (CV%) values were 14610 (40), 29870 (25), 39470 (18), 56000 (27), and 72090 (15) ng*hr/mL for 10mg, 20mg, 30mg, 40mg, and 50mg doses respectively. Upon validation, ONA CL and concentrations were well predicted (precision 20%, α = 5%). Conclusions: Our PPK model satisfactorily described the plasma time-concentration curves of ONA in pts with solid tumors. ONA has extensive tissue diffusion and AUC increased proportionally with dose. External validation of the model was successful. ONA ER PK is compatible with clinical use in patients with PRpos tumors. Clinical benefit was observed and phase 2 studies are underway in uterine endometrioid and prostate cancers. Clinical trial information: NCT02052128 and NCT02049190.
Outcomes of spinal stabilization in multiple myeloma with unstable vertebral lesions background.
Authors: Tara Rajendran, Ishwara Keerthi
Journal: Journal of Clinical Oncology (2018)

e20028 Background: Patients with multiple myeloma often present with bone pain. The main determinant of vertebral lesion is the possibility of neurological deficit. In such cases there is an opinion between radiotherapy and surgery. The advantages of surgical intervention grant immediate stability and early mobility. Methods: We present patients who underwent instrumentation surgery for symptomatic Multiple myeloma at KMC, India. NOMS paradigm was used to determine the surgical indications. Radiographs, CT and MRI are used to evaluate the lesion, presence/absence of pathological fracture and neural/spinal cord compression. Radiological features of vertebral lesions, implant positioning were evaluated for relapse/recurrence. Surgical outcome is assessed by Oswestry Disability Index (ODI). Results: Between 2012 and 2016, there were 40 patients who underwent posterior open pedicle fixation with/without spinal decompressions warranted by the neurological involvement, with average age at operation 65 years (range 40–85).There were 70% male and 30% female. 80% patients had pathological fracture and 20% had large vertebral lesions with impending fracture. 55% had neurological deficit in the form of paraparesis but none of them were paraplegic. All patients underwent spinal decompression and/or posterior pedicular instrumentation. Median survival of 3.5 years (range 30 days – 6.5 years). Pre ODI – 60 – 80% (crippling backpain), Post ODI : NIL, Radiological Outcome : 80% showed sclerosis of the vertebral lesions and 5% patients showed additional vertebral lesions in the rest of the spine and pelvis. At 1 year of follow up 80% patients were showing good response to myeloma treatment and 1 patient died. 5% patients showed disease progression and 12.5% are continuing chemotherapy. 30% were given Radiotherapy and others managed with chemo. Conclusions: Systematic symptom monitoring and prompt surgical intervention on time confers great outcome with no implant failure. Surgery also keeps the mobile soon avoiding further procoagulative diseases/infections. Quality of life and survival outcome is improved significantly.
The impact of molecular profiling guided targeted gold nanoparticles on radiosensitivity of metastatic salivary gland adenoid cystic carcinoma.
Authors: Aron Popovtzer, Inbal Hazkany, Izhak Haviv, Dimitry Bragilovski, Baruch Brenner, Rachela Popovtzer
Journal: Journal of Clinical Oncology (2016)

e17558 Background: Molecular Profiled has an established role in selection of treatment for metastic disease treatment. However its role in improving radiosensitivity and improving functional imaging has not been evaluated. The main goal of this study was evaluate the role of molecular profiling as a method to target gold nanoparticles (GNP) in order to enhance radiosensitivity in treatment of Adenoid Cystic Carcinoma (ACC). A second goal was to evaluate the effect of targeted GNP on imaging of metastatic ACC. Methods: 16 nude mice were implanted with parotid ACC found to have an Anaplastic Lymphoma Kinase (Alk) receptor mutation .The mice were treated with radiation, Crizotinib, GNP and radiation , and GNP conjugated to Crizotinib with radiation, alone or in various combinations,The mice were followed for four weeks. Results: We demonstrated that Alk targeted GNP enhanced the radiation effect and had a significant impact on tumor growth (P < 0.01) relative to radiation alone . Additionally, we demonstrated that targeted GNP had a significant effect on tumor visualization and imaging enhancement. Four weeks post injection, an ex vivo analysis using flame atomic absorption spectroscopy was conducted,The amount of GNP in the tumor after 4 weeks in the group that was irradiated with targeted GNP was twice as high as in the non targeted group. The GNP was proven to be safe as no evidence of toxicity has been observed. Conclusions: Molecular profiling can serve as a method to enhance radio- sensitivity and improve imaging in salivary gland ACC.