bluuebunny/crossref_metadata_2025 huggingface dataset:
Advancing tools to promote health equity across European Union regions: the EURO-HEALTHY project
Authors:   on behalf of the EURO-HEALTHY investigators, Santana Paula , Freitas Ângela , Stefanik Iwa , Costa Cláudia , Oliveira Mónica , Rodrigues Teresa C. , Vieira Ana , Ferreira Pedro Lopes , Borrell Carme , Dimitroulopoulou Sani , Rican Stéphane , Mitsakou Christina , Marí-Dell’Olmo Marc , Schweikart Jürgen , Corman Diana , Bana e Costa Carlos A.
Published: February 2020

Background

Population health measurements are recognised as appropriate tools to support public health monitoring. Yet, there is still a lack of tools that offer a basis for policy appraisal and for foreseeing impacts on health equity. In the context of persistent regional inequalities, it is critical to ascertain which regions are performing best, which factors might shape future health outcomes and where there is room for improvement.

Methods

Under the EURO-HEALTHY project, tools combining the technical elements of multi-criteria value models and the social elements of participatory processes were developed to measure health in multiple dimensions and to inform policies. The flagship tool is the Population Health Index (PHI), a multidimensional measure that evaluates health from the lens of equity in health determinants and health outcomes, further divided into sub-indices. Foresight tools for policy analysis were also developed, namely: (1) scenarios of future patterns of population health in Europe in 2030, combining group elicitation with the Extreme-World method and (2) a multi-criteria evaluation framework informing policy appraisal (case study of Lisbon). Finally, a WebGIS was built to map and communicate the results to wider audiences.

Results

The Population Health Index was applied to all European Union (EU) regions, indicating which regions are lagging behind and where investments are most needed to close the health gap. Three scenarios for 2030 were produced – (1) the ‘Failing Europe’ scenario (worst case/increasing inequalities), (2) the ‘Sustainable Prosperity’ scenario (best case/decreasing inequalities) and (3) the ‘Being Stuck’ scenario (the EU and Member States maintain the status quo). Finally, the policy appraisal exercise conducted in Lisbon illustrates which policies have higher potential to improve health and how their feasibility can change according to different scenarios.

Conclusions

The article makes a theoretical and practical contribution to the field of population health. Theoretically, it contributes to the conceptualisation of health in a broader sense by advancing a model able to integrate multiple aspects of health, including health outcomes and multisectoral determinants. Empirically, the model and tools are closely tied to what is measurable when using the EU context but offering opportunities to be upscaled to other settings.
The efficacy and safety comparison of first-line chemotherapeutic agents (high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide) for osteosarcoma: a network meta-analysis
Authors: Zhang Bin , Zhang Yan , Li Rongzhen , Li Jiazhen , Lu Xinchang , Zhang Yi
Published: February 2020

Background

Osteosarcoma, a primary malignant bone tumor derived from mesenchymal tissue, is the most common type of pleomorphic tumor that occurs in children and adolescents. The aim of this study was to compare the efficacy and safety of high-dose methotrexate (M), doxorubicin (D), cisplatin (C), and ifosfamide (I) in the management of osteosarcoma.

Methods

Electronic databases including PubMed, Cochrane Library, and Embase database were searched for studies published from when the databases were established to July 13, 2019. The network meta-analysis was performed using software R 3.3.2 and STATA version 41.0 after demographic and outcome data extraction. The ranks based on probabilities of interventions for each outcome were performed. In addition, the consistency of direct and indirect evidence was assessed by node splitting.

Results

The network meta-analysis results revealed that MDCI had a significant lower hazard risk of overall survival [MDCI vs MDC: HR = 0.74, 95% CrI (0.23, 0.87); MDCI vs DC: HR = 0.60, 95% CrI (0.16, 0.92)]. In addition, MDCI had a clearly longer progression-free survival time than that of DC [MDCI: HR = 0.88, 95% CrI (0.46, 0.98)]. No significant difference was detected in MDC and DC in OS, PFS, and AEs. The probabilities of rank plot showed that MDCI ranked first in OS (73.12%) and PFS (52.43%). DC was the best treatment in safety, ranked first (75.43%).

Conclusions

MDCI showed its superiority among all chemotherapeutic agents in relation to efficacy and safety, followed by MDC. In addition, MDCI was associated with an increased risk of AEs. According to our analysis, DC was less effective but safer for MDC and MDCI.
Outcomes of fertility preservation in women with endometriosis: comparison of progestin-primed ovarian stimulation versus antagonist protocols
Authors: Mathieu d’Argent Emmanuelle , Ferrier Clément , Zacharopoulou Chrysoula , Ahdad-Yata Naouel , Boudy Anne-Sophie , Cantalloube Adèle , Levy Rachel , Antoine Jean-Marie , Daraï Emile , Bendifallah Sofiane
Published: February 2020

Background

PPOS protocols, initially described for FP in women with cancer, have many advantages compared to antagonist protocols. PPOS protocols were not evaluated for women with endometriosis. The objective of the study was to describe fertility preservation outcomes in women with endometriosis and to compare an antagonist protocol with a Progestin-Primed Ovarian Stimulation (PPOS) protocol.

Method

We conducted a prospective cohort study associated with a cost-effectiveness analysis in a tertiary-care university hospital. The measured outcomes included the numbers of retrieved and vitrified oocytes, and direct medical costs. In the whole population, unique and multiple linear regressions analysis were performed to search for a correlation between individual characteristics and the number of retrieved oocyte.

Results

We included 108 women with endometriosis who had a single stimulation cycle performed with either an antagonist or a PPOS protocol. Overall, 8.1 ± 6.6 oocytes were retrieved and 6.4 ± 5.6 oocytes vitrified per patient. In the multiple regression model, age (p = 0.001), prior ovarian surgery (p = 0.035), and anti-Mullerian hormone level (p = 0.001) were associated with the number of retrieved oocytes. Fifty-four women were stimulated with an antagonist protocol, and 54 with a PPOS protocol. A mean of 7.9 ± 7.4 oocytes were retrieved in the antagonist group and 8.2 ± 5.6 in the PPOS group (p = 0.78). A mean of 6.4 ± 6.4 oocytes were vitrified in the antagonist group and 6.4 ± 4.7 in the PPOS group (p = 1). In the cost-effectiveness analysis, the PPOS protocol was strongly dominant over the antagonist protocol.

Conclusion

Fertility preservation procedures are feasible and effective for patients affected by endometriosis. Antagonist and PPOS protocols were associated with similar results but the medico-economic analysis was in favor of PPOS protocols.
Imaging of skull vault tumors in adults
Authors: Pons Escoda Albert , Naval Baudin Pablo , Mora Paloma , Cos Mònica , Hernandez Gañan Javier , Narváez José A. , Aguilera Carles , Majós Carles
Published: February 2020

The skull vault, formed by the flat bones of the skull, has a limited spectrum of disease that lies between the fields of neuro- and musculoskeletal radiology. Its unique abnormalities, as well as other ubiquitous ones, present particular features in this location. Moreover, some benign entities in this region may mimic malignancy if analyzed using classical bone-tumor criteria, and proper patient management requires being familiar with these presentations. This article is structured as a practical review offering a systematic diagnostic approach to focal calvarial lesions, broadly organized into four categories: (1) pseudolesions: arachnoid granulations, meningo-/encephaloceles, vascular canals, frontal hyperostosis, parietal thinning, parietal foramina, and sinus pericrani; (2) lytic: fibrous dysplasia, epidermal inclusion and dermoid cysts, eosinophilic granuloma, hemangioma, aneurysmal bone cyst, giant cell tumor, metastasis, and myeloma; (3) sclerotic: osteomas, osteosarcoma, and metastasis; (4) transdiploic: meningioma, hemangiopericytoma, lymphoma, and metastasis, along with other less common entities. Tips on the potential usefulness of functional imaging techniques such as MR dynamic susceptibility (T2*) perfusion, MR spectroscopy, diffusion-weighted imaging, and PET imaging are provided.
Correction to: Interoperable chemical structure search service
Authors: Kratochvíl Miroslav , Vondrášek Jiří , Galgonek Jakub
Published: February 2020

It was highlighted that the original article [1] contained an error in the last paragraph of the section ‘Structure search using SPARQL’, specifically in the radius of the used fingerprint. This Correction article shows the incorrect and correct paragraph of this section.
Effective dose and image optimisation of lateral lumbar spine radiography: a phantom study
Authors: Lai Zer Hau , Sá dos Reis Cláudia , Sun Zhonghua
Published: February 2020

Background

To investigate lateral lumbar spine radiography technical parameters for reduction of effective dose whilst maintaining image quality (IQ).

Methods

Thirty-six radiograms of an anthropomorphic phantom were acquired using different exposure parameters: source-to-detector distance (SDD) (100, 130 or 150 cm), tube potential (75, 85 or 95 kVp), tube current × exposure time product (4.5, 9, 18 mAs) and additional copper (Cu) filter (no filter, 0.1-, 0.2-, or 0.3-mm thickness. IQ was assessed using an objective approach (contrast-to-noise-ratio [CNR] calculation and magnification measurement) and a perceptual approach (six observers); ED was estimated using the PCXMC 2.0 software. Descriptive statistics, paired t test, and intraclass correlation coefficient (ICC) were used.

Results

The highest ED (0.022 mSv) was found with 100 cm SSD, 75 kVp, 18 mAs, and without Cu filter, whilst the highest CNR (7.23) was achieved at 130 cm SSD, 75 kVp, 18 mAs, and without Cu filter. The lowest ED and CNR were generated at 150 cm SDD, 95 kVp, 4.5 mAs, and 0.3-mm Cu filter. All observers identified the relevant anatomical structures on all images with the lowest ED and IQ. The intra-observer (0.61–0.79) and inter-observer (0.55–0.82) ICC ranged from moderate to excellent.

Conclusion

All relevant anatomical structures were identified on the lateral lumbar spine radiographs despite using low-dose protocols. The lowest ED (0.002 mSv) was obtained with 150 cm SDD, 95 kVp, 4.5 mAs, and 0.3-mm Cu filter. Further technical and clinical studies are needed to verify these preliminary findings.
Treatment outcomes in metastatic prostate cancer patients with DNA damage repair mutations.
Authors: Kwon Daniel , Wright Francis , Zhang Li , Chou Jonathan , Borno Hala , Desai Arpita , Oh David Yoonsuk , Pollock YaoYao Guan , Bose Rohit , Huang Franklin W. , Hope Thomas , Friedlander Terence W. , Fong Lawrence , Feng Felix Y , Small Eric Jay , Aggarwal Rahul Raj , Koshkin Vadim S
Published: February 2020

187

Background: DNA damage repair mutations (DDM) are common in prostate cancer (PCa). Optimal treatment sequence and outcomes of androgen signaling inhibitors (ASIs) and chemotherapy in this population are unclear. Methods: A retrospective, single-institution study of patients (pts) with mPCa and DDM detected on next-generation sequencing between January 2016 and July 2019 was conducted. For pts with metastatic castration-resistant prostate cancer (mCRPC), chi-squared and Wilcoxon sum rank tests were used to compare PSA50 and Time to Next Treatment (TNT) among different treatment groups, respectively. Results: Among 70 pts with mPCa and DDM, the most common mutations were BRCA2 (24, 27%), ATM (20, 22%), CDK12 (19, 21%), and MLH1/MSH2/MSH6/PMS2 (10, 11%). Fifty-seven pts (81%) received systemic treatment for mCRPC and 68% received ≥3 mCRPC treatments. Among 57 pts with ≥1 mCRPC treatment, 19 (33%) received first abiraterone, and 18 (32%) first enzalutamide. There was a trend toward higher PSA50 (74% vs 47%, P=0.196) and longer TNT (55 vs 34 wk, P=0.286) with first abiraterone vs enzalutamide. Upon switching between ASIs, 0 of 10 pts had a PSA50 response. When given chemotherapy at any point during CRPC treatment, 16/27 (59%) pts had a PSA50 response to docetaxel alone and/or cabazitaxel alone, and 14/24 (58%) to carboplatin-based regimens. Conclusions: To our knowledge, this is the largest single-institution cohort providing real-world treatment data for pts with mPCa and DDM. In the frontline mCRPC setting, abiraterone had a trend suggesting increased activity over enzalutamide that was not statistically significant. Switching ASIs at progression produced no additional responses, suggesting cross-resistance. Responses to taxanes were similar to previously reported data in all-comers. Validation in a larger, prospective cohort is needed to confirm these preliminary findings.
A multivariate logistic regression model based on 3T mpMRI, clinical, and biopsy parameters for the prediction of prostate cancer extracapsular extension.
Authors: Afshari Mirak Sohrab , Raman Steven
Published: February 2020

27

Background: Extracapsular extension (ECE) of prostate cancer (PCa) is a poor prognostic factor associated with progression, recurrence after treatment and increased PCa- related mortality. Accurate staging prior to radical prostatectomy is crucial in avoidance of positive margins and when planning nerve-sparing procedures. This study investigated the predictive value of clinical, biopsy & 3TmpMRI parameters using a multivariate logistic model for per-lesion detection of PCa ECE with wholemount histopathology (WMHP) as reference. Methods: This IRB approved, HIPAA compliant study included 575 patients with 774 true positive PCa lesions, who underwent radical prostatectomy between 7/2010-2/2019. The relationship between pathologic ECE & parameters including clinical; age, prostate specific antigen (PSA) & PSA density (PSAD), biopsy; percentage of positive systematic cores & Gleason score (GS) & 3TmpMRI; prostate volume, number of lesions per patient, size, location, level, PIRADSv2 score, laterality, apparent diffusion coefficient (ADC) value & risk of ECE on MRI was evaluated using bivariate and multivariate analysis. The accuracy of the final model was evaluated using ROC analysis. Results: 27.8% (215/774), 42.9% (332/774) & 29.3% (227/774) of the lesions were PIRADSv2 score 3, 4 & 5 & 59.9% (464/774), 24.7% (191/774) & 17.7% (137/774) were low, intermediate & high risk for ECE, respectively. 23.6% (183/774) of the lesions had ECE on WMHP. On bivariate analysis higher PSA, PSAD, percentage of positive biopsy cores, biopsy GS, size, PIRADSv2 score, ADC value, risk of ECE on MRI, location (posterior), level(midgland & base), bilaterality & lower number of lesions per patient were significant for ECE prediction. The multivariate logistic model included age, PSAD, number of lesions per patient, size, location, level, PIRADSv2 score & risk of ECE on MRI. The AUC for the prediction of ECE for this model was 0.85. Conclusions: This multivariate regression model based on clinical, biopsy & 3TmpMRI parameters have a high predictive value for pathology ECE detection.
Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): Update from the CHHiP Trial.
Authors: Dearnaley David P. , Griffin Clare , Syndikus Isabel , Khoo Vincent , Birtle Alison Jane , Choudhury Ananya , Ferguson Catherine , Graham John , O'Sullivan Joe , Panades Miguel , Rimmer Yvonne L. , Scrase Christopher D. , Staffurth John , Cruickshank Clare , Hassan Shama , Pugh Julia , Hall Emma ,   on behalf of the CHHiP Investigators
Published: February 2020

325

Background: CHHiP is a non-inferiority trial to determine efficacy and safety of hypofractionated radiotherapy for localised prostate cancer (PCa). Five year results indicated that moderate hypofractionation of 60 Gray (Gy)/20 fractions (f) was non-inferior to 74Gy/37f (Lancet Oncology, 2016). Moderate hypofractionation is now an international standard of care but with patients remaining at risk of recurrence for many years, information on long-term outcomes is important. Here we report pre-planned analysis of 8 year outcomes. Methods: Between October 2002 and June 2011, 3216 men with node negative T1b-T3a localised PCa with risk of seminal vesical involvement ≤30% were randomised (1:1:1 ratio) to 74Gy/37f (control), 60Gy/20f or 57Gy/19f. Androgen deprivation began at least 3 months prior to radiotherapy (RT) and continued until end of RT. The primary endpoint was time to biochemical failure (Phoenix consensus guidelines) or clinical failure (BCF). The non-inferiority design specified a critical hazard ratio (HR) of 1.208 for each hypofractionated schedule compared to 74Gy/37f. Late toxicity was assessed at 5 years by RTOG and LENT-SOM scales. Analysis was by intention-to-treat. Results: With a median follow up of 9.2 years, 8 year BCF-free rates (95% CI) were 74Gy: 80.6% (77.9%, 83.0%); 60Gy: 83.7% (81.2%, 85.9%) and 57Gy: 78.5% (75.8%, 81.0%). For 60Gy/20f, non-inferiority was confirmed: HR60=0.84 (90% CI 0.71, 0.99). For 57Gy/19f, non-inferiority could not be declared: HR57=1.17 (90% CI 1.00, 1.37). Clinician assessments of late toxicity were similar across groups. At 5 years, RTOG grade≥2 (G2+) bowel toxicity was observed in 14/879 (1.6%), 18/908 (2.0%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. RTOG G2+ bladder toxicity was observed in 17/879 (1.9%), 14/908 (1.5%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. Conclusions: With BCF rates over 80%, long-term follow-up confirms that 60Gy/20f is non-inferior to 74Gy/37f. Late side effects were very low across all groups. These results support the continued use of 60Gy/20f as standard of care for men with localised PCa. Clinical trial information: 97182923.
Significant localized reduction in cerebral blood flow (CBF) in regions relevant to cognitive function with enzalutamide (ENZA) compared to darolutamide (DARO) and placebo (PBO) in healthy volunteers.
Authors: Williams Steven , Mazibuko Ndaba , O’Daly Owen , Zurth Christian , Patrick Fiona , Wooldridge Caroline , Graudenz Kristina , Kuss Iris , Cole Patricia
Published: February 2020

326

Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant after correction for multiple comparisons. A linear mixed effects model was used for predetermined region of interest (ROI) analysis, with physiological parameters as nuisance regressors. Results: Drug-concentration data confirmed similar unbound exposure during MRI scans and a complete washout between treatments. No unexpected safety concerns were noted in the study. Whole-brain analysis showed a significant localized 5.2% reduction in CBF for ENZA in temporo-occipital cortices but no significant CBF reduction with DARO compared to PBO. A significant 5.9% localized reduction in CBF was measured for ENZA vs DARO. ROI analysis showed a significant reduction in CBF for ENZA vs PBO (p = 0.045) and for ENZA vs DARO (p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. A significant reduction was noted in CBF for ENZA vs PBO in right amygdala (p = 0.047). Conclusions: Compared to PBO and DARO, significant localized reductions in CBF were noted for ENZA. These results may be relevant to cognitive function (executive function, memory, and anxiety) with extended treatment and warrant further investigation. Clinical trial information: NCT03704519.
Effect of prophylactic anticoagulation on incidence of venous thromboembolism in testicular germ cell tumor patients.
Authors: Hapakova Nikola , Chovanec Michal , Rejlekova Katarina , Kalavska Katarina , Obertova Jana , Palacka Patrik , De Angelis Valentina , Sycova Zuzana , Mardiak Jozef , Mego Michal
Published: February 2020

422

Background: Testicular germ cell tumors (GCTs) are among the most common solid tumors in young males. With the availability of highly effective treatment, improving patients’ quality of life has gained more focus in recent years. Venous thromboembolism (VTE), commonly occurring in GCT patients, is associated with increased morbidity and mortality. Prophylactic anticoagulation has been shown to decrease the risk of VTE in cancer patients. In this retrospective study we evaluated the effect of low molecular weight heparin (LMWH) prophylaxis during hospitalization on incidence of VTE and outcome in GCT patients treated with first-line chemotherapy. Methods: Study population included 394 chemotherapy-naive GCT patients treated with first-line chemotherapy at the National Cancer Institute, Bratislava, Slovakia from January 2000 to December 2017. VTE was defined as any venous thrombosis or pulmonary embolism, confirmed by imaging, occurring during first-line chemotherapy. No visceral thromboses were observed. Results: Forty-one out of 394 patients (10.4%) were diagnosed with VTE on initial staging and were excluded from the analysis. Final cohort included 353 patients. LMWH prophylaxis was administered to 104 patients (29.5%), 249 patients (70.5%) did not receive prophylaxis. We observed 14 (4.0%) VTE events. The difference in VTE incidence between patients with and without prophylaxis was not statistically significant (5.8% vs. 3.2% p = 0.37). We have observed a trend to longer overall survival in patients without prophylaxis (HR = 0.61, 95%CI = 0.32-1.13, p = 0.08). Patients with extragonadal GCT receiving VTE prophylaxis had significantly shorter survival compared to patients without prophylaxis (HR = 0.29, 95%CI = 0.08-1.12, p = 0.04). Conclusions: LMWH prophylaxis was not associated with decreased VTE incidence. Moreover, it was associated with shorter survival in extragonadal GCTs. Taking into account these data, LMWH prophylaxis during hospitalization should not be used in GCT patients receiving chemotherapy.
A phase II trial of durvalumab (MEDI4736) and tremelimumab in metastatic, nontransitional cell carcinoma of the urothelial tract.
Authors: Sarfaty Michal , Ostrovnaya Irina , Teo Min Yuen , Iyer Gopa , Lee Chung-Han , Peters Vanessa , Durocher Jennifer , Regazzi Ashley Marie , McCoy Asia S. , Hettich Grace , Al-Ahmadie Hikmat , Chaim Joshua , Bajorin Dean F. , Rosenberg Jonathan E. , Funt Samuel Aaron
Published: February 2020

514

Background: Non-transitional cell carcinoma of the urothelial tract (non-TCC) includes several distinct histologies and is associated with a poor prognosis. Prospective data regarding management of patients with metastatic non-TCC is scarce. In this single-arm, phase II study, we assessed the activity and safety of durvalumab and tremelimumab in patients with metastatic non-TCC (NCT03430895). Methods: Eligible patients had unresectable/metastatic non-TCC with ECOG PS 0-1 regardless of prior therapy (except for patients with small cell carcinoma who must have progressed after chemotherapy). Patients received treatment with durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 cycles, then durvalumab 1500 mg IV Q4W for a total treatment duration of 12 months. The primary endpoint was overall response rate by RECIST 1.1. The study was planned as a Simon’s minimax two-stage design, with 13 patients planned for stage 1. If 1 or more responses were seen in stage 1, an additional 14 patients were planned to be accrued for a total of 27. Results: Thirteen patients were treated (median age 57 years; range, 33-76), including 7 (54%) with small cell carcinoma, 3 (23%) with squamous cell carcinoma, and 3 (23%) with adenocarcinoma. 11 patients (85%) had visceral metastases, and 6 patients (46%) had liver metastases. The study was terminated after stage 1 as no responses were seen; 11 patients (85%) had PD and 2 patients (15%) had SD as their best response. Median PFS was 1.8 months (95% CI 1.25, not reached [NR]) with a median follow-up of 6.8 months (range 4.3 – 18.1 months). Median OS was 6.43 months (95% CI 4.36, NR). Grade 3-4 treatment-related adverse events occurred in 31% of patients. Conclusions: In this poor prognosis cohort of patients with non-TCC, no responses were seen with durvalumab and tremelimumab. Immune correlative studies to help determine mechanisms of resistance will be presented. Novel therapeutic strategies are urgently needed for patients with metastatic non-TCC. Clinical trial information: NCT03430895.
Tumor infiltrating lymphocytes (TIL) assessment in muscle invasive bladder cancer (MIBC) patients treated with cisplatin-based neoadjuvant chemotherapy (NAC) and surgery.
Authors: Martinez Chanza Nieves , Hamid Anis , Salgado Roberto , Gevaert Thomas , Maetens Marion , Rorive Sandrine , Aftimos Philippe Georges , Sideris Spyridon , Gil Thierry , Awada Ahmad , Roumeguere Thierry Andre
Published: February 2020

547

Background: Cisplatin-based NAC followed by surgery is the gold standard treatment of non-metastatic MIBC. However, predictive biomarkers have not been established yet. Here, we addressed the relevance of TILs for NAC response and prognosis in MIBC patients (pts). Methods: We conducted a single center, retrospective cohort analysis of consecutive MIBC pts treated with cisplatin-based NAC followed by surgery. Pts with pathological complete response (pCR; ypT0/isN0) were grouped as responders, pts with pathological residual disease as non responders. TIL stromal count were assessed pre- and post-NAC. Next Generation Sequencing of selected genes was performed on pre-NAC samples. We catalogued the 3-years(y) relapse free rate and 3-y overall survival rate (OS, Kaplan Meier) for the overall cohort and by subgroups. Results: Of the 25 pts who received cisplatin-gemcitabine NAC, a total of 14 (56%) pts achieved a pCR and 11 (44%) had residual disease. NAC was discontinued in 17 (65%) after completing treatment; and in 8 (32%) pts after 2 cycles due to toxicity. Median follow-up was 54.2 months(mos). At baseline, median TIL count was 60% in the overall cohort. Numerically higher TIL count was observed among responders (80%) compared to non-responders (50%) ( p=0.22). Median TIL count post-NAC in residual samples was 40%, not significantly different to matched pre-NAC samples ( p=0.93). Overall, 3-y relapse free rate was 74.7% (95%CI 51.7-87.9); 3-y OS rate was 79.6% (95%CI 57.6-91) with 6 deaths of which 4 were related to metastatic disease. Table reports subset analyses. Most frequently altered genes were PIK3CA and TP53 in the overall cohort (each 20%) and in the responders subgroup (each 29%). Conclusions: In our study, pts who achieved pCR had numerically greater TIL infiltrate in baseline samples and pCR was associated with reduced risk of recurrence. TILs did not increase in residual tumors after NAC. The independent predictive value of TILs warrants assessment in large cohorts.[Table: see text]
Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Tannir Nizar M. , McDermott David F. , Escudier Bernard , Hammers Hans J. , Aren Osvaldo Rudy , Plimack Elizabeth R. , Barthelemy Philippe , Neiman Victoria , George Saby , Porta Camillo , Powles Thomas , Donskov Frede , Grimm Marc-Oliver , Amin Asim , Tykodi Scott S. , Tomita Yoshihiko , Rini Brian I. , McHenry M. Brent , Saggi Shruti Shally , Motzer Robert J.
Published: February 2020

609

Background: N+I demonstrated superior OS and ORR v S in intention-to-treat (ITT) and intermediate/poor-risk (IP) pts with aRCC in CheckMate 214. Here, we report OS, response outcomes per independent radiology review committee (IRRC), and safety with extended min follow-up of 42 mo. Methods: Pts with clear cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg Q3W×4 and then N 3 mg/kg Q2W, or S 50 mg daily for 4 wk on, 2 wk off. Endpoints were OS, ORR, and PFS per IRRC using RECIST v1.1 in IP (primary), ITT (secondary), and favorable pts (FAV; exploratory). Results: OS remained superior in ITT (HR 0.72) and IP (HR 0.66) pts with N+I v S (Table). ORR per IRRC was higher and more responses were ongoing with N+I v S (68% v 53% [ITT] and 68% v 52% [IP]). More pts achieved complete response (CR) with N+I and these were ongoing in 86% [ITT] and 84% [IP] of pts. The PFS probability with N+I stabilized after 24 mo at ~35% in ITT and IP pts, whereas probabilities declined over time with S. Among FAV pts, while ORR was 29% with N+I v 54% with S, more pts achieved CR (13% v 6%), and more responses were ongoing (69% v 54%) with N+I v S; 94% of CRs in FAV pts were ongoing with N+I. OS benefits were similar in both arms and PFS probabilities are stabilizing with N+I and declining with S in FAV pts. The incidence of any and grade 3–4 treatment-related AEs was consistent with previous reports and no new drug-related deaths occurred in either arm. Response outcomes per investigator will also be reported. Conclusions: Superior OS and ORR with N+I v S was maintained in ITT and IP pts. More pts treated with N+I experienced CR compared with S, responses and CRs were durable, and PFS probabilities stabilized with N+I after extended follow-up. No new safety signals emerged. Clinical trial information: NCT02231749 .[Table: see text]
Cabozantinib real-world effectiveness in the first through fourth-line settings for the treatment of metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Gan Chun Loo , Dudani Shaan , Wells Connor , Donskov Frede , Pal Sumanta K. , Dizman Nazli , Rathi Nityam , Beuselinck Benoit , Yan Flora , Lalani Aly-Khan A. , Hansen Aaron Richard , Szabados Bernadett , de Velasco Guillermo , Tran Ben , Lee Jae-Lyun , Vaishampayan Ulka N. , Bjarnason Georg A. , Subasri Mathushan , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2020

639

Background: Cabozantinib (Cabo) is approved for mRCC patients based on the METEOR and CABOSUN trials. The real-world effectiveness of Cabo in mRCC patients in the first- (1L), second- (2L), third- (3L) and fourth-line (4L) settings requires characterization. Methods: This retrospective analysis included mRCC patients who were treated with Cabo and stratified using IMDC risk groups. Overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were calculated. Results: A total of 413 patients (82.6% with clear cell and 17.4% non-clear cell) were identified. The median age was 57 years. Overall, 63% of patients had a Karnofsky performance status score of >80 and 82.6% had prior nephrectomy. 23.1%, 75.4% and 88.3% of patients received immunotherapy as a prior line of treatment, before receiving Cabo in the 2L, 3L and 4L settings, respectively. For patients treated with 1L PD(L)1 combination or monotherapy (n=31), 2nd line Cabo had ORR of 20.8%, median TTF of 5.4 months and median OS of 17.4 months. When segregated into IMDC favorable, intermediate, and poor risk groups, the median OS was 34.8 months (95% CI 5.52-NR), 18.0 months (12.3-35.6) and 9.8 months (7.4-20.8), p=0.0088, respectively for 2L Cabo; and 31.5 months (23.6-39.3), 20.5 months (10.1-21.8), and 6.9 months (4.1-10.9), p=<0.0001), respectively for 3L Cabo. Conclusions: The ORR and TTF of Cabo were maintained from the 1L to the 4L therapy settings. In the 2L and 3L settings, the IMDC criteria appropriately stratified patients into favorable, intermediate and poor risk groups for OS. Cabo has activity after first line immunotherapy.[Table: see text]
Expectations for overall survival in mRCC patients who were selected for upfront cytoreductive nephrectomy in the targeted therapy era.
Authors: Abel E. Jason , Karam Jose A. , Spiess Philippe E. , Raman Jay D. , Sexton Wade J. , Zemp Logan , Bilotta Alyssa , Patil Dattatraya , Allen Glenn O. , Lauer Kate V. , Shapiro Daniel D. , Matin Surena F. , Wood Christopher G.
Published: February 2020

646

Background: Surgical selection is critical to obtain the best outcomes for mRCC patients treated with cytoreductive nephrectomy (CN). Prior studies suggest that international metastatic disease consortium (IMDC) poor risk patients should not be considered for upfront CN because of expectation for short overall survival (OS). The purpose of this study is to evaluate OS among IMDC risk categories for patients treated with upfront cytoreductive nephrectomy during the targeted therapy era at five independent institutions. Methods: After IRB approval, data for consecutive mRCC patients treated with CN at 5 institutions from 2006-2017 was analyzed. Kaplan-Meier method was used to estimate survival from date of surgery and univariate/multivariable Cox models were used to evaluate associations with OS. Results: Of 1163 patients who were treated with CN at 5 institutions, 914 (79%) patients were treated without neoadjuvant systemic therapies. Preoperative IMDC risk category for upfront CN patients was favorable in 71 (8%), intermediate in 598 (65%), and poor in 245 (27%) patients. Median age was 61 (53-68) and median Charlson co-morbidity index was 1 (0-2). Median (IQR) patient follow-up for patients alive at last follow-up was 42.7 months (23, 69). The median OS (IQR) following upfront nephrectomy was 115.4 months (33,NR) for favorable risk patients, 28.6 months (9-65) for intermediate risk patients and 21.8 months (10-47) for poor risk patients. No differences were identified in OS among 5 different institutions (p=0.11) Of 245 poor risk patients, OS was not associated with co-morbidity status or age were not associated with OS (p=0.77, 0.92). Percentage survival at 1, 2, 3 and 5 years was 69%, 48%, 34%, and 20% in the poor risk cohort. Conclusions: Conclusions: After stratification by the IMDC model, observed survival following upfront cytoreductive nephrectomy in this multi-institutional cohort was longer than expected from prior studies, which may be partially attributed to surgical selection bias.
SHR3680, a novel antiandrogen, for the treatment of metastatic castration-resistant prostate cancer (mCRPC): A phase I/II study.
Authors: Qin Xiaojian , Han Weiqing , Luo Hong , Du Chuanjun , Zou Qing , Sun Zhongquan , He Chaohong , Zhu Shaoxing , Chong Tie , Yao Xin , Wan Ben , Gu Weijie , Ye Dingwei
Published: February 2020

90

Background: SHR3680 is a novel and pure androgen-receptor (AR) antagonist that shows a potent antitumor activity against CRPC but with much less brain distribution than enzalutamide in preclinical study. In this first-in-human phase 1/2 study, the safety and efficacy of SHR3680 were assessed in patients with mCRPC. Methods: This phase 1/2 study was conducted in 11 hospitals in China. Patients with progressive mCRPC that was not previously treated with novel AR-targeted agents were eligible for this study. In the phase 1 part, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg. In phase 2, patients were randomized to receive one of three daily doses of SHR3680 (80 mg, 160 mg, and 240 mg). The primary endpoint in phase 1 was safety and tolerability, and in phase 2 was the proportion of patients with a PSA response (≥50% decrease of PSA level at week 12). Results: From Apr 2016 to Sep 2018, a total of 197 patients (median age 67 years, range 45−80; visceral metastases in 29 patients; previous chemotherapy history in 80 patients) were enrolled (phase 1, n = 18; phase 2, n = 179). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Most adverse events were grade 1/2 (87.3%). The most common adverse events were anemia (22.8%), back pain (16.2%), and proteinuria (13.2%). The antitumor activity was observed at all doses, including PSA response in 134 (68.7%) of 195 evaluable patients, stabilized bone disease in 169 (86.7%) of 195 patients at week 12, and responses in soft tissue lesions in 22 (36.7%) of 60 patients. No obvious dose-related activity benefits were found. As of Sep 26, 2019, the median time to PSA progression was 36 weeks (95% CI 24−47), while that to radiological progression was 73 weeks (95% CI 49−96). As expected, patients without previous chemotherapy showed relatively longer time to PSA and radiological progression than those with previous chemotherapy. Conclusions: SHR3680 is safe and well tolerated, and exhibits high efficacy in mCRPC patients. Clinical trial information: NCT02691975.
A phase Ib/II open-label study of tazemetostat (TAZ) plus enzalutamide (E) or abiraterone/prednisone (A/P) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Abida Wassim , Bradley Thomas Paul , Rezazadeh Arash , Karsh Lawrence Ivan , Ross Ashley , Saltzstein Daniel , Argon Evren Kocabas , Hamlett Anthony , Tang Jeanie , Adib Deyaa
Published: February 2020

TPS255

Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors (AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily [BID]) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.
A phase II pilot study of the efficacy and safety of nivolumab and ipilimumab in T1aN0M0 renal cell carcinoma patients ineligible for surgical treatment.
Authors: Tsimafeyeu Ilya , Volkova Maria , Gafanov Rustem Airatovich , Nosov Dmitry , Bex Axel
Published: February 2020

TPS769

Background: Surgery remains the standard curative-intent therapy for localized renal cell carcinoma (RCC). Thus, systemic therapy for RCC should only be considered in patients who have contraindications to surgery. The phase 3 CheckMate 214 trial showed that a combination of nivolumab and ipilimumab has a significant impact on tumor burden in intermediate- and poor-risk metastatic RCC patients with a complete response rate of 11%. Median time to objective response was 2.8 months. Among all complete responders to nivolumab plus ipilimumab in the intention-to-treat population, 5% achieved a complete response at the first scan. We hypothesize that this combination could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) for any reason (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.) or with preference to have no surgery or intervention for any reason will receive combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint is complete response rate. Simon's two-stage design (Simon, 1989) is used. The null hypothesis that the true complete response rate is 11% will be tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). In the first stage, 3 patients will be accrued. If there are no complete responses in these 3 patients, the study will be stopped. Otherwise, 5 additional patients will be accrued for a total of 8. The null hypothesis will be rejected if 3 or more responses are observed in 8 patients. Clinical trial information: NCT04134182.
Utility of Circulating Tumor DNA in the Management of Patients With GI Stromal Tumor: Analysis of 243 Patients
Authors: Arshad Junaid , Roberts Ali , Ahmed Jibran , Cotta Jared , Pico Brian A. , Kwon Deukoo , Trent Jonathan C.
Published: February 2020

PURPOSE

GI stromal tumor (GIST) is the most common sarcoma of the GI tract. Management of patients with GIST is determined by KIT, PDGFRA, or other genomic alterations. Tissue-based next-generation sequencing (NGS) analysis is the standard approach for diagnosis, prognosis, and treatment selection. However, circulating tumor DNA (ctDNA)–based NGS is a novel and noninvasive alternative.

METHODS

ctDNA sequencing results were evaluated in blood samples from 243 de-identified patients within the Guardant360 database. Under an approved institutional review board protocol, a retrospective analysis was performed on 45 single-institution patients.

RESULTS

Of 243 patients, 114 (47%) were women, and the median age was 59 years (range, 17-90 years). Patients with no alterations and variations of uncertain significance were excluded. Of the 162 patients with known pathogenic mutations, KIT was the most common (56%), followed by NF (7%), PDGFRA (6%), PI3KCA (6%), KRAS (5%), and others (6%). Most tumors harbored an actionable KIT or PDGFRA mutation. Our institutional cohort (n = 45) had 16 (35%) KIT exon 11 mutations, 3 (6%) KIT exon 9 mutations, and 1 (2%) PDGFRA mutation detected on ctDNA. Resistance mutations were observed in KIT exon 17 (8 patients), exon 13 (3 patients), and in both (3 patients). Our comparison of ctDNA with tissue NGS revealed a positive predictive value (PPV) of 100%. Failure of concordance was observed in patients with localized or low disease burden. From the time of ctDNA testing, the median overall survival was not reached, whereas the median progression-free survival was 7 months.

CONCLUSION

ctDNA provides a rapid, noninvasive analysis of current mutations with a high PPV for patients with metastatic GIST. ctDNA-based testing may help to define the optimal choice of therapy on the basis of resistance mutations and should be studied prospectively.
Disease recovery in bats affected by white-nose syndrome
Authors: Fuller Nathan W. , McGuire Liam P. , Pannkuk Evan L. , Blute Todd , Haase Catherine G. , Mayberry Heather W. , Risch Thomas S. , Willis Craig K. R.
Published: February 2020

Processes associated with recovery of survivors are understudied components of wildlife infectious diseases. White-nose syndrome (WNS) in bats provides an opportunity to study recovery of disease survivors, understand implications of recovery for individual energetics, and assess the role of survivors in pathogen transmission. We documented temporal patterns of recovery from WNS in little brown bats (Myotis lucifugus) following hibernation to test the hypotheses that: 1) recovery of wing structure from WNS matches a rapid timescale (i.e., about 30 days) suggested by data from free-ranging bats; 2) torpor expression plays a role in recovery; 3) wing physiological function returns to normal alongside structural recovery; and 4) pathogen loads decline quickly during recovery. We collected naturally infected bats at the end of hibernation, brought them into captivity, and quantified recovery over 40 days by monitoring body mass, wing damage, thermoregulation, histopathology of wing biopsies, skin surface lipids, and fungal load. Most metrics returned to normal within 30 days although wing damage was still detectable at the end of the study. Torpor expression declined overall throughout the study but bats expressed relatively shallow torpor bouts, with a plateau in minimum skin temperature, during intensive healing between about days 8 and 15. Pathogen loads were nearly undetectable after the first week of the study , but some bats were still detectably infected at day 40. Our results suggest that healing bats face severe energetic imbalance during early recovery from direct costs of healing and reduced foraging efficiency. Management of WNS should not rely solely on actions during winter but should also aim to support energy balance of recovering bats during spring and summer.
Dithiazolylthienothiophene Bisimide-Based π-Conjugated Polymers: Improved Synthesis and Application to Organic Photovoltaics as P-Type Semiconductor
Authors: Teshima Yoshikazu , Saito Masahiko , Mikie Tsubasa , Komeyama Kimihiro , Yoshida Hiroto , Osaka Itaru
Published: February 2020

Dithiazolylthienothiophene bisimide (TzBI) is a promising building unit for donor-acceptor π-conjugated polymers due to its strong electron-deficiency and high coplanarity. We previously reported a TzBI-based π-conjugated polymer functioned as n-type semiconductor in organic photovoltaic cells. However, a critical deficiency was that the molecular weight of the polymer was not sufficiently high. It is also important to investigate the possibility of TzBI-based polymers as a p-type semiconductor. In this study, we show that a new synthetic approach gave a new TzBI-based polymer with an improved molecular weight relative to the previously reported polymer. Further, having a co-building unit with a more electron-rich nature, the polymer functioned as p-type semiconductor in organic photovoltaic cells when the PC61BM was used as n-type material. This study shows that TzBI is a versatile building unit for π-conjugated polymers that can be used in organic electronic devices.