bluuebunny/crossref_metadata_2025 huggingface dataset:
Stroke progression and clinical outcome in ischemic stroke patients with a history of migraine
Authors: Mulder Inge A , Holswilder Ghislaine , van Walderveen Marianne AA , van der Schaaf Irene C , Bennink Edwin , Horsch Alexander D , Kappelle L Jaap , Velthuis Birgitta K , Dankbaar Jan Willem , Terwindt Gisela M , Schonewille Wouter J , Visser Marieke C , Ferrari Michel D , Algra Ale , Wermer Marieke JH ,   for the DUST investigators
Published: May 2019

Background

Patients with migraine might be more susceptible of spreading depolarizations, which are known to affect vascular and neuronal function and penumbra recovery after stroke. We investigated whether these patients have more severe stroke progression and less favorable outcomes after recanalization therapy.

Methods

We included patients from a prospective multicenter ischemic stroke cohort. Lifetime migraine history was based on the International Classification of Headache Disorders II criteria. Patients without confirmed migraine diagnosis were excluded. Patients underwent CT angiography and CT perfusion <9 h of onset and follow-up CT after three days. On admission, presence of a perfusion deficit, infarct core and penumbra volume, and blood brain barrier permeability (BBBP) were assessed. At follow-up we assessed malignant edema, hemorrhagic transformation, and final infarct volume. Outcome at three months was evaluated with the modified Rankin Scale (mRS). We calculated adjusted relative risks (aRR) or difference of means (aB) with regression analyses.

Results

We included 600 patients of whom 43 had migraine. There were no differences between patients with or without migraine in presence of a perfusion deficit on admission (aRR: 0.98, 95%CI: 0.77–1.25), infarct core volume (aB: -10.8, 95%CI: -27.04–5.51), penumbra volume (aB: -11.6, 95%CI: -26.52–3.38), mean blood brain barrier permeability (aB: 0.08, 95%CI: -3.11–2.96), malignant edema (0% vs. 5%), hemorrhagic transformation (aRR: 0.26, 95%CI: 0.04–1.73), final infarct volume (aB: -14.8, 95%CI: 29.9–0.2) or outcome after recanalization therapy (mRS > 2, aRR: 0.50, 95%CI: 0.21–1.22).

Conclusion

Elderly patients with a history of migraine do not seem to have more severe stroke progression and have similar treatment outcomes compared with patients without migraine.
A controlled trial to investigate whether the orientation of the bevel and angle of approach determine the side of endobronchial intubation in an adult manikin
Authors: Dawson SR , McConaghy PM , Barr RC
Published: May 2019

One of the commonest complications of endotracheal intubation occurs when the tip of the endotracheal tube passes distal to the carina and enters one of the main bronchi. The perioperative practitioner may observe high airway pressures, hypoxia or even pneumothorax. The most common reason given for the high incidence of right endobronchial intubation is that the right main bronchus comes off the trachea at a more acute angle from the midline. We sought, however, to explore two other factors which may explain this phenomenon – the angle of the tube’s bevel and its trajectory of approach. We conducted a prospective controlled trial in which doctors from our department intubated the trachea of an adult manikin in three distinct sets using standard tube, reversed tubes and reversed laryngoscope blades. We found that the angle of the bevel and trajectory of approach determines the side of endobronchial intubation in an adult manikin.
Risk factors and mitigation of influenza among Indigenous children in Australia, Canada, United States, and New Zealand: a scoping review
Authors: McLeod C , Adunuri N , Booth R
Published: May 2019

Aim:

This review considers prominent risk factors and mitigation strategies of influenza among Indigenous children.

Methods:

Seven electronic databases were searched from the period of 2004–2017 to locate articles discussing influenza among Indigenous children in the developed circumpolar nations of Australia, Canada, United States, and New Zealand. Articles selected for inclusion discussed influenza among Indigenous children as either individuals or as a part of a community. Ancestry searches of articles meeting the review criteria were also undertaken to discern seminal research in this topic area.

Results:

From the 39 primary research studies included, marked risk factors and mitigation strategies of influenza among Indigenous children were identified using inductive analysis. Notable risk factors included age under 2 years, cigarette smoke exposure, presence of a chronic illness, and crowded living conditions. Successful mitigation of influenza for Indigenous children included strategies to improve vaccine coverage, provision of health education, and policy change.

Conclusion:

In the past, the impact of influenza upon Indigenous communities has been devastating for both children and their families. By utilizing existing public health infrastructure and collaborating with culturally unique Indigenous groups, preventive action for Indigenous children at significant risk of contracting influenza can be realized.
Cloning, Expression, Purification, and Preliminary Characterization of Single-Crystal X-Ray Diffraction of Glucosyltransferase B of Streptococcus mutans
Authors: Mieher Joshua L. , Schormann Norbert , Patel Manisha , Wu Hui , Deivanayagam Champion
Published: May 2019

Dental caries characterized by acid damage of tooth enamel is a persistent disease that begins with the formation of biofilms on the tooth surface. The secreted glucosyltransferases enable Streptococcus mutans to synthesize extracellular glucan polymers using ingested starch within the oral cavity, which eventually results in the production of acid, a contributing factor to cariogenesis. In this paper, we report the cloning, expression, purification, crystallization, and preliminary X-ray diffraction characterization of glucosyltransferase B.
Quassinoids and Alkaloids From the Roots of Eurycoma longifolia
Authors: Dang Nguyen Hai , Lan Do Thi Ngoc , Thu Minh Nguyen Thi , Khanh Nguyen Duy , Trang Duong Thu , Cuong Pham Van , Hiep Nguyen Tuan , Nam Vu Duc , Trung Nguyen Quang , Dat Nguyen Tien
Published: May 2019

Five quassinoids and 2 alkaloids were isolated from the roots of Eurycoma longifolia. The structures of 3 new quassinoids, eurycomalide F, G, and H (1-3), were elucidated using a variety of spectroscopic methods. The known compounds were identified as eurycomalide A (4), laurycolactone B (5), 5-methoxycanthin-6-one (6), and canthin-6-one (7). Among the isolated compounds, canthin-6-one (7) exhibited the strongest inhibitory effect on nitric oxide production (IC50 = 16.9 μM). 5-Methoxycanthin-6-one (6) and eurycomalide F (1) exhibited weak inhibition with IC50 values of 23.4 and 32.7 μM, respectively.
Langerin-Heparin Interaction: Analysis of the Binding to the Non-Lectin Site
Authors: José García-Jiménez M. , Corzana Francisco , De Paz José L. , Nieto Pedro M.
Published: May 2019

Langerin is a C-type lectin involved in the immune response that forms a trimer in its active form. It can interact with carbohydrates using 2 sites with different selectivity, the C-lectin site, a Ca2+-mediated binding, and the cleft between chains. Here we report the complementary analysis of the interaction between a heparin-like hexasaccharide 1 and langerin at the second site.
Impact of Platelet-Rich Plasma Use on Pain in Orthopaedic Surgery: A Systematic Review and Meta-analysis
Authors: Johal Herman , Khan Moin , Yung Shu-hang Patrick , Dhillon Mandeep S. , Fu Freddie H. , Bedi Asheesh , Bhandari Mohit
Published: May 2019

Context:

Amid extensive debate, evidence surrounding the use of platelet-rich plasma (PRP) for musculoskeletal injuries has rapidly proliferated, and an overall assessment of efficacy of PRP across orthopaedic indications is required.

Objectives:

(1) Does PRP improve patient-reported pain in musculoskeletal conditions? and (2) Do PRP characteristics influence its treatment effect?

Data Sources:

MEDLINE, EMBASE, Cochrane, CINAHL, SPORTDiscus, and Web of Science libraries were searched through February 8, 2017. Additional studies were identified from reviews, trial registries, and recent conferences.

Study Selection:

All English-language randomized trials comparing platelet-rich therapy with a control in patients 18 years or older with musculoskeletal bone, cartilage, or soft tissue injuries treated either conservatively or surgically were included. Substudies of previously reported trials or abstracts and conference proceedings that lacked sufficient information to generate estimates of effect for the primary outcome were excluded.

Study Design:

Systematic review and meta-analysis.

Level of Evidence:

Level 1.

Data Extraction:

All data were reviewed and extracted independently by 3 reviewers. Agreement was high between reviewers with regard to included studies.

Results:

A total of 78 randomized controlled trials (5308 patients) were included. A standardized mean difference (SMD) of 0.5 was established as the minimum for a clinically significant reduction in pain. A reduction in pain was associated with PRP at 3 months (SMD, –0.34; 95% CI, –0.48 to –0.20) and sustained until 1 year (SMD, –0.60; 95% CI, –0.81 to –0.39). Low- to moderate-quality evidence supports a reduction in pain for lateral epicondylitis (SMD, –0.69; 95% CI, –1.15 to –0.23) and knee osteoarthritis (SMD, –0.91; 95% CI, –1.41 to –0.41) at 1 year. PRP characteristics did not influence results.

Conclusion:

PRP leads to a reduction in pain; however, evidence for clinically significant efficacy is limited. Available evidence supports the use of PRP in the management of lateral epicondylitis as well as knee osteoarthritis.
When Is It Safe to Return to Sport After ACL Reconstruction? Reviewing the Criteria
Authors: Kaplan Yonatan , Witvrouw Erik
Published: May 2019

Context:

There is an ever-increasing trend toward sports, fitness, and recreation activities, so the incidence of anterior cruciate ligament sports injuries has increased. Perhaps the greatest challenge for sports clinicians is to return the injured athlete back to his/her original sport at an even greater level of functional ability than preinjury. For this, rigorous and well-researched criteria are needed.

Evidence Acquisition:

Using medical subject headings and free-text words, an electronic search was conducted up to October 2018. Subject-specific search was based on the terms return to play and return to sport in combination with guidelines, criteria, and anterior cruciate ligament reconstruction.

Study Design:

Descriptive review.

Level of Evidence:

Level 2.

Results:

Five principal criteria were found, including psychological factors, performance/functional tests, strength tests, time, and modifiable and nonmodifiable risk factors.

Conclusion:

The psychological readiness of the player is a major factor in successful safe return to sport (SRTS) decision making. Although strength, performance, and functional tests presently form the mainstay of SRTS criteria, there exists very little scientific evidence for their validity. More protection should be provided to athletes with known risk factors. Movement quality is important, if not more important than the quantifiable measures. As a result of the significantly high rerupture rate in young individuals, delayed SRTS should be considered preferably beyond 9 months postsurgery.
Psychometric and Clinimetric Validity of the Modified 25-Item Sino-Nasal Outcome Test
Authors: Tait Sarah D. , Kallogjeri Dorina , Chidambaram Smrithi , Schneider John , Piccirillo Jay F.
Published: May 2019

Background

Productivity losses are a significant part of the disease burden associated with rhinosinusitis, but existing measures of disease-specific quality of life exclude explicit assessment of the impact of the disease on productivity.

Objective

The objective of this study was to evaluate the clinimetric and psychometric validity of the 25-item Sino-Nasal Outcome Test (SNOT-25), a modified version of the SNOT-22.

Methods

This was a prospective cohort study conducted at an academic medical center. Participants included adult patients with rhinosinusitis who presented for routine visits to the Washington University in St. Louis School of Medicine otolaryngology clinic between August 2016 and March 2017.

Results

The SNOT-25 was created with the addition of three productivity-specific items to the SNOT-22 instrument. A total of 120 rhinosinusitis patients completed all baseline measurements and 94 (78.3%) completed 3-month follow-up. The Cronbach’s α was 0.83, indicating high internal consistency. Rhinosinusitis patients had on average a 24-point higher baseline SNOT-25 score (95% confidence interval [CI]: 13–35) as compared to healthy controls indicating good discriminative validity. There was high correlation between SNOT-25 scores at 3 months and 3.5 months ( r = .81; 95% CI, 0.73–0.87) confirming strong test–retest reliability. SNOT-25 had a strong correlation with the overall score of the Nasal Obstruction Symptom Evaluation instrument ( r = .55; 95% CI, 0.42–0.65), and among Short Form-36 subscales, the strongest correlations existed between SNOT-25 and the fatigue scale ( r = −.522; 95% CI, −0.63 to −0.39). Exploratory factor analysis revealed that the 3 new questions of SNOT-25 loaded together with reduction in productivity and concentration items on a new “productivity” factor.

Conclusion

The SNOT-25 is a valid instrument that can be used to assess rhinosinusitis disease burden including the impact on productivity and may be a better predictor of treatment decisions and outcomes.
Prolonged Response to Pembrolizumab in Spindle Cell Squamous Cell Carcinoma Metastatic to the Central Nervous System
Authors: Liu Yuxin , Fitzgerald Bailey , Perry Edward , Pathak Ashutosh , Chao Herta H.
Published: May 2019

Background. Cutaneous squamous cell carcinoma is a common type of skin cancer, with aggressive metastatic or locally advanced disease representing an uncommon minority of presentations. Emerging data have supported the Food and Drug Administration approval of the anti-PD1 human monoclonal antibody cemiplimab in select patients with advanced disease. However, there is limited data regarding durability of effect and generalizability of anti-PD1 effectiveness across therapies. Additionally, information regarding applicability of these regimens to the rare spindle cell variant and to central nervous system metastases for cutaneous squamous cell carcinoma is unfortunately limited. Case Presentation. A 72-year-old gentleman presented with facial neurological deficits and a dermal nodule and was diagnosed with spindle cell squamous cell carcinoma with perineural invasion. His course was notable for early intracranial metastasis with progressive neurological deficits despite recurrent radiation therapy with intermittent response. When progressive left-sided weakness prompted imaging evaluation that was concerning for disease recurrence after exhaustion of radiation therapy options, the patient was started on systemic therapy with the anti-PD-1 monoclonal antibody treatment prior to the approval of cemiplimab. Pembrolizumab was chosen due to the fact that the patient was ineligible for clinical trials and for its every 21-day dosing. With this treatment, he has achieved a durable clinical response, resulting in near resolution of neurological deficits and more than a year of progression-free survival to date, despite aggressive intracranial disease. Conclusions. This case suggests that anti-PD-1 therapy with pembrolizumab may represent an effective and well-tolerated treatment for patients with metastatic spindle cell squamous cell carcinoma including patients with metastatic disease to the central nervous system.
Comparing Rapid and Traditional Forward-Masked Spatial Tuning Curves in Cochlear-Implant Users
Authors: Kreft Heather A. , DeVries Lindsay A. , Arenberg Julie G. , Oxenham Andrew J.
Published: May 2019

A rapid forward-masked spatial tuning curve measurement procedure, based on Bekesy tracking, was adapted and evaluated for use with cochlear implants. Twelve postlingually-deafened adult cochlear-implant users participated. Spatial tuning curves using the new procedure and using a traditional forced-choice adaptive procedure resulted in similar estimates of parameters. The Bekesy-tracking method was almost 3 times faster than the forced-choice procedure, but its test–retest reliability was significantly poorer. Although too time-consuming for general clinical use, the new method may have some benefits in individual cases, where identifying electrodes with poor spatial selectivity as candidates for deactivation is deemed necessary.
Using a Health Economic Framework to Prioritize Quality Indicators: An Example With Smoking Cessation in Chronic Obstructive Pulmonary Disease
Authors: Nam Austin , Naimark David M. J. , Stanbrook Matthew B. , Krahn Murray D.
Published: May 2019

Background. Health care performance monitoring is a major focus of the modern quality movement, resulting in widespread development of quality indicators and making prioritizations an increasing focus. Currently, few prioritization methods of performance measurements give serious consideration to the association of performance with expected health benefits and costs. We demonstrate a proof-of-concept application of using a health economic framework to prioritize quality indicators by expected variations in population health and costs, using smoking cessation in chronic obstructive pulmonary disease (COPD) as an example. Methods. We developed a health state transition, microsimulation model to represent smoking cessation practices for adults with COPD from the health care payer perspective in Ontario, Canada. Variations in life years, quality-adjusted life years (QALYs), and lifetime costs were associated with changes in performance. Incremental net health benefit (INHB) was used to represent the joint variation in mortality, morbidity, and costs associated with the performance of each quality indicator. Results. Using a value threshold of $50,000/QALY, the indicators monitoring assessment of smoking status and smoking cessation interventions were associated with the largest INHBs. Combined performance variations among groups of indicators showed that 81% of the maximum potential INHB could be represented by three out of the six process indicators. Conclusions. A health economic framework can be used to bring dimensions of population health and costs into explicit consideration when prioritizing quality indicators. However, this should not preclude policymakers from considering other dimensions of quality that are not part of this framework.
A family-based multimedia intervention to enhance the uptake of colorectal cancer screening among older South Asian adults in Hong Kong: a study protocol for a cluster randomized controlled trial
Authors: So Winnie K. W. , Law Bernard M. H. , Choi Kai Chow , Chan Dorothy N. S. , Chan Carmen W. H.
Published: May 2019

Background

Colorectal cancer (CRC) screening, such as fecal occult blood test (FOBT), is an effective way to prevent CRC, one of the most common cancers worldwide. However, studies found that South Asian ethnic minorities tend not to utilize CRC screening, whose importance on CRC prevention shall be educated among those from ethnic minorities, especially older adults. The purpose of this study is to develop and implement a family-based, multimedia intervention to augment the knowledge of CRC prevention among older South Asian adults in Hong Kong and enhance their motivation for undergoing FOBT. The acceptability and effectiveness of the intervention will be assessed using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework.

Methods

A cluster randomized controlled trial will be carried out. Three hundred and twenty South Asian dyads, comprising an older adult aged between 50 and 75 and a younger family member aged between 18 and 49, will be recruited in ten districts in Hong Kong through community organizations that provide support services for South Asians in local communities. Dyads will be randomly allocated to either the intervention or wait-list control group. Intervention dyads will receive intervention, whose contents are based on the health belief model, via multiple forms of media including PowerPoint presentation, video clip and health information booklet. Control dyads will receive intervention after post-intervention data are collected. For dyads in both groups, an appointment with a family doctor will be arranged for those willing to undergo FOBT. Outcomes will be assessed at baseline and post-intervention. Data will be analysed using the Generalised Linear Models Procedure in an intention-to-treat manner.

Discussion

Findings of this study will provide evidence of the benefits of utilizing multimedia and family-based approaches in intervention development to enhance the effectiveness of health promotion interventions for ethnic minorities. Further, the findings would provide reference to the potential incorporation of the intervention in the existing support services for South Asian ethnic minorities in local communities.

Trial registration

This trial is registered at the ISRCTN Registry (ISRCTN72829325) on 19th July 2018.
Clinical outcomes of patients with or without common AEs in anlotinib cohort: Subgroup analysis of the ALTER0303 trial.
Authors: Zhe-Hai Wang , Han Baohui , Li Kai , Cheng Ying , Liu Jie , Guo Jun , Liu Liyan , Xie Chao , Han Xiao , WANG Haiyong , Wang Qiming , Zhang Li , Shi Jianhua , He Jianxing , Shi Yuankai , Chen Weiqiang , Luo Yi , Wu Lin , Wang Xiuwen , Nan Kejun ,   Anlotinbi authors' group
Published: May 2019

e20507

Background: In ALTER 0303, the common adverse reaction (AE) included hypertension (HTN) and hand foot syndrome (HFS). In this subgroup analysis, we aim to assess the relationship between common AEs and clinical benefit in anlotinib cohort. Methods: Eligible patients showed disease progression after second-line or further treatment were randomly assigned in a 2:1 ratio to receive 12 mg/day of anlotinib or placebo. The primary endpoint was overall survival (OS). This subgroup analysis was based on anlotinib cohort. Results: Patients with HTN had significantly improved median OS, median progress-free survival (PFS), objective response (ORR) and disease control rate (DCR) compared with patients without HFS in anlotinib cohort. Similarly, patients with HFS had better clinical outcomes in anlotinib cohort. Not surprisingly, patients occurred both HFS and HTN had more superior medium OS compared with only HFS, only HTN and neither HFS nor HTN. Conclusions: HTN or HFS is associated with better clinical outcomes in advanced NSCLC patients received anlotinib. Clinical trial information: NCT02388919. [Table: see text]
Comparative genomic profiling of paired tissue and blood samples from advanced non-small cell lung cancer patients.
Authors: Wang Xiaoyun , Gao Chan , Wang Guoqiang , Cai Shangli , Fang Zheng
Published: May 2019

e20521

Background: While tissue-based next generation sequencing (NGS) ushered in a new era of precision medicine, profiling of circulating tumor DNA (ctDNA) has also emerged as a minimally invasive alternative to inform clinical decisions. In non-small cell lung cancer (NSCLC), data describing comparison between mutational profiles of paired tissue and blood samples remained scarce. Methods: Matched formalin-fixed paraffin-embedded tissue and peripheral blood samples (≤14 days apart) were collected from treatment naïve advanced NSCLC patients. Genomic profiling was performed using whole exome sequencing (WES) for tissues and a 150-gene panel for ctDNA, with a mean sequencing depth of 239× and 3417× respectively. Tumor- and blood-based tumor mutational burdens (tTMB and bTMB) were defined as the sum of missense, stop-loss, in-frame and frameshift mutations in protein coding regions and the number of somatic single nucleotide variations and indels in targeted coding regions respectively. Maximum somatic allele frequency (MSAF) was also determined for each case as a measure of ctDNA quantity. Results: Matched tissue and blood samples from 48 patients were included for sequencing. A total of 410 mutations were identified, where 84 (20.5%) were covered in both sample types. Sixty-three (15.4%) alterations were only detected in tissues while 263 (64.1%) were exclusively seen in ctDNA. The most frequently altered genes were SMARCA2 (62.5%), TP53 (54.2%), and AR (47.9%) in ctDNA and were TP53 (37.5%) and EGFR (22.9%) in tissues. Aberrations in all genes, except for FAT1 and KRAS, occurred at a higher frequency in ctDNA. The median tTMB and bTMB were 75 and 7, respectively. bTMB displayed a moderate linear relationship with tTMB as indicated by a Spearman correlation of 0.62 (P < 0.01). Patients with bTMB ≥ 7 had significantly higher MSAF (Mann-Whitney P < 0.001), suggesting a positive correlation between bTMB and ctDNA fraction in blood. Conclusions: Mutational profiles as well as TMB levels were in general consistent between blood and tissue samples, further corroborating a role for ctDNA testing as a complementary approach to tissue testing in advanced NSCLC.
Phase II multicenter study of antroquinonol in patients with stage IV non-small cell lung cancer who have failed at least two lines of anti-cancer therapy.
Authors: Ho Ching-Liang , Ettinger David S. , Chen Pei-Ni , Cheng Howard , Wen Wu-Che , Wu Shang-Yin , Jahan Thierry Marie , Fidler Mary J. , Lash Bradley Walter , Rybkin Igor I. , Stanton Natalie
Published: May 2019

e20522

Background: The aim of this study was to assess the efficacy of Antroquinonol in patients with stage IV NSCLC after failure in two-lines of anti-cancer therapy. Methods: Patients with stage IV non-squamous NSCLC who have failed at 2-4 lines of anti-cancer therapy were eligible, though early stage or naïve patients may voluntarily participate. A maximum of 30 evaluable patients were to receive Antroquinonol 600mg per day, of which 15 patients were to be KRAS-positive and 15 patients KRAS negative. The primary endpoint of the study was progression-free survival from the start of treatment to week 12 with disease control rate and overall survival as key secondary endpoints. Results: There were 31 patients enrolled with evaluable population 30 patients, of which 15 patients were KRAS positive and 15 patients KRAS negative. 73% were with at least two prior chemotherapy. The median PFS of 7 patients with 2 prior chemotherapy was 22.9 weeks (95% confidence interval [CI]: 5.0, 31.1); and 11 patients with more than 2 prior chemotherapy was 11.9 weeks (95% confidence interval [CI]: 6.0, 14.1), with a 1-year PFS of 11.4%. Of 11 patients who had had more than 2 prior chemotherapy, the median OS was 47.3 weeks (95% CI: 14.1,-), with a 1-year OS of 39.3%, and the overall disease control rate was 72.7%, with 100% in KRAS negative and 50% in KRAS positive. No systemic toxicities were observed. Conclusions: The monotherapy of Antroquinonol brought up higher disease control rates and longer progression-free survival and overall survival, compared with historical data. Although KRAS negative shows much better than KRAS positive group, Antroquinonol still work well with KRAS positive patients. Clinical trial information: NCT02047344.
Platinum based chemotherapy in elderly patients with non-small cell lung carcinoma (NSCLC): Experience from an Indian tertiary cancer center.
Authors: Sharma Aparna , Khurana Sachin , Pramanik Raja , Kumar Sunil , Pathy Sushmita , Malik Prabhat Singh
Published: May 2019

e20528

Background: Instituting platinum based chemotherapy in elderly population is often associated with poor tolerance and attending toxicities. We present our limited center experience of chemotherapy in the geriatric population group. Methods: This is a retrospective single center experience of all registered patients in lung cancer clinic (LCC) in the department of medical oncology, Dr. B.R.A. IRCH, AIIMS. All histopathologically proven cases of NSCLC with age more than 70 years who received platinum based chemotherapy (single/doublet) with complete patient records were analysed. The study was carried out between November 2016 and August 2018.Data was analysed using STATA v13. Results: The cohort consisted of 25 patients who satisfied the inclusion criteria. Males comprised 84%(n = 21) of the cohort. Median age of study population was 72.7 years years (Range 70-84). 36%(n = 9) of the study population had one comorbidity while 8% (n = 2) had multiple comorbidities. 68% (n = 17) of the cohort were smokers. ECOG(Eastern cooperative oncology group) PS (performance status) 1 was seen in 48% (n = 12) and PS 2 in 32% (n = 8) and PS 3 in 16% (n = 4) respectively of the patients. Histopathologically, 48% (n = 12) of the population constituted squamous cell carcinoma while 40%(n = 10) had adenocarcinoma. 76%(n = 19) patients had Stage 4 NSCLC. Most common chemotherapy regimes used were weekly Paclitaxel carboplatin (n = 11, 44%), three weekly paclitaxel carboplatin (n = 8 , 32%) Pemetrexed carboplatin (n = 5, 20%) and gemcitabine carboplatin (n = 1, 4%). Only 12% (n = 3) could complete more than 4 cycles of chemotherapy and 3 could receive maintenance chemotherapy. Best responses according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria v1.1 achieved were complete response in 12%(n = 3), partial response in 16% (n = 4), stable disease 24%(n = 6) and progressive disease in 48%(n = 12). Most common grade 3 and 4 adverse events according to CTCAE (common terminology criteria for adverse events) v4.03 were mucositis 29.17%(n = 7), diarrhea 12% (n = 3), peripheral neuropathy 12.5 (n = 3) and hematological toxicity 16%(n = 4). Conclusions: The patient number in this study cohort is limited.However, our experience demonstrates that abbreviated therapy in elderly subgroup is fairly well tolerated. Various tools like comprehensive geriatric assessment need to be utilized to provided tailored therapy in the elderly subgroup. A prospective study is required to address the efficacy and toxicity profile of chemotherapy in this select population.
Clinical importance of long noncoding RNA LINC00460 expression in plasma cell-free tumor RNA in EGFR-mutant adenocarcinoma.
Authors: Isobe Kazutoshi , Nakano Yuta , .Kobayashi Hiroshi , Kaburaki Kyohei , Sano Go , Sakamoto Susumu , Takai Yujiro , Tochigi Naobumi , Mikami Tetsuo , Iyoda Akira , Homma Sakae
Published: May 2019

e20529

Background: Long noncoding RNA (lncRNA) is longer than 200 nucleotides and does not encode proteins. The IncRNA LINC00460 was reported to be involved in physiological and pathological processes such as proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT). However, its role in epidermal growth factor receptor ( EGFR)-mutant lung adenocarcinoma is unclear. Methods: Non–small cell lung cancer (NSCLC) cells with knockout of LINC00460 were generated with a CRISPR-Cas9 system and used to investigate the effect of LINC00460 on gefitinib-induced cell death in an MTT assay. Western blot was used to observe change in EMT-related proteins, and changes in expression of EMT-related proteins were detected with an immunofluorescence assay. In addition, among 38 EGFR mutant lung adenocarcinomas treated by EGFR-TKI, cell-free tumor RNA extracted from blood plasma samples was analyzed for LINC00460 by using a real-time PCR assay. In addition, we assessed the association between LINC00460 expression and progression-free survival (PFS) after EGFR-TKI therapy. Results: LINC00460 was up-regulated by EGFR activation. LINC00460 expressions were significantly greater in NSCLC tumors than in adjacent normal tissues (p < 0.01). H1299 cells with LINC00460 knockout were more sensitive to gefitinib. LINC00460 was induced by transcription factors such as FOS and NF-κB in EGFR-mutant lung adenocarcinoma and gefitinib-resistant cells. LINC00460 overexpression was involved in gefitinib resistance. The MTT assay showed that LINC00460 expression was greater in cells with acquired resistance to EGFR-TKIs (gefitinib, erlotinib, and osimertinib). Western blot and immunofluorescence revealed that LINC00460 expression was associated with changes in the expression of EMT-related proteins. Patients with high LINC00460 expression in plasma cell-free tumor RNA had significantly shorter PFS after EGFR-TKI therapy than did those with low expression (median PFS: 688 vs 1089 days, respectively; p = 0.024). Conclusions: LINC00460 appears to be a novel factor involved in malignant transformation of EGFR mutant–positive lung adenocarcinoma and increased EGFR-TKI resistance. LINC00460 expression in plasma cell-free tumor RNA in EGFR-mutant adenocarcinoma was associated with shorter PFS after EGFR-TKI therapy.
Clinical outcomes of various resistance mechanisms of osimertinib in Chinese advanced non-small cell lung cancer patients.
Authors: Xing Puyuan , Junling Li , Hao Xuezhi , Mu Yuxin , Wang Shouzheng , Ma Di , Lin Jing , Liu Hao , Han-Zhang Han , Lizaso Analyn , Xiang Jianxing , Mao Xinru
Published: May 2019

e20530

Background: Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance. Methods: 103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses. Results: Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations ( p= 0.014) and were more likely to acquire mutations in MAP/PI3Kpathway ( p= 0.04) and TP53 at PD ( p= 0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients ( p= 0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) ( p= 0.047) and overall survival (OS) ( p= 0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS ( p= 0.031), while patients with acquired MET amplifications had significantly shorter PFS ( p= 0.033). Conclusions: Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.
Treatment beyond RECIST-defined progression in relapsed EGFR-mutated non-small cell lung cancer (NSCLC) patients treated with 2nd line osimertinib.
Authors: Eide Inger Johanne Zwicky , Helland Aslaug , Ekman Simon , Cicenas Saulius , Koivunen Jussi , Grønberg Bjørn Henning , Brustugun Odd Terje
Published: May 2019

e20544

Background: After progression on osimertinib in the 2nd line setting, treatment options are few and include combination chemotherapy. Some patients might benefit from continuing osimertinib despite RECIST-defined progression and thus defer time to more toxic treatments. Methods: The investigator-initiated TREM-study is a multicenter, phase 2, single-arm clinical trial conducted in five Northern European countries. Patients with advanced EGFR-mutated NSCLC who progressed on at least one EGFR-TKI and with measurable disease by RECIST 1.1. were assigned to treatment with osimertinib 80 mg daily until radiological progression or death. Patients showing clinical benefit could continue treatment after radiological progression. Both T790M pos and T790M neg patients were included (assessed in tissue biopsy). The primary endpoint was overall response rate (ORR). Results: 199/200 included pts received at least one dose of osimertinib. T790M status was assessable in biopsies from 167 pts. Of these, 110 pts (66 %) were T790M pos and 57 (34 %) T790M neg. Median age was 66 years (range 33-90), 70 % were women and 53% never-smokers. 24 % had CNS metastases at inclusion. Confirmed ORR was 47.1 % (95% CI 39.9 %, 54.3 %) for 189 evaluable pts. T790M pos pts had an ORR of 58.7 % (49.0 %, 68.3 %) and T790M neg 30.9 % (18.3 %, 43.5 %). Median PFS (all pts) was 9.0 months (7.5, 10.6). Median PFS for T790M pos was 10.8 months (8.1, 13.5) vs 5.5 (4.4, 6.5) for T790M neg, p = 0.014. 126/199 pts (63 %) received treatment beyond RECIST-defined progression (TBP). Median duration of TBP was 0.69 months overall, range 0.03-27.6+ months. Median duration of TBP was 1.8 vs 0.4 months in T790M pos and neg, respectively, p = 0.005. There was no significant difference in the proportion of T790M neg and T790M pos pts receiving TBP (63.2 vs 57.3 %), p = 0.82. At 6 months 23/126 (18.3 %) were still on TBP, including 14/63 (22.2 %) T790M pos and 3/36 (8.3 %) T790M neg. At 12 months 8/126 (6.3 %) were on TBP, including 3 T790M pos and one T790M neg pt. Conclusions: A substantial proportion of the patients received TBP regardless of T790M status and some had durable clinical benefit, suggesting this as a treatment option in selected patients. Clinical trial information: NCT02504346.
Estimating long-term survival of previously untreated patients with EGFR mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC) who received osimertinib in the FLAURA study.
Authors: Dyer Matthew , Green Matthew , jones simon , Hodge Rachel
Published: May 2019

e20560

Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third-generation EGFR-TKI, provided clinically and statistically significantly longer progression-free survival versus gefitinib/erlotinib as first-line treatment for patients with EGFRm advanced NSCLC. At the time of analysis, data on overall survival (OS) were immature (25% maturity). To better understand the long-term survival potential of osimertinib beyond the observed trial follow-up period, mathematical parametric survival models were used to estimate clinically plausible survival rates up to 5 years from FLAURA. Methods: Following published best-practice guidelines, candidate parametric survival models were evaluated based on both statistical and visual goodness-of-fit to the observed FLAURA OS data. Two modeling approaches were considered: single models with treatment included as a covariate; and separate models fitted to the osimertinib and gefitinib/erlotinib arms. Point estimates of 5-year survival rates with 95% confidence intervals (CIs) are reported for the best fitting model. Results: The best fitting parametric survival model to the FLAURA OS data was the Weibull model with treatment included as a covariate. Based on this model, estimated median OS was longer with osimertinib than with gefitinib/erlotinib (41.4 months vs 30.6 months). The estimated 3- and 5-year survival rates with osimertinib were 57.3% (95% CI 46.6%, 69.2%) and 31.1% (95% CI 23.7%, 41.8%), respectively. In comparison, the estimated 3- and 5-year survival rates with gefitinib/erlotinib were 41.1% (95% CI 31.9%, 52.9%) and 15.5% (95% CI 11.6%, 22.1%), respectively. Conclusions: Based on the best fitting parametric survival model to FLAURA OS data, the estimated 5-year survival rate with osimertinib was double that with gefitinib/erlotinib (31.1% vs 15.5%) in patients with EGFRm advanced NSCLC. Long-term follow-up data from FLAURA (60% OS maturity) will further validate this finding. Clinical trial information: NCT02296125.
Using single cell genomics to change the treatment of lung cancer.
Authors: Chin Venessa T. , Al Eryani Ghamdan , McCloy Rachael , Stone Emily , Havryk Adrian , Plit Marshall , Field Andrew , Watkins Neil , Swarbrick Alex , Powell Joseph
Published: May 2019

e20563

Background: Lung cancer (LC) is common with a dismal prognosis. Although treatment with immunotherapy (IO) has improved survival outcomes, these therapies remain expensive. Even using biomarker selection, response rates still fall short of 50%. The majority of immune cell profiling done previously uses samples taken from early stage patients focusing on a single immune cell subtype. Here we use single cell RNA sequencing (scRNA-seq) and Cellular Indexing of Transcriptome and Epitopes by sequencing (CITE-seq) to characterise the innate and adaptive immune cell activation state and assess the response to exposure to IO in vitro from patients with advanced LC. Methods: Patients with locally advanced or metastatic LC having an Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) have biopsies collected for analysis. Cells are grown in culture +/- nivolumab for 48 hours. scRNA-seq and CITE-seq is conducted using established protocols. Transcriptomic and proteomic data on the innate and adaptive immune cell subsets assess markers of immune activation and/or suppression and the changes after nivolumab are quantified. Results are correlated with clinical outcomes. Results: In a locally advanced/metastatic population, EBUS-TBNA biopsies yield highly cellular samples with a heterogeneous population of immune cells able to be cultured +/- IO using novel, inclusive techniques. Transcriptomic clustering reveals distinct sub-populations within the T-cell, B-cell and innate immune cell compartments. Within these clusters, CITE-seq shows protein expression on individual cells can determine states of exhaustion, cytolytic ability, migratory potential and innate immune activation. Conclusions: Single cell genomics is feasible and informative in patients with advanced LC. This work will form the basis of a functional, real-time assay to assess individualised responses to IO therapy that has the potential to predict IO response.
Methylation profiling of EGFR mutant primary and metastatic lung cancer with brain metastasis.
Authors: Mamatjan Yasin , Cabanero Michael , Weiss Jessica , Zuccato Jeffrey , Sorotsky Hadas , Tsao Ming Sound , Aldape Kenneth D. , Zadeh Gelareh , Shepherd Frances A.
Published: May 2019

e20574

Background: EGFR-mutant lung cancer is a key molecular subtype of lung cancer. In recent years there is clear recognition in the value of using methylation signature of cancer for improving diagnosis and predicting outcome as well as understanding the biology of cancer progression. Methods: In this study we chose to characterize the methylome signature of early stage surgically resected EGFR-mutant lung adenocarcinomas in the primary lung tumor. 90 NSCLC cases and 7 matched metastatic brain samples were profiled using Illumina Infinium MethylationEPIC Beadchip. We compared methylation profiles of 1) smokers versus lifetime non-smokers and 2) matched primary lung versus brain metastasis to identify methylation biomarkers. We performed supervised analysis and unsupervised clustering of the methylation data. Results: Unsupervised clustering of all lung and brain samples based on 10K most variable probes showed a similar methylation signature between metastatic brain samples and lung samples. The 7-matched brain and lung samples formed close cluster groups based on matching pairs for the most variable probes from 2.5K to 10K, reflecting the same cell of origin. Supervised analysis of smokers versus lifetime non-smokers did not show any significant methylation differences between the two groups, while unsupervised analysis did not create clusters of smokers and non-smokers based on various number of probe sets we analyzed. Conclusions: Lung tumors that metastasized to the brain share similar methylation features with primary lung tumors. Comprehensive methylation profiling demonstrated no difference between EGFR mutant tumors in smokers versus non-smokers, suggesting that the EGFR mutation is a stronger determinant of outcome independent of smoking.
EATON: An open-label, multicenter, phase I dose-escalation trial of nazartinib (EGF816) and trametinib in patients with EGFR-mutant non-small cell lung cancer – preliminary data on safety and tolerability.
Authors: Michels Sebastian Yves Friedrich , Nogova Lucia , Deschler-Baier Barbara , Felip Enriqueta , Rodriguez-Abreu Delvys , Rosell Rafael , Sebastian Martin , Schuler Martin H. , Wermke Martin , Fischer Rieke Nila , Koleczko Sophia , Abdulla Diana S.Y. , Riedel Richard , Scheffler Matthias , Fassunke Jana , Hellmich Martin , Merkelbach-Bruse Sabine , Buettner Reinhard , Wolf Juergen
Published: May 2019

e20577

Background: Multiple mechanisms of resistance to EGFR TKIs therapy in EGFR-mutant non-small cell lung cancer (NSCLC) have been described, most often including the acquisition of the secondary resistance mutations in exon 20 of EGFR. Preclinical models and clinical findings have also shown that co-occurring activation of the RAS/MEK pathway may result in reduced EGFR dependency, which may be overcome by co-inhibition of MEK. We thus hypothesize that the combined inhibition of EGFR and MEK may restore sensitivity to EGFR inhibition in patients with acquired resistance to EGFR inhibition and may as well prolong the acquisition of resistance in treatment-naïve patients. Methods: EATON is an international, multicenter, phase I, dose escalation investigator-initiated trial investigating the recommended phase 2 dose (RP2D), safety and preliminary efficacy of the combination of the third-generation EGFR inhibitor EGF816 with the MEK inhibitor trametinib (NCT03516214). Eligibility criteria: Advanced NSCLC harboring EGFR del19 or p.L858R, first-line or after failure of any EGFR TKI including osimertinib, independently of p.T790M status. Patients with high-level MET amplification are excluded. Dose level escalation will be based on a modified traditional cumulative 3+3 design, i.e. “up and down” (dose level 1: 100 mg nazartinib (EGF816) QD + 1 mg trametinib QD). A total number of 24 patients is planned to be enrolled in 8 trial sites in Germany and Spain. At a first stage, 18 (6´3) patients will be treated and evaluated. Exploratory endpoints aim at the identification of potential mechanisms of resistance to the trial treatment by massively parallel sequencing (MPS), FISH, phospho-protein analyses and whole exome/genome sequencing of baseline and PD biopsy tumour tissue. Additionally blood samples for MPS of cell free DNA will be collected throughout the trial treatment. Results: At the time of data-cut off for this abstract, one patient received treatment at dose-level 1. Treatment was withdrawn due to a serious, bacterial soft tissue infection of the hand outside the DLT period. Conclusions: Data on safety and tolerability of the combination of nazartinib and trametinib is premature. Updated results will be presented at the conference. Clinical trial information: NCT03516214.