bluuebunny/crossref_metadata_2025 huggingface dataset:
The unforeseen business and medical consequences of EHR data collection for a real-world data multiple myeloma registry.
Authors: Keogh Kevin M. , Belli Andrew J. , Matta Monica M. , Tanenbaum Kathryn A. , Farrish Kaeleigh , Mulcahy Michael , Mathura Shivam , Williams Christopher , Mehr Shaadi , Auclair Daniel , Norden Andrew David , Labkoff Steven E.
Published: March 2020

e19528

Background: Record retrieval on behalf of a consenting patient within the context of real-world data is not well understood. As the need for real-world data continues to expand, methods for the efficient transfer of information across consenting parties will be critical to enable research collaborations. This need was highlighted through a partnership between COTA and the Multiple Myeloma Research Foundation (MMRF). As one component of the pilot study, COTA managed the record retrieval of consenting patients before going on to abstract the data for use in a registry. Methods: The pilot study identified 23 patients that consented to the release of medical records at 54 institutions across 20 states. COTA partnered with a retrieval vendor and employed its own outreach efforts for acquisition. Outreach and retrieval techniques were similar across COTA and the vendor, including targeted calls, delivery of IRB-approved consent materials, and on-site requests. The 30-day release parameter for a covered entity under 45 CFR 164.524(b)(2) of HIPAA’s Privacy Rule was used to evaluate the observed return rates. Results: A total of 56 medical records were requested, and 48 records were retrieved. The mean (±SD) retrieval time across all sites was 33 (±58) days. We found that 54% of records were released in < = 30 days, and 32% of records > 30 days. 14% of requested records were never released, despite a median of 19 outreach attempts (range 10 to 43). Cited issues for delay or non-release consisted of 22 institutions questioning the validity of the certified electronic patient signature, 6 requiring a physical signature, and 5 requiring their own authorization forms. In no cases did the records contain structured metadata, such as LOINC, MedDRA, and RxNorm. Conclusions: This pilot showed an unpredictable variance associated with the release of records in the context of real-world data. This variance contributed to barriers and delays in broader research efforts. The lack of accompanying metadata with released records resulted in additional required data processing. Future studies should be conducted to establish best practices in the release and retrieval of medical records used to support real-world data research.
Role of investigational monoclonal antibodies in the treatment of multiple myeloma: A systematic review.
Authors: Hassan Hamza , Iftikhar Ahmad , Iftikhar Nimra , Mushtaq Adeela , Rafae Abdul , Razzaq Faryal , Valent Jason Neil , Kanate Abraham Sebastian , Chakraborty Rajshekhar , Anwer Faiz
Published: March 2020

e19533

Background: Immunotherapy for multiple myeloma (MM) has been of focus in recent years due to its myeloma-specific immune responses. We reviewed literature on non-FDA approved monoclonal antibodies (MoAbs) to highlight future perspectives. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane and Clinicaltrilas.gov to include phase I/II clinical trials. Results: 40 studies (1917 patients) were included. Isatuximab (anti-CD38) and F50067 (anti-CXCR4) were the only MoAbs which produced encouraging results as monotherapy with ORR of 66.7% and 32% respectively. Isatuximab use in combination with Len-Dex produced CBR of 83%, and in combination with pomalidomide and dexamethasone CBR of 73%. Indatuximab Ravtansine, an antibody-drug conjugate, produced ORR 78% and 79% in combination with Len-Dex and pomalidomide + dexamethasone respectively. Conclusions: CD38 remains an important target for further clinical trials in combination therapy. Trials using indatuximab, pembrolizumab, lorvotuzumab, siltuximab, and dacetuzumab in combination therapy produced better outcomes as compared to monotherapies. [Table: see text]
Primary tumor location as an important predictor for survival in pulmonary adenocarcinoma.
Authors: Wang Zhe , Li Minghuan , Teng Feifei , Yu Jinming
Published: March 2020

e20000

Background: The prognostic value of tumor location in pulmonary adenocarcinoma (ADC) is controversial. We compared the prognosis and relevant data between central-type (CT-ADC) and peripheral-type ADC (PT-ADC) in order to identify the reasons for the different outcomes between them and to improve the treatment strategy and prognosis of these two types. Methods: Data on 256 patients with pathologically diagnosed ADC were retrospectively reviewed. The prognostic factors for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate analyses. Results: 124 and 132 patients had CT-ADC and PT-ADC respectively. CT-ADC was associated with an earlier age, poorer Karnofsky Performance Status (KPS), higher rates of advanced stage, bone metastasis, contralateral pulmonary metastasis and pleural effusion. Besides, CT-ADC showed a trend toward lower rate of epidermal growth factor receptor (EGFR) mutation. Patients with CT-ADC had a significantly shorter PFS/DFS and OS than did those with PT-ADC. Multivariate analysis revealed that advanced stage, central-type location, EGFR wild-type, no surgery, presence of chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) were independent poor prognostic factors for OS. The rate of surgery was significantly lower in patients with CT-ADC. Among patients with ILD or COPD, OS is shorter in patients with central- than peripheral-type tumors. Conclusions: CT-ADC is associated with poorer survival than PT-ADC and the lower rate of surgery in patients with CT-ADC is an important reason for this. Tumor location of pulmonary adenocarcinoma plays a critical role in predicting prognosis and choosing therapeutic strategies.
Comparison of preoperative and prechemotherapy lymphocyte counts to predict outcome of non-small cell lung cancer patients treated with adjuvant chemotherapy.
Authors: Lee Hyun Woo , Choi Yong Won , Ahn Mi Sun , Kang Seok Yun , Choi Jin-Hyuk
Published: March 2020

e20002

Background: Several systemic inflammatory markers in blood have been suggested as prognostic factors in various cancers. We investigated the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) in patients (pts) with non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy. Methods: A retrospective review was conducted on 108 pts who received adjuvant chemotherapy after surgical resection of NSCLC. Disease-free survival (DFS) and overall survival (OS) of pts with high NLR and ALC ( > median value) before surgery or chemotherapy were compared to those of pts with low NLR and ALC (≤median value). Results: The number of pts at AJCC stage IB, IIA, IIB, IIIA, and IIIB were 1, 38, 9, 58, and 2, respectively. Adenocarcinoma, squamous cell carcinoma, and other histologic types were present in 66 (61.1%), 32 (29.6%), and 10 (9.3%) pts, respectively. The most frequently used chemotherapy regimen was vinorelbine/cisplatin (81 pts), followed by paclitaxel/carboplatin (22 pts), and others (5 pts). A total of 61 (56.5%) pts received adjuvant radiotherapy (before adjuvant chemotherapy: 53 pts). Preoperative NLR and ALC were not associated with clinicopathologic characteristics including stage and histologic types. High prechemotherapy NLR and low ALC were more frequently observed in pts who underwent radiotherapy before chemotherapy (p < 0.0001). The median follow-up duration was 70 (38-162) months for survivors. Pts with stage III demonstrated poor DFS (p = 0.019) and OS (p = 0.028) compared to those with stage IB or II. The shorter median DFS was observed in pts with low prechemotherapy ALC (20 vs. 65 months, p = 0.021), without significant difference in OS (p = 0.088). On the other hand, NLR and preoperative ALC were not associated with outcome of pts. Conclusions: The present study suggests that high prechemotherapy ALC is associated with poor outcome in stage IB-III NSCLC pts who received adjuvant chemotherapy after surgical resection.
Impact of decision-support system and guideline treatment concordance on response rate in advanced lung cancer.
Authors: Liang Jun , Tang Chuanhao , Wang Xiangyi , Guo Ziwei , Ni Jun , Xu Weiran , Dankwa-Mullan Irene , Willis Van , Chen Alan , Jackson Gretchen Purcell , Rhee Kyu , Li Tianle
Published: March 2020

e20006

Background: Clinical decision-support systems (CDSS) provide up-to-date evidence to practitioners overwhelmed by the deluge of clinical findings. Few studies, however, have evaluated their impact on patient outcomes. This cross-sectional retrospective study was conducted to: 1) measure concordance of real-world clinical decisions with therapeutic options from the IBM Watson for Oncology (WfO) CDSS and the Chinese Society of Clinical Oncology (CSCO) guidelines, 2) the effect of concordance on objective response rate (ORR). Methods: Health records from patients receiving 1stline treatment at Peking University International Hospital Oncology Center in China between January 2016 and December 2018 (69 stage IV NSCLC, 30 with SCLC) with documented tumor progression after 2+ cycles of treatment, were reviewed to determine concordance of actual treatment with WfO therapeutic options and CSCO guidelines. Patients’ treatments were grouped as concordant with: WfO+CSCO, WFO only, CSCO only, or neither. ORR, defined as partial or complete response after 2+ treatment cycles (RECIST criteria)was determined for each group. Results: For NSCLC, ORR ranged from 21.4% for discordance with both WfO and CSCO to 100.0% for WfO only concordance. For SCLC, ORR ranged from 37.5% for CSCO only concordance to 73.3% for WfO+CSCO concordance (Table). The main reasons for discordance were: 1stgeneration TKIs like Gefitinib and Erlotinib (vs. Osimertinib) are standard of care for EGFR mutant patients in China, (2) Local CSCO guideline drugs like Lobaplatin and Icotinib are not included in WfO. Conclusions: This study provides preliminary evidence to suggest that treatment concordance with WfO may be associated with improved ORR in some cases of NSCLC (WfO only) and SCLC (WfO + CSCO). ORR in NSCLC patients who were discordant with both WFO and CSCO guidelines was the lowest at 21.4%. Larger studies are needed to understand the effect of guideline and WfO concordance on ORR. [Table: see text]
Evaluation of tumor infiltrating lymphocites (TILs) and survival in patients with resected non-small cell lung cancer.
Authors: Cárdenas Quesada Nuria , Ortega Granados Ana Laura , Márquez Lobo Bélgica , Rosa Garrido Carmen , Sanchez Rovira Pedro , Núñez Torres María Isabel
Published: March 2020

e20010

Background: Due to the prognosis of non-small cell lung cancer (NSCLC), even at initial stages we need to characterise better our patients in order to know their prognosis. The purpose of our study is to find some prognostic factors to help us to choose the best therapeutic approach. We found some data about histology and tumor lymphocytic infiltration. Methods: We followed outcome of 94 patients diagnosed of initial stage NSCLC that underwent surgery in our institution between 2010-2013, for more than 5 years, and related survival with findings in tumor samples. Results: Tumor samples were classified in order to establish 4 variables related to tumor lymphocitic inflltration (TILs, as it was established by Brambilla et al): absent, mild, moderate and intense. 20 (21.3%) patients were considered TILs intense, 36 (38.3%) moderate, 33 (35.1%) mild and 5 absent (5.3%). We found some significative differences in disease free survival (DFS, more favorable for TILs absent group), but none for overall survival (OS). Conclusions: TILs and tumor stage could be part of an immunoscore to classify initial stage NSCLC, this score should be validated in future studies [Table: see text]
Identification of MET Exon 14 skipping by targeted RNA-based next-generation sequencing in Chinese Patients with NSCLC.
Authors: Che Nanying , Xu Ziguang , Dong Yujie , Cheng Peng , Gao Yun , Yu Yang , Fu Shijun , Gao Min , Kong Lingfei
Published: March 2020

e20018

Background: MET (mesenchymal-epithelial transition) exon14 skipping mutations have been reported to represent a clinically unique molecular subtype of NSCLC. The prevalence rates of MET exon 14 skipping in lung adenocarcinoma are quite different, from 0.9% to 4.0% in Asian populations. Since some somatic variants not covering the MET exon 14 splice sites might also induce MET exon 14 skipping, we believed that RNA-based sequencing is the most accurate method to detected exon 14 skipping. Methods: A total of 951 NSCLC patients from two hospitals were enrolled in this study. We detected MET exon14 skipping using both targeted DNA- and RNA-based next generation sequencing and elucidated the driver gene mutation profile of Chinese NSCLC patients. Results: The overall estimated prevalence of MET exon 14 skipping was approximately 1.8% (14 of 772) in adenocarcinomas and 1.7 % (16/951) in NSCLCs. Furthermore, we compared the detection rate of MET exon 14 skipping from different specimen source, including surgical resection, percutaneous transthoracic needle biopsy (PTNB) and transbronchial lung biopsy (TBLB). Notably, the detection rate of MET exon 14 skipping from surgical resection specimen is 2.3% in NSCLCs and 2.0% in adenocarcinomas, respectively. MET exon 14 skipping was identified in 7.1% of EGFR/KRAS/ALK/ROS1/RET negative adenocarcinomas (13 of 196). In addition, PD-L1 trended to be highly expressed in NSCLC patients harboring MET exon 14 skipping (55.6% vs 17.3%, p = 0.022). Conclusions: In this study, the prevalence of MET exon14 skipping in lung adenocarcinomas in East Asian population was very close to that of West population using RNA-based NGS. The NSCLC patients with Met exon 14 skipping tended to be older than patients with other oncogenic driver mutations, such as EGFR, ALK, ROS1. In addition, PD-L1 trended to be highly expressed in NSCLC patients with MET exon 14 skipping.
Haematological biomarkers of pathological response on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA non-small cell lung cancer (NSCLC) patients.
Authors: Laza Briviesca Raquel , Cruz Bermudez Alberto , Barquin Miguel , Nadal Ernest , Insa Amelia , Garcia-Campelo Rosario , De Dios Alvarez Noemi , Domine Manuel , Massuti Bartomeu , Majem Margarita , Rodriguez-Abreu Delvys , Martinez Marti Alex , Cobo Manuel , Lopez-Vivanco Guillermo , del Barco Elvira , Bernabé Reyes , Vinolas Nuria , Barneto Isidoro , Viteri Santiago , Provencio-Pulla Mariano
Published: March 2020

e20026

Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (< 10% viable tumour) and incomplete response (> 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.
Impact of resectable lung adenocarcinoma pathological subtypes on patients prognosis and surgical strategies determination: A SEER population-based data analysis.
Authors: Lu Di , Yang Jianjun , Feng Siyang , Liu Xiguang , Dong Xiaoying , Wang Zhizhi , Wang He , Shi Xiaoshun , Wu Hua , Cai Kaican
Published: March 2020

e20035

Background: The prognosis difference among lung adenocarcinoma patients with different pathological subtypes remains controversial. Furthermore, the appropriate surgical plan according to each subtype for early-staged adenocarcinoma patients is undetermined. Methods: We retrospectively analyzed patients with solid, papillary and acinar lung carcinoma from 2004 to 2015 using SEER*Stat 8.3.4. The primary readout of this study were overall survival (OS). The Kaplan–Meier method was used to determine OS. Results: 2282 patients with lung adenocarcinoma were finally included (solid, N = 117, papillary, N = 739, acinar, N = 1426). For patients received radical resection (lobectomy/bilobectomy, radical and extended pneumonectomy), those with acinar adenocarcinoma had the best survival (median OS: solid, 59 months, papillary, 91 months, acinar,102 months, solid VS papillary, P = 0.258, solid VS acinar, P = 0.014, papillary VS acinar, P = 0.008). For early diagnosed patients in stage I, those with acinar adenocarcinoma who received radical resection had a better OS compared to those received partial resection (wedge resection and segmentectomy) (median OS: wed&seg, 88 months, radical 106 months, P = 0.024). Particularly, patients underwent radical resection or segmentectomy had a better OS compared to those received wedge resection (mean OS of seg: 99.175±5.336 months; median OS: wed, 67 months, radical, 106 months, wed VS radical, P = 0.001, wed VS seg P = 0.026, seg VS radical, P = 0.353), while those treated with radical resection had comparable prognosis compared with patients with segmentectomy. As for patients with stage I papillary adenocarcinoma, those who received partial resection tended to have a worse prognosis compared to those who received lobectomy, although no significant difference was detected (median OS: wed&seg, 74 months, radical 111 months, P = 0.151. N of patients: wed, N = 72, seg, N = 20, radical, N = 415). Conclusions: Patients with acinar lung adenocarcinoma have a better prognosis than solid and papillary adenocarcinoma patients after radical resection. For patients with stage I acinar adenocarcinoma, segmentectomy and radical resection have similar therapeutic effects. For patients with stage I papillary adenocarcinoma, radical resection is the first option.
The cross talk between the molecular alterations and tumor immunity in the microenvironment in non-small-cell lung carcinoma.
Authors: Zhou Chengzhi , Chen Yanhui , Hu Ying , Liu Yang , Zhang Henghui
Published: March 2020

e20043

Background: The previous study indicated that the biomarkers of molecular alterations and tumor immunity in the microenvironment could predict the response of immunotherapy in NSCLC patients. However, the cross talk between the two factors is unclear. This study was designed to investigated the features of tumor immunity in the microenvironment of deferential molecular characterization in NSCLC patients. Methods: Tumor tissue and matched blood samples from 62 patients with NSCLC were collected. The mutation profiles were sequenced by a cancer gene-targeted NGS panel. The PD-L1 expression and immune cells infiltrated in tumor microenvironment were detected by multiplex immunofluorescence staining. Results: The distinct of molecular alterations showed the different tumor microenvironments in terms of immune cell composition and of PD-L1 expression by tumor cells in NSCLC. KRAS-mutated tumors were characterized by higher level of PD-L1 expression and lower NK cells infiltrated in tumor area than KRAS-wild type tumor. TP53-mutated tumors were characterized by higher CD8+T cell and lower NK cells infiltrated in tumor area. In contrast, EGFR-mutated tumors were characterized by lower level of PD-L1 expression and higher NK cells. Moreover, we found that the PD-L1 expression increased in MET gene CNV gain tumors than MET wild type tumors. Conclusions: The features of tumor immunity in the microenvironment changed in deferential molecular characterization in NSCLC. it may help to explain the phenomenon that the efficacy of immunotherapy changed in deferential molecular characterization of NSCLC.
Mutational landscape of early-stage non-small cell lung cancer patients using a 451 gene panel.
Authors: Mao Guanxian , Xuxing Peng , Hao Wu , Junbing Wang , Suyue Liu , Qiang Wu , Ying Liu , Ren Qiang , Liu Jixian , Melançon Charles E.
Published: March 2020

e20048

Background: Many studies have reported mutation landscapes of non-small cell lung cancer (NSCLC), but most of the data were from advanced-stage patients. This study reports the mutation landscape of early-stage NSCLC patients. Methods: Many studies have reported mutation landscapes of non-small cell lung cancer (NSCLC), but most of the data were from advanced-stage patients. This study reports the mutation landscape of early-stage NSCLC patients. Results: In all, 74 tDNA and ctDNA samples were analyzed. A total of 285 mutations were identified, including 174 in tDNA and 111 in plasma ctDNA. Genes with the highest -frequencies of mutations in tDNA were EGFR, TP53, KMT2B, BRAF, PIK3CA, CDKN2A, and KRAS,while TP53, EGFR, NOTCH3, PIK3CA, andATM were the genes with the highest frequencies of mutations in ctDNA. The detection rate of driver mutations in tDNA and ctDNA, respectively, were: 42.9% (15/35) and 12.8% (5/39) for EGFR, 5.7% (2/35) and 2.6% (1/39) for ALK, 5.7% (2/35) and 2.6% (1/39) for ERBB2, 11.4% (4/35) and 0%)0/39) for BRAF,5.7% (2/35) and 0%)0/39) for RET, 37% (13/35) and 23.1% (9/39) for TP53. Conclusions: In all, 74 tDNA and ctDNA samples were analyzed. A total of 285 mutations were identified, including 174 in tDNA and 111 in plasma ctDNA. Genes with the highest -frequencies of mutations in tDNA were EGFR, TP53, KMT2B, BRAF, PIK3CA, CDKN2A, and KRAS,while TP53, EGFR, NOTCH3, PIK3CA, andATM were the genes with the highest frequencies of mutations in ctDNA. The detection rate of driver mutations in tDNA and ctDNA, respectively, were: 42.9% (15/35) and 12.8% (5/39) for EGFR, 5.7% (2/35) and 2.6% (1/39) for ALK, 5.7% (2/35) and 2.6% (1/39) for ERBB2, 11.4% (4/35) and 0% )0/39) for BRAF,5.7% (2/35) and 0% )0/39) for RET, 37% (13/35) and 23.1% (9/39) for TP53.
Selection of patients for stereotactic body radiation therapy (SBRT) or (bi)lobectomy (L) for the treatment of cT1-T2N0M0 NSCLC by the risk of node involvement using readily available preoperative factors.
Authors: Griffin Molly , Hebert Christine , Voland Rick , Varlotto John M. , DeCamp Malcolm , Flickinger John Charles , Ali Suhail M. , Maddox Debra , McIntosh Lacey , Baima Jennifer , Uy Karl , Lou Ferian , Maxfield Mark , Oliveira Paulo , Emmerick Isabel M , Fitzgerald Thomas J. , Walsh William Vincent
Published: March 2020

e20055

Background: Currently it is not known whether certain patients with early-stage non-small cell lung cancer(NSCLC) would be better served with stereotactic body radiation (SBRT) or surgery. The purpose of our investigation is to see if patients who are at higher risk of node involvement based upon pre-operative factors would be preferentially served with (bi)Lobectomy(L). Methods: The NCDB was queried for the years 2004-2014 to find patients with cT1-T2N0M0 NSCLC (excluding lepidic adenocarcinoma and their variants) < 5cm treated via L or SBRT(N = 16,722). Recursive partition analysis was used in the L group to develop high, medium, and low risk node involvement groups in those patients having complete node assessment (10 or more nodes examined) by American College of Surgeons commission on cancer quality care measures(ACOS coc), N = 83,890. The L and SBRT groups were then propensity matched based upon factors associated with OS to assess whether there was an OS benefit for either the L or SBRT treatments by node risk category. OS was calculated by log-rank testing. Results: The high, medium, and low risk categories had an average risk for node involvement of 20.12, 11.3, and 4.57%, respectively. The low risk group was defined as tumors < 21mm for all squamous cell carcinomas(SQ) and adenocarcinoma(AD) in the right upper lobe only. High risk categories were associated tumors > 21 mm in the RUL in white Hispanics; and ages < 60yr old for SQ, large cell ca, and NSCLC-NOS; and > 21mm with non-RUL location and < 55yr old. OS was significantly better in patients treated by L for the high, medium, and low risk groups with all p-values of < 0.0001. Conclusions: When patients undergo a complete lymph node dissection by the ACOScoc quality measures and have (bi)lobectomy, their OS is superior to patients undergoing SBRT whether they are at high, low or medium risk of lymph node involvement.
Use of surgery and stereotactic body radiotherapy (SBRT) in very elderly patients with early-stage non-small cell lung cancer (NSCLC): A national cancer database (NCDB) analysis.
Authors: Kharouta Michael , Grubb William , Podder Tarun Kanti , Biswas Tithi
Published: March 2020

e20058

Background: SBRT treatment for very elderly ( > 80 years) patients with early stage NSCLC has been reported to be well tolerated with good short term efficacy. Using a large hospital based registry, we report a comparison of patterns of practice, outcomes, and prognostic factors for very elderly patients undergoing any treatment for early-stage NSCLC. Methods: The NCDB was queried for patients with clinical Stage I-IIA NSCLC with age ≥ 80 years diagnosed from 2001-2015 treated with surgery or SBRT alone. Patients were excluded if they received chemotherapy /immunotherapy or non-standard SBRT doses (i.e. > 5 fractions of RT, < 30 Gy or > 70 Gy total dose). Survival analyses were performed with propensity-matching, Kaplan-Meier estimates, Cox proportional hazards regression, and log rank testing. Results: 26039 patients met search criteria, median age 83 (80-90) years. 17141 (65.8%) patients underwent surgery, and 8898 (34.2%) underwent SBRT. Median follow up was 31 months. Median survival was 52 and 35 months for surgery and SBRT. Of patients receiving SBRT, 2044 (23%) had a contraindication to primary surgery due to patient risk factors. Age, clinical stage, tumor size, surgery type, CDCC score, BED, bronchial involvement, and type of treatment facility were predictive of median survival. BED > 154 Gy was associated with greater median survival (p < 0.01). Lobectomy was associated with greater median survival vs sub-lobar resection/pneumonectomy (p < 0.0001). For stage I tumors, surgery was associated with better median survival (56 vs. 35 months, p < 0.0001), but for stage IIA patients both modalities had similar median survival (30 vs 29 months, p = 0.04). Conclusions: Surgery remains the predominant treatment modality for early stage NSCLC in this very elderly population, and is associated with good outcomes for patients with stage I tumors. For elderly patients who are poor surgical candidates due to medical co-morbidities SBRT is associated with reasonable median survival. With limited information on patient comorbidities, more robust studies are needed to determine the effects of patient selection on treatment outcomes in this population.
Prognostic value of tumor infiltrating lymphocytes in epithelioid malignant pleural mesothelioma.
Authors: Adashek Michael , Chan Abigail Sy , Heath Johnathan , Fanaroff Rachel , Kallen Michael E , Friedberg Joseph S. , Culligan Melissa , Khashab Tamara , Miller Kenneth David
Published: March 2020

e20064

Background: Malignant Mesothelioma (MM) is an aggressive malignancy with survival of 4-12 mo. without treatment and 10% 5-year survival. The response of patients with MM to immunotherapy has increased interest in the tumor immune microenvironment. The purpose of this study was to determine if tumor infiltrating lymphocytes (TIL) are correlated with survival in epithelioid MM. Methods: Immunohistochemistry was performed on specimens from 27 patients with epithelioid mesothelioma using CD4, CD8, and CD68 antibodies. Infiltrate density was scored (0-3+) by pathologist estimate in intratumoral and adjacent tumoral tissue. ANOVA and regression analysis were performed. Overall survival (OS) for the entire group and time to progression (TTP) for nine patients with known time from surgery until tumor recurrence were also studied as a surgical resection subgroup (SRG). Results: For the small SRG the relationship between (TTP) and TIL score of CD8 at the edge of the tumor was significant (F[2,6]=5.64, P=.042) however TIL score of intratumoral CD8 cell infiltrates and TTP did not demonstrate statistical significance. The relationship between OS with CD8 infiltrate at the tumor edge, for the entire group, approached significance at (F [3,22]=2.93, P=0.056). TTP and OS and the TIL score of CD4, CD68 at both tumor center and tumor edge did not demonstrate statistical significance. Conclusions: CD8+ lymphocytes are an important component of host immune defense against cancer. We found that in epithelioid MM the cellular infiltrate of CD8 lymphocytes at the edge of the tumor (but not with intratumoral CD8) was associated with longer time to recurrence. TTP and OS were not associated with CD4 and CD68 within or at the tumor edge. The role of CD8 T-cells and the quantitative difference between CD8 at the edge of tumor and intratumoral CD8 should be further investigated in order to optimize immunotherapy.
Survival impact of thoracic cavity reduction during neoadjuvant chemotherapy in patients undergoing surgery for malignant pleural mesothelioma.
Authors: Kuroda Ayumi , Nakamichi Toru , Nakamura Akifumi , Hashimoto Masaki , Matsumoto Seiji , Kondo Nobuyuki , Hasegawa Seiki
Published: March 2020

e20067

Background: It is difficult to predict prognosis for malignant pleural mesothelioma (MPM). The association of thoracic asymmetry and survival in patients with MPM was reported by Cho et al. in at the 18th World Conference on Lung Cancer. Here we investigated the survival impact of thoracic cavity reduction during neoadjuvant chemotherapy (NAC). Methods: The subjects were patients with resectable epithelioid MPM who underwent NAC with platinum and pemetrexed followed by surgery at the Hyogo College of Medicine from Jan 2009 to Aug 2018. The length of the ant-post and med-lat extent of both hemithoraces at the level of carina was measured before and after NAC. Asymmetric ratio (ASR) was defined as the product of the ant-post and med-lat extent of affected side divided by those of healthy side. Results: One hundred thirty-three patients were enrolled: median age 66 (16-79) years, M/F 112/21, R/L 70/63, extrapleural pneumonectomy 40 and pleurectomy/decortication 93. Significantly poor prognosis was associated with ≥ 10mm reduction of the med-lat extent of affected side during NAC and ≥ 10% reduction of the product of the ant-post and med-lat extent of affected side during NAC (p = 0.0021). ASR ≤ 0.9 before or after NAC was not associated with significantly poor survival. Conclusions: This study revealed that thoracic cavity reduction during NAC was associated with significantly poor prognosis of MPM.
Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment.
Authors: Messaritakis Ippokratis , Nikolaou Michail , Koinis Filippos , Politaki Eleni , Koutsopoulos Anastasios , Lagoudaki Eleni , Georgoulias Vassilis , Kotsakis Athanasios
Published: March 2020

e20086

Background: The aim of the study was to characterize and evaluate the presence of DLL3-positive Circulating Tumor Cells (CTCs) in SCLC patients receiving front-line chemotherapy and assess their clinical relevance. Methods: Peripheral blood was obtained from treatment-naïve patients with SCLC (n = 108 patients), after one-etoposide/platinum cycle (n = 68 patients) and on disease progression (n = 48 patients). CTCs were detected after immunofluorescence staining using antibodies against the DLL3, cytokeratins (CK), CD45 and vimentin (Vim). Results: Before treatment, 74.1% of patients had detectable CTCs (DLL3+/CD45-). One-treatment cycle significantly decreased both the detection rate of DLL3+/CD45- CTCs ( p< 0.001) and their absolute number ( p< 0.001). Triple immunofluorescence staining using anti-CK, anti-Vim and anti-DLL3 antibodies revealed an important CTC heterogeneity since DLL3 could be detected in Vim+, Vim-, CK+ and CK- CTCs. On disease progression, both the detection rate of DLL3+/CD45- CTCs as well as their number were significantly increased compared to post-1st cycle values ( p< 0.001 and p= 0.002, respectively). In addition, 22.7% of patients had detectable DLL3+/CD45- cells which could not be captured by the CellSearch assay. In multivariate analysis, the detection of DLL3+/CD45- CTCs at baseline was significantly associated with decreased progression-free survival (HR = 10.8; p= 0.005) whereas their detection on disease progression was associated with decreased overall survival (HR: 28.2; p= 0.016). Conclusions: These findings demonstrate an important heterogeneity of CTCs, based on the expression of CK, Vim and DLL3, in patients with SCLC and the changes of DLL3+/CD45- CTCs during treatment seem to be a dynamic biomarker associated with treatment efficacy and patients’ clinical outcome.
Proteomics analysis discovers biomarkers in serum months to years before small cell lung cancer: The HUNT study.
Authors: Nguyen Olav Toai Duc , Markaki Maria , Chatzipantsiou Christina , Sharma Animesh , Lagani Vincenzo , Tsamardinos Ioannis , Røe Oluf D.
Published: March 2020

e20095

Background: The high incidence and high mortality rate of small-cell lung cancer (SCLC) calls for identification of methods for early diagnosis. Searching of cancer-related proteins and proteins signature in biofluids is an emerging approach in early diagnostic of malignancies. In the present study we have used proteomics-based profiling of serum collected 2 months to 5 years before SCLC diagnosis to search for early diagnostic biomarkers. Methods: All serum samples in this study were obtained from the Nord-Trøndelag Health Study (HUNT) Research Centre’s Biobank. Discovery sample set (Cohort I): Serum samples from 12 individuals that subsequently developed SCLC and 12 matched controls were obtained. Validation sample set (Cohort II): Serum samples from 5 future SCLC patients and 5 matched controls were obtained. The serum samples in both cohorts were collected in a time frame of 2 months to 5 years before diagnosis. All controls included in the study were matched to the cases for smoking status (pack years and quit time), gender and age, and were cancer-free at least 5 years before blood sampling. All subjects were smokers or ex-smokers. Twenty (20) µl of serum was depleted of its high-abundant proteins and the cleaned-up peptides were analysed by LC- MS with an Orbitrap Elite mass spectrometer. Data were processed/analysed using MaxQuant software. Using Cohort I as training set, proteins most related to diagnosis were identified at first with limma univariate analysis. Reference and equivalent signatures were identified using JADbio with SES as feature selection algorithm. The JADbio matched pipeline with 50 repetitions for performance assessment (AUC with 95% CI) was used. Results: In each serum sample the analysis detected 435 proteins in Cohort I and 609 proteins in Cohort II. Reference signature for 12 SCLC future cases vs 12 matched controls had a conservative AUC of 0.686 (95% CI: 0.557, 0.765) in the discovery cohort. Three proteins in the reference and equivalent signatures were also found to be differentially expressed in validation Cohort II; all three proteins discriminated small-cell lung cancer patients from their respective controls (AUC 0.757-0.826 in the discovery Cohort I and AUC 0.68-0.84 in the validation Cohort II). Conclusions: The results indicate that differential levels of a few proteins in serum may help detecting SCLC 2 months to 5 years prior to clinical diagnosis. This is one of the first large-scale proteomics screening studies of pre-diagnostic serum of future SCLC patients. Further validation studies are in progress.
KMT2C mutation associated with tumor mutational burden in small cell lung cancer.
Authors: Gu Weiguang , Wang Hongbiao , Li Kunsong , Wei Ge , Zhang Junkai , Zhang Shiyue , Zhang Lin , Shi Xiaoliang , Liu Angen
Published: March 2020

e20098

Background: Immune checkpoint inhibitors are used to treat small cell lung cancer (SCLC). Tumor mutational burden (TMB) emerges as a promising predictor of immunotherapy efficacy, but the relationship between TMB and genetic features of SCLC remains unclear. In this study, we explored the correlation between genetic profiles and TMB in SCLC. Methods: FFPE tumor and matched blood samples were collected from 119 SCLC patients for panel targeted based next-generation sequencing. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. Results: This study enrolled 114 SCLC and 5 mixed SCLC patients (91 males and 28 females) with a median age of 59 years. Median TMB was 9.3 muts/Mb (25% quantile: 6.3 muts/Mb, 75% quantile: 13.2 muts/Mb). For all patients, 31 (26%) had low TMB (≤6.3 muts/Mb), 55 (46%) had intermediate TMB (6.4-13.1 muts/Mb), and 33 (28%) had high TMB (≥13.2 muts/Mb). KMT2D mutations (mut), included substitution/indel (6/25) and truncation (19/25). KMT2D exhibited substitution/indel (6/25) and truncation (19/25) mutations in 19% of SCLC tumors while KMT2C exhibited substitution/indel (11/17), gene homozygous deletion (1/17) and truncation (5/17) mutations in 12% of SCLC tumors. Tumors with KMT family gene mut (KMT2C and KMT2D) (n = 33) had higher TMB (11.7 vs. 8.5 muts/Mb, p = 0.009). KMT2C mut tumors had higher TMB than KMT2C wildtype (wt) tumors (15.2 vs. 9.2 muts/Mb, p = 0.0036). TP53 mut occurred in 86% of KMT2C mut tumors and KMT2C/TP53 co-mutated tumors had higher TMB than KMT2C wt/TP53 mut tumors (17.8 vs. 9.3 muts/Mb, p = 0.0035) or KMT2C wt/TP53 wt tumors (17.8 vs. 5.4 muts/Mb, p = 0.027). Conclusions: Our data indicates that KMT family genes were frequently mutated in SCLC. KMT2C mut positively correlated with higher TMB and KMT2C co-mutated with TP53 or FAT1 may have a synergic effect on TMB. Our study explored a novel relationship between GAs and TMB that may greatly improve immunotherapeutic strategies for SCLC.
Early assessment of therapy response in non-small cell lung cancer (NSCLC) via longitudinal ctDNA analysis.
Authors: Ma Xiaoju Max , Ju Christine , Woestmann Corinna , Xi Liu , Yaung Stephanie J. , Hinzmann Bernd , Thomas Michael , Heussel Claus Peter , Lasitschka Felix , Meister Michael , Schneider Marc , Herth Felix , Muley Thomas , Wehnl Birgit , Palma John F.
Published: March 2020

e20701

Background: Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. Despite disease heterogeneity in NSCLC, we set out to identify a broadly applicable ctDNA-based method for disease monitoring. By employing plasma taken during early treatment cycles, we tested whether early response assessed by ctDNA level could predict treatment effect. Methods: Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), we measured ctDNA levels in post-treatment plasma samples based on variants identified at baseline. We used samples from an observational German Lung Cancer Multi-Marker Study. In a cohort of 83 stage IV lung adenocarcinoma treated with first-line chemo or chemoradiation therapies, we evaluated the association between survival and ctDNA levels in the first available post-treatment plasma sample (median number of days after start of treatment = 23). We used a ctDNA-based monitoring algorithm, and applied it to an independent set of 22 late stage lung squamous cell carcinoma (SCC) that also underwent chemo or chemoradiation therapies to further evaluate the algorithm in different histology subtypes. Results: We divided the 83 adenocarcinoma cohort into training (n = 53) and test (n = 30) sets. We found that subjects with longer progression free survival (PFS) had mean allele fraction (AF) < 1% in the training set. We applied the classifier to our validation set and found that subjects with mean AF < 1% had longer PFS (HR 0.35; 95% CI 0.12 - 0.93; log-rank P = 0.028) and overall survival (OS) (HR 0.29; 95% CI 0.09 - 0.89; log-rank P = 0.021). Using cutoffs identified in adenocarcinoma, we applied the same algorithms to the SCC cohort. Subjects with mean AF < 1% had longer PFS (HR 0.26; 95% CI 0.10 - 0.71; log-rank P = 0.005) and OS (HR 0.12; 95% CI 0.05 - 0.51; log-rank P = 0.001). Conclusions: Even in heterogeneous diseases such as NSCLC, changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects who may not benefit, which is earlier than current standard of care methods like computed tomography (CT) scan. Future prospective studies to confirm these results are warranted.
Totality of evidence in development of the bevacizumab biosimilar ABP 215: Central and investigator evaluation of efficacy from the MAPLE study.
Authors: Thomas Michael , Thatcher Nick , Goldschmidt Jerome H , Ohe Yuichiro , McBride Helen , Hanes Vladimir
Published: March 2020

e20708

Background: ABP 215 (MVASI™ [bevacizumab]) is the first biosimilar to Avastin (bevacizumab) approved in the US and EU. This phase 3, double-blind study compared efficacy of ABP 215 with bevacizumab reference product (RP) in patients with advanced non-squamous NSCLC. Here we report the totality of evidence supporting similarity between ABP 215 and RP, including preclinical VEGF-A isoform binding relevant to the mechanism of action across indications, and clinical results of central and investigator evaluation of tumor response. Methods: VEGF-A kinetic parameters were compared for common isoforms 121, 165 and 189. Patients were randomized 1:1 to ABP 215 or RP 15 mg/kg Q3Wx6 cycles. All patients received carboplatin and paclitaxel Q3W for up to 6 cycles. Disease assessments (CT/MRI) were performed at screening, weeks 7, 13, 19, and Q9W thereafter by the investigator and, independently, by central, blinded radiologists. Efficacy was based on objective tumor assessments according to RECIST 1.1. Copies of all radiographs were submitted for central analysis. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% CI of the risk ratio was within the margin of 0.67-1.5. Additional efficacy analyses included duration of response (DOR) and progression-free survival (PFS). Results: Binding to all 3 isoforms was similar for ABP 215 and RP. In the MAPLE study, 642 patients (ABP 215, 328; RP, 314) were randomized. Based on central analysis, ORR was achieved in 128 (39.0%) patients in the ABP 215 and 131 (41.7%) in the RP groups, (ORR risk ratio: 0.93 [90% CI: 0.80, 1.09]). Based on investigator analysis, ORR was achieved in 157 (47.9%) patients in the ABP 215 and 151 (48.1%) in the RP groups (ORR risk ratio: 1.01 [90% CI: 0.88, 1.16]). Hazard ratio (HR, ABP 215 vs RP) for DOR was 1.08 (95% CI, 0.76, 1.54) and 0.76 (95% CI, 0.48, 1.23) per investigator and central assessment. PFS HR was 1.10 (90% CI, 0.92, 1.33) and 1.03 (90% CI, 0.83, 1.29) per investigator and central assessment. Conclusions: These results further confirm the similarity of ABP 215 and RP and support extrapolation to all available bevacizumab indications. Clinical trial information: NCT01966003.
Economic evaluation crizotinib, alectinib and brigatinib in anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Choi Briana , Alkhatib Nimer S , Pae Elizabeth , Babiker Hani M. , Garland Linda L. , Henglefelt Alyssa , McBride Ali , Abraham Ivo
Published: March 2020

e20714

Background: Crizotinib and alectinib are approved as 1st and brigatinib as 2nd line (post crizotinib) therapy for ALK+ NSCLC. Alectinib and brigatinib are more expensive but potentially clinically more beneficial in terms of progression free survival (PFS). We performed cost-effectiveness/utility analyses based on published PFS data. Methods: The Bücher method was used to indirectly estimate comparative PFS hazard ratios (HR) for PFS between the 3 agents. A 2-state Markov model (progression, death) was specified, PFS survival curves were digitized, and Weibull distributions fitted with life time horizon. Drug costs were per RedBook (US$ 2018). Cost of adverse event management, disease progression and follow up were per published data. Outcomes included PFS life years (PFSLY) and quality adjusted life years (PFSQALY). Incremental cost effectiveness/utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained were estimated. Deterministic results were verified by probabilistic sensitivity analyses (PSA). Analyses were from the US payer perspective. Results: In indirect comparisons, alectinib (HR 0.47, 95%CI 0.34-0.65) and brigatinib (HR 0.49, 95%CI 0.33-0.74) were superior, but equivalent to each other (HR 1.04, 95%CI 0.62-1.75), in PFS over crizotinib in their respective lines. Deterministic (probabilistic) PFSLY, PFSQALY and cost estimates were 0.86 (0.91), 0.54 (0.57) and $193,544 ($203,881) for crizotinib; 1.27 (1.36), 0.80 (0.85) and $236,279 ($251,183) for alectinib; 1.25 (1.33), 0.79 (0.83) and $492,681 ($522,533) for brigatinib. See Table for deterministic (probabilistic) ICER/ICUR results ($ in parentheses denote savings). Conclusions: In this independent economic evaluation not considering intracranial metastasis, brigatinib had the highest life time cost compared to alectinib and crizotinib (all drugs as approved). Comparable gains in PFSLY and PFSQALY for brigatinib can be achieved with alectinib at lower cost, making alectinib the most cost-effective treatment option for ALK+ NSCLC. [Table: see text]