bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep infiltrating endometriosis: Interest of the robotic approach for a fledgling team
Authors: Poujois Julie , Mézan De Malartic Cécile , Callec Ronan , Bresler Laurent , Hubert Nicolas , Judlin Philippe , Morel Oliver
Published: May 2019

Introduction:

Mini-invasive surgery of deep endometriosis is challenging. Surgical difficulties related to the technical limitations of classical laparoscopic approach might be overcome with the use of robotic assistance. The aim of this study was to evaluate the safety and feasibility of robotic surgery for deep infiltrating endometriosis in the learning phase of our team.

Methods:

The 20 first cases of robotic-assisted laparoscopies for endometriosis were included over a 2-year period. Baseline characteristics of patients and surgical data were reviewed. Surgical outcomes and follow-up information of the patients were analyzed.

Results:

Twenty women were included. The mean age was 31.9 years (range: 25–44) and mean body mass index was 23 kg/m2 (range: 16–35). Ten patients had rectovaginal or uterosacral location only (50%) and nine women had deep infiltrating endometriosis with digestive or urinary tract lesions (45%). In addition to the gynecologic surgeon, urologic or visceral surgeons were required in 10 cases, and there were 3 cases where the three specialties were needed. The mean operative time was 183.9 min (range: 85–398) and no difference was observed between the first five cases and the last five cases. There was one laparoconversion, and only two urologic postoperative complications occurred.

Conclusion:

Thanks to the use of robotic surgical assistance and a multidisciplinary approach, and despite the start of the team for deep endometriosis care, no learning curve effect was observed regarding surgical procedures’ success, safety, or duration. The use of robotic assistance might improve the quality of care for women facing deep endometriosis.
Peripheral Neuropathy Due to Common Variable Immunodeficiency: Case Report and Narrative Review
Authors: Long Christopher P. , Suzuki Hiroshi , Vitale Kenneth
Published: May 2019

A 63-year-old woman with common variable immunodeficiency (CVID) presented with 1 year of insidious onset lower extremity pain and weakness. She underwent a circuitous workup, failed to improve despite treatment for various presumed diagnoses. She presented to a University physical medicine and rehabilitation clinic with continued symptoms. Electrophysiologic testing was recommended revealing a lower extremity motor greater than sensory axonal neuropathy. While CVID has known central nervous system complications, to our knowledge, this represents the second known reported case of peripheral neuropathy. We review the literature on CVID and summarize neurological disease mechanisms and manifestations. Although peripheral neuropathy is a rarely documented complication of CVID, providers need to be aware of potential peripheral nervous system complications of primary immune deficiencies such as CVID due to its significant impact on physical performance, balance, and fall risks.
Assessing Patient Interest in Individualized Preventive Care Recommendations
Authors: Taksler Glen B. , Beth Mercer Mary , Fagerlin Angela , Rothberg Michael B.
Published: May 2019

Background. Few Americans obtain all 41 guideline-recommended preventive services for nonpregnant adults. We assessed patient interest in prioritizing their preventive care needs. Methods. We conducted a mixed-methods study, with 4 focus groups ( N = 28) at a single institution and a nationwide survey ( N = 2,103). Participants were middle-aged and older adults with preventive care needs. We obtained reactions to written materials describing the magnitude of benefit from major preventive services, including both absolute and relative benefits. Recommendations were individualized for patient risk factors (“individualized preventive care recommendations”). Focus groups assessed patient interest, how patients would want to discuss individualized recommendations with their providers, and potential for individualized recommendations to influence patient decision making. Survey content was based on focus groups and analyzed with logistic regression. Results. Patients expressed strong interest in individualized recommendations. Among survey respondents, an adjusted 88.2% (95% confidence interval [CI] = 86.7% to 89.7%) found individualized recommendations very easy to understand, 77.2% (95% CI = 75.3% to 79.1%) considered them very useful, and 64.9% (95% CI = 62.8% to 67.0%) highly trustworthy (each ≥6/7 on Likert scale). Three quarters of participants wanted to receive their own individualized recommendations in upcoming primary care visits (adjusted proportion = 77.5%, 95% CI = 75.6% to 79.4%). Both focus group and survey participants supported shared decision making and reported that individualized recommendations would improve motivation to obtain preventive care. Half of survey respondents reported that they would be much more likely to visit their doctor if they knew individualized recommendations would be discussed, compared with 4.2% who would not be more likely to visit their doctor. Survey respondents already prioritized preventive services, stating they were most likely to choose quick/easy preventive services and least likely to choose expensive preventive services (adjusted proportions, 63.8% and 8.5%, respectively). Results were consistent in sensitivity analyses. Conclusions. Individualized preventive care recommendations are likely to be well received in primary care and might motivate patients to improve adherence to evidence-based care.
Alerting Doctors About Patient Life Challenges: A Randomized Control Trial of a Previsit Inventory of Contextual Factors
Authors: Weaver Frances M. , Binns-Calvey Amy , Gonzalez Beverly , Kostovich Carol , LaVela Sherri , Stroupe Kevin T. , Kelly Brendan , Ashley Naomi , Miskevics Scott , Gerber Ben , Burkhart Lisa , Schwartz Alan , Weiner Saul J.
Published: May 2019

Objective. Effective care attends to relevant patient life context. We tested whether a patient-completed inventory helps providers contextualize care and increases patients’ perception of patient-centered care (PCC). Method. The inventory listed six red flags (e.g., emergency room visits) and if the patient checked any, prompted for related contextual factors (e.g., transportation difficulties). Patients were randomized to complete the inventory or watch health videos prior to their visit. Patients presented their inventory results to providers during audio-recorded encounters. Audios were coded for physician probing and incorporating context in care plans. Patients completed the Consultation and Relational Empathy (CARE) instrument after the encounter. Results. A total of 272 Veterans were randomized. Adjusting for covariates and clustering within providers, inventory patients rated visits as more patient-centered (44.5; standard error = 1.1) than controls (42.7, standard error = 1.1, P = 0.04, CARE range = 10–50). Providers were more likely to probe red flags (odds ratio = 1.54; confidence interval = 1.07–2.22; P = 0.02) when receiving the inventory, but not incorporating context into care planning. Conclusion. A previsit inventory of life context increased perceptions of PCC and providers’ likelihood of exploring context but not contextualizing care. Information about patients’ life challenges is not sufficient to assure that context informs provider decision making even when provided at the point of care by patients themselves.
Amikacin exposure and susceptibility of macrolide-resistantMycobacterium abscessus
Authors: Daniel-Wayman Shelby , Shallom Shamira , Azeem Nabila , Olivier Kenneth N. , Zelazny Adrian M. , Prevots D. Rebecca
Published: May 2019

Mycobacterium abscessusis associated with antibiotic resistance and poor treatment outcomes. We described within-patient changes inM. abscessusresistance to clarithromycin and amikacin.

Patients with amikacin exposure and a >50-month interval betweenM. abscessusisolates were identified. Antimicrobial susceptibility testing was performed on the first and last isolates by broth microdilution, and genetic markers of resistance were identified.

16 patients were identified with a median amikacin exposure of 2.3 years (range 0.6–8.6 years). 15 patients also received macrolides (median 7.2 years, range 1.3–10.7 years). All initial isolates were resistant to clarithromycin (minimum inhibitory concentration (MIC) ≥8 µg·mL−1). Two patients had later susceptible isolates, which were of a different subspecies (M. abscessussubsp.massiliense) than the initial isolates (M. abscessussubsp.abscessus). All initial isolates were susceptible or intermediately resistant to amikacin, and only one patient had a resistant final isolate (MIC >64 µg·mL−1), accompanied by an A→G mutation at position 1408 of the 16S ribosomal RNA. Forced expiratory volume in 1 s decreased significantly over the study period, while smear quantity and the proportions of patients with elevated C-reactive protein or cavitary lesions all increased significantly.

Despite prolonged, mostly inhaled amikacin exposure, development of amikacin resistance was uncommon in this patient population; however, disease progression continued.
Quality of life outcomes including neuropathy‐associated scale from a phase II, multicenter, randomized trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine as first‐line chemotherapy for HER2‐negative metastatic breast cancer: Korean Cancer Study Group Trial (KCSG BR13‐11)
Authors: Kim Ji‐Yeon , Park Seri , Im Seock‐Ah , Kim Sung‐Bae , Sohn Joohyuk , Lee Keun Seok , Chae Yee Soo , Lee Ki Hyeong , Kim Jee Hyun , Im Young‐Hyuck , Kim Tae‐Yong , Lee Kyung‐Hun , Ahn Jin‐Hee , Kim Gun Min , Park In Hae , Lee Soo Jung , Han Hye Sook , Kim Se Hyun , Jung Kyung Hae , Park Yeon Hee ,   Korean Cancer Study Group
Published: May 2019

Background

A phase II clinical trial of the comparison between eribulin plus gemcitabine (EG) and paclitaxel plus gemcitabine (PG) as first‐line chemotherapy for patients with metastatic breast cancer (MBC) found that the EG regimen was less neurotoxic, but was similar in efficacy to the PG regimen. In the present study, we analyzed functional assessment of cancer therapy‐taxane (FACT‐Taxane) questionnaires from patients in this clinical trial to determine their quality of life (QoL).

Methods

QoL was assessed using the Korean version of the FACT‐Taxane questionnaires. After baseline assessment, QoL was assessed every 2 cycles for 12 cycles and every 3 cycles thereafter. The linear mixed model was used to evaluate the difference in QoL between the EG and PG arms.

Results

Of the 118 enrolled patients, 117 responded to the FACT‐Taxane questionnaires at baseline, 1 in the PG arm did not. Baseline QoL scores were not different between the EG and PG arms. During treatment, taxane subscale scores were significantly higher in the PG arm than in the EG arm after 2–13 cycles of chemotherapy (all P < 0.05), except for the 11th cycle. Neuropathy‐specific analysis showed that patients in the PG arm had earlier and more severe neuropathic symptoms than those in the EG arm (P< 0.001).

Conclusions

In our QoL analysis, the EG regimen delayed and decreased neuropathy as compared with the PG regimen. Therefore, eribulin would be a reasonable substitute for paclitaxel as first‐line chemotherapy for MBC.
Immunohistochemical expression of GRP78 in relation to angiogenesis markers VEGF-a and CD31 and other histopathological parameters in NSCLC.
Authors: Al-Keilani Maha S. , Almomani Basima A. , Alqudah Mohammad A. , Alrjoub Moath M. , Alzoubi Hiba W. , Shhabat Batool A.
Published: May 2019

e20500

Background: Neovascularization is essential for the growth and progression of tumor tissues. GRP78 is frequently overexpressed in various types of cancers and has been suggested as a proangiogenic factor. Methods: In order to evaluate GRP78 expression and its role in angiogenesis of non-small cell lung cancer (NSCLC), paraffin-embedded NSCLC tissue samples (66 adenocarcinoma and 24 squamous cell carcinoma) were retrospectively collected from 90 patients who underwent surgical resection between 2008 and 2015; and did not receive chemotherapy or radiotherapy prior to surgery. Then we performed immunohistochemistry to examine GRP78 expression and we analyzed the relationships between GRP78 and the angiogenesis marker VEGF-A and the microvessel density marker (MVD) CD31. Additionally, we analyzed the association of GRP78 with clinicopathological characteristics of the patients. Results: Strong GRP78 expression was evident in about 86% of the tumor tissues (77/90). There was significant difference in GRP78 expression between poorly-differentiated and well-differentiated tumors (OR = 0.023, 95% CI = 0.001-0.419, p = 0.011). Moreover, there was a statistically significant association between VEGF-A and CD31 (χ² = 12.00, p = 0.001). Indeed, CD31 and VEGF-A expression significantly associated with histological type. Among the tissues expressing high CD31, approximately 86% of them were adenocarcinoma (χ² = 5.009, p = 0.025); and among the tissues expressing positive VEGF-A, about 79% were adenocarcinoma tissues (χ² = 6.545, p = 0.021). Conclusions: Strong GRP78 may be related to good prognosis of NSCLC. Nevertheless, further studies investigating large number of samples of all histological subtypes are required.
The depth of response was associated with the progression-free survival in advanced non-small cell lung cancer patients treated with EGFR-TKI.
Authors: Liu Yutao , Zhang Kai , Li Chengcheng , Hu Xingsheng , Jiang Jun , Hao Xuezhi , Wang Yan , Li Junling , Xing Puyuan , Yang Sheng , Zhang Xin , Wang Guoqiang , Cai Shangli , Shi Yuankai
Published: May 2019

e20509

Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate the new therapeutic strategies in cancer, however, RECIST fails to differentiate the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as maximum percent change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or 19del) treated with EGFR-TKI from August 2014 to July 2017 in two sites were retrospetively collected for analysis. Patients were divided into four groups by maximal tumor shrinkage (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS by DepOR and the hazard ratio (HR) was determined through univariable and multivariable Cox regression models. Results: In total, 265 patients were included for analysis. The number for Group Q1-Q4 was 91, 73, 65 and 36, respectively. The greater DepOR was significantly associated with a longer PFS (Log-rank P for trend < 0.0001). The DepOR vs PFS analyses HR were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3 and 0.33 (0.22-0.50) for Q4 compared with Q1. In the multivariable cox regression model, abnormal LDH, brain metastasis and male were also found to be associated with poorer PFS (P < 0.05). Conclusions: Greater DepOR was significantly associated with a longer PFS in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to more efficiently evaluate the response of targeted therapy.
PD-1 versus PD-L1 inhibitors for previously treated advanced non-small cell lung cancer (NSCLC): Bayesian network meta-analysis (NMA).
Authors: Almutairi Abdulaali , McBride Ali , Garland Linda L. , Abraham Ivo
Published: May 2019

e20511

Background: PD-1 (pembrolizumab, nivolumab; PD-1i) and PD-L1(atezolizumab, avelumab; PD-L1i) inhibitors have been evaluated in patients with advanced NSCLC who failed first line therapy. We performed a Bayesian NMA to compare PD-1i and PD-L1i as groups as to efficacy and safety. Methods: Medline and Embase were searched for phase 2/3 randomized controlled trials (RCT) of PD-1i/PD-L1i in pretreated NSCLC setting. Bayesian NMA with fixed effect model was used to compare efficacy (overall survival (OS), progression-free survival (PFS), objective response rate (ORR)) and safety (grade 3-5 adverse events (AE), pneumonitis, and discontinuation rate due to AEs ). Outcomes were expressed as hazard (HR) or odds ratio (OR) with 95% credible interval (Crl). Results: 6 RCTs (3 PD-1i, 3 PD-L1i) involved comparison to docetaxel and were included. Table summarizes the results. PD-1i were ranked as the first therapy for the efficacy measures (OS (96.5%), PFS (98%), and ORR (99.92%)), and for the rate of grade3-5 AEs (60.17%). PD-L1 ranked first for the discontinuation rate due to AEs (56,51%) and docetaxel ranked first for pneumonitis (99.98%). Conclusions: PD-1i had better PFS/ORR benefits and similar OS benefit and safety profile compared to PD-L1i. Compared to docetaxel, PD-1i showed better PFS/ORR benefits and both PD-1i/PD-L1i had better OS benefit, lower grade 3-5 AEs and AE related discontinuation rate, and higher risk of pneumonitis. [Table: see text]
Angiotensin-converting enzyme inhibitor prescription is associated with decreased progression-free survival (PFS) and overall survival (OS) in patients with lung cancers treated with PD-1/PD-L1 immune checkpoint blockers.
Authors: Medjebar Soleine , Richard Corentin , Fumet Jean-David , Malo Julie , Elkrief Arielle , Blais Normand , Tehfe Mustapha , Florescu Marie , Boidot Romain , Truntzer Caroline , Routy Bertrand , Ghiringhelli François
Published: May 2019

e20512

Background: Angiotensin converting enzyme (ACE) inhibitors are used to treat hyperblood pressure and congestive heart failure. Preclinical evidence show that ACE has a role in both innate and adaptive responses thus suggesting a capacity of ACE to promote antitumor immunity. Interaction between ACE inhibitors and Immune checkpoint blockers (ICB) has not been investigated in cancer patients (pts). Our study evaluated the effect of ACE inhibitors in Non Small cell lung cancer (NSCLC) pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective multicohort retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for NSCLC at Dijon Cancer Center, and at the University of Montreal Hospital. ACE inhibitors groups were defined as pts treated with ACE inhibitors given during the treatment with ICB. PFS and OS were compared between both groups among all pts. Statistical analyses were performed using the Kaplan-Meier method and Cox univariate analysis. Multivariate Cox regression analyses was used to adjust for classical prognostic factors. Tumor RNA sequencing were performed and CIBERSORT was used to estimate immune cell infiltration in ACE inhibitors group and None ACE inhibitors group. Results: Among 283 pts included (177 pts from Dijon, and 106 pts from Montreal), 27 (10%) received ACE inhibitors. ACE inhibitors group did not differ from None ACE inhibitors group for main clinical prognostic characteristics. However, ACE inhibitors group are more frequently treated with statin, beta blocker and metformin. ACE inhibitors group had shorter median PFS compared to None ACE inhibitors group : 2.5 vs. 3.8 months, p = 0.02 (HR = 1.7 IC95% 1.1-2.5 p = 0.02 Cox Univariate). The negative impact of ACE inhibitors group was maintained after multivariate analyses adjusting for risk factors (HR = 1.9 IC95% 1.1-3.5 p = 0.02 for PFS and HR = 2.3 IC95% 1.2-4.4 p = 0.01 for OS). RNA sequencing and CIBERSORT analysis underlines that ACE inhibitors group has lower M1 macrophage, activated Mast cells, NK cells and memory activated T cells thus suggesting an immunosuppressive state. Conclusions: ACE inhibitors prescription concomitant to the PD-1/PD-L1 inhibitors treatment impairs the outcome in patients with advanced NSCLC pts. This reduction is independent of classical prognostic factors. Biological date underlines an immunosuppressive state in ACE inhibitors group. These data should be validated in larger cohort.
EGFR extracellular domain mutation in patients with lung cancer.
Authors: Guo Renhua , Gu Dejian , Zhao Jun , Zhu Lingjun , Chen Mingjiu , Liu Shuoyan , Tang Bo , Chen Rongrong , Xia Xuefeng
Published: May 2019

e20532

Background: Missense mutations in the EGFR extracellular (EC) domain are found in 10% to 15% of glioblastomas(GBM). However, little is known about EGFR EC domain mutations in lung cancer. In this study, we retrospectively analyzed distribution of EGFR EC domain mutation in lung cancer. Methods: A total of 10100 lung cancer patients were analyzed in this study. EGFR mutations were detected by hybridization capture-based NGS panel sequencing with tumor biopsy, ctDNA or pleural effusion samples. Results: We identified gain-of-function mutations in the EC domain of EGFR in 36 (0.36%, 36/10100) patients with 23 patients carrying EGFR A289D/V/T/Y mutation, 10 patients harboring EGFR R108K/S mutation, 2 patients having EGFR T263P mutation, and 1 patient with EGFR G598R mutation. The EGFR EC domain mutation was detected in 23 patients with lung adenocarcinoma and 13 patients with other types of lung cancer (P = 0.018). Notably, 29 (80.56%) patients were detected with EGFR EC domain mutation and EGFR intracellular kinase domain (KD) mutation (P = 2.15×10-7). The incidence of L858R concomitant EC domain mutation was significantly higher compared with 19del (72.41% vs 17.24%, p = 28.64×10-5) or other EGFR KD mutations (72.41% vs 10.34%, p = 6.79×10-6). To further study whether L858R concomitant with EC domain mutation affected the efficiency of targeted therapy, we analyzed 6 patients who were treated with EGFR-TKIs. Among them, disease control rate of 2 months was 83.33% (5/6). Two patients had 10 months PFS. Three patients have been treated for 2, 5 and 12 months respectively, and are still on treatment. Conclusions: Our study reveals the distribution of EGFR EC domain mutation in lung cancer. EGFR EC domain mutation are more likely to occur concomitantly EGFR KD mutation, especial L858R. Meanwhile, our study shows that concomitant EC domain mutation and L858R may not affect the efficiency of targeted therapy.
Overall survival in PEMVITASTART randomized trial comparing immediate vs. conventional strategies of vitamin supplementation in NSCLC patients on 1st line pemetrexed-platinum chemotherapy.
Authors: Singh Navneet , Muthu Valliappan , Prasad Kuruswamy Thurai , Baldi Milind
Published: May 2019

e20538

Background: PEMVITASTART ( NCT02679443 ) was an open label phase II randomized trial [Singh N, et al. Cancer (DOI: 10.1002/cncr.32028)] involving locally advanced/metastatic non-squamous NSCLC patients treated with 1st line pemetrexed-platinum chemotherapy (CTx). The trial assessed the hematological toxicity profile in Delayed Arm (DA; conventional strategy) in whom CTx was initiated after 5-7 days of vitamin B12/folate supplementation (B12-FAS) vs. Immediate Arm (IA) in whom patients received B12-FAS simultaneously (≤24 hours) with CTx initiation. All outcomes were reported in modified ITT population (patients who received ≥1 cycle). A non-significant trend towards better radiological responses was observed in IA (PR 33% vs. 18%; p = 0.06). Herein, we report exploratory post-hoc analysis of overall survival (OS) for the mITT population (n = 150; 77 IA, 73 DA) of PEMVITASTART. Methods: OS was calculated from date of enrolment to date of death/last follow up. Survival cutoff date was 28 months after last patient enrolment. Median OS was calculated by Kaplan-Meier method and group differences analyzed by log-rank test. Factors affecting OS were assessed by Cox proportional hazards (CPH) analysis and hazard ratios [HRs] with 95% confidence intervals (CIs) calculated (from univariate and stepwise multivariate models). Results: Median OS was 12.7 m (95% CI 8.0–17.4) and did not differ between IA [15.0 m (10.5-19.4)] and DA [11.7 m (4.1-19.3)]. 1 yr and 2 yr survival rates were similar (IA 42% and 21% vs. DA 44% and 23%). On univariate CPH analysis, factors associated with better OS were female gender, ECOG PS 0, absence of metastatic disease and receipt of maintenance pemetrexed CTx (mPEM) while current/ex-smoker status, disease progression (as best response) and age ≥70 years were a/w worse OS. Baseline Hb and homocysteine (both assessed as continuous variables) and receipt of packed RBC transfusions/ESAs for anemia correction did not influence OS. On multivariate CPH analysis, current/ex-smokers HR 2.2 (95% CI 1.3-3.7; p < 0.01) and mPEM HR 0.5 (95% CI 0.3-0.9; p = 0.01) were both significant. Median OS for current/ex-smokers was 7.4m (95% CI 5.4-9.4) vs. 25.6m (95% CI 16.2-35.0) for non-smokers (log rank p < 0.001) while for patients receiving mPEM, it was 22.7m (95% CI 9.9-35.4) vs. 9.7m (95% CI 4.9-14.5) for those not receiving mPEM (log rank p = 0.02). Conclusions: Smoking status and mPEM were strong and independent prognostic factors for OS in the PEMVITASTART trial. Clinical trial information: NCT02679443.
Multiple mutations in the EGFR gene in patients diagnosed with lung cancer.
Authors: Omelchuk Ekaterina P. , Kit Oleg I. , Petrusenko Natalia A. , Timoshkina Natalya N. , Gvaldin Dmitry Yu. , Kalabanova Elena Aleksandrovna , Kabanov Sergey N. , Svetitskaya Yana V. , Snezhko Tatiana A. , Mitashok Irina S , Vladimirova Liubov Yu
Published: May 2019

e20542

Background: Lung cancer is the most common malignant tumor after breast cancer and is the main cause of cancer mortality. Mutations in the EGFR gene typical of lung cancer lead to constitutive activation of the epidermal growth factor receptor and malignant cell transformation. The purpose of this study was to identify associations between double and triple mutations in EGFR and clinical and pathological characteristics of patients in the South of Russia diagnosed with lung cancer. Methods: DNA was extracted from FFPE samples of 240 patients. Mutations in EGFR were detected using Cobas EGFR Mutation Test detection kit (Roche). Results: The mutant type of EGFR was identified in 24.6% of cases, and the most common activating mutations were ex19del (47.5%) and L858R (30.5%). Insertion in exon 20 was detected in 5.1% of mutation cases, G719X - in 3.4%. We also registered cases of identification of two or three mutations in one tumor: ex19del - L858R, ex19del - T790M, L858R - T790M with a frequency of 3.4% and G719X - ex20ins, ex19del - L858R - ex20ins with a frequency of 1.7%. Similar frequency is characteristic of the Caucasoid population of the USA. Multiple mutations in EGFR are associated with early manifestations of lung cancer and rapid progression of the disease. Two patients with two mutations EGFR T790M and L858R were of particular interest. According to the literature data, T790M is the most common somatic mutation that causes resistance to targeted therapy; however, rare cases could be associated with germinal variation of T790M. The primary T790M mutation is more common in patients with two or three mutations in EGFR. Conclusions: Mutations in the EGFR gene were detected in 24.6% of lung cancer cases in a patient population in the South of Russia. The frequency of two or three mutations in the EGFR gene was 0.33%. The timely detection of these mutations is particularly important for family cases when the risk group can be determined.
Cost-effectiveness analysis of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.
Authors: Li Wenqian , Bai Rilan , Qian Lei , Chen Naifei , Zhao Yuguang , Han Fujun , Bai Ling , Li Jiaxuan , Yu Yu , Cui Jiuwei
Published: May 2019

e20556

Background: Non-small-cell lung cancer (NSCLC) patients with brain metastases had a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with WBI with or without chemotherapy for NSCLC patients with brain metastases. Methods: A markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]). Results: When considering progression as intracranial progression and overall progression respectively, the incremental cost-effectiveness ratio (ICER) was $930.17/QALY and $842.76/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (average CE) and net benefit showed advantage of icotinib (average CE: $2157.59/QALY for intracranial progression, $2285.16/QALY for overall progression; net benefit: $372153.35 for intracranial progression, $349938.32 for overall progression). One-way sensitivity analyses demonstrated the impact of the utilities of icotinib group. The probabilistic sensitivity analyses showed even at a WTP under $6000/QALY, icotinib could be cost-effective. Conclusions: Icotinib was cost-effective compared with WBI with or without chemotherapy. [Table: see text]
Chemotherapy in combination with immune checkpoint inhibitors for the first-line treatment of patients with advanced non-small cell lung cancer: A systematic review and literature-based meta-analysis.
Authors: Addeo Alfredo , Banna Giuseppe Luigi , Metro Giulio , Di Maio Massimo
Published: May 2019

e20565

Background: Checkpoint inhibitors plus platinum-based chemotherapy have shown superiority compared to chemotherapy alone as first-line therapy in advanced non–small cell lung carcinoma (NSCLC),To evaluate the relative benefit in term of Overall Survival (OS) and Progression-free Survival (PFS) of checkpoint inhibitors plus chemotherapy versus chemotherapy alone, overall and in subgroups defined by PDL1 expression we have performed a meta-analysis Methods: This meta-analysis searched PubMed and checked references of the selected English language articles to identify further eligible trials. Furthermore, proceedings of the main International meetings (American Society of Clinical Oncology [ASCO] annual meeting, European Society of Medical Oncology [ESMO] annual meeting, International Association for the Study of Lung Cancer [IASLC] World Conference on Lung Cancer), were searched from 2010 onwards for relevant abstracts. Data collection for this study took place from October 1 to October 24, 2018. Results: In total, 8 trials involving 4646 patients with advanced NSCLC, 3.314 (71%) and 1.332 (29%) with a non-squamous and squamous histology, respectively, were included in this meta-analysis. Four trials used atezolizumab, 3 pembrolizumab and 1 nivolumab, accounting for 2.985 (64%), 1.298 (28%) and 363 (8%) of patients, respectively. Checkpoint inhibitors plus chemotherapy were associated with prolonged OS, compared with chemotherapy in the ITT population (HR, 0.74; 95% CI, 0.64-0.87; p = 0.0002, with significant heterogeneity among trials). Within the PDL1 low group (1-49) there was a significant heterogeneity (p = 0.06) between type of drug and efficacy: the combination of chemotherapy plus pembrolizumab showed an OS benefit (HR, 0.56; 95% CI, 0.40-0.78; P< .00007) unlike the atezolizumab backbone trials (HR, 0.92; 95% CI, 0.62-1.37; P< 0.69). However, checkpoint inhibitors plus chemotherapy were associated with prolonged PFS in the ITT (HR, 0.61; 95% CI, 0.56-0.66; P < 0.00001) and across PDL1 subgroups. Conclusions: Checkpoint inhibitors plus chemotherapy compared with chemotherapy, are associated with significantly prolonged OS and PFS in first-line therapy in NSCLC. In the low PDL1 subgroups the benefit was statistically significant only in the pembrolizumab backbone trials.
The impact of systemic treatment on brain metastasis in patients with non-small-cell lung cancer: A retrospective nationwide population-based cohort study.
Authors: Ko Yoon Ho , Hong Ji Hyung , Sun Der Sheng , Won Hye Sung , Kang Seok Yun , Lee Jung Soo , Lee Hyun Woo
Published: May 2019

e20572

Background: We performed a large-scale, retrospective, nationwide, cohort study of the incidence of brain metastasis in patients with advanced non-small-cell lung cancer (NSCLC) according to the systemic treatment administered. Methods: The data were extracted from the Health Insurance Review and Assessment Service of Korea database from January 1, 2011 to November 30, 2016. Of the 29,224 patients newly diagnosed with stage IIIB or IV NSCLC who received first-line cytotoxic chemotherapy (CC group) or targeted therapy (TT group), 22,508 patients without brain metastasis were analyzed. Results: In total, 1,131 (5.0%) patients subsequently developed brain metastasis. The overall cumulative incidence of brain metastasis was significantly higher in the TT group than in the CC group (1-year cumulative incidence: 8.7 ± 0.6% vs. 3.8 ± 0.3%; 3-year: 17.2 ± 0.7% vs. 5.0 ± 0.3%, respectively; P < 0.001), despite the higher rate of brain metastasis in the CC group at < 3 years after diagnosis. Younger age, female sex, living in a rural area, anticoagulant use, and first-line TT (relative risk, 2.17 ± 0.03; 95% confidence interval, 1.92–2.50, P < 0.0001) retained significant associations with subsequent brain metastasis after adjusting for all variables. Conclusions: In the Korean population, the overall cumulative incidence of brain metastasis was significantly higher in patients in the TT group than in those in the CC group; the former could be regarded as having mutations in the EGFR or ALK gene.
The impact of steroid use on efficacy of immunotherapy among patients with lung cancer who have developed immune-related adverse events.
Authors: Wakuda Kazushige , Miyawaki Taichi , Miyawaki Eriko , Mamesaya Nobuaki , Kawamura Takahisa , Kobayashi Haruki , Omori Shota , Nakashima Kazuhisa , Ono Akira , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Mori Keita , Endo Masahiro , Takahashi Toshiaki
Published: May 2019

e20583

Background: Systemic steroids use before starting immune checkpoint inhibitors (ICI) has negative impacts on survival. The aim of this study was to evaluate whether steroid against immune-related adverse events (irAE) reduces efficacy in patients with non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed patients who had advanced NSCLC and undergone ICI therapy between December 2015 and June 2018. Patients whose irAE was treated with ≥ 10mg/day of predonisone were classified into steroid group (S), otherwise into non-steroid group (N). Results: A total of 257 patients (pts) were treated with ICI and irAEs was observed in 103 pts (40%). Twenty-eight pts were S-group and 75 patients were N-group. There was no significant difference in age, sex, stage, performance status, histology, smoking status, gene alteration, expression of PD-L1, or treatment line between the groups. Main irAEs included pneumonitis (43% in S-group / 12% in N-group), diarrhea or colitis (25% / 9%), rash (21% / 20%), and hypothyroidism (14% / 37%). Grade 2 or higher irAEs were pneumonitis in 39% / 0%, diarrhea or colitis in 21% / 5%, hypothyroidism in 7% / 19%. Among S-group, steroids were used for pneumonitis in 11 pts, diarrhea or colitis in 7 pts, stomatitis in 2 pts, and rash in 2 pts. There was no significant difference in overall survival (median; 14.5 vs 30.0 months, P = 0.30, Hazard ratio, 0.69), progression-free survival (median; 7.8 vs 9.6 months, p = 0.11, Hazard ration, 0.65), and objective response rate (46% vs 41%, p = 0.64), respectively. Conclusions: Systemic steroid was mainly used in pts with ≥Gr2 pneumonitis or colitis. This study indicated that steroids use did not reduce efficacy of ICI. Thus, steroid should not be avoided in patients with moderate to severe irAEs with concern over reducing efficacy.
EGFR-A763_Y764insFQEA: A unique exon 20 insertion mutation that displays sensitivity to all classes of approved lung cancer EGFR tyrosine kinase inhibitors.
Authors: Gergis Carol , Rangachari Deepa , Fujii Masanori , Varkaris Andreas , VanderLaan Paul A , Kobayashi Susumu , Costa Daniel Botelho
Published: May 2019

e20593

Background: The epidermal growth factor receptor (EGFR)-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation (accounting for ~10-20% of all EGFR exon 20 insertions) that more closely resembles EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants (i.e. EGFR-exon 19 deletions and L858R) at the structural and enzymatic level as compared to other non-classical mutations. A limited number of preclinical models and clinical reports have detailed the response of EGFR-A763_Y764insFQEA-driven lung tumors to approved or in-development TKIs. Methods: Multiple preclinical models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations were used to probe representative 1st generation (gefitinib, erlotinib), 2nd generation (afatinib, dacomitinib), 3rd generation (osimertinib), and in-development EGFR exon 20 specific (poziotinib, others) TKIs. Clinical outcomes and prior reports of EGFR-A763_Y764insFQEA mutated lung adenocarcinomas treated with EGFR TKIs were compiled. Results: Cell lines driven by EGFR-A763_Y764insFQEA were consistently sensitive to 1st, 2nd and 3rd generation EGFR TKIs, while models driven by other EGFR exon 20 insertions (i.e. D770_N771insSVD and H773_V774insH) were only inhibited by in-development EGFR TKIs and at doses below those affecting the wild-type receptor. The majority of patients with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinical doses of 1st, 2nd, and 3rd generation EGFR TKIs; and lung cancers with these mutants are currently enrolled in clinical trials of in-development EGFR exon 20 specific TKIs. Conclusions: This is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is a unique exon 20 insertion mutation sensitive to 1st, 2nd, 3rd generation and in-development EGFR exon 20 specific TKIs. Mechanisms of acquired resistance of this mutant to different EGFR TKIs remain unreported.
Chemoimmunotherapy combination: Potential option for metastatic NSCLC patients with EGFR mutation resistant to osimertinib.
Authors: Yang Bo , Long Yaping , Hu Yi
Published: May 2019

e20618

Background: Osimertinib has been emerged as the standard selection in EGFR T790M-positive NSCLC patients who failed prior treatment with EGFR TKIs. However, acquired resistance to osimertinib is a growing clinical challenge. Despite the significant antitumor activity of Chemoimmunotherapy (CIT) combinations in NSCLC, clinical benefit in patients with EGFR mutations has not been shown obviously. Our objective was to assess the effectiveness and tolerability of CIT for metastatic EGFR-mutant NSCLC patients with acquired resistance to Osimertinib. Methods: We conducted a retrospective study in patients with sensitizing EGFR-mutant NSCLC who were resistant to Osimertinib and received anti-PD1 immunotherapy combined with chemotherapy at Chinese PLA General Hospital. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities were examined. Results: Between Oct 2015 and Nov 2018, 11 patients were available for analysis, 45.5% male, 45.5% ECOG PS 0-1, median age 54 years, all pts who failed treatment with Osimertinib had received previously targeted therapies. In this CIT combination group, 6 [54.5%] of 11 pts received pembrolizumab and 5[54.5%] of 11 pts received Nivolumab anti-PD1 therapy, 8 [72.7%] of 11 pts received mono-chemotherapy and 3 [27.3%] of 11 pts received platinum-based doublet chemotherapy. The median PFS was 7.47 months (95% CI 3.04 to 11.89). Despite Median OS was not reached, the OS rate at one year was 6 [54.5%] of 11. The ORR was 5 [45.5%] of 11. Treatment-related adverse events (TRAE) of grade 3 or higher were reported in 6 [54.5%] of 11 patients. The most common grade 3 or worse TRAEs were fatigue (3 [27.3%] of 11) and anemia (3 [27.3%] of 11); The following ≥Grade 3 TRAEs occurred once: decreased neutrophil count, acute kidney injury, gastrointestinal bleeding. One patient discontinued treatment because of immune-associated gastroenteritis. Conclusions: In metastatic NSCLC patients with activating EGFR mutation resistant to Osimertinib, our single institution real-world experience in Chemoimmunotherapy combination shows promising activity and acceptable toxicity profile. Given the small number of patients studied, further clinical trials are warranted.
Effect of immunotherapy at any line of treatment on survival in Hispanic patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP).
Authors: Cardona Zorrilla Andres Felipe , Ruiz-Patiño Alejandro , Arrieta Oscar , Martin Claudio , Raez Luis E. , Zatarain Barrón Zyanya Lucia , Barron Feliciano Barron , Ricaurte Luisa , Bravo Maria , Mas Luis , Rojas Leonardo , Lupinacci Lorena , Perazzo Florencia , Puparelli Carmen , Rizzo Manglio Miguel , Rolfo Christian Diego , Rodriguez July , Sotelo Rodríguez Diana Carolina , Carranza Hernan , Rosell Rafael ,   ONCOLGroup
Published: May 2019

e20637

Background: To compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy. Methods: A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted. Results: Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival was 4.27 months (95% CI 3.97-5.0). Factors associated with increased survival included treatment as first-line (p < 0.001), type of response (p < 0.001) and PD-L1 status (p = 0.0039). Compared to the historical cohort, immunotherapy proved to be superior in terms of OS (p = 0.05) but not PFS (p = 0.2). Conclusions: Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless treatment line.
Autoantibodies indicating diagnostic or prognostic value in NSCLC patients were identified by protein microarrays.
Authors: Luo Rongrong , Liang Caixia , Yao Jiarui , Wu Di , Zhang Zhishang , Shi Yuankai , Han Xiaohong
Published: May 2019

e20638

Background: Autoantibodies(AAbs) have been recently recognized as auxiliary diagnostic biomarkers in lung cancer. Applying high-throughput protein microarrays to address AAbs profile of non-small cell lung cancer(NSCLC) is rarely studied. Herein, we aimed to discover AAbs possessing diagnostic or prognostic value in NSCLC patients. Methods: We collected pretreatment plasma samples and survival data of 258 NSCLC patients and 343 controls. The advanced NSCLC patients were divided into subgroups according to different epidermal growth factor receptor(EGFR) gene status, therapies and therapeutic response. We utilized human proteomic(HuprotTM) microarrays to screen differential AAbs and customized microarrays to validate. Statistical methods were Chi-square test and ROC analysis. Results: We found 8 AAbs(p < 0.05 or AUC > 0.6) with underlying diagnostic or prognostic value of NSCLC patients after screening and validation. The positive rate of 4 AAbs including anti-TP53, XAGE1A1,2 and KCNAB1 in NSCLC group were higher than that in controls. Among them, anti-KCNAB1 increased in early-stage group compared with controls, indicating early diagnostic value. The other three AAbs level raised as disease progressed to advanced-stage. For advanced NSCLC patients, the differential AAbs of EGFR+ patients receiving either first generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy or chemotherapy were identified with higher positive rate in poor response subgroups compared with good response subgroups(Table1). However, for EGFR- patients with chemotherapy, the differential AAbs in different response subgroups were not found. Conclusions: We found AAbs with underlying diagnostic or prognostic value for advanced NSCLC patients receiving EGFR-TKI or chemotherapy, which should be further investigated to confirm their clinical value. [Table: see text]
Impact of antibiotics (ABX) on overall survival (OS) in patients (pts) with advanced non-small-cell lung cancer (aNSCLC) and melanoma (aMel) treated with first-line immune checkpoint inhibition (ICI).
Authors: Bagley Stephen Joseph , Dhopeshwarkar Neil , Narayan Vivek , Meropol Neal J. , Mamtani Ronac , Boursi Ben
Published: May 2019

e20643

Background: Recent data suggest that modulating the microbiome may affect response to ICI. Using electronic health record (EHR) data, we examined whether use of ABX influences OS in pts with aNSCLC and aMel treated with ICI. Methods: We performed two retrospective cohort studies (aNSCLC, aMel) of pts who received ICI +/- chemotherapy as first-line treatment in the nationwide Flatiron Health EHR-derived database. The impact of ABX exposure on OS was assessed using Cox regression, adjusting for age, sex, body mass index (BMI), performance status (ECOG PS), Elixhauser Comorbidity Index, glucocorticoid (GC) use, and smoking. In the primary analysis, ABX exposure was defined as use from -6 to +4 weeks around start of ICI. In secondary analyses, we separately evaluated ABX use within 6 weeks pre- and 4 weeks post-initiation of ICI. Results: Baseline characteristics are displayed (Table). In the primary analysis, there was no association between ABX use and OS in aNSCLC (HR 1.16, 95% CI 0.54-2.47, p = 0.7) or in aMel (HR 0.70, 95% CI 0.17-2.81, p = 0.6). The only secondary analysis to reveal a negative impact of ABX on OS was the time window of 0 to +4 weeks after ICI start in aNSCLC (HR 3.41, 95% CI 1.38-8.39, p = 0.008). Conclusions: In this large, real-world dataset, ABX exposure around the start of front-line ICI did not influence OS in pts with aNSCLC or aMel. However, ABX exposure was associated with inferior OS in the subgroup of aNSCLC pts who received ABX within 4 weeks following start of ICI. Further characterization of completeness of ABX exposure data in the oncology EHR will assist with interpretation of these results. [Table: see text]