bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-brain radiotherapy in NSCLC patients with brain metastasis: Who benefits and by how much?
Authors: Jain Pooja , Montazeri Amir H , Alam Farida , Eswarvee Chinnamani , Husband David J. , Ibrahim Azman , Malik Zafar I , Schofield Penny , Shenoy Aditya , Sivapalasuntharam Asha , Whitmarsh Karen A , Wong Helen , Littler John
Published: March 2020

e18068

Background: NSCLC patients with brain metastasis have poor survival even with whole brain radiation therapy (WBRT) alone or in combination with surgery (S+WBRT). The aim of the audit was to identify any prognostic factors which can aid treatment decisions. Methods: A retrospective study of patients with brain metastasis from NSCLC, diagnosed between July 2008 and December 2010 was carried out. Patient characteristics, RPA score at the time of presentation, treatment modality, radiotherapy dose fractionation, time to progression, date of death and primary or secondary presentation were collected. The data was analysed using descriptive statistics; overall survival was calculated using the Kaplan-Meier estimates and compared with the Log-rank test. Multivariate analysis was carried using the Proportional Hazards Model. Results: Of the 156 patients included, 52% presented as primary manifestation and 48% as secondary. The mean age of the audit population was 64.4 year, with 60% of patients falling in the RPA II category. Histology was not available in 27 (18%) of the patients. Majority (79%) were treated with WBRT alone, 3 patients had stereotactic radiosurgery in combination with WBRT and 19% had S+WBRT. 9 (6%) patients did not complete WBRT. Median follow up is 3.8 months (0.5-34.5). Overall survival (OS) for the whole group is 4 months. Better survival was seen with S + WBRT (8 vs. 4 months, p <0.01) and primary presentation (5 vs. 4 months, p=0.009). RPA classification significantly influenced survival in the S + WBRT arm (12 months vs. 7 months for RPA I, p=0.009). On multivariate analysis of the various prognostic factors in the WBRT group, RPA classification and higher RT dose (30 Gy/10#) were associated with better survival (OR 2.3 95%CI 1.6-3.4). Patients treated with SRS have the best survival (11 months). Conclusions: RPA classification is the strongest predictor for outcome following treatment for brain metastasis. These findings can assist in better patient selection and optimising radiotherapy dose fractionation to improve survival outcome. It will be interesting to see if QUARTZ trial supports these findings and clarify the benefit of WBRT in patients with NSCLC.
A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Kim Han Sang , Cho Byoung Chul
Published: March 2020

e18080

Background: Nimotuzumab (TheraCIM) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Methods: Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100 mg or 200 mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We designed to enroll additional 10 patients at RPIID for the safety analysis. EGFR mutations and KRAS mutations were analyzed from available tumor samples. Results: A total of 16 patients were enrolled (3 in 100 mg cohort, 13 in 200 mg cohort). Six patients (40%) were female, and 5 (33.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%).Treatment was well-tolerated without dose-limiting toxicity (DLT). Three patients (18.7%) experienced grade 2 skin toxicity (1 in 100 mg cohorts, 2 in 200 mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (28.6%) achieved partial response and 5patients (35.7%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Conclusions: Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC.
Neutrophil to lymphocyte ratio as a prognostic indicator for advanced non-small cell lung cancer patients: A retrospective study.
Authors: Yao Yanwen , Yuan Dongmei , Liu Hongbing , Gu Xiaoling , Song Yong
Published: March 2020

e18082

Background: Neutrophil to lymphocyte ratio (NLR) has been shown to be a prognostic indicator for different types of cancer. We aimed to investigate the prognostic significance of NLR in advanced non-small cell lung cancer (NSCLC) patients. Methods: From January 2007 to December 2010, total 201 patients who were histologically diagnosed NSCLC, staged for the TNM stage III or IV and chemotherapy-naïve were included. All patients were followed up until August 1st 2011. NLR was calculated from lymphocyte and neutrophil count on routine blood tests taken before diagnosis or first-line therapy. Results: The median survival time of all included patients was 354 days and mean value of NLR was 4.06. Cases were distributed into two groups at NLR value of 4.06. Multivariate analysis demonstrated that NLR was an independent and significant prognostic factor in overall survival (OS) (Hazard Ratio, HR=1.659, 95% Confidence Interval, CI=1.075-2.559, p=0.022). Conclusions: The results suggested that the elevated NLR predicted poor OS for advanced NSCLC patients. It may be a potential biomarker to stratify higher risk of death in advanced NSCLC patients, and this kind of patients may be supposed to more aggressive treatment to pursuit longer survival.
Prospective correlative study of FDG-PET SUV and proteomic profile (VeriStrat) of non-small cell lung cancer patients treated with erlotinib.
Authors: Lazzari Chiara , Tiseo Marcello , Gregorc Vanesa , Latteri Fiorenza , Ippolito Massimo , Balderi Segio , Cosentino Sebastiano , Scarlattei Maura , Roder Heinrich , Grigorieva Julia , Roder Joanna , Bordonaro Roberto , Ardizzoni Andrea , Gianni Luca , Soto Parra Hector J.
Published: March 2020

e18096

Background: Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI TOF MS) was used to create and validate a plasma proteomic algorithm VeriStrat (VS), based on 8 m/z peaks, and able to select advanced NSCLC pts who may benefit from EGFR TKIs. The algorithm was associated with PFS and OS of patients treated with EGFR TKIs and not with chemotherapy. Standardized Uptake Value (SUV) is of prognostic value for survival in non-small cell lung cancer. Aim of the current study was to analyze the OS and TTP in advanced NSCLC pts treated with erlotinib (E) according to baseline VeriStrat classification and baseline SUVs of FDG-PET. Methods: Plasma samples were collected before the beginning of E from metastatic NSCLC patients. Acquired spectra were classified according to the VeriStrat algorithm. The FDG-PET was performed the day before the beginning of E. Results: Thirty eight NSCLC pts on E therapy with the following characteristics were analyzed: median age 62 years old, 63% were males, 53% had adenocarcinoma histology, response rate was 26%, median OS 10 mos and (TTP) 3.4 mos. Twenty-six (68%) were classified as VS Good, 12 (32%) as Poor. TTP and OS for VS Good and Poor were 4.1 vs 2.1 mos (HR 0.86, log-rank p=0.6) and 11.1 vs 4.1 mos (HR 0.45,log-rank p=0.02), respectively. Baseline SUV levels were associated with TTP (Wilcoxon test p=0.001) but not with OS (all pts progressed, 5 still alive). All Poor classified pts had SUV ≥ 7 and had the worst TTP and OS; VS Good classified patients had worse TTP and OS if their baseline SUV level was > 7 than those who were VS Good and had SUV<7(see Table: 3-curves comparison log-rank test p value for a trend). Conclusions: We confirmed that pts with VS Poor classification have significantly shorter OS than those classified as VS Good. Pts with VS Good profile and with low baseline SUV levels may benefit more from EGFR TKI than VS Good pts with high SUV.
Response to afatinib in patients with advanced NSCLC previously treated with reversible EGFR inhibitors in a mono-institutional experience.
Authors: Bennati Chiara , Currà Maria Francesca , Chiari Rita , De Angelis Verena , Minotti Vincenzo , Metro Giulio , Duranti Simona , Molica Carmen , Scafati Chiara , Paglialunga Luca , Pistola Lorenza , Flacco Antonella , Tofanetti Francesca Romana , Siggillino Annamaria , Baldelli Elisa , Ludovini Vienna , Crinò Lucio
Published: March 2020

e18101

Background: All mutated non-small cell lung cancer (NSCLC) patients (pts) previously treated with an EGFR reversibile inhibitor, develop, soon or later, resistance. Afatinib is a potent irreversible HER family inhibitor, with preclinical data suggesting activity against the resistance mutation EGFR T790M. From August 2005 to January 2011, in a retrospective observational study at our Division of Medical Oncology, we have evaluated 22 advanced NSCLC pts, who have been treated with Afatinib, after disease progression with Erlotinib or Gefitinib. Methods: 22 advanced NSCLC pts who have previously received a reversible EGFR-TKI (gefitinib or erlotinib), and subsequently have been treated with Afatinib in a different setting of their medical history, were included in the analysis. Afatinib was provided in an expanded access program by Boehringer. Results: Patients characteristics: median age 64 ys (34-85); PS 0-1; most of pts were never smokers (82%) with non-squamous histology. 12 pts (54%) had multi-metastatic sites at diagnosis, 4 of which (33%) had brain lesions. Nineteen pts (86%) were found to be EGFR mutated (15 patients with EGFR-sensitizing mutations at exon 19 and 21). No one was K-RAS mutated. Eighteen pts (82%) received Afatinib in a second line TKI setting and 4 pts (18%) in a third line. Overall, 4 pts (18%), 2 of which had a multi-metastatic disease at diagnosis, had a partial response to Afatinib and 11 pts (50%) achieved a stable disease. Of the 16 pts evaluable for response in the second line setting, median progression-free survival (PFS) was 5,2 months. Diarrhea and skin rash were the most common adverse events but a dose-limiting toxicity was observed in only three patients. Conclusions: Our experience confirmed Afatinib clinical activity in patients with acquired resistance to prior reversible TKI. The treatment has been well tolerated and there were no new or unexpected safety findings.
Survival data and toxicity profile in advanced non-small cell lung cancer (NSCLC) patients (PTS) treated within or outside controlled clinical trials.
Authors: Vavala Tiziana , Rovere Giulia , Rapetti Simonetta , Capelletto Enrica , Longo Marina , Giaj Levra Matteo , Crida Benedetta , Novello Silvia
Published: March 2020

e18103

Background: Even without well defined data, a common perception is that clinical trials inclusion improve outcomes in pts with cancer. We conducted a retrospective analysis, in a single institution, evaluating survival data and tolerability in advanced NSCLC pts treated with standard therapy or within phase II/III clinical trials. Methods: We analysed 300 consecutive pts treated at the Thoracic Oncology Unit at San Luigi Gonzaga Hospital from 2004, January the 1st to 2011, December 31st having these characteristics: histo/cytological diagnosis of NCSLC, stage IV who received at least 3 chemotherapy cycles, minimum follow-up of 6 months. In this pts population 180 (60%) were enrolled in controlled clinical trials (T), while 120 (40%) were treated with standard therapy (S). Results: The most important differences between the two groups were about median age at the time of starting first line treatment (61.2 in group T vs 64 years in group S), pts older than 70 years (19% vs 27%, respectively) and ECOG/PS distribution (PS=2: 0 vs 9 pts, PS=1: 33 vs 53 pts, PS=0: 145 vs 60 pts in T and S group, respectively). Evaluating T and S population: 106 (59%) vs 43 (36%) pts were eligible for second line treatment and 45 (25%) vs 19 (16%) pts for third line treatment. Median OS was 16,3 in T population vs 14,4 months in S population and PFS was 7.1 vs 6.3 months respectively. Any relevant differences was seen between group T and S in terms of toxicity. Conclusions: This single institution retrospective analysis documented a trend of better outcome for pts enrolled in clinical trials compared to those treated with standard therapy (even without a statistical significance) with an higher percentage of pts reaching second and third line therapies. A larger multicenter prospective dedicated trial is needed to have further, more cleaned, data about this item.
Diagnostic and prognostic significance of circulating endothelial cell in advanced non-small cell lung cancer.
Authors: Yuan Dongmei , Lv Yanling , Ma Xingqun , Liu Hongbing , Shi Yi , Song Yong
Published: March 2020

e18116

Background: The aim of this study was to evaluate the diagnostic and prognostic value of circulating endothelial cells (CECs) during first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). Methods: 102 newly diagnosed advanced NSCLC patients were enrolled in this study. The amount of CECs (CD45- CD31+ CD146+) was enumerated by flow cytometry at baseline and after two cycles of treatment. We correlated CEC counts and the reduction of CECs with objective response rate (ORR) and progression-free survival (PFS). Results: The CECs level was significantly higher in advanced NSCLC patients, ranging from 57 to 1300 cells/105 cells (n=102, mean±SD=299±221 cells/105 cells), than patients with benign lesions (n=35, 205±97 cells/105 cells), and healthy volunteers (n=34, 117±33 cells/105 cells). When the cut off value of CEC counts was 210 cells/105 cells, there was no significant association between CEC counts and OR/PFS of the enrolled patients. However, patients with CECs response after chemotherapy has more chances to achieve OR (P<0.001), and such patients showed longer PFS than those without CECs response (P = 0.041). In the multivariate analysis, the independent prognostic roles of performance status (HR: 3.245, 95% CI: 1.189-8.854), brain metastasis (HR: 3.673, 95% CI: 1.062-12.704), and CECs response (HR: 0.046, 95% CI: 0.188-0.984) were found. Conclusions: The CEC counts could be considered as the diagnostic biomarker for advanced NSCLC patients. And the reduction of CECs after treatment might be more ideal than the CEC counts as a predictive or prognostic factor in patients treated with platinum-based chemotherapy.
A phase I/II clinical trial of intravenous (I.V.) calcitriol with fixed doses of cisplatin and docetaxel in advanced non-small cell lung cancer.
Authors: Ramnath Nithya , Daignault-Newton Stephanie , Dy Grace K. , Muindi Josephia , Adjei Araba , Kalemkerian Gregory Peter , Cease Kemp Bailey , Stella Philip J. , Brenner Dean E. , Johnson Candace S. , Trump Donald L.
Published: March 2020

e18118

Background: In vitro and in vivo studies have demonstrated the antiproliferative effects of 1, 25 (OH)2D3 (calcitriol) as single agent and antitumor synergy with cisplatin. The goals of this Phase I/II study were to determine the maximum tolerated dose (MTD) of 1, 25 (OH)2 D3 in combination with cisplatin and docetaxel, and to evaluate the efficacy in patients (pts) with metastatic NSCLC.Methods: The study was a multicenter, open-label study in pts with metastatic NSCLC. Pts were adults 18 yrs., PS 0-1 with normal liver/kidney function. For the phase I study, pts (3–6 per cohort) received 1, 25 (OH)2 D3 I.V. every 21 days prior to docetaxel and cisplatin. The starting dose of 1,25 (OH)2D3 was 15 mcg/m2 at sequential ascending dose levels (DL) (15, 30, 60 and 80 mcg/m2) using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of <33%. Docetaxel was administered at 75 mg/m2 and cisplatin 75mg/m2 following 1, 25 (OH)2 D3 for 4 cycles. We analyzed SNPs in the CYP24A1 gene.Results: 37 pts were enrolled (16 in phase I and 21 in phase II) with a median age of 54 (range 34–79) yrs.; M: F, 12:17. At the 80 mcg/m2 dose level, 2/4 pts had DLT of grade 4 neutropenia. There were no cases of hypercalcemia or azotemia. The MTD and recommended Phase II dose was 60 mcg/m2. Among 6 response-evaluable Phase I pts, and 21 phase II pts, there were: 2 confirmed partial responses (PR), 6 unconfirmed PRs and 10 pts with stable disease. The median time to progression was 6.9 months (95% CI 4.4, 12.9) and the median overall survival was 8.3 months (95% CI 5.8, 14.9). Of the CYP24A1 SNPs, the IVS4-308C>G was associated with progressive disease (Chi-Square=0.0062)Conclusions: The MTD of 1,25 (OH)2D3 in combination with docetaxel and cisplatin was 60 mcg/m2 IV every 21 days. Pre-specified endpoint of a 50% response rate was not met in the phase II study. However, disease control in 66% of patients argues for further study of 1,25 (OH)2D3 as maintenance therapy. The CYP24A1 polymorphism IVS4-308C>G may be associated with resistance to a 1,25 (OH)2D3 based therapeutic regimen
Assessment of human papilloma virus in non-small cell lung cancer in never-smokers: A study from a prospective registry of never-smokers.
Authors: Kawaguchi Tomoya , Shimizu Shigeki , Itoh Norimasa , Kubo Akihito , Isa Shunichi , Utsumi Tomoki , Sakaguchi Masahiro , Yoon Hyungeun , Ou Sai-Hong Ignatius , Kitaichi Masanori , Matsumura Akihide
Published: March 2020

e18126

Background: Driver mutations have been identified in most non-small cell lung cancers (NSCLC) from never-smokers. However, a small percentage of the tumors still have no its mutations detected. Human papillomavirus (HPV) has been hypothesized to contribute to lung carcinogenesis in East Asia. Methods: We started a prospective registry of never-smokers with NSCLC at the Kinki-chuo Chest Medical Center, Japan, in 2008. We consecutively enrolled all the never-smokers after obtaining written informed consent. Among these, we selected the 114 patients treated with surgery to obtain a large amount of DNA. After exclusion of samples with suboptimal quality, DNA was extracted from 93 formalin-fixed paraffin-embedded surgical tissues. HPV genotyping was performed using a PCR-based microarray system for detecting 23 HPV types, including high-risk (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) and low-risk or risk-unknown types (HPV types 6, 11, 30, 34, 40, 42, 53, 54, 61, and 66). Epidermal growth factor receptor (EGFR) and KRAS mutations were examined with real time PCR (genotyping), and EML4-ALK rearrangements were detected using immunohistochemical staining and fluorescence in-situ hybridization. Results: There were 80 female (86.0%) and 13 male patients (14.0%), with a median age of 67 years (range 29-83). Almost all cases were of the adenocarcinoma histological subtype (92.5%). Molecular analysis of these 93 patients detected 59 EGFR mutations (63.4%), 5 K-ras mutations ( 5.4% ) and 4 EML4-ALK rearrangements (4.3%). These abnormalities were mutually exclusive except for one case who had both EGFR and KRAS mutations. HPV 6 was detected in only one case (1.1%), a 49-year-old female who had an EGFR mutation with wild type KRAS and ALK. No others examined were positive for any HPV type. Conclusions: The three driver mutations accounted for 72.0% of NSCLC in never-smokers. Although a low-risk HPV type was evident in one case, no high-risk HPV types were detected in the tumors with or without the mutations. Our results suggest that HPV does not play a major role as the driving oncogenic event in adenocarcinoma in never-smokers in Osaka, the central area of Japan.
Circulating tumor cells and T790M in metastatic non-small cell lung cancer patients with EGFR mutations and acquired resistance to TKI.
Authors: Isobe Kazutoshi , Hata Yoshinobu , Sato Keita , Sugino Keishi , Sano Go , Sakamoto Susumu , Takai Yujiro , Shibuya Kazutoshi , Takagi Keigo , Homma Sakae
Published: March 2020

e18127

Background: This study assessed correlations between the presence of circulating tumor cells (CTCs), detection of T790M in organs with metastases or circulating-free DNA (cfDNA), and prognosis in metastatic NSCLC patients with acquired resistance to EGFR-TKI. Methods: Metastatic NSCLC patients with activating EGFR mutations, who initially responded but subsequently experienced disease progression while on EGFR-TKI treatment, were defined as having ‘acquired resistance’. Blood samples were collected after development of such acquired resistance and CTCs were counted using the CellSearch system (Veridex). At the same time, T790M in affected organs or cfDNA was analyzed with cycleave real-time PCR assay and fragment analysis. Results: : Six men and 14 women with a mean age of 63.5 yrs (22-84) were enrolled. Histological subtypes were adenocarcinoma in 19 and squamous cell carcinoma in the remaining one. Clinical stages were stage IV in 14 and recurrence with distant metastases after surgical resection in 6. EGFR mutations in tumors at the primary site were G719C in 1, exon 19 deletion in 7, L858R in 10, and G791C + L858R in 2. CTCs were detected in 8 (40%). Numbers of CTCs (per 7.5 ml blood) were 1 in 4 cases, and 3, 4, 8, and 24 in 1 case each. Patients without CTCs survived significantly longer than those with CTCs (≥1 per 7.5 ml). Mean survival time from first detection of CTCs was 3.0 months in patients with CTCs and not reached in patients without CTCs (p < 0.001). T790M was detected in 6 cases (30%). T790M was found in 75% (n = 6/8) of patients without CTCs but in 0% (n = 0/12) of those with CTCs (p < 0.05). Conclusions: The presence of CTCs was correlated with poorly prognosis and lack of T790M in affected organs or cfDNA. The presence of CTCs was informative for distinguishing patients with or without T790M.
Changing causes of death post-epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) era in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Wu Wen Shuo , Chen Yuh-Min , Tsai Chun-Ming , Shih Jen-Fu , Lee Yu-Chin , Perng Reury-Perng
Published: March 2020

e18132

Background: EGFR-TKIs are effective against tumor EGFR-mutated NSCLC. Patients with tumor EGFR activating mutation (EGFRmu) (exon 19 deletions or exon 21 L958R) had better survival than those with EGFR wild-type tumors (EGFRwt). Many EGFRmu patients have had disease progression with EGFR-TKI treatment due to central nervous system (CNS) metastases, including meningeal carcinomatosis. The objective of this retrospective study is to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR-TKIs. Methods: We retrospectively reviewed the chart records of our advanced NSCLC patients who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. Tumor EGFR mutation status was analyzed using the DNA sequence method. All enrolled patients had a documented cause of death. Results: Ninety-four patients had documented tumor EGFR data, had received EGFR-TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of them, 36 were EGFRwt and 58 were EGFRmu. Overall survival after starting EGFR-TKI treatment was significantly longer in EGFRmu than in EGFRwt patients (median 68.9 weeks vs. 46.3 weeks, p=0.0058). Twenty-nine patients died of CNS metastases and 65 died of organ(s) failure other than the CNS. Patients who died of CNS metastases had undergone EKGF-TKI treatment significantly longer than those who died of other organ(s) failure (median 32 weeks vs. 7.7 weeks, p=0.0003), with a hazard ratio of 2.308 (95% C.I. 1.452-3.668, p=0.0004). A significantly higher proportion of EGFRmu patients died of CNS metastases (26 of 58, 44.8%) than EGFRwt patients (3 of 36, 8.3%) (p<0.001). Conclusions: EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases than EGFRwt patients. This change in the causes of death due to NSCLC was noted after an era of EGFR-TKI treatment, and will have an important impact on the strategies or management of patient supportive and hospice care.
Detection of EGFR and KRAS somatic mutations in tumor tissue and peripheral blood by a liquidchip technology for patients with advanced non-small cell lung cancer.
Authors: Zhang Shucai , Zhang Hui , Yang Xinjie , Li Xi , Qin Na , Xu Jiasen , Yang Huiyi , Zheng Yong-Qing , Yu Gang
Published: March 2020

e18142

Background: Responsiveness of non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors has been confirmed to relate to mutations in the epidermal growth factor receptor (EGFR) signaling pathway genes. This study’s aim is to detect mutations in two important components of the EGFR signaling pathway, EGFR and KRAS, using a novel liquidchip technology, and to evaluate the correspondence between tumor and plasma DNA in the same patient. Methods: 58 advanced primary NSCLC ( IIIB or ‡W) tumor tissues and matched peripheral blood samples (MPBS) were obtained. The procedures for multiplex PCR, allele specific primer extension (ASPE) and hybridization were performed after DNA extraction. A novel liquidchip platform for simultaneous detection multiple alleles of DNA somatic mutations was applied to detect the EGFR and KRAS status in matched samples. Results: EGFR exon 19 and exon 21 mutation rate was detected to be 29.3% (17/58) and 17.2% (10/58) respectively in tumor tissues, while 20.7% (12/58) and 12.1% (7/58) in MPBS. Among those 27 patients who harbor either EGFR exon 19 or exon 21 mutations in tissues, 19 (70.4%) of them were detected to have the same mutations in their peripheral blood samples. EGFR exon 20 T790M mutations were found in one of the paired samples. All the patients who were detected to have wild-type EGFR in tissues were detected to have wild-type in MPBS as well. In 50 of 58 (86.2%) of the paired samples, the EGFR mutation status in the tumors was consistent with those in the MPBS. The KRAS exon 2 mutation was also found in both blood and tumor samples in one patient; however only in the blood of another patient, not in his tumor. Conclusions: The liquidchip technology may serve as an effective method for detecting multiple gene mutations. EGFR and KRAS gene mutations in blood DNA were highly consistent with the corresponding tissue samples, and therefore, peripheral blood could be used as an alternative sample to predict patients’ response to the anti-EGFR targeted therapy. Further studies to evaluate the clinical application are suggested.
Association of p53 mutations with progression-free survival (PFS) and overall survival (OS) in EGFR-mutated non-small cell lung cancer (NSCLC) patients (p) treated with erlotinib.
Authors: Gasco Amaya , Molina-Vila Miguel Angel , Bertran-Alamillo Jordi , Mayo Clara , Costa Carlota , Gimenez Capitan Ana , Massuti Bartomeu , Camps Carlos , Carcereny Costa Enric , Viteri Ramirez Santiago , Martinez-Bueno Alejandro , Benlloch Susana , Capdevila Laia , Cros Sara , Porta Rut , Cardenal Felipe , Bosch Joaquim , Sanchez Jose Javier , Taron Miquel , Rosell Rafael
Published: March 2020

e18143

Background: Advanced NSCLC p with EGFR mutations have a median PFS of 14 months (m) and OS of 27 m when treated with erlotinib. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent upregulation of Fas and caspase activation leading to apoptosis, but this mechanism was defective in p53-null cells. We tested whether TP53 mutations influence outcome to erlotinib in EGFR-mutated p. Expression levels of the p53 repressor MDM2 were also examined. Methods: We assessed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR-mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis followed by sequencing of the amplified products with non-wild-type (wt) melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of TP53 were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations were less frequent in p with ECOG PS >2 and more frequent in p with the T790M mutation. OS was 15 m in the 16 p with missense mutations 31 m in p with wt p53 and not reached in p with non-missense mutations (P=0.04). PFS was 9 m for 14 p with mutations in one of the p53 DNA binding motifs (DBMs), compared to 19 m for wt p and 27 m for p with non-DBM mutations. MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially in DBM mutations. In the case of wt p, high MDM2 expression correlated with longer PFS and OS in p with wt p53. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; missense mutations correlate with shorter OS and mutations in DBMs correlate with shorter PFS. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring certain types of mutations in the TP53 gene.
Predicting sensitivity to azacytidine in non-small cell cancer lines by absence of activating mutations.
Authors: Wrangle John , Mohammad Helai P , Abukhdeir Abde , Juergens Rosalyn A. , Harbom Kirsten , Rodgers Kristen , Shin James , Zahnow Cynthia A. , Baylin Stephen , Herman James Gordon , Rudin Charles M. , Brock Malcolm
Published: March 2020

e18147

Background: A completed clinical trial has demonstrated activity of a combination of epigenetic therapies: entinostat, a histone deacetylase inhibitor, and azacytidine (AZA), a hypomethylating agent. A plasma-based biomarker assaying methylation status of key gene promoters from circulating DNA was developed. In order to test the relationship of activating mutations to sensitivity to epigenetic therapy, we treated non-small cell lung cancer (NSCLC) lines with AZA and assessed tumor growth in xenografts. Tumor from patients on trial was analyzed for mutational status. Methods: Nine NSCLC lines were treated in vitro for 72 hours with 500 nM AZA and injected to form flank tumors in NOG mice. Four lines contain no activating mutations. Of the five mutant lines, three were KRAS and two were EGFR mutations. Lines with no activating mutations are termed “mutation-negative” for known oncogenic drivers. Growth of mock versus treated tumors was compared over time to determine treatment phenotypes. Lines were grouped into four categories: augmented growth compared to mock, no treatment effect, mild inhibition of tumor growth, and marked inhibition. Seventeen tumors from the clinical trial were analyzed by SNaPshot multiplex PCR. Results: Among mutation negative lines three showed marked tumor growth inhibition and one showed mild inhibition. Among cell lines with activating mutations, one showed mild inhibition, three showed no effect, and one showed augmented tumor growth. Among 17 tumor samples from patients on study, four driver mutations were identified: 3 KRAS and one PTEN mutation. All four patients experienced progressive disease on study. Among thirteen patients with mutation negative tumors, three had stable disease and one had a complete response. Conclusions: The association between driver mutation negative status and treatment outcome in NSCLC cell lines in patients receiving AZA and entinostat merits further exploration. Future trials of epigenetic therapy in NSCLC may benefit from a biomarker enrichment strategy and the data presented here represents a potential way forward.
Metabolic response evaluated by 18F-FDG PET/CT as a potential tool in identifying subgroup of patients with advanced non-small cell lung cancer for immediate maintenance treatment after first-line chemotherapy.
Authors: Cho Su-Hee , Park Silvia , Park Lee Chun , Ji Jun Ho , Lee Ji Yean , Hwang Deok Won , Maeng Chi Hoon , Ahn Hee Kyung , Ahn Myung-ju , Park Keunchil , Ahn Jin Seok , Sun Jong-Mu
Published: March 2020

e18148

Background: Platinum-based doublet regimens have been a mainstay of first-line treatment with advanced non–small cell lung cancerand ans the present guidelines recommend four to six cycles and waiting until disease progression. However subsequent disease progression is often rapid so sequential and maintenance therapy was performed in many studies. But almost studies didn’t show the significant survival benefit. Thus, we supposed that FDG PET may be a useful to determine what subgroup have better prognosis Methods: We founded out fifty-two patients who diagnosed to underwent baseline and follow-up FDG PET after 4 cycles of first-line platinum based chemotherapy. We obstained patient's characteristics and response rate (RR), progression-free survival (PFS), and overall survival (OS) from the medical records. And we checked maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG) from FDG PET. Results: Univariate analysis showed that MTV (hazard ratio = 1.032, P = 0.007) and TLG (hazard ratio = 1.030, P = 0.001) were independent predictive factors associated with decreased PFS and gender (hazard ratio = 5.248, P = 0.026), smoking (hazard ratio = 7.798, P = 0.006), EGFR mutation (hazard ratio = 0.106, P = 0.030) and TLG (hazard ratio = 1.027, P = 0.046) were significant predictors of OS. Histopathology was a marginally significant prognostic factor (P = 0.058). Multivariate analysis showed that TLG (hazard ratio = 1.030, P = 0.001) were independent predictive factors associated with decreased PFS and smoking (hazard ratio = 10.588, P = 0.002) and TLG (hazard ratio = 1.043, P = 0.007) were significant predictors of OS. Conclusions: There is a correlation between TLG and PFS significantly. We suggest that follow-up FDG PET after 4 cycle chemotherpy can help to discriminate patients who have benefit through sequential and maintenance therapy. But it need specific value for clinical use, so more large-scale prospective study is warranted.
Toxicity in patients (pts) age 65 or older with dose-adjusted REPOCH (DA-REPOCH) for untreated diffuse large B-cell lymphoma (DLBCL).
Authors: Stephens Deborah Marie , Ruppert Amy S. , Christian Beth , Jones Jeffrey Alan , Flynn Joseph M. , Porcu Pierluigi , Baiocchi Robert A. , Byrd John C. , Dotson Emily K. , Crawford Brooke S. , Blum Kristie A.
Published: March 2020

e18508

Background: ORR of 97-99% and 5-yr PFS of 75-79% are reported with front-line DA-REPOCH in pts age 19-85. In these prospective series, 72% of pts escalated ≥ 1 dose level (DL), febrile neutropenia (FN) occurred in 36-51% pts, and 3-4% died of toxicity. Methods: We performed retrospective analysis of pts ≥ 65 treated with DA-REPOCH front-line for DLBCL at Ohio State University from 2002-2011. PFS estimates were calculated by the Kaplan-Meier method. Logistic regression and proportional hazards models were fit to identify variables associated with ORR and PFS, respectively. Results: 69 pts ≥ 65 yrs (range, 65-92) received DA-REPOCH for de novo (n=42) or transformed (prior CLL=16, FL=9, HL=2) DLBCL, including 28 pts ≥ 75. Performance status (PS) was ≥ 2 in 43%, 86% were stage III-IV, 77% had an aaIPI ≥ 2, 19% had bulky disease ≥ 10 cm, 83% had extranodal disease, and median creatinine clearance (CrCl) was 64 ml/min. Median number of cycles was 5 (range 1-7). Max DL was 1, 2, and 3 in 72, 13, and 6% of pts, respectively, and 9% received all cycles below DL 1. Max DL and number of cycles were similar between pts 65-74 and > 75. Dose reductions (DR), delays, FN, and hospitalization occurred in 48, 39, 38, and 42% of pts, respectively. DR were associated with age ≥ 75 (p=0.001) or reduced CrCl (p=0.02) and delays strongly associated with PS ≥ 2 (p=0.001). FN was associated with bulky disease (p=0.03); 31% of pts without bulky disease developed FN compared to 67% with bulk. Nine pts (13%, 3 pts ≥ 75) died of toxicity (7 pts at DL 1 and 2 at DL < 1). ORR was 67% (95% CI 52-75%). Median PFS was 17 mos (95% CI 6-43). Increased LDH (p=0.008 and p<0.001) and number of prior chemotherapies (p=0.04 and p<0.001) were independently predictive for ORR and PFS, respectively. DR and age were not associated with ORR or PFS, controlling for LDH and number of prior regimens. In 42 pts with de novo DLBCL, ORR was 71% (95% CI 54-85%) and median PFS was 36 mos (95% CI 7-94). Conclusions: In this retrospective study, toxicity is increased with DA-REPOCH in pts ≥ 65 with DLBCL, compared to published results in a younger population. Age ≥ 75, impaired CrCl, and poor PS are associated with increased risk of DR and delays, although age and DR do not appear to impact ORR and PFS.
Rituximab hypersensitivity reactions (HSR): Predictors of recurrent and severe reactions based on severity of reaction, NHL histologic subtype, and burden of disease.
Authors: Sallman David A , Macklin Eric , Ali Shihab , Michaelson James , Barnes Jeffrey A. , Abramson Jeremy S. , Banerji Aleena , Hochberg Ephraim P.
Published: March 2020

e18520

Background: Rituximab is an anti-CD20 monoclonal antibody with efficacy in B-cell malignancies. Grade II-IV HSR occur in 5-10% of patients. There are no data to predict which patients are at risk for more severe rituximab HSR as well as no data on eventual successful rituximab administration in this population. Methods: We analyzed all rituximab HSR in patients at Massachusetts General Hospital between 2006-2010. Patients included had documented HSR on the chemotherapy infusion sheet on our electronic medical record or via referral to allergy for desensitization. Control rituximab-treated patients were identified from tumor registry data. ICD3 codes were used to determine the histologic subtypes. Rates of HSR were analyzed by logistic regression and Fisher's exact test. Severity of HSR was based on an established classification system. Results: Immediate HSR occurred in 9% of patients (79/901) treated with rituximab and premedications. A majority of patients with a HSR developed symptoms on their initial infusion (76%); however, 46% of moderate or severe HSR occurred on subsequent infusions. Severity of HSR was directly correlated to the risk of a recurrent reaction where all patients with severe HSRs and 56% of patients with moderate HSRs had a recurrent reaction in contrast to only 36% of patients with mild reactions (p = 0.005). Advanced stage of disease increased the risk of a moderate or severe HSR (HR = 4, p = 0.02). Waldenstrom’s Macroglobulinemia (WM) accounted for 10% of all HSR while representing only 1% of rituximab treated pts (p < .003 adjusting for multiple comparisons) and 70% of these patients had a HSR. All patients with complex HSR who were referred to allergy for desensitization (n=14) were able to complete therapy safely. Conclusions: Severe rituximab HSR commonly occurs after the initial infusion. Severity of the HSR predicted recurrent HSR and an advanced stage of disease predicted more severe reactions. WM had a disproportionately higher risk for HSR. Despite HSR, we found that all patients were able to tolerate the recommended number of infusions without severe adverse events utilizing medical management and/or desensitization.
Geographic variation of extranodal sites of mucosal associated lymphoid tissue lymphoma (MALToma): Analysis of series from two institutions.
Authors: Adab Kalid , Persky Daniel Oscar , Guillen-Rodriguez Jose , Rimsza Lisa M. , Frutiger Yvette M. , Haidau Augustin , Telfer Margaret C. , Braik Tareq , Catchatourian Rosalind , Miller Thomas P.
Published: March 2020

e18534

Background: MALToma represents about 5% of Non-Hodgkin lymphomas (NHL). Prior studies report stomach to be the most common site of involvement (35-50%), while skin (16%) or salivary glands (26%) were reported to be the 2nd most frequent site in 2 different studies. Geographical variation may affect the proportions of primary sites of MALToma, which could provide further clues to investigating their causes. Methods: The data was obtained on 91 consecutive patients from the University of Arizona Cancer Center (UACC) clinical and pathological databases, and 25 patients from the Cook County Hospital (CCH) database, seen between 2005 and 2011.The frequency of clinical characteristics and their relation to survival were analyzed and compared between UACC and CCH. Results: UACC and CCH cohorts were balanced for gender (M:F ratio 0.65) and age (median 63 y (range, 26-88), but not for race or/and ethnicity. While at CCH 36% of pts were African-American (AA), 28% Hispanic (any race), 12% Caucasian and 20% unknown; at UACC 88% of pts were Caucasian, 10% Hispanic and 1% AA (p<0.0001). UACC had 8% pts with > 1 extranodal site, while CCH had none. The primary sites of MALToma were also different. At CCH, similarly to what’s commonly reported in the literature, 40% of pts had primary gastric involvement, 20% salivary gland, 12% lung, 8% orbit, 8% thyroid, 4% intestine, 4% skull base tumor, and 4% breast. At UACC, however, 22% of pts had primary skin involvement, 19% gastric, 16% lung, 13% orbit, 8% salivary gland, 6% intestine, 5% breast, 3% thyroid and 8% other. The difference was statistically significant for the frequency of primary skin (p=0.006) but not gastric involvement (p=0.084). 80% of patients with primary skin involvement were Caucasian. The median follow-up of the survivors was 18 months for both groups, with no statistically significant difference in median progression-free (7.5 years) or overall survival (14.6 years). Conclusions: There was higher prevalence of Caucasian race and skin involvement at UACC than at CCH. We speculate that sun-induced photodamage causes chronic inflammation contributing to eventual malignant transformation to primary skin MALToma.
Alternating non-cross-resistant multiagent chemotherapy (ANCRC) and high-dose chemotherapy followed by autologous stem cell support (HDC-ASCS) in first remission to improve outcome in patients with T-cell lymphoma.
Authors: Jitawatanarat Potjana , Dawar Richa , Chittawatanarat Kaweesak , Batty Nicolas , Czuczman Myron Stefan , Hernandez-Ilizaliturri Francisco J.
Published: March 2020

e18538

Background: T-cell lymphomas represent a challenge for the practicing oncologist as evidence-based medicine is limited and the ORR to chemotherapy, PFS and OS rates are inferior when compared to B-cell lymphoma. CHOP offers limited activity, and there is a growing consensus that alternative regimens should be tested. We studied the impact of ANCRC or HDC-ASCS vs. CHOP in outcome of T-cell lymphoma. Methods: We retrospectively analyzed differences between the ORR, PFS and OS of T-cell lymphoma patients excluding ALCL treated with CHOP or HyperCVAD regimen alternating with HDAM in the front-line setting following by observation or HDC-ASCS. Pre-treatment demographic, clinical, and pathological characteristics were collected. Differences in outcomes were analyzed using a Cox proportional analysis. Results: ALCL, PTCL-NOS and AITL were the most common subtypes. After excluding ALCL (N=29), a total of 49 patients were included in the final analysis; 23 pts treated with CHOP; 12 pts with HyperCVAD/HDAM and 14 pts treated with other induction regimens. After induction therapy, 12 patients underwent HDC-ASCS in first remission. There were no differences in demographic and clinical characteristics between groups analyzed. There was a higher ORR and PFS among patients treated with hyperCVAD/HDAM (83.3%) vs. pts treated with CHOP (62%). However it did not improved OS when compared to CHOP. The use of HDC-ASCS in first remission was associated with improved OS. The median OS for pts observed after front-line chemotherapy was 32 months and 59 months for pts that received HDC-ASCS [Hazard ratio 0.54 (95% CI 0.16-1.83) (p=0.32)]. Conclusions: Our data suggest that hyperCVAD/HDAM results in higher ORR and PFS in T-cell lymphoma than CHOP. More importantly, the use of HDC-ASCS in first remission appears to improve the OS of non-ALCL T-cell lymphoma patients. ANCRC regimens incorporating novel agents follow by HDC-ASCS in first remission is emerging as an attractive therapeutic intervention for a selected group of T-cell lymphoma patients been evaluated in ongoing clinical trials.
The natural history of intravascular lymphoma.
Authors: Fonkem Ekokobe , Robison David J , Lok Edwin , Gautam Shiva , Wong Eric
Published: March 2020

e18541

Background: The diagnosis of IVL is often delayed or found at post-mortem because this disease is rare. Published data consist of case reports or series, which are insufficient to offer a global perspective of this disorder. Methods: We included cases of IVL published between 1957 and 2011, and performed Wilcoxon rank sum test to evaluate survival differences. Results: There were 191 B-cell and 7 T-cell lymphomas. Median age was 65 (range 12-87) years. Central nervous system (CNS) was the first site of disease in 92(47%), skin in 41(21%), and lung in 22(11%) individuals. Forty-five% of CNS IVL was diagnosed at postmortem versus 12% for skin and 27% for lung IVL. Age is a significant prognostic factor and patients <75 years had a median survival of 14.0(range 0.1-165.0) months versus those ≥75 years had a median survival of 6.0(range 0.1-178.0) months (P=0.05). There is a trend favoring women, median survival 14.0(0.3-96) months, over men, median survival 7.0(0.1-178.0) months (P=0.07). Gender, ethnicity, organ site involvement, hemoglobin, LDH, bone marrow involvement and MRI were not significant. There is no difference in patient survival when treated with Adriamycin-based versus non-Adriamycin-based chemotherapies. Among the 12 CNS IVL patients with recurrence, 3(25%) recurred in CNS while 2(14%) recurred in skin and 7(58%) in lungs. Among the 9 patients with skin IVL, 4(45%) recurred in skin while 1(11%) in CNS, 1(11%) in lungs, and 3(33%) in other organs. Two (50%) of 4 patients with lung IVL had recurrence in the lungs and the other 2(50%) recurred in other organs. Conclusions: The treatment of CNS IVL is hampered by lack of timely diagnosis. The prognosis and pattern of relapse of CNS IVL patients is significantly different from those with skin and lung IVL, suggesting variations in the underlying biological mechanism of disease.