bluuebunny/crossref_metadata_2025 huggingface dataset:
Are sarcomatoid lung cancers resistant tumors to conventional chemotherapy?
Authors: Wislez Marie , Vieira Thibault , Ung Mony , Antoine Martine , Monnet Isabelle , Bonnette Pierre , Cazes Aurelie , Duruisseaux Michael , Belmont Laure , Mazieres Julien , Cadranel Jacques , Girard Nicolas
Published: March 2020

e19036

Background: Pulmonary sarcomatoid carcinomas (SC) account for about 0.4% of non-small cell lung carcinoma. These tumors have a poor prognosis due to high aggressiveness and maybe chemotherapy (CT) resistance. Methods: From 1995 to 2012, all consecutive patients with SC from 7 French hospitals and who underwent a 1st-line chemotherapy were included. Clinical characteristics and effect of CT (best response by RECIST 1.1 and progression-free survival [PFS]) as well as overall survival (OS) were collected. Results: Ninety-seven patients were included. Mean age was 62±1 years, 70% were men, 84% smokers, 84% symptomatic, 25% had a stage III and 75% a stage IV disease. At 1st-line, 73% received a platinum-based CT and 27% received a non-platinum-based CT. Progression (PR), stable disease (SD) and response (RR) rates were 69, 14.5 and 16.5%, respectively. For patients with platinum-based CT, PR, SD and RR rates were 69, 11 and 20%, respectively. RR rate was higher for platinum- than for non-platinum-based CT (p=0.018). Median PFS and OS were 2.0 mo [1.8 ; 2.3] and 6.7 mo [5.1 ; 8.2], respectively. No statistical difference in PFS (p=0.264) and OS (p=0.096) was observed between platinum and non-platinum based CT. In multivariate analysis, factors associated with better OS were disease control (HR=0.36 [0.21;0.59]), platinum-based CT (HR=0.92 [0.85;0.99]) and tobacco status (HR=0.92 [0.85 ; 0.99]). Conclusions: Two-thirds of patients with SC had early progression during 1st-line CT. Platinum-based regimen increased response rate for a few and was an independent factor for better OS with a 8% decreased risk of death. Overall, SC appear to be chemoresistant suggesting that new therapeutic strategies based on a better knowledge of its carcinogenesis should be tested for these patients.
Clinical outcome of treatment with pemetrexed/cisplatin in patients with EGFR-mutation negative (EGFR–) metastatic non-small cell lung cancer (NSCLC).
Authors: Storozhakova Anna E , Vladimirova Liubov Yu , Kit Oleg Ivanovich
Published: March 2020

e19047

Background: Althogh some improvements of the treatment of NSCLC were achieved recently the results of therapy in patients with EGFR– adenocarcinoma are still poor. The purpose of the study was to evaluate the effectiveness and toxicity of the treatment in these patients. Methods: Pts with EGFR– adenocarcinoma were recruited in 2010-2011. Key elegibility criteria included measurable EGFR– adenocarcinoma, confirmed stage IV, ECOG ≤2, adequate organ function, CT-naïve pts. Pemetrexed/cisplatin was administered 500/75 mg/ m² 1 day q3w up to 6 cycles. Treatment was continued until progression or unacceptable toxicity. A total of 94 cycles were estimated. Endpoints include response rate, OS, PFS and safety. Results: 16 pts (12 male and 4 female) were recruited. Mean age was 56.6±5.6. Infiltrative EGFR– adenocarcinoma was found in 93.75%, adenocarcinoma mixed with squamous cancer – 6.25% (1pt). All the pts had ≥2 disease sites: lung 16 (100%), lymph nodes 16 (100%), bones 5 (31.25%), liver 7 (43.75%), brain 1 (6.25%). Mean number of disease sites = 2.8. Overall RR was 43.75% (7) including 2 CR (12.5%), 3 PR (18.75%) and 2 SD (12.5%). Med OS = 16.1 mo ±1.5, Med PFS = 7.4 mo ±0.8. 6 pts (37.5%) are alive till the abstract submission. Most common adverse events in 94 cycles were neutropenia 1/2 Gd. -30.85, 3/4 Gd. -6.4%, thrombocytopenia 1/2 Gd .-2.1% cycles. Nonhematological toxicity included nausea 1/2 Gd.- 74.5%, 3/4 Gd.- 12.7%, vomiting 1/2 Gd.- 43.6%, 3/4 Gd.- 6.4%, hyperthermia 2 Gd. –6.4%, fatigue 1/2 Gd.-15.95%, hiccough 2 Gd.-2.1%. No treatment-related mortality occurred. Conclusions: Pemetrexed/cisplatin combination had a satisfactory efficacy and controlled toxicity as well in patients with EGFR-mutation negative (EGFR–) metastatic NSCLC. The favorable PFS and OS allow to use it in clinical setting widely.
Development and clinical validation of an adeno/squamous multiplexed diagnostic assay for NSCLC.
Authors: Hembrough Todd A. , Liao Wei-Li , Thyparambil Sheeno , Erickson Heidi S. , Carey George , Guiel Thomas , Heaton Robert B. , Krizman David , Wistuba Ignacio Ivan , Salgia Ravi , Burrows Jon
Published: March 2020

e19057

Background: The diagnosis of adenocarcinoma (ADC) vs. squamous cell carcinoma (SCC) in NSCLC is critical since new therapies (e.g. pemetrexed) are restricted to non-squamous NSCLC. Most diagnoses are made based on histopathology, though IHC is often performed as well. Since IHC is not quantitative, interpretation of intensity is subjective, and reproducibility can be problematic. Using the Liquid Tissue-SRM mass spectrometry (MS) platform, we have developed a quantitative, multiplexed clinical diagnostic assay to measure the adeno/squamous markers TTF-1/CK7 (ADC) and K5 and p63/40 (SCC) in FFPE tissue. This proteomic assay is epitope independent, and highly reproducible. Methods: Recombinant K5, K7, TTF-1 and p63/p40, were subjected to trypsin digestion mapping to identify peptides for MS analysis. Heavy isotope labeled peptides were synthesized as positive control peptides for quantitation. The multiplexed assay was technically validated on cell lines, and human tumor tissues. Results: ADC/SCC proteomic analysis was performed on a training set of 39 NSCLC tissues from U. of Chicago (20 ADC and 19 SCC). Principal Component Analysis was used to define optimal quantitative cutoffs for each of the four markers for the two tumor subtypes. The ADC diagnosis was unequivocal for all 20 ADC samples, however within the 19 SCC’s, one sample appeared to be ADC and two samples had markers for both ADC and SCC. Proteomic analysis of a test set of 194 NSCLC tumors (98 ADC and 98 SCC based on pathology reports) from MD Anderson Cancer Center was consistent with the observations in the training set. 93/98 ADC cases were confirmed by proteomic analysis, four ADC cases showed mixed or SCC phenotypes. Proteomic analysis confirmed 58/98 SCC cases but identified 27 cases as mixed ADC SCC or ADC based on TTF1/K5 expression. Further studies are ongoing to determine the clinical utility of these findings. Conclusions: These data demonstrate that quantitative proteomic analysis can define cut offs for ADC and SCC Biomarkers profiles in NSCLC tumors. These profiles can determine ADC, SCC and mixed phenotypes and provide physicians with accurate information to help them stratify their patients to the right evidence based treatment therapy.
Patterns of presentation and management of non-small cell lung cancer in an Algerian cancer center.
Authors: Jamous Houda , Filali Taha
Published: March 2020

e19063

Background: To evaluate the pattern of management and outcome of patients with NSCLC in our cancer center over the last 8 years. Methods: A retrospective study of all NSCLC patients seen between January 2005 and December 2012 in Medical Oncology Center, Constantine, Algeria. All demographic, clinical data, management and outcome were captured and analyzed. Results: 581 patients with NSCLC, male-female ratio 10:4, median age 59.7 years (21-85), 64.2% were smokers (0.8% were females), and 15% exposed to alcohol. Diagnostic specimens were obtained by CT scanguided biopsy in 62% of cases, bronchoscopy in 26.2%, and surgical biopsy in 9.6%. Median time to diagnosis was 6.1 months (0 months -6 years). During the study period, incidence of squamous cell carcinoma declined from 62.1% to 37.5% and adenocarcinoma incidence doubled(from 29.5% to 57.5%). Most of the patients had an advanced stage disease, 58.5% stage IV, 15.3% stage IIIB, 14.5% stage IIIA, stageIIB 4.1%, stage IIA 0.9%, stage IB 1.9%, and stage IA 0.9%. 8.6% underwent surgery, 13.9% received radiotherapy, 88.6% with PS≤ 2 received first-line chemotherapy which was platinum-based in 95.1% of the cases. 17.2% second-line, and 3.6% third-line. Most used chemotherapy regimens are: etoposide-cisplatin (EP) in 2005-2006, cisplatin-gemcitabine (P/GMZ) 2007-2009, taxotere-cisplatin (TP) 2010-2012. Outcome of these regimens ranged for response rate (RR) between 12.8% and 23.8% and overall disease control (ODC) ranged between 17.8% and 30.5%. Pemetrexed/platinum administered to 20 patients, RR 10.5%, ODC 26.1%. Bevacizumab/carboplatin-paclitaxel to 8 patients, RR 12.5%, ODC 25%. Outcomes in nonsmokers are better compared to smoker patients: RR 16.6% vs 12.1%. ODC 22.5% vs 18.2%. Longer survival (2.3 months more) and higher survival rate noted for women than that for men at all stages of the disease. RR is 16.3% in adenocarcinoma cases, 12.5% in squamous cell. For all groups: One year survival 16.5%, 2 years 5.5%, and 5 years 1%. Conclusions: Patients with NSCLC present with advanced stages. The management of NSCLC at our Center mirrored the evolution of management using conventional chemotherapy.
Comorbidity and survival for patients with advanced-stage non-small cell lung cancer.
Authors: Chrischilles Elizabeth A. , Abu Hejleh Taher , Carter Knute D. , Pendergast Jane F , Halfdanarson Thorvardur Ragnar , Fletcher Robert H. , Wallace Robert B
Published: March 2020

e19065

Background: Treatment decisions for patients with advanced stage (stages IIIB and IV) non-small cell lung cancer (AS NSCLC) are influenced by comorbidity at time of diagnosis. We studied the effects of comorbidity on survival and whether effects differ for short-term (120 days) vs. for long-term (>120 days) survival. Methods: Data were from surveys and medical records of 1498 patients withnewly diagnosed AS NSCLC in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS). Respiratory disease severity and comorbidities at diagnosis were measured from the Adult Comorbidity Evaluation (ACE-27) index and model fitting used the Akaike Information Criteria. The log-rank test was used for univariable survival models, and Cox proportional hazards regression for multivariable survival models. Results: Five comorbidities were significantly associated with survival and 437 (29.2%) patients had one or more of these. Survival to 120 days was significantly poorer for patients with a baseline diagnosis of stroke [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.26–2.93], diabetes (HR 1.33, 95% CI 1.08–1.65), or congestive heart failure (HR 1.45, 95% CI 1.07–1.96), controlling for age, gender, smoking status, stage, severe respiratory disease, and brain metastases. Given survival to 120 days (885 pts, 59%), survival beyond that was significantly poorer only for patients with baseline arrhythmia (HR 1.47, 95% CI 1.15–1.87) or end stage renal disease (HR 1.82, 95% CI 1.09–3.04), controlling for the covariates above. Adjustment for chemotherapy use had no effect on these associations. Conclusions: Several comorbidities present at diagnosis affected survival for AS NSCLC, with some comorbidities having a more immediate relationship to survival than others. Our finding provides information that could be used to tailor treatment decisions to patients’ comorbidities at diagnosis.
Icotinib and whole brain radiotherapy (WBRT) for patients with brain metastases from non-small cell lung cancer (NSCLC): Preliminary results of a phase II study.
Authors: Yun Fan , Huang Zhiyu , Gong Lei , Yu Haifeng , Yang Haiyan , Lu Maio lu , Mao Weimin
Published: March 2020

e19073

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have shown efficacy in advanced NSCLC with brain metastases (BM). Icotinib is a new EGFR-TKI. A randomized, double blind phase III trial proved that icotinib was non-inferior to gefitinib in advanced NSCLC. We have conducted a phase II study to evaluate the efficacy and safety of icotinib in combination with WBRT in Chinese NSCLC patients with BM. Methods: From January 2012 to January 2013, 20 patients aged 18-75 years with ECOG PS 0-2 and BM from NSCLC,were recruited regardless of EGFR status. The treatment comprised icotinib 125mg, TID concurrently with WBRT (30Gy/10f/2w). CSF and plasma samples were collected at the same time from 10 patients at least 5 days after icotinib treatment. The concentrations of icotinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The primary end point was progression-free survival (PFS) . Additional end points were response rate, safety and CSF concentrations of icotinib. Results: The median PFS was 7.3 months [95% confidence interval (CI) 4. 2-9.8]. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [NR versus 4.2 months (95% CI 2.9-5.1); P = 0.000]. The CNS response rates were 25% complete response (n=5), 55% partial response (n= 11), 15% stable disease (n=3), and 5% progressive disease (n =1). The overall CNS response rate was 80% (n = 16). The most common adverse events were rash (40.0%), diarrhea (15.0%),nausea (45.0%), vomiting (20.0%), headache (35.0%)and fatigue (45.0%). And no patient experienced grade ≥ 3 toxicity. The mean plasma and CSF concentrations of icotinib were 936.47 ± 503.80 and 8.93 ± 8.01 ng/ml, respectively, and the mean ratio of CSF-plasma concentration was 1.04% ± 0.95. Conclusions: Icotinib was well tolerated and showed promising activity in combination with WBRT in patients with BM from NSCLC. The concentrations of icotinib in CSF were low. Further randomized trials are warranted. Clinical trial information: NCT01514877.
CT image characteristics of anaplastic lymphoma kinase fusion gene positive (ALK-P) advanced stage non-small cell lung cancer (NSCLC).
Authors: Oyakawa Takuya , Takahashi Toshiaki , Imai Hisao , Akamatsu Hiroaki , Ono Akira , Taira Tetsuhiko , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Endo Masahiro , Yamamoto Nobuyuki
Published: March 2020

e19074

Background: Although several clinical and pathological characteristics of ALK-P NSCLC have been reported, to our knowledge, only one report regarding CT findings of resected early stage ALK-P NSCLC have been published (Fukui T et al. Lung Cancer 2012). They concluded resected ALK-P tumors exhibited a solid pattern without ground glass opacities (GGO). However, there is no report regarding CT image characteristics of advanced stage ALK-P NSCLC. Methods: We retrospectively reviewed CT image findings of 20 patients with advanced ALK-P NSCLC and 32 patients with ALK-negative (ALK-N) NSCLC between November 2010 and January 2013 at Shizuoka Cancer Center in Japan. Primary lesion (PL) was classified into three types: GGO (Type G), focal GGO with solid central components (Type GS), solid nodules without GGO (Type S). Results: Characteristics of patients with ALK-P (N=20)/ ALK-N (N=32) were: 7 /17 males and 13/15 females, median age ;51/63 years, non-smokers 13/8 and smokers 7/24, adenocarcinoma;19/32, stage III; 2 /9, stage IV;18/23. None of PL of both ALK-P and ALK-N showed type G. PL of ALK-P (type GS/S;13/7) had a significant high frequency of type GS than that of ALK-N (type GS/S;8/24) (p=0.004). Lymph node metastases were observed in 16 of 20 ALK-P cases, and 26 of 32 ALK-N. The frequency of fusions of metastatic lymph nodes in ALK-P cases (75%) was significantly higher than that in ALK-N cases (31%) (p=0.010). And the frequency of increased concentration of mediastinal fat tissues around metastatic lymph nodes in ALK-P cases (50%) was also significantly higher than that in ALK-N cases (12%) (p=0.011). Intrapulmonary metastases on the initial CT were observed more frequently in ALK-P (12 of 20 cases) than in ALK-N (6 of 32 cases) (p=0.013). There were no specific features regarding liver, bone and brain metastases in ALK-P cases. Conclusions: Advanced stage ALK-P NSCLC has several CT image characteristics. These findings may reflect biological features of ALK-P NSCLC, and can help clinicians suspect their NSCLC patients of having ALK rearrangement.
Study KBP-2010-CPHG: Characteristics and management of 968 new cases of small-cell lung cancer (SCLC).
Authors: Dayen Charles , Coëtmeur Daniel , Lecerf Celine , Diximier Adrien , Lemaire Bertrand , Martin Michel , Lafourcade Marie-Pierre , Fraboulet Gislaine , Leveiller Guillaume , Lecuyer Emmanuelle , Mathieu Jean-Pierre , Nocent-Ejnaini Cecilia , Dumont Patrick , Peureux Marc , Dehette Stephanie , Locher Chrystele , Le Treut Jacques , Debieuvre Didier , Martin Francis , Grivaux Michel
Published: March 2020

e19078

Background: In recent years, many major advances have been made in non-small-cell lung cancer (NSCLC), and in particular in adenocarcinoma, but not in SCLC. In 2010, the French College of General Hospital Respiratory Physicians (CPHG) performed a prospective multicentre epidemiological study (KBP-2010-CPHG) to describe the baseline characteristics and management of all new cases of primary lung cancer and to evaluate survival. The present abstract reports results in SCLC patients. Methods: 7,051 patients ≥18 years presenting with a new case of primary lung cancer, histologically or cytologically diagnosed between 1 January and 31 December 2010 and managed in the respiratory department of one of the 104 general hospitals participating in the study, were included. A standardised form was completed for each patient. A steering committee checked data collection exhaustiveness. SCLC data were analysed separately. Results: There were 968 SCLC patients: mean age, 65.6 years (+/-10.6); 23.2% female; 4.4% non-smokers (11 % in women), 35.8% ex-smokers, 59.8% current smokers; 63.4% with performance status 0 or 1; 59.9% having lost weight within the previous 3 months (19.8% of whom had lost >10 kg). Main tumour characteristics at diagnosis were: 71.2% stage IV, 24.7% stage IIIA or IIIB, 4.1% of stage 70 (59.1%) than <70 years of age (40.9 %). One-year mortality was 64.2%. Compared with NSCLC patients, patients with SCLC more frequently were active smokers (59.8% vs.47.6%), lost weight (59.9% vs. 52.4%), and presented with stage IV tumour at diagnosis (71.2% vs. 58.3%); first line therapy was more frequently platinum-based chemotherapy (86.2% vs. 61.2%) and less frequently curative surgery (1.6% vs. 19%), and mortality was higher (64.2% vs. 55.2%). Conclusions: In 2010, prognosis remains poor in SCLC. Compared with NSCLC, it was more frequently associated with active smoking and stage IV disease, and showed a lower rate of surgery.
Natural history of malignant bone disease in non-small cell lung cancer: Preliminary results of a multicenter bone metastasis survey.
Authors: Santini Daniele , Intagliata Salvatore , Ibrahim Toni , Ferraù Francesco , Barni Sandro , Moscetti Luca I. , Mansueto Giovanni , Comito Francesca , Pantano Francesco , Longo Flavia , Russo Antonio , Satolli MAntonietta , Adamo Vincenzo , La Verde Nicla Maria , Badalamenti Giuseppe , Ottaviani Davide , Ferzi Antonella , Addeo Raffaele , Vasile Enrico , Tonini Giuseppe
Published: March 2020

e19084

Background: Bone metastases represent an increasing clinical problem in advanced non-small cell lung cancer (NSCLC) as disease-related survival improves. This is a multicenter, retrospective survey aimed to explore the impact of bone involvement in this severe, life-threatening disease. Methods: Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 421 deceased NSCLC patients (48.6% aged >66 years) with evidence of bone metastasis were statistically analyzed. Results: ECOG performance status at diagnosis of NSCLC was 0 in 41.4% of patients, 1 in 42.8% and 2 in 13.9%. The most frequent stage at diagnosis was IV (76.8%). Adenocarcinoma was the commonest histotype (70.3%) and EGFR status was unknown in 77.7%. Chemotherapy was the preferred I line treatment in 82.2%. Lung cancer frequently spreaded to bone, with metastases evident at diagnosis in up to 57.2% of patients. In the remaining cases median time to bone metastases was 9 months. Patients ECOG performance status when bone metastases were detected was 1 in 46.6% and 2 in 22.9%. In our sample multiple bone metastases were detected in 82.5% of patients and 71.2% were osteolitic. Axial skeleton was interested in 74.6% of cases, pelvic bones in 46.7% and limb bones in 29.3%. Bone metastases related pain was reported by 84% of patients. Median Verbal Numerical Rating Scale (VNRS) for pain was 4 and it measured >4 in 47.2% of cases. Bisphosphonates was administered in 65.6% of patients; zoledronic acid was mainly used (61.1%). Osteonecrosis of the jaw was reported in only 1.1 % of cases. Median number of SREs/patient was one, less than half of the patients (41.7%) experienced at least one SRE, 21.2% experienced at least two SREs, and only 2.1% experienced at least three SREs. The most common SRE was the need of radiotherapy (73.8%). Median time to first SRE was 3 months. Median survival after bone metastases diagnosis was 8 months and after first SRE was 6 months. Conclusions: These preliminary data suggest that bone metastases are a relevant clinical event in the natural history of patients affected by NSCLC. Final results will be available next ASCO meeting.
Racial disparities and survival with non-small lung cancer (NSCLC) at an urban safety net hospital.
Authors: Ernst David J.
Published: March 2020

e19102

Background: Disparities in cancer outcomes have been documented for many tumor types. This study aims to investigate the influence of race on clinical presentation, treatment and outcome of non-small cell lung cancer at a safety net hospital. Methods: A retrospective review of all patients with NSCLC diagnosed at an urban safety net hospital was done. Demographic data, diagnostic approach, primary therapy, and survival were analyzed. Results: There were 359 patients with NSCLC who met study inclusion criteria. There were 179 Caucasian, 177 African American, and 3 Asian patients. Nearly half of all patients had metastatic disease at the time of diagnosis (Stage I 15%, Stage II 5%, Stage III 28%, and Stage IV 49%). Treatment varied by disease stage, but not by race, 35.2% Caucasians and 39.5% African Americans were treated with radiation, 42.5% Caucasians and 44.6% African Americans were treated with chemotherapy, and 26.3% Caucasians and 20.9% African Americans were treated with surgery. Median survival was very short and again, did not vary by race: for Caucasians diagnosed with any stage of NSCLC was 6.439 months, whereas in African Americans it was 7.852 months. Conclusions: In a safety net hospital setting, there were no disparities in treatment based on race and median survival in this study was uniformly poor. Significant comorbidity was likely and will be investigated further.
Role of IGF-1/IGFBP3 in non-small cell lung cancer sensitivity to therapy.
Authors: Ibañez de Cáceres Inmaculada , Holgado Esther , Pernia Olga , De Castro Javier , Hitt Ricardo , Conde Esther , López-Ríos Fernando , Cortes Semperes Maria , Perona Rosario , Belda-Iniesta Cristobal
Published: March 2020

e19123

Background: Molecular mechanisms of drug-resistance remain still unclear; it is believed multifactorial, involving host factors, numerous molecular events as well as genetic and epigenetic changes. We were aimed to use massive expression assays before and after epigenetic treatment to explore predictors for platinum and radiation therapy in NSCLC. Methods: By using an expression microarray analysis, we looked for those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Then, to investigate the importance of methylation in radiosensitivity, we have developed radiation clonogenic cell survival assays with three paired Sensitive/CDDP-Resistant cell lines that present a different gene expression and promoter methylation profile. Finally, we have explored in vitro data into three cohorts of patients from different institutions that were treated with radio, chemoradiation or chemotherapy alone. Results: IGF-1/IGFBP3 axis was significantly associated with response to therapy and promoter methylation of IGFBP3 was critical to predict biological behavior. In this regard, hypermethylated and semimethylated cell lines presented a higher sensitivity to radiotherapy and cisplatin than cell lines completely unmethylated for IGFBP3 promoter. However, when resistance to cisplatin treatment was not mediated by IGFBP3 promoter methylation there were also not significant changes regarding sensitivity to radiotherapy treatment. Finally, in vitro data for IGF-1/IGFBP3 axis were confirmed in three cohorts of patients. Conclusions: IGF-1/IGFBP3 axis plays a central role in resistance to chemo- and radiation therapy in NSCLC patients.
Quantitative identification of mutant alleles derived from lung cancer in plasma cell-free DNA via anomaly detection using deep sequencing data.
Authors: Uchida Junji , Kukita Yoji , Taniguchi Kazuya , Oba Shigeyuki , Nishino Kazumi , Kumagai Toru , Okuyama Takako , Niki Toshie , Imamura Fumio , Kato Kikuya
Published: March 2020

e19153

Background: Selection of lung cancer patients to be treated with EGFR-TKI (gefitinib and erlotinib) is currently based on the presence of activating mutations in the EGFR kinase domain. The diagnosis of the mutations is based on biopsy samples; the procedure is invasive, and often difficult to perform. A non-invasive diagnostic procedure is desirable. Methods: We established a non-invasive diagnostic system to detect somatic mutations including three activating mutations (exon 19 deletion, L858R, L861Q) and one resistant mutation (T790M) with single-pass deep sequencing of EGFR gene fragments amplified from patients’ plasma DNA using Ion Torrent PGM. In principle, substitutions or deletions significantly higher (p=0.00002) than the error rates determined with the normal samples were judged as mutations. Read errors of the system were determined with deep sequencing (>100,000 reads) of EGFR fragments. The detection limits were less than 0.01% for the exon 19 deletion and L858R, 0.01% for L861Q, and 0.05% for T790M. Results: We examined 155 samples, mostly plasma cell-free DNA, with mutation data of primary lesions. Exon 19 deletion, L858R, and L861Q were detected in 44 out of 72 samples (61.1%), 32 out of 56 (57.1%), and four out six, respectively. T790M was found in 26 samples, five of which did not accompany activating mutations. Considerable numbers of samples were collected from the same patients at different time points in the disease course. A temporal analysis revealed rapid disappearance of mutations by the EGFR-TKI therapy before radiological changes. Conclusions: Deep sequencing of amplified EGFR fragments from plasma DNA could detect mutations in lung cancer tissues. Results of the temporal analysis suggested potential applications for disease management and for therapeutic decision making to select EGFR-TKI. Clinical trial information: UMIN000006762.
Predictive value of serum nitric oxide for bevacizumab response in patients with non-small cell lung cancer.
Authors: Suzuki Hiroyuki , Ohsugi Jun , Hasegawa Takeo , Yaginuma Hiroshi , Okabe Naoyuki , Muto Satoshi , Owada Yuki , Gotoh Mitsukazu
Published: March 2020

e19162

Background: Bevacizumab (BEV), an inhibitory monoclonal antibody to VEGF, is widely used to treat patients with non-small cell lung cancer (NSCLC), but biomarkers that predict BEV response are controversial. Reportedly, hypertension is linked to response to BEV therapy, possibly because BEV might suppress vascular nitric oxide (NO) production. However, the usefulness of serum NO (NOs) as a predictive biomarker for BEV therapy has not previously been shown. Here, we studied the predictive value of NOsin BEV-treated patients with NSCLC. Methods: Fifteen patients with advanced or recurrent NSCLC treated with BEV-based regimens were evaluated retrospectively. Blood samples were taken before treatment (Pre), and after the 1st and 2nd chemotherapy courses (Post1 and Post2, respectively). NOs (NO2–/NO3–) was assayed by the Griess method. Relationships between clinical parameters (e.g., clinical responses, adverse events) were analyzed against NOs. This study was approved by the ethics committee of Fukushima Medical University. Results: Mean Pre NOs was 70.3 ±10.5 μmol/L (range: 7.7–138.6 μmol/L). Significant decreases were observed at Post1 (34.6 ± 6.4 μmol/L; P = 0.013) and Post2 (29.6 ± 7.6 μmol/L; P = 0.046) compared to Pre values. Post/Pre NO ratios correlated significantly with hypertension onset (Post1/Pre: P = 0.012; Post2/Pre: P = 0.001). Notably, Post/Pre NO ratios correlated with clinical treatment responses—significantly so for Post2/Pre (Post1/Pre: P = 0.06; Post2/Pre: P = 0.005). Conclusions: NOs, could be a predictive biomarker for response to BEV in patients with NSCLC. Prospective confirmation is needed; we are conducting a prospective translational study of NO in BEV therapy. [Table: see text]
A phase II pilot efficacy trial of the combination regimen peg asparaginase/peg liposomal doxorubicin/dexamethasone (ODD) in patients with refractory lymphoid malignancies (NCT00837200).
Authors: Drabick Joseph J. , Lapsiwala Ritu , Talamo Giampaolo , Epner Elliot E , Supko Jeffrey G. , Claxton David , Ehmann W. Christopher , Lander Mary , St. Pierre Michelle , Rybka Witold B.
Published: March 2020

e19502

Background: Asparaginase is a mainstay of the treatment for ALL depriving the malignant cells of asparagine leading to cell death. There are reports of asparaginase activity in non-ALL malignancies including CLL, NHL, and multiple myeloma. We developed a combination regimen with full dose PEG-Asparagase (O) together with low dose liposomal doxorubin (D) and dexamethasone (D) (ODD regimen) as a non-myelotoxic regimen for pts with advanced lymphoid malignancies and impaired bone marrow function, hoping this novel approach of inducing asparaginine deficiency would translate into benefit. Methods: A phase II trial of ODD with the O given D1 and D15 at 2500 IU/m2, D given D1 and D15 as 20 mg/m2 and the Dex given as 20 mg D1, D8, D15 and D22 of a 28 day cycle was initiated. Pts with any non-ALL lymphoid malignancy were eligible if they had failed at least one prior standard regimen. The study had a Simon 2-stage design with Response Rate as the primary endpoint. Secondary endpoints were safety and correlation of asparginase levels with response/toxicity. Results: 13 pts enrolled of 16 screened of whom 12 were evaluable for response. These included 7 MM pts and 6 with diffuse large B-cell lymphoma. The pts were heavily pre-treated with 3 (range 1 to 8) median prior regimens. 6 of the13 pts were over 70 yrs. One pt progressed before one complete cycle was given so was not evaluable for response. 2 pts (both MM) had a response which was defined as Stable Disease > 2 months; the other 10 had Progressive Disease. One responding pt was later taken off for O-related toxicities (DVT/PE, elevated enzyme levels). Effective Asparaginase levels were obtained in the serum of most tested pts. In general, the regimen was well tolerated considering the advanced nature of these cases, but typical O related toxicities were observed. Conclusions: We conclude that the ODD regimen, although well tolerated, had little appreciable activity in this heavily pre-treated group of pts with refractory DLBCL and MM. Whether it would have meaningful activity in less advanced states of these diseases or other lymphoid neoplasms remains an open question. Clinical trial information: NCT00837200.
Predictive factors for plasma cell disorders in African American patients: A community practice perspective.
Authors: Tun Nay Min , Joseph Gardith , Soe Aye Min
Published: March 2020

e19508

Background: African Americans have over two-fold higher incidence of multiple myeloma (MM) compared to other ethnic groups in the United States. Screening tests for MM are most often done when patients present with features suggestive of anemia, renal impairment, hypercalcemia, hypergammaglobulinemia or lytic bone disease, although MM may present with other manifestations. We carried out a retrospective study to investigate the potential clinical variables predictive of plasma cell disorders (PCD) in African American population. Methods: We reviewed the charts of African American patients who had serum protein electrophoresis, immunofixation and serum free light chain levels from 2007 to 2012. We defined traditional triggers for MM workup as hemoglobin (Hb) < 11 g/dL, serum creatinine (Cr) > 1.3 mg/dL, corrected serum calcium (Ca) > 10.5 mg/dL, albumin to globulin ratio (A:G ratio) < 1, and osteopenia or lytic lesion on DEXA scan/X-ray. PCD was defined as monocloncal gammopathy of unknown significance (MGUS), smoldering MM, MM, light chain MGUS or light chain only MM. Results: 254 patients were eligible. Mean and range of age, Cr, Ca, A:G ratio, Hb, total white blood cell, absolute neutrophil and platelet counts were 60 years (21 - 95), 1.05 mg/dL (0.49 - 9.6), 9.5 mg/dL (8.5 - 11), 1.07 (0.31 - 3.08), 11.7 g/dL (5.7 - 16.5), 6 x 103/mm3 (1.9 - 26), 3675 x 103/mm3 (192 - 11765) and 237 x 103/mm3 (22 - 1262), respectively. Twelve (13%) out of 92 patients without traditional trigger variables had PCD. In contrast, 50 (31%) out of 162 patients with trigger variables had PCD (composed of 48% MGUS, 8% smoldering MM, 14% MM, 25% light chain MGUS and 2% light chain only MM). There is a significant association between the presence of trigger variables and PCD (χ2= 9.16, p = .002). The number of trigger variables is positively correlated with the likelihood of a PCD (Spearman’s rho = .22, p < .001). So is increasing age (Spearman’s rho = .29, p < .001) in patients with trigger variables. However, age is not predictive of PCD in patients without trigger variables (rho = .1, p = .34). Conclusions: The number of traditional trigger variables and increasing age (especially over 50 years) are predictive of PCD in African American population.
Use of a mathematical model of serum-free light chain decline to identify a kinetic predictive marker of survival in patients with newly diagnosed multiple myeloma treated with bortezomib plus dexamethasone and autologous stem cell transplantation.
Authors: Mael Heiblig , Florence Lachenal , Colomban Olivier , Karlin Lionel , You Benoit
Published: March 2020

e19515

Background: According to 2011 International Myeloma Working Group recommandations, serum-free light chain (sFLC) assessment is indicated in non secretory Multiple Myeloma (MM). sFLC monitoring is now routinely used for diagnosis and early response treatment assessment but its actual prognosis values regarding survival is not clear. Based on mathematical modeling, this study aimed at evaluate the predictive value on progression free survival (PFS) of modeled sFLC kinetics during frontline treatment. Methods: Model-based analysis of sFLC kinetics from 28 newly diagnosed MM patients treated at a single institution with 4 cycles of bortezomib and dexamethasone plus autologous stem cell transplantation (ASCT). MONOLIX program was used to fit Box-Cox transformed [sFLC] concentration-time profiles to the equation : [sFLC(t) = [sFLC1*exp(-KDEC1*t)]+[sFLC2*exp(-KDEC2*t)]+[sFLC3*exp(KPROD*t)] ] where KDEC1 and KDEC2 represent the decline rates of sFLC while KPROD is the involved light chain production rate observed after the end of the decrease. The predictive values of the modeled kinetic parameters , regarding PFS were tested using logistic regression, and survival analysis. Results: Median PFS was 17.9 months . Three modeled kinetic parameters categorized by their medians had strong predictive values regarding PFS using univariate tests: sFLC decline rate KDEC1 (median PFS = 38.6 months if KDEC1 ≥ median vs 14 months if KDEC1 < median, P=0.01); light chain production rate KPROD (median PFS = 24.9 months if KPROD < median vs 7.8 months if KPROD ≥ median, p=0.01); and initial SFLC production slope sFLC3 (median PFS = 24.9 months if sFLC3 < median vs 14 months if sFLC3 ≥ median, p=0.03). The same kinetic model for M-protein decline was not significant (p=0.53). Using multivariate analysis, the only remaining significant predictive factor of PFS was: KDEC1 (HR, 0.11; 95% CI 0.01-0.88; P=0.04). Conclusions: The modeled kinetic parameter of sFLC decline KDEC1, may be easily used as an early predictor of survival after frontline ASCT in MM. Validation in larger studies is warranted.
Prothrombotic profile in multiple myeloma: Response to treatment and associated thrombotic complications: A prospective observational study.
Authors: Panda Dipanjan , Sharma Atul , Raina Vinod , Kumar Lalit , Saxena Renu , Thulkar Sanjay
Published: March 2020

e19531

Background: Venous thromboembolism (VTE) is a major complication of Multiple myeloma. The exact cause of thrombosis, role of anti myeloma drugs especially immunomodulators and steroids and the relation of thrombosis with alteration of thrombotic profile is not clear. While some available data is suggestive of low incidence of VTE in Asian population, true incidence and risk factors of VTE in Indian population is not known.So the present study was undertaken to have an evaluation of prothrombotic factors in Indian population. Methods: A prospective observational study was conducted from July 2008 to November 2009 at All India Institute of Medical Sciences (AIIMS), New Delhi, India. Thirty patients of newly diagnosed myeloma were recruited and were treated with thalidomide and dexamethasone for 4 months. Prothrombotic profile including protein Cand S, activated protein C resistance, plasma fibrinogen, factor VII and von Willebrand factor level was measured and Doppler study was done at baseline and after 4 months. Statistical analysis was done using SPSS 15 software. Frequency distribution, mean, median, range, standard deviation, Inter Quartile Range were calculated. To find out difference between pre and post treatment, Macnemar chi-square test (for proportion) and paired t test (mean) were done. Results: At the base line 4 patients (13%) had low protein C, 3 (10 %) had low protein S and 2 patients (6%) had high factor VIII. Post induction therapy 7 patients showed low protein C, 1 had low protein S and 1 had high factor VIII value. Rest of the factors was within normal limit both at baseline and post treatment in other patients. During the study period 2 subjects developed DVT. While one had low protein S, other patient had low protein C and low anti thrombin III which was done to find out the cause of DVT. Conclusions: Incidence of DVT in our patients seems to be less than western published data. Although thrombotic factors abnormalities are present in myeloma patients but the relation of coagulation factor abnormalities and development of DVT require further study. A larger prospective trial may be required to get a clear picture.
Gemcitabine and plasmacytic non-Hodgkin lymphoma response.
Authors: Jajeh Ahmad
Published: March 2020

e19537

Background: Lymphomas are highly sensitive to chemotherapy. Gemcitabine is an active agent in non-Hodgkin lymphomas NHL. It is a diflourinated analogue of deoxycytadine which acts as antimetabolite. It is cell cycle specific and blocks cells in the G1/S interface. Gemcitabine is a better substrate for transport into cells. Active phosphorylated form is more readly and is excreted more slowly than other drugs. It inhibit DNA synthesis via depletion of cellular deoxynucleotide pools and by way of masked DNA chain termination. Gemcitabine seem to work it best on indolent and plasmacytoid low grade and intermediate NHL. Gemcitabine is also an active agent in Hodgkin lymphoma, Diffuse large B Cell NHL and T cell lymphomas. Methods: Retrospective reviews of patients with B cell NHL treated with gemcitabine as a single agent or in combination was carried out in one single institution over the last 13 years. Reveiw of biopsy reports and histology with immunostaining and flowcytometry done. This include CD20, CD10, BCL2, BCL6, MUM1, CD5, and cyclin D1. Clinical correlation with outcome CR, PR and Overall survival was done. Results: Forty patients with B cell lymphoproliferative disorders NHL were identified; five with mantle cell, ten with marginal zone and plasmacytoid morphology, fifteen with Diffuse Large B Cell Lymphoma DLBCLand ten with other low grade morphology. No correlation with germinal type versus post germinal (activated type) found in term of response. Plasmacytoid/ marginal zone type and mantle cell seem to have the best significant durable response when compared to DLBCL and other low grade NHL. Of note most patients received gemcitabine after failure to rituximab-CHOP and as salvage therapy in post second- and third-line failure. Conclusions: Gemcitabine may have more durable activity if used as a first-line combination therapy. Larger group of patients analysis needed to see if this agent has more activities in germinal than activated type of DLBCL. Plasmacytoid NHL seem to have more rapid and durable respone in our analysis.
Two rare presentations and treatments of Ewing's sarcoma: A need for a standard treatment approach.
Authors: Ayyanar Kanyalakshmi , Narayan Nitya , Moeller Karen , Gump William , Moriarty Thomas , Silverman Craig I. , Balasa Vinod , Bertolone Salvatore J.
Published: March 2020

e21000

Background: We describe two Caucasian boys with rare presentations of non-metastatic Ewings sarcoma (ES) with atypical primary sites. One was extradural but FISH negative for 22q11.2. Another was intradural but extramedullary, and FISH positive. Literature search showed few publications which describe such cases, and there is currently no standard of care. Methods: MG, an 11 year old male, presented with a frontal skull mass, with an intracranial epidural extension of about 5 mm. Biopsy confirmed ES. MG was treated with Vincristine, Doxorubicin, and Cyclophosphamide, alternating with Ifosfamide and Etoposide every 2 weeks, for 6 weeks. He underwent tumor excision for local control with good response. Chemotherapy continued, completing 14 cycles total. He is in remission 15 months after completion. AH, a 13 year old male, presented with lower back pain and paraesthesias of feet. MRI revealed an intradural, extra-medullary L1-L3 mass. Intra-operatively, all visible tumor peeled off readily, except for the L2 nerve root. The tumor was FISH positive for EWSR1. He was treated with the same regimen as MG for 6 cycles. Local control was done with radiation. He then continued chemotherapy, completing a total of 14 cycles. MRI scans 3 months later revealed enhancing intradural lesions along the spinal cord (involving C5, T5 and T8) and two lesions along the cerebellum. He was started on cyclophosphamide and topotecan and has completed 8 cycles without disease progression. Results: MG was diagnosed based solely on histo-pathological diagnosis. While MG’s lesion was extra-osseus in nature, more unusual presentations demonstrate the importance of molecular diagnostic techniques. AH was diagnosed based on chromosomal analysis. Progression is presumably from microscopic residual disease in intradural space that invaded CSF. He is presently on salvage chemotherapy. Nine months after relapse, disease is stable, with plans to minimize disease and consolidate. Conclusions: Intradural tumors tend to progress rapidly, maybe more so than extradural tumors. Future suggestions include developing a standard approach that will improve both treatment of Ewing’s sarcoma and prognostic outcomes for rare initial presentations.
Outcome of leiomyosarcoma of bone: A single center experience.
Authors: Rajendra Rajeev , Pollack Seth , Rodler Eve T. , Conrad Ernest U. , Davidson Darin J , Chai Xiaoyu , Jones Robin Lewis
Published: March 2020

e21502

Background: Leiomyosarcoma (LMS) of bone is a very rare sarcoma subtype. These tumors are managed akin to osteosarcoma, with neoadjuvant chemotherapy followed by surgery. The precise role of chemotherapy remains to be defined. Methods: Patients treated with primary bone LMS at the University of Washington between 2002 and 2012 were included. Patients with high grade tumors were treated with neoadjuvant chemotherapy and surgery; whereas those with low grade tumors were treated with surgical resection alone. Chemotherapy consisted of doxorubicin and ifosfamide x 2 cycles. Treatment details included: initial treatment (surgery versus chemo), surgical and pathological margins, and timing of chemotherapy. Follow-up data included: time to local recurrence, time to metastasis, time to last follow up if alive, or time to death. Results: Ten patients were identified, 4 male and 6 female. Median age at diagnosis: 52 years (range 29 - 91). The primary site was the distal femur in 5 patients, and the hemipelvis, acetabulum, proximal femur, distal clavicle and mid-shaft of femur in 1 patient each. Median tumor size at diagnosis was 8 cm. Five were high-grade tumors; 3 were intermediate and 2 were low grade. Four of 10 patients received neoadjuvant chemotherapy, with the following histological response; 70%, 30%, 15% and <5%. None of these patients had a dimensional radiological response to chemotherapy. Of the patients treated with surgery alone, one developed a local recurrence and another developed metastatic disease. Of the patients treated with chemotherapy and surgery, 1 died from an unrelated cause. Median follow-up was 9 months (range 0 - 83). Median DFS was 9 months (range 0 - 83). OS has not yet been reached. Conclusions: Surgical resection remains the mainstay of management of LMS of bone. The role of neoadjuvant chemotherapy requires further evaluation. Larger collaborative studies and biomarker analyses are essential to evaluate optimal treatment strategies for this rare disease.
Tumor characteristics and treatment (trt) patterns following disease recurrence in gastrointestinal stromal tumor (GIST) patients (pts) who received adjuvant imatinib (IM) as primary trt: A retrospective chart extract-based approach.
Authors: Gauthier Geneviève , Sasane Medha , Guérin Annie , Schwiep Frances Annelies , Keir Christopher Hunt , Magestro Matt , Wu Eric Q. , Conley Anthony Paul
Published: March 2020

e21514

Background: Though adjuvant IM trt is associated with a reduced risk of GIST recurrence, little is known about tumor characteristics and trt patterns at the time of recurrence. The study describes tumor characteristics and trt patterns in pts with recurrent disease after completing treatment with adjuvant imatinib for resectable disease. Methods: An online tool was developed to collect clinical information for 410 pts treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, discontinued, had a recurrence following discontiuation, and then restarted IM or initiated sunitinib. Data were collected at two specific time points: primary diagnosis and disease recurrence. Results: Pts were, on average, 60.2 years of age, mostly male, and Caucasian. At primary diagnosis, most pts had intermediate/high risk profiles based on Fletcher score. Pts received adjuvant IM for a median of 360 days for primary GIST before discontinuing trt; the first recurrence occurred 281 days after IM discontinuation. At the time of recurrence, most patients had a multifocal (62%), unresectable (45%) or metastatic (40%) tumor and did not have a surgery (80%). Most patients had intermediate/high risk profiles at recurrence. 23% of pts had a recurrence outside the gastrointestinal (GI) system (39% of pts initiated on sunitinib; 19% of those who restarted IM, p=<.001). 93% had recurrence inside the GI (85% of pts initiated on sunitinib; 95% of those who restarted IM; p=.002).The majoritiy of patients were restarted on IM (with surgery:74% without surgery:77%), with a 400mg dose (with surgery:79% without surgery: 63%). Conclusions: At the time of recurrence, most pts had high risk, unresectable/mestatstic multifocal tumor and re-started IM 400mg. [Table: see text]