bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction gefitinib followed by concurrent chemoradiotherapy in patients with unresectable stage IIIA/b lung adenocarcinoma harboring mutations of epidermal growth factor receptor: Three case reports.
Authors: Horio Yoshitsugu , Kondo Chiaki , Park Jangchul , Shimizu Junichi , Yoshida Kimihide , Hida Toyoaki
Published: March 2020

e17510

Background: Gefitinib has shown good activity in lung cancer harboring mutations in the epidermal growth factor receptor (EGFR) gene. However, how to integrate gefitinib into concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC) with EGFR mutations is uncertain. Methods: We present three cases of locally advanced lung adenocarcinoma with EGFR mutation, which were treated with gefitinib followed by weekly paclitaxel and carboplatin concurrent with radiation. Three female patients (median age, 73 years; range, 61–77 years) received induction gefitinib 150 mg daily for 1-2 months followed by weekly paclitaxel 40 mg/m2 weekly over 1 hour; carboplatin at AUC (area under the curve) of 2 weekly over 1 hour; and radiation therapy of 60 Gy in 30 fractions. Results: Gefitinib induced very rapid response within the first month without pulmonary toxicity. Subsequent concurrent chemoradiotherapy was performed with safety. One patient recurred as hematogenous lung metastases at 5 months after treatment. The remaining two patients are well doing without adverse events. Conclusions: The very quick response to induction gefitinib and sequential chemoradiotherapy may be an effective treatment with good tolerance. We believe that this treatment strategy deserves further evaluation in unresectable locally advanced NSCLC with EGFR mutations.
Analysis of regulatory T cells in patients of NSCLC with malignant pleural effusion.
Authors: Malik Prabhat Singh , Raina Vinod , Singh Amar , Mitra Dipendrea Kumar
Published: March 2020

e17511

Background: Enrichment of regulatory T (Treg) cells at the affected anatomic site in cancer may suppress the anti-tumor immune response influencing the cancer progression. Understanding of the clinical relevance of Treg mediated suppression of anti-tumor immune response and mechanisms underlying their preferential trafficking to the affected anatomic site is still limited. The aim of this study was to enumerate the frequencies of Treg cells in malignant pleural effusion and peripheral blood of patients with advanced NSCLC and it’s trend after treatment. Methods: Treg frequencies were evaluated in pleural effusion and peripheral blood of the patients with advanced NSCLC (n=27) using flowcytometry and compared with peripheral blood of age and sex matched healthy controls (n=15) and tubercular pleural effusions (n=10). The Treg cells were characterized as CD4+CD25+Foxp3+ T cells gated on CD4+CD25+ T cells. We assessed the effect of treatment response on Treg frequency. We have also looked for the expression of chemokine receptors CCR4 and CCR6 on the Tregs in pleural effusion and peripheral blood of the patients. Results: Compared to healthy controls, frequency of CD4+CD25+Foxp3+ Tregs was significantly increased in peripheral blood of patients with NSCLC (p=0.0036). In pleural effusion of patients, Treg frequency was higher than their corresponding peripheral blood (p=0.025). As compared to tubercular pleural effusion Treg frequency was higher in malignant effusion (p<0.0001). We had 12 patients who completed treatment and in whom response evaluation was available. Treg frequency reduced at the time of response (PR or SD) and increased again at disease progression. Surface expression of CCR4 and CCR6 was higher on Treg cells as compared to non Treg CD4 cells among the patients (p=0.0001; p=0.001 respectively). However, there was no difference in expression of these chemokine receptors on Tregs in pleural fluid and peripheral blood. Conclusions: Tregs are increased in patients of NSCLC, both at disease site and in systemic circulation. This increase may be chemokine receptors mediated. Treg frequency changes with treatment and response. Modulation of Tregs may have therapeutic implication in the management of advanced NSCLC.
Efficacy and safety of amrubicin in patients with advanced or recurrent thymoma.
Authors: Yoh Kiyotaka , Goto Koichi , Niho Seiji , Umemura Shigeki , Ohmatsu Hironobu , Ohe Yuichiro
Published: March 2020

e17513

Background: Thymoma is rare thoracic tumor, which is chemoresponsive with anthracycline or cisplatin-containing regimen in advanced or recurrent setting. Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small-cell lung cancer. The purpose of this study was to determine the efficacy and safety of amrubicin in patients with advanced or recurrent thymoma. Methods: We reviewed 11 consecutive patients with advanced or recurrent thymoma treated with single-agent amrubicin therapy at our institution from May 2006 to September 2010, retrospectively. Amrubicin was administered intravenously at 40 or 45 mg/m2 on day 1 to 3 of 3-4 weeks until disease progression or development of intolerance. Results: Profile of patients included: median age was 57 years (range 25–74); Male/Female=5/6; PS 0/1= 7/4; and Masaoka stage IVA/IVB/recurrence=7/2/2. All patients had received no prior chemotherapy. The median number of treatment cycles was 4 (range 3-6). A partial response was achieved in 1 patient and 10 patients exhibited stable disease. The overall response rate was 9%, but 3 patients had at least a 20% reduction in tumor size with amrubicin. The median reduction rate in tumor size was 13% (range 0-40). The median progression-free survival period was 5.4 months (range 2.3-15.8 months). The median overall survival has not been reached although a median follow-up time was 2.5 years. Based on the Kaplan-Meier method, the estimated 3-year survival rate was 83%. The most common adverse events were hematological toxicities. Five patients had grade 3/4 neutropenia, but febrile neutropenia was not observed. Non-hematological grade 3 toxicities were less frequent. There were no treatment-related deaths. Conclusions: Single-agent amrubicin showed modest activity and acceptable safety profile as chemotherapy for advanced or recurrent thymoma. Additional testing of amrubicin combined with cisplatin in this disease is warranted.
Effect of thoracic radiotherapy in extensive-disease small cell lung cancer on progression-free and overall survival: A retrospective review.
Authors: Wilson James Matthew , Grundy Anna , Best Kate , Mulvenna Paula M , McMenemin Rhona
Published: March 2020

e17519

Background: Extensive-disease small cell lung cancer (ED-SCLC) carries a poor prognosis. The current standard practice of 4-6 cycles of a platinum based chemotherapy (PC) leads to a median survival of only 9-11 months. The role of thoracic radiotherapy (TRT) in ED-SCLC remains controversial. We report patient outcomes with ED-SCLC with respect to whether they received TRT or not. Methods: The practice of two oncologists from 2005-2009 was retrospectively reviewed. Patient age, performance status (PS) at presentation and site of progression were recorded. Progression-free survival (PFS) and overall survival (OS) were calculated with respect to the patient receiving 4-6 cycles of PC or not and then again in this subgroup with respect to whether or not they had TRT at any time after chemotherapy. Survival data was compared using the log-rank test. Results: 141 patients age 42-86 years old (mean 67.4 years) were identified. 58% were PS 0-2. 56 patients (40%) completed 4-6 cycles of PC with a median PFS of 8.4 months compared to 2.4 months in those that did not (p<0.001), median OS was 8.9 and 3.1 months (p<0.001). Of the 45 who had the site of progression recorded - 49% progressed within the thorax. Of 87 patents who received any chemotherapy, 43 received TRT and 44 did not with median PFS of 7.8 and 5.4 months respectively (p= 0.003) and median OS of 8.9 and 5.9 months (p=0.002). In the 56 patients who received 4-6 cycles of PC, median PFS was 9.2 with and 7.7 months without TRT (p=0.02). Median OS was 10.2 months with and 7.7 without TRT (p=0.02). Conclusions: Patients who received TRT at some point in their treatment demonstrated improved median PFS and OS. The role of TRT in ED-SCLC warrants further evaluation. The results of the REST trial are eagerly anticipated.
The utility of DR-70, a novel blood biomarker, in the early detection of lung cancer.
Authors: Motamed-Khorasani Afsaneh , Etemadi Hooman
Published: March 2020

e17521

Background: Lung cancer accounts for the largest percentage of cancer in adults in North America. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers with a death rate of 85%. Early diagnosis is the only chance of a cure when surgery or chemo-radiotherapy can be performed. Chest X-ray is the routine first diagnostic step but is not confirmatory. The purpose of this study was to further validate DR-70 utility in lung cancer early detection considering the relatively high sensitivity of this test. Onko-Sure is a regulatory approved blood test for detection/monitoring of lung cancer treatment/recurrence. It measures the accumulation of fibrin/fibrinogen degradation products in the serum using anti-DR-70 antibody. Methods: A total of 239 serum samples were retrospectively obtained from a serum bank and were tested with DR-70. There were two arms: healthy controls (n= 120) and biopsy-confirmed lung cancers (n= 119) including: small cell lung cancer (SCLC) (n=7) and NSCLC (n=112). The NSCLC included adenocarcinoma (n=65), squamous carcinoma (n=37), large cell lung cancer (n=4) and others (n=6). The data were analyzed to find the optimal cut point, sensitivity and specificity of DR-70. Results: The sensitivity and specificity of 63% and 87.5% were achieved, respectively (cut-point of 1.2 ug/ml). For SCLC, the sensitivity and specificity of 57.1% and 82.5% were achieved (cut-point: 1.1 ug/ml). For NSCLC, the sensitivity and specificity of 65.2% and 87.5% were achieved (cut-point: 1.2 ug/ml). Among the subcategories of NSCLC, DR-70 showed the highest sensitivity for acinar cell carcinoma (81.8%). Furthermore, DR-70 showed sensitivity of 59.5%, 70.4, 66.7 and 70% for stages I, II, III, and IV. Conclusions: Chest X-Ray is the routine first step in lung cancer detection with the sensitivity of 78.3%. It is not confirmatory and it can miss lesions smaller than 1 cm. These findings are promising and highlight DR-70 test as an additional first line diagnostic tool that can potentially replace X-ray to increase the diagnosis sensitivity as early as stage I. An enhanced ability to diagnose NSCLC in an early stage (I/II) should significantly improve prognosis, treatment options and survival rate for patients with lung cancer.
Surgical outcomes of advanced NSCLC (stage IIIB and IV).
Authors: Kim Jae Hyun , Park Jong Ho , Lee Hae Won , Hwang Jin Wook , Kang Moon Chul , Baek HeeJong
Published: March 2020

e17523

Background: The role of surgery in the stage IIIB or IV NSCLC (AJCC 6th edition) patients is has been controversial. Now in AJCC 7th edition, the operable T4 and M1 stages were regrouped to IIIA. We analyzed the clinical outcome of the surgical resection for the patients with operable NSCLC of stage IIIB or IV in AJCC 6th edition to evaluate the role of surgery in this group. Methods: From January 1990 to Desember 2009, the 102 patients with stage IIIB(T4) NSCLC and the 36 patients with stage IV (separate tumor in ipsilateral different lobe) NSCLC had been operated in Korean cancer center. We analyzed the long term survival and the risk factors for long term survival of the 138 patient retrospectively. Results: 59 (42.7%) patients had the invasion of major mediastinal organ, and 43 (31.1%) had separate tumor nodules in ipsilateral different lobe, and 36 (26%) had satellite nodules in same lobe. N0 stage was identified in 42 (30.4%) patients, N1 stage in 29 (21%), and N2 stage in 67 (48.6%). Lobectomy was performed in 56 (40.5%) patients, bilobctomy in 14 (10.1%) and pneumonectomy in 68 (49.2%). Complete resection was achieved in 123 (89.1%) and operation mortality rate was 6.5% (9/138 patients). Median survival was 34 months and 5-year and 10-year survival rate was 34.6% and 21.9% respectively. Recurrence, surgery alone, N2 stage, incomplete resection were risk factors of long term survival in multivariate analysis. Conclusions: Although the role of a surgery in the stage IIIB, IV NSCLC patients is very limited, the long term outcomes of surgical resection of them are tolerable in Korean cancer center. So we thought the shifting of stage of the group with operable stage IIIB or IV NSCLC to IIIA is appropriate.
Mixed-histology small cell lung cancer: The University of Missouri, Columbia, experience.
Authors: Wallace Audrey S , Doll Donald C.
Published: March 2020

e17525

Background: In 1999, we reported demographics, staging, and treatment outcomes of patients with mixed histology small cell lung cancer (MHSCLC). The purpose of this abstract is to report pattern of presentation and survival in patients during 2000-2009. Methods: Records from 24 patients diagnosed with MHSCLC were reviewed under an institutional review board outcomes study. One patient was excluded as records were missing. Patient and disease characteristics, treatment, and outcomes were analyzed. Results: Twenty-three patients were analyzed, with median age at diagnosis of 63 (range 50 to 84). Twenty (86%) patients were Caucasian. Fourteen (61%) patients were female, 9 (39%) were male. Twenty-one (91%) patients were current or former smokers. Staging was as follows: 1-2: 3, 3: 6, 4: 11, extensive-stage: 1, limited-stage: 2. Sites of diagnosis were lung in 18 (78%), and metastatic sites in 5 (22%). Presenting symptoms were cough or shortness of breath in 12 (52%), CNS in 4 (17%), chest pain in 2 (9%), various others in 5 patients. Paraneoplastic syndrome was seen in 2 patients, and 6 patients reported weight loss of 10-15 lbs within 3-6 months of diagnosis. Metastatic presentation was as follows: 4 brain, 1 bone, and 1 soft tissue. Histology included 15 large cell, 6 adenocarcinoma, and 1 squamous cell. Seventeen patients were treated as follows: chemotherapy (14), 5 thoracic radiotherapy (RT), 3 cranial RT, with treatment status unknown in 1 patient with 3 year survival. Twenty-one (91%) patients had expired, with median survival of 4.6 months (range <1 month-53 months). Two patients were alive at 24.1 and 38.5 months. Conclusions: This review revealed female predominance, which is in line with the increasing number of women diagnosed with small cell lung cancer (SCLC), but could be due to exclusion of veteran administration patients. Best survival was seen in one patient with squamous cell carcinoma, followed by patients with adenocarcinoma, opening a possible role for targeted biologics in this subset of MHSCLC. In memory of Michael Perry, MD, 1945-2011, dedicated physician, researcher, and teacher who started as primary mentor on this project before his passing.
Association between genetic variations in transforming growth factor beta pathway and overall survival in patients with non-small cell lung cancer treated with definitive radiotherapy.
Authors: Wang Weili , Shedden Kerby A , Kong Feng-Ming (Spring)
Published: March 2020

e17530

Background: The transforming growth factor beta (TGFβ) pathway, an important regulator in cellular metabolic process, has been reported for significant association with cancer prognosis. This study was to exam the association between single nucleotide polymorphisms (SNPs) of TGFβ pathway and overall survival (OS) in subjects with non-small cell lung cancer (NSCLC). Methods: Patients with stage I-III NSCLC received definitive radiotherapy with/without chemotherapy were eligible to this prospective study. The primary endpoint was OS which was calculated from radiation treatment start to death or censored. DNA samples for genotyping were extracted from buffy-coat which was collected before commencement of treatment. 19 SNPs in 10 genes (BMP1, BMP2, INHBC, SMAD1, SMAD3, SMAD4, SMAD6, SMAD7, SMAD8, TGFβ1), which was reported to have significant correlation with OS of lung cancer, were selected. MassArray System (Sequenom Company) was used for genotyping. Cox regression was performed for multivariate analysis to examine the effects of genotypes on OS using dominant and recessive genetic model. Results: 126 consecutive patients, 91% of them were Caucasian, were recruited in this study. All SNPs call rates were over 90%. Assay reproducibility was over 99% by random double-blinding duplicate or triplicate genotyping. Among clinical factors analyzed, radiation dose was only significant independent factor predicting OS (P=0.001). Genotypic association study showed that 7 SNPs (rs235756, rs11939979, rs12102171, rs6494633, rs12456284, rs12906898 and rs4803455) were significantly associated with OS, adjusted for age, gender, smoking, histology, clinical stage, tumor volume, Karnofsky Performance Status, radiotherapy dose, and chemotherapy. The strongest association was in SMAD3: rs12102171 (P=0.004, HR=2.28, 95%CI, 1.26-4.15). Conclusions: This study partly validated findings from previous studies that genetic variations in the TGFβ pathway are significant predictors of overall survival in NSCLC patients treated with definitive radiotherapy with/without chemotherapy.
Stage III NSCLC: How many patients are really suitable for radical treatment approaches?
Authors: Al-Shamsi Humaid Obaid , Ellis Peter Michael
Published: March 2020

e17532

Background: Stage III NSCLC represents a heterogeneous population. Patients with good performance status (PS) and weight loss < 10% (WL<10) are generally considered for radical treatment with chemoradiation or trimodality approaches. Outcome data from Cancer Care Ontario show 30% of stage III NSCLC (6th edition TNM) patients receive chemoradiation.There is significant variation between local health networks. We examined the proportion of patients with stage III NSCLC suitable for radical treatment. Methods: We conducted a retrospective cohort study of patients diagnosed with stage III NSCLC at the Juravinski Cancer Center from July 2007 to June 2009. Demographic, pathologic and treatment data were abstracted from patients’ records. The primary outcome was the proportion of stage III NSCLC patients eligible for radical treatment. We also compared patients treated radically versus palliatively. Results: 159 stage III NSCLC patients (staged by 6th edition TNM) were seen. The median age was 69 yrs (sd 12) with 58% men and 42% women. There were 40% stage IIIA, 37% IIIB and 23% IIIB (wet). 61 (38%) patients were treated with radical intent and 98 (62%) were treated palliatively. Reasons for palliative treatment approach were WL >10% (7%), PS >2 (10% ), both WL >10% and PS >2 (20%), significant comorbidities (9%),patient declined (9%) and stage IIIB wet(23 %).The median OS for patients treated radically was 23.3 months v 7.1 months for those treated palliatively. Stage IIIA patients treated radically had better OS than IIIB (27m v 14m). Patients with poor PS, or WL>10% had similar OS to patients with wet stage IIIB (7.1m v 7.2m), whereas the survival of patients with poor PS and WL >10% was worse (3m). Conclusions: Using eligibility criteria from clinical trials of stage III NSCLC, only 40% of patients appear eligible for radical treatment approaches. Our data are consistent with published data. Significant WL>10% or poor PS (>2) predicted poor outcome. Combined WL>10% and poor PS predicted a very poor prognostic group. Criteria for radical treatment of stage III NSCLC should not be extrapolated beyond the eligibility criteria used in clinical trials.
Blood vessel invasion (BVI) in curatively (R0) resected stage II and IIIA non-small cell lung (NSCLC) cancer patients.
Authors: Brueckl Wolfgang M. , Wuerflein Dieter , Kraus Dietmar , Meyer Christian , Wagner Manfred , Ficker Joachim H
Published: March 2020

e17536

Background: A single center study was conducted to identify the prognostic and predictive value of blood vessel invasion (BVI) in surgically R0 resected stage II and IIIA non-small cell lung cancer patients. Methods: A total of N=105 consecutive patients who had undergone complete (R0) resection for stage II/IIIA primary non-small cell lung cancer (NSCLC) between 01/2008 and 12/2010 at the Lung Cancer Center Nuremberg were evaluated. All pathological specimens were examined for evidence of BVI. All patients were followed for tumour recurrence and survival. Differences between groups were calculated with Chi-square test. Recurrence and survival data were analyzed for all patients using Kaplan-Meier test. Significance was univaratiately calculated by log-rank and multivariately by Cox-regression analysis. Results: The baseline clinical data showed no significant differences between patients with adjuvant chemotherapy (aCTx; cisplatin/vinorelbine; N=46) and without aCTx (N=59) beside of age (aCTx treated patients were younger p=0.03). Demographic data were as follows: male 64%; age <65 years 53%; ECOG 0/1/2 (47%/35%/3%); histology AC/SCC/other (53%/37%/10%); stage IIA/IIB/IIIA (13%/31%/55%); BVI 29%; pneumonectomy 19%. ECOG-PS 0 and no BVI were positive prognostic factors for both recurrence free survival (RFS) and overall survival (OS) in the group without aCTx and remained independent prognostic factors in the multivariate analysis (p<0.001; p=0.002). Additionally, ECOG-PS 0 and no BVI were independent predictive factors for RFS and OS in the aCTx treated group. Conclusions: BVI is an independent prognostic and predictive factor in R0 resected stage II/IIIA NSCLC patients. This subset of patients may have a greater benefit from aCTx and may need to be followed-up more closely.
NY-ESO-1 as a predictive and prognostic marker in NSCLC.
Authors: John Tom , Russell Prudence , Barnett Stephen , Wainer Zoe , White Shane , Mitchell Paul , Walkiewicz Marzena , Boutros Paul C , Starmans Maud HW , Chen Yao-Tseng , Wright Gavin , Knight Simon , Cebon Jonathan S.
Published: March 2020

e17539

Background: Cancer-testis antigens (CTAgs) have previously been shown to be markers of poor prognosis and to be associated with chemoresistance in short interference RNA screens. In contradistinction, we recently reported the CTAg NY-ESO-1 predicted improved responses to neoadjuvant chemotherapy in pathological stage IIIA NSCLC. Despite this, no significant survival benefit was seen in NY-ESO-1 positive (NY-ESO-1+) patients. Given that tissues available for staining in the neoadjuvant setting were limited, we investigated a retrospective cohort of patients who underwent curative surgery for pathological N2 disease. As some of these patients were operated on prior to the broad acceptance of adjuvant chemotherapy (ACT), half did not receive chemotherapy. We investigated NY-ESO-1 as a prognostic and/or predictive marker in these patients. Methods: Formalin fixed paraffin embedded tissues were reviewed and stained using standard methods for a panel of CTAgs including NY-ESO-1 by immunohistochemistry. Tumors were categorized as NY-ESO-1+ or NY-ESO-1-. Isolated DNA was subjected to mutation profiling using Sequenom’s MassArray platform. Molecular markers were correlated with clinicopathological features and survival. Results: NY-ESO-1 stained 26/104 (25%) samples, including 15 cases that received ACT and 11 that did not. NY-ESO-1+ tumors were enriched for squamous cell carcinomas over adenocarcinomas (12/29 vs. 8/57; p = 0.01). They also lacked EGFR mutants and were enriched for KRAS mutants amongst adenocarcinomas relative to NY-ESO-1- tumors (5/8 vs. 9/49; p=0.02). NY-ESO-1+ patients who did not receive ACT had significantly worse outcome than NY-ESO-1- patients who did not receive ACT (HR 2.66 1.2-5.86, p=0.01). Median survival favored NY-ESO-1+ patients who received chemotherapy (37.7 months) compared to NY-ESO-1- patients regardless of chemotherapy (28.2 ACT vs 15.7 No ACT; p= 0.25) and NY-ESO-1+ patients who did not receive ACT (7.75). Conclusions: In this dataset, NY-ESO-1 was poorly prognostic but also predictive for more favorable outcomes with chemotherapy. These data support our previous observation of increased responses to chemotherapy in NY-ESO-1+ N2 patients and warrant further study.
Prognostic impact of c-Met/phospho-Met, and topoisomerase I in small cell lung cancer.
Authors: Ikeda Hideko , Koba Hayato , Kurokawa Koji , Nishikawa Shingo , Araya Tomoyuki , Tambo Yuichi , Sakai Asao , Sone Takashi , Fukuoka Junya , Kasahara Kazuo
Published: March 2020

e17540

Background: The hepatocyte growth factor/MET pathway has been shown to cause tumor progression in several types of carcinomas. We reported that c-Met up-regulated topoisomease I (Topo I) in non-small cell lung cancer cell lines (submitted for publication). The aims of this study were 1) to examine the prognostic influence of c-MET/phospho-MET (p-Met), or Topo I expression and 2) to elucidate correlation between c-Met/p-Met expression and Topo I expression in small cell lung cancer (SCLC). Methods: This retrospective study included 72 SCLC patients (pts) with available tumor tissue from primary lung tumor or metastatic lesions and clinical data including survival. We performed immunohistochemistry to detect c-MET/phospho-MET and Topo I expression. Results: Tumor tissues were obtained from 72 SCLC pts. Sixty-six pts, (51 male, 15 female, median age 67.5 range 43-91, LD/ED 38/28, PS0,1/2,3,4 57/9) were evaluated. c-Met overexpression was seen in 40.9%, p-Met in 74.2%, and Topo I expression in 59.1%, respectively. High expression of Topo I associated with lower response rate (RR) (96.7% in low group vs 78.4% in high group, p=0.029) and shorter progression-free survival (PFS) (65W vs 39W, p=0.040) but did not correlate with overall survival (OS). Phosphorylation of Met protein did not correlate with RR, PFS or OS. Interestingly, intensity of p-Met significantly correlated with Topo I expression (p=0.048). High expression of c-Met protein did not associated with RR or PFS but significantly associated with shorter OS (high 53W, low 95W, p=0.018). Multivariate analysis which included c-Met, stage, PS, and age resulted that c-Met was an independent prognostic factor for OS of pts with SCLC (HR; 2.144, 95% confidence interval 1.162-3.956, p=0.015). Conclusions: This study suggested c-Met high expression was an independent prognostic factor, and Topo I was up-regulated by Met in SCLC.
MUC4 expression in non-small cell lung cancer.
Authors: Ganti Apar Kishor , Kaur Sukhwinder , West William W , Dhangada Majhi Prabin , Lakshmanan Imayavarambam , Smith Lynette , Rolle Cleo E , Carey George , Sharma Poonam , Salgia Ravi , Batra Surinder
Published: March 2020

e17549

Background: MUC4 has been shown to play a key role in breast and pancreatic cancer. MUC4 expression is seen in the normal bronchial epithelium, but its role in non-small cell lung cancer (NSCLC) is unclear. Here we study the association between MUC4 overexpression and clinical features of NSCLC. Methods: The diagnosis of lung cancer was confirmed in H&E sections. MUC4 level was semi-quantified by immunohistochemistry. Each sample was given a composite score based on intensity and extent of staining. The intensity was graded on a 4 point scale: – (0), + (1), ++ (2), and +++ (3). The extent of staining too was graded on a 4 point scale: 1 (1-25%), 2 (26-50%), 3 (51-75%), and 4 (76-100%). The composite score was obtained by multiplying the two values, with possible scores of 0-12. Poisson mixed effects models were used to compare the score between groups. Kaplan-Meier method was used to estimate survival distributions and the log-rank test was used to compare them. Wilcoxon sign rank test was used to compare the difference in score between lung tissue and corresponding lymph node. P value <0.05 was considered to be statistically significant. Results: 167 samples from 54 non-metastatic NSCLC patients were analyzed. Of these, 13 (25%) patients had stage I, 33 (63%) had stage II and 6 (12%) patients had stage III disease. Distribution of the composite score differed significantly by stage (p=0.0043). A higher proportion of patients with stage I NSCLC had a score of 12 (77%) compared to stage II (18%) and stage III (57%) (p=0.0001). When patients who had data for both the primary tumor and corresponding metastatic lymph node were analyzed, MUC4 expression was higher in the primary tumor compared to the metastasis (p=0.05). The effect of MUC4 expression on survival was analyzed in 29 patients with survival data. Of these, 16 had a composite score of 12, while 13 had a score <12. Patients with a score <12 had significantly worse survival than those with a score of 12 (p<0.045). Conclusions: MUC4 expression is more common in early stage NSCLC and appears to be associated with a better outcome in patients with non-metastatic NSCLC. The therapeutic implications of this finding need to be investigated further.
Neoadjuvant concurrent chemoradiation therapy followed by surgical resection in patients with non-small cell lung cancer invading chest wall.
Authors: Yamaguchi Yoko , Yoh Kiyotaka , Hishida Tomoyuki , Ohmatsu Hironobu , Goto Koichi , Niho Seiji , Umemura Shigeki , Ishii Genichiro , Akimoto Tetsuo , Nagai Kanji , Ohe Yuichiro
Published: March 2020

e17554

Background: The treatment approach of patients with non-small-cell lung cancer (NSCLC) invading the chest wall (stage T3N0M0) is still controversial. The clinical outcome of NSCLC patients with chest wall invasion has remained poor. The purpose of this study was to determine the efficacy and safety of neoadjuvant concurrent chemoradiation therapy followed by surgical resection in NSCLC patients with chest wall invasion. Methods: We retrospectively reviewed medical records of 19 patients with NSCLC invading chest wall (T3N0M0 or T4N0M0), who underwent neoadjuvant concurrent chemoradiation therapy followed by surgical resection between April 2003 and October 2009. Neoadjuvant chemotherapy was administered intravenously at cisplatin 80 mg/m2 on day 1 and vinorelbine 20 mg/m2 on days 1 and 8, q4w, with a maximum of 2 cycles. Radiotherapy directed at the primary tumor invading chest wall was started in cycle 1, at the total dose of 45Gy in 25 fractions. Surgical resection of the tumor was performed 4 to 8 weeks after the completion of neoadjuvant therapy. Results: Patient characteristics included: median age 61 years (range 43-68); Male/Female=17/2; and stage T3N0M0/T4N0M0=18/1. Six patients (32%) had superior sulcus tumors. Neoadjuvant chemoradiation therapy was generally well tolerated. All patients underwent surgical resection, and complete resection was achieved in 18 patients (95%). There were 10 (53%) patients with pathologic complete response. There were no treatment-related deaths. The 3-year disease-free and overall survival rates for all patients were 58% and 81%, respectively, with a median follow-up of 37 months. The 3-year disease-free survival rate was 78% for patients with a pathologic complete response compared with 25% for those who did not achieve a pathologic complete response. Disease progression occurred mainly in distant sites. Conclusions: Neoadjuvant chemotherapy consists of cisplatin-vinorelbine and radiotherapy followed by surgical resection is effective and tolerable in patients with NSCLC invading chest wall (T3N0M0). This treatment approach produces high rates of pathologic complete response.
Modern imaging technique assessment of small cell lung cancer doubling time.
Authors: Mohd Sharial Mohd Syahizul Nuhairy , Teo MinYuen , Doherty Mark , McDermott Raymond S. , Walshe Janice Maria
Published: March 2020

e17561

Background: Doubling time in non-SCLC tumors has been well studied, but this is less so in SCLC. We aim to study in vivo doubling time in SCLC using modern imaging techniques. Methods: Patients (pts) with SCLC with both diagnostic computed tomography (CT) and subsequent staging Positron Emission Tomography (PET)/CT were identified from institutional database. Primary lesion and nodal disease on the initial CT scan and on the CT component of PET/CT scan was measured. Diameter Doubling Time (D-DT) = [(dt)*log 2] / [3(log D2 – log D1)], where dt was time interval between scans, D2 and D1 are diameters of lesion on second and first scan respectively. Volume Doubling Time (V-DT) = [(dt)*log 2] / (log V2 – log V1), where V2 and V1 are volume of 2nd and 1st CT. Results: 18 eligible pts were identified. 61% were males, median age 63. Primary lesion was assessable in 14 pts and nodal disease in 17. Mean interval between scans was 19.7 days (range: 6 – 67). Mean diameter of primary lesion on 1st and 2nd scans: 4.17 cm +/- 2.11 and 4.63 cm +/- 2.26. Mean diameter of lymph nodes on 1st and 2nd scans: 4.24 cm +/- 1.72 and 4.78 cm +/- 1.81. Mean volume of primary lesion on 1st and 2nd scans: 35.56 cm3 (=/- 43.34) and 45.52 cm3 (+/- 55.66). Mean volume of nodal disease on 1st and 2nd scans: 32.77 cm3 (+/- 44.52) and 44.16 cm3 (+/- 55.06). For primary tumor, mean D-DT was 70.0 days +/- 16.4, with mean V-DT 60.5 days +/- 11.8, p=.64. There is a significant correlation between D-DT and V-DT with Pearson rho of 0.7691 (p=0.0013). For nodal disease, mean D-DT = 51.1 days +/- 15.1 and mean V-DT 42.2 days +/- 9.3, p= .62, with correlation between D-DT and V-DT, Pearson rho of 0.7609, p=.0004. There was higher doubling time in extensive stage (ES) SCLC primary tumors compared with limited stage (LS), with mean D-DT 24.0 days vs 97.6 days, p=.046. When all lesions analyzed collectively, mean D-DT = 59.6 days, 95% CI 37.1 – 82.2 and mean V-DT = 50.5 days, 95% CI 35.3 – 65.7. Conclusions: Our data demonstrate more rapid doubling time of SCLC compared to historical data. The differential in growth between LS and ES points to a biologic dichotomy. This has a significant impact in the timely management of SCLC, and potential avenues for therapeutic development.
Brain metastasis in a series of NSCLC: Egyptian experience.
Authors: Elmesidy Salah Eldeen , Abdelsalam Mahmoud , Zawam Husam
Published: March 2020

e18001

Background: Incidence of cerebral metastasis is increasing among lung cancer patients. Many factors have been reported associated with increase risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in lung cancer patients. Methods: We retrospectively analyzed histologically proven lung cancer patients radiologically diagnosed of having brain metastases who presented to Kasr Al-Eini Center for Oncology (NEMROCK) in the period from 2004 till 2010, with follow up period of 6 months at least. The following factors were analyzed: age, gender, PS, smoking history, tumor size & grade preceding development of brain metastasis. Results: Our study included 403 patients. 67 patients (16.6%) experienced brain metastasis during the course of their disease. 40 (10%) patients had brain metastasis among other sites of distant spread at first presentation which represent 88.9% of patients presented with metastatic disease. In a median follow-up of 17.1 months (6-77) the time to develop brain metastasis (TTBM) for the whole group was 5 months (range 2-22 months) (95% CI : 4.3-7.7). The most important factor affecting the TTBM was the use of chemotherapy before developing brain metastasis with a median TTBM of 5.9 months (95%CI : 3.2-6.8) among those who received chemotherapy compared to 2 months among the patients who didn't receive chemotherapy (P= <0.0001). The second factor was PS at time of initial diagnosis (P= 0.027). The median OS after brain metastasis was 6 months (95% CI : 4.26-7.74). On univariate analysis, PS and use of chemotherapy after developing brain metastases showed statistically significant difference affecting OS. Conclusions: We concluded that PS as well as use of chemotherapy are the 2 main factors associated with shorter time to develop brain metastasis. PS and use of chemotherapy after developing brain metastases showed longer OS after developing brain metastases. Keywords: NSCLC, Brain metastasis, Egypt
What factors affect long-term survival after responding to gefitinib in advanced non-small cell lung cancer? Real-world evidence.
Authors: Takeuchi Yoshiko , Imamura Fumio , Morita Satoshi , Mori Masahide , Komuta Kiyoshi , Kijima Takashi , Namba Yoshinobu , Nishino Kazumi , Yamamoto Suguru , Takahashi Ryo , Nakazawa Yukie , Minami Seigo , Ogata Yoshitaka , Kumanogoh Atsushi
Published: March 2020

e18007

Background: After gefitinib was approved in July 2002, we experience long-term surviving patients in the actual clinical setting. However, it is not clear how the factors or treatment strategy are contributing to the long-term surviving patients.We evaluated the effects of clinical backgrounds and treatment histories on overall survival (OS). Methods: We extracted information on advanced NSCLC patients with the following inclusion criteria from the medical records: 1) Patients who were diagnosed by October 2010 and treated with gefitinib after July 2002: 2) Performance status (PS) 0 – 2, 3) PR, CR, or long SD (6 months or more) by gefitinib treatment : 4) Patients who had not received curative surgical operation or curative radiation therapy. Primary objective is to evaluate survival time of the patients who responded to gefitinib and clarify the relationship between clinical factors and survival time. We also conducted “Dynamic Treatment Regimen Analysis (DTRA)” to explore key treatment regimen and sequence of regimens contributing to long-term survival. Results: The medical records of total of 275 patients were extracted. 44% (122/275) were EGFR mutation examined and 93% (114/122) has shown the EGFR mutation positive. The mean age was 65 years, 72% (198/275) were women, 66% (182/275) were non-smokers, and 90% (247/275) had adenocarcinoma histology. 20% (54/275) and 21% (58/275) underwent re-administration and beyond PD administration of gefitinib respectively. Median survival time (MST) was 615 day (95% C.I; 519-691). 10% patients survived for more than 5 years. The multivariate Cox analysis demonstrated that sex (p=0.0108) and gefitinib re-administration (p=0.0012) were significant independent factors for long-term OS. Grade 3/4 interstitial lung disease, skin, diarrhea, and liver dysfunction were observed in 1.5%, 4.4%, 1.1%, and 13.1% of the patients, respectively. Conclusions: This study suggests that sex and gefitinib re-administration, may have significant affects on OS in long survivors after responding gefitinib treatment.
Analysis of neuroendocrine marker synaptophysin and stem-cell related marker CD133 on circulating tumor cells (CTC) in patients with metastatic non-small cellular lung cancer (NSCLC).
Authors: Kuemmerlen Verena , Puggina Anna , Fusi Alberto , Keilholz Ulrich
Published: March 2020

e18010

Background: In NSCLC heterogeneity or switch to neuroendocrine phenotype and the expression of stem-cell related markers have been associated with higher tumor aggressiveness. We evaluated the presence of CTC bearing stem cell-related marker CD133+ and the neuroendocrine marker synaptophysin (SYP) in patients with metastatic non small cellular lung cancer (NSCLC). Methods: Forty-four blood samples (20 mL) were collected after informed consent from 16 consecutive patients (pts) with metastatic NSCLC before and during chemotherapy at our Institution. Blood was enriched for tumor cells by CD45 depletion using a magnetic bead separation technique and potential CTC were identified by flow cytometry. CTC were defined as EpCAM+ CK7/8 + CD45-CD53-. Multiparameter cytometry assessed surface expression of the combinations of CD133 and SYP. Results: CTC phenotype: Twenty-five of all 44 samples (57%) were found positive for presence of at least 1 CTC. The median number of CTC was 4 (range: 1-9) / 10mL blood. Twelve samples (27%) showed to be positive for the cancer putative stem cell marker CD133. The median number of CD133+ CTC was 2 (range: 1-7) / 10mL. Seventeen samples (38%) were positive for SYP with a median number of 2 SYN+ CTC (range: 1-6 ) /10ml. Eleven samples (25%) resulted double positive for CD133 and SYP. Tumor heterogeneity: Twelve of the 16 patients (75%) had at least one sample positive for CTC. In 3 pts (25%) CTC expressed only SYP, in 5 pts (42%) both the markers and in 4 pts (33%) neither CD133 nor SYP were expressed. Conclusions: A higher rate of CD133-SYP-double positive CTC compared to the single positive CTC was observed. This suggests that the switch to the neuroendocrine phenotype might occur concomitantly with a stem-cell like more resistant and aggressive phenotype. It needs to be clarified, whether the presence of stem-cell like and neuroendocrine CTC may be a predictive factor for treatment response and outcome in patients with metastatic NSCLC.
Prospective study into the necessity of hemogram on day 8 in oral vinorelbine and cisplatin regimen.
Authors: Provencio Mariano , Sánchez Antonio , Domine Manuel , Artal Angel , Garcia-Gomez Ramon , Constenla Manuel , Sanchez Torres Jose Miguel , Castro Javier , Vinolas Nuria , Huelves Miriam , Perez Javier , Sanchez-Hernandez Alfredo
Published: March 2020

e18011

Background: One of the standard treatments for metastatic non-small-cell lung cancer patients is the combination of cisplatin plus vinorelbine. This regimen is associated with a high rate of severe neutropenia, and a hemogram is therefore routinely performed on day 8 before the administration of vinorelbine. However, no prospective study has ever examined the rate of neutropenia detected in this hemogram or the rate of discontinuation of chemotherapy as a result. Since one of the objectives in the treatment of advanced lung cancer is to maintain quality of life, we performed this prospective study of cisplatin plus vinorelbine to address the question of whether this hemogram on day 8 could be avoided, thus eliminating unnecessary venipunctures without endangering patient safety. Methods: We included 58 chemotherapy-naïve advanced NSCLC patients from 10 centers. They received intravenous doses of cisplatin on day 1 plus oral vinorelbine on days 1 and 8, every 3 weeks, for a maximum of six cycles. Median age was 61 years; 87% were males; ECOG 1: 66%. Results: Of 189 cycles analyzed, vinorelbine was administered on day 8 in 661 (97.8%), and the dose was reduced or canceled in 15 (2.2%; IC 95%: 0.5 - 5.45) due to hematological toxicity. Conclusions: The hemogram on day 8 could potentially be avoided in patients ECOG 0-1 while still maintaining an acceptable safety margin.
Serum CYFRA 21-1 as a biomarker of pemetrexed plus cisplatin treatment in nonsquamous non-small cell lung cancer.
Authors: Sakatani Toshio , Ohyanagi Fumiyoshi , Tanimoto Azusa , Kawano Yuko , Saito Ryota , Kaburaki Kyohei , Yanagitani Noriko , Kudo Keita , Horiike Atsushi , Hagiwara Sachiko , Horai Takeshi , Nishio Makoto
Published: March 2020

e18014

Background: Pemetrexed (P) is a key drug in the treatment of advanced non-squamous (N-Sq) non-small cell lung cancer (NSCLC). Although differential efficacies of P between squamous (Sq) and N-sq subtypes have been reported, it is difficult to get a clear histological diagnosis from a small biopsy sample. Therefore, a more objective, yet simple, biomarker for histology-based treatment is needed. Previously, we reported that serum Cytokeratin fragment 21-1 (CYFRA) was related to the outcome of P monotherapy. In this study, we examined whether serum CYFRA could predict the efficacy of the cisplatin-pemetrexed (CP) combination regimen as well as it did for P monotherapy. Methods: Pre-treatment serum concentrations of CYFRA, carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) antigen, and sialyl Lewis X-I antigen (SLX) were measured in 50 N-sq NSCLC patients who were enrolled in a phase II study of C (75 mg/m2 and 500 mg/m2) against N-Sq NSCLC. Eligibility criteria consisted of histologically or cytologically confirmed recurrent or metastatic N-Sq NSCLC previously untreated with chemotherapy, ECOG performance status (PS) 0-1. The primary endpoint was response rate, which was evaluated with RECIST. The planned sample size was 50 patients. We analyzed possible associations between these NSCLC marker levels and the efficacy of the CP regimen. Results: From April 2010 to June 2011, 50 N-sq NSCLC patients (male/female, 34/16; median age 60 y (28-74 y)) were enrolled in this study. Patients’ histological characteristics were: adeno/large/not otherwise specified (NOS), 39/5/6; PS: 0/1, 31/19. In these 50 patients, elevated levels of serum CYFRA, CEA, SCC and SLX were found in 25, 32, 5 and 32 patients, respectively. CYFRA was significantly associated with progression-free survival (PFS) (median PFS: 5.53 vs. 3.29 months; p < 0.05), whereas no significant associations were observed between PFS and CEA, SCC or SLX. In addition, multivariate analysis showed that higher CYFRA and PS levels were significant factors associated with a shorter PFS. (p < 0.05) Conclusions: Serum CYFRA is related to the outcome of CP treatment; our results suggest that serum CYFRA is a promising predictive marker of CP therapy.
ALK and EGFR mutation analysis in a phase II trial of cisplatin/pemetrexed in Japanese patients with advanced nonsquamous non-small cell lung cancer.
Authors: Kaburaki Kyohei , Ohyanagi Fumiyoshi , Tanimoto Azusa , Sakatani Toshio , Kawano Yuko , Saito Ryota , Yanagitani Noriko , Kudo Keita , Horiike Atsushi , Hagiwara Sachiko , Motoi Noriko , Takeuchi Kengo , Ishikawa Yuichi , Horai Takeshi , Nishio Makoto
Published: March 2020

e18017

Background: Recently, ethnic differences and genotypes such as EGFR mutation (EGFRm) or fusion gene (ALK translocation: ALKt) are important factors in non-small cell lung cancer (NSCLC) treatment. Pemetrexed (P)/cisplatin (C) is one of the standard care for advanced non-squamous (Nsq) NSCLC. However, the efficacy of the CP regimen has not been well examined in Japanese Nsq NSCLC patients (pts); furthermore, the difference in efficacy between genotypes was not thoroughly examined. Therefore, the present study was conducted to evaluate the efficacy of the CP regimen in Japanese Nsq NSCLC pts, and to determine whether EGFRm and ALKt impacted the treatment. Methods: This study was conducted from May 2009 to December 2010. Pts were eligible for this study if they had histologically or cytologically confirmed recurrent or metastatic Nsq NSCLC previously untreated with chemotherapy, an ECOG performance status of 0 or 1, life expectancy of more than 12 weeks, and adequate organ function. Pts received C (75 mg/m2) plus P (500 mg/m2) on day 1 every 3 weeks. Of the 50 pts initially enrolled, 49 were evaluated, and 43 tumor samples were available for analysis. Most pts were male (80%), and 80% of the pts had adenocarcinoma. The primary endpoint was the response rate that was evaluated according to RECIST. EGFRm was examined using PCR-based methods, and the ALK fusion protein was examined using a highly sensitive IHC method in the available tumor specimens. Although the CP regimen demonstrates consistent efficacy in Japanese Nsq NSCLC pts, EGFRm and ALKt may have impacted this treatment. Results: The objective response rate and disease control rate in all pts were 44.9% and 79.6%, respectively. The median progression-free survival was 4.4 months, and the 1-year survival was 73.5%. Toxicities were mild; no new toxicity profile was identified. Among the 43 samples, the following mutations were identified: 9 EGFRm (21%), 5 ALKt (12%), and 29 wild-type (67%). Objective response was observed in 6 (66.7%) EGFRm, 2 (40%) ALKt, and 13 (44.8%) wild-type. Conclusions: Although the CP regimen demonstrates consistent efficacy in Japanese Nsq NSCLC pts, EGFRm and ALKt may have impacted this treatment.