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J. Molina



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.08 - Genomic alterations in pulmonary carcinoid tumors (ID 3162)

      16:55 - 17:00  |  Author(s): J. Molina

      • Abstract
      • Presentation
      • Slides

      Background
      Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Relatively little is known about bronchopulmonary carcinoid tumorigenesis, and understanding of these tumors has yet to benefit from the insight of genomic studies. This unfortunately has translated into relatively limited treatment options for these patients and no recent advances in therapy. We aimed to characterize genomic alterations in pulmonary carcinoid tumors under the hypothesis that a better molecular understanding may lead to improved therapeutic approaches and patient outcomes.

      Methods
      We characterized genomic alterations in pulmonary carcinoid tumors using whole genome, exome, and RNA sequencing, in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Fresh-frozen specimens from 54 patients with primary lung neuroendocrine tumors were obtained from our lung specimen registry and clinical data collected. This included a total of 31 typical and 11 atypical carcinoid tumors with associated normal tissue, and 12 SCLC. Whole transcriptome mRNA expression profiling and SNP genotyping for evaluating copy number variation was performed using Illumina array platforms. For a subset of tumors, whole genome sequencing was performed through Complete Genomics, and exome and RNA sequencing performed through BGI and the Mayo Clinic Genomics Facility. These data were correlated with the histologic subtype, stage and survival data available from this cohort of patients.

      Results
      Gene expression clearly identified distinct profiles differentiating carcinoid tumors from SCLC, though not between typical and atypical carcinoids. Copy number variations (CNV) were widely prevalent in SCLC, less frequent in AC, while TC had the lowest frequency of CNV. Validated sequencing data from exome and WGS platforms revealed a number of novel mutations for pulmonary carcinoid tumors, including ADNP, BRIP1, cyclin B3, CREBL2, GLI3, HERC1, IRAK3, NEDD4L, PRRX2, and ZDBF2, among others. RNA sequencing data did not reveal any novel fusions from analysis to date. Despite a low overall mutation frequency versus other forms of lung cancer, each carcinoid tumor had at least one potential driver mutation, suggesting possible targeted therapy opportunities for a disease where currently none exist.

      Conclusion
      Despite a low overall mutation frequency and an absence of frequently recurring mutations from the tumors sequenced to date, targeted therapy opportunities may exist through mutation profiling in broncopulmonary carcinoid tumors.

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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.07 - Identification of New Chemotherapeutic Strategies in Mesothelioma and Non-Small Cell Lung Cancer Using a Drug-Induced Apoptosis Assay (MiCK Assay) (ID 3158)

      11:10 - 11:15  |  Author(s): J. Molina

      • Abstract
      • Presentation
      • Slides

      Background
      Given limited progress in developing novel chemotherapies for mesothelioma and multi-negative NSCLC, new technology is needed to identify promising drug strategies. A drug-induced apoptosis assay has been developed that has been applied in acute myelocytic leukemia, ovarian cancer, and a variety of solid tumors including breast cancer (Cancer Research 2012; 72:3901). We explored the use of the MiCK assay in mesothelioma and NSCLC tumor specimens.

      Methods
      Fresh tumor specimens from resected tissue or malignant effusions were processed in a central laboratory. Cell separation techniques were used to prepare >95% tumor cell suspensions for the MiCK assay (as described in Cancer 2012; 118: 4877). Over 48 hours in short term culture, optical techniques based on Mie light scattering measured apoptosis in control wells and test wells containing different chemotherapy drugs or combinations. Significant apoptosis gave results over 1.0 kinetic units (KU). Drugs or combinations producing the highest KU +/- 1 SD compared to other drugs were defined as best regimens. Differences of over 0.57 KU correlated with clinically significant better responses.

      Results
      15 specimens have been submitted with 9 successfully assayed to date. Mean numbers of drugs or combinations assayed successfully were 32 in mesothelioma and 20 in NSCLC. New treatment strategies in individual patients with mesothelioma were: epirubicin 5.0 and 9 KU, idarubicin 4.0 KU, pemetrexed+doxorubicin 4.9 and 4.6 KU, ifosfamide 3.4 and 2.2 KU, bendamustine 4.0 KU, dactinomycin 4.7 and 3.4 KU, vinorelbine 4.7 KU, asacytidine 3.8 KU, bortezomib 3.0 KU, doxorubicin 3.9 KU, cyclophosphamide+doxorubicin+vincristine 3.0 KU and cisplatin+irinotecan 3.1 KU. New treatment strategies in individual patients with NSCLC were: doxorubicin 2.0, 1.7 and 1.7 KU, epirubicin 1.6 KU, 5-fluorouracil+leucovorin 1.3 KU, and cyclophosphamide+doxorubicin+vincristine 2.3 KU. In class differences in drug activity were apparent in individual patients: cisplatin>carboplatin, epirubicin>doxorubicin, and docetaxel>paclitaxel. In one mesothelioma patient with paired specimens from malignant effusion and solid tumor the most active (pemetrexed+doxorubicin) and least active regimens (cisplatin+paclitaxel) were concordant. In mesothelioma, the most active chemotherapy regimens in individual patients were epirubicin, idarubicin, pemetrexed+doxorubicin, vinorelbine, cisplatin+etoposide, cisplatin+irinotecan, cyclophosphamide+doxorubicin+vincristine, and dactinomycin. In NSCLC, the most active regimens were doxorubicin, cisplatin, docetaxel, irinotecan, and cyclophosphamide+doxorubicin+vincristine.

      Conclusion
      Use of the MiCK assay in mesothelioma and NSCLC can identify unexpected new leads for innovative therapeutic strategies for individual patients, and for candidate enrollment in phase II and III studies. The MiCK assay may play a role in designing precision therapeutics for patients with mesothelioma and NSCLC. Marked differences between patients in individual drug activities, and discordant in-class drug effectiveness indicate the need for individualized patient tumor testing of drug-induced apoptosis. Since use of the MiCK assay has correlated with improved clinical outcomes in prior studies, clinical trials of drugs with unexpected activity may be warranted in mesothelioma and NSCLC patients.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-014 - A nomogram for predicting 5-year RFS in patients with pulmonary carcinoid tumors incorporating Ki-67 and clinical variables (ID 1567)

      09:30 - 09:30  |  Author(s): J. Molina

      • Abstract

      Background
      Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in cohort of 262 patients seen at Mayo Clinic, and subsequently developed a nomogram for predicting recurrence-free survival (RFS).

      Methods
      A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 448 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1 of 3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The associations of the factors with RFS were explored using multivariable Cox proportional Hazards models, including concordance (c) index. A nomogram was developed using the variables from the final multivariate model.

      Results
      Age, smoking history, lymph node (LN) involvement, tumor size, and Ki-67 index were significant prognostic factors for RFS from a multivariate model (Table 1). Median follow-up on alive-patients was 5.6 years (0.008-16.2). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P<0.0001), respectively. The multivariable model with Ki-67 index showed a c-index of 0.79 which was identical to a multivariable model with pathological diagnosis (c-index 0.79). The nomogram showing the probability of 5-year RFS estimates is shown in Figure 1. Figure 1

      Variables Adjusted by Ki-67 and Clinical Variables HR; 95% CI (P) Adjusted by Pathological Diagnosis and Clinical Variables HR; 95% CI (P)
      Ki-67 1.25; 1.11-1.41 (0.0016) --
      AC vs. TC -- 2.01; 1.05-3.88 (0.0436)
      Age 1.05; 1.03-1.08 (<0.0001) 1.06; 1.03-1.09 (<0.0001)
      Smoking Never Former Current (<0.0001) -- 3.11; 1.68-5.74 4.34; 1.94-9.74 (0.0003) -- 2.86; 1.56-5.24 3.74; 1.67-8.40
      Size of Tumor 1.42; 1.20-1.67 (0.0002) 1.33; 1.13-1.56 (0.0012)
      Metastatic LN Negative Positive (0.0007) -- 3.05; 1.66-5.59 (0.0068) -- 2.51; 1.33-4.76

      Conclusion
      Ki-67 index is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. The nomogram based on Ki-67 index, age, smoking history, LN involvement, and tumor size is a useful clinical tool for predicting the 5-year RFS rate. Updating this nomogram with additional clinical follow-up, as well as external validation of this nomogram is critical before routine clinical use.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-005 - Preliminary Results - "A Phase I Trial of Oncolytic Measles Virotherapy in Mesothelioma" Investigating the Intrapleural Administration of the Modified Vaccine Strain Measles Virus (MV-NIS) to Patients with Malignant Pleural Mesothelioma (ID 1922)

      09:30 - 09:30  |  Author(s): J. Molina

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) remains an almost universally fatal disease. Preclinical models indicate that the oncolytic modified vaccine strain measles virus (MV) carrying the gene for the human sodium-iodine symporter (NIS) - MV-NIS preferentially targets MPM tumors cell. In patients with refractory ovarian cancer the intraperitonial administration of MV-NIS was recently found to be safe and induced an anti-tumor immune response.

      Methods
      Phase I dose escalation study (3+3 design). MV-NIS is administered intrapleurally. Starting dose level was 10[8] TICID 50 (Level 1) and the current dose level is 3 x 10[8] TICID 50 (Level 2). In the absence of dose limiting toxicity and disease progression patients continue MV-NIS therapy for up to six 28-day cycles. MV-NIS infection and replication is monitored by Iodine[123] SPECT/CT and RT-PCR and anti-tumor and anti-viral immunity are monitored in correlative studies. Patients are followed clinically using modified RECIST criteria.

      Results
      Up to now 4 patients have received MV-NIS therapy. Three patients were treated at Level 1 and the fourth patient at Level 2. No dose limiting adverse events occurred. The best therapeutic response was stable disease, observed in patient #1 for 6 months and patient #2 for 2 months. The remaining two patients progressed radiologically after one treatment cycle. I[123] SPECT-CT imaging did not demonstrate changes in iodine uptake compared to baseline in any of these patients. However, we detected MV RNA by QRT-PCR within the pleural cells 24-48 hours after the intrapleural administration of MV-NIS in 3/4 patients. In patient #4, treated with 3x10[8] TCID 50, MV replication was detectable within the pleural space by plaque assay 24 hours after MV-NIS administration. Following MV-NIS therapy a profound influx of neutrophils into the pleural space occurred in 3/4 patients and pleural fluid cytokine concentrations changed significantly. In addition, a humoral anti-tumor immune response emerged in patients #2.

      Patient # Age Disease Stage Histology Line therapy
      1 75 II (T2N0M0) Epitheloid First
      2 53 IV (T4N0M0) Epitheloid Second
      3 84 IV (T4N0M0) Epitheloid First
      4 73 IV (T2N3M0) Mixed First

      Conclusion
      Thus far the intrapleural administration of MV-NIS appears to be safe and well tolerated in MPM. Our study will continue to enroll patients.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-018 - Outcomes of lung adenocarcinoma patients with signet ring cell tumors: a three-way evaluation (ID 2884)

      09:30 - 09:30  |  Author(s): J. Molina

      • Abstract

      Background
      Pathologically, signet ring cells (SRC) describe singly dispersed tumor cells with intracytoplasmic mucin vacuoles, which eccentrically displace and compress the nucleus. SRCs are traditionally associated with adenocarcinoma of the gastrointestinal tract and are rare in lung adenocarcinoma (LACA). Patients with primary LACA with SRC features (SRC+) have been associated with poor clinical outcome and ALK gene rearrangement (ALK+). However, the impact of SRC+ on clinical outcome is not well delineated. We systematically studied LACA survival outcomes for the impact of SRC status.

      Methods
      Three distinct groups of surgically treated patients with LACA (n=763) that were followed for ≥5 years were reviewed: never smokers (n=266), 2006-2007 cohort (n=222), and smokers enriched for various degrees of lepidic growth pattern (LGP, n=275). Two pulmonary pathologists reviewed all cases; SRC+ tumors were defined as having >10% SRCs, agreed by both pathologists. SRC+ tumors were TTF1+, and generally cytoplasmic mucin+ and CDX2-. ALK immunostain was performed on all SRC+ cases, and ALK status was confirmed by FISH for cases with any degree of immunoreactivity. Impact of SRC+ on patients’ survival outcomes (overall and disease-free, OS and DFS) were analyzed using Cox models (by hazard ratio, HR) separately for the three groups, with careful evaluation of known prognostic factors: age at diagnosis; gender; smoking status; lung cancer history; tumor subtype; grade and stage; and treatment (surgery, chemotherapy and/or radiation).

      Results
      In the total of 763 patients (61% women, mean age at diagnosis 68 years), 53 (7%) were SRC+. In never smokers (73% women), 9% were SRC+; 33% of the SRC+ were ALK+ vs. 5% among the SRC- cases (p<0.0001). In the 2006-2007 cohort (55% women), 9% were SRC+; in LGP-smokers (54% women), 3% were SRC+. Across all three groups, SRC+ tumors were more likely to occur in men and have higher stage. Univariate analysis showed SRC+ never smokers had shorter survival: median DFS was 2.4 years (vs. 5.2 in SRC- never smokers, p=0.0004), and median OS was 3.7 years (vs. 7.6, p=0.0064). However, multivariate analysis did not confirm a significant impact of SRC+ on survival. In contrast, for the other two groups, crude 5-year survival was 6%-27% decreased in SRC+ cases compared to SRC- cases (none reached statistical significance); however, multivariate analysis revealed a 2-fold higher mortality (HR=2.30, 95% CI=1.01-5.27, p=0.048) for smokers with SRC+ tumors.

      Conclusion
      Based on results from three patient groups, we confirmed that SRC+ is significantly associated with ALK+. Worse survival in patients with SRC+ tumors was observed in never smokers by univariate analysis. A potential negative impact of SRC+ tumors on OS in LGP-smokers was only uncovered after adjusting for known prognostic factors. These results need to be furthered confirmed.