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Jackman, David M

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Jackman

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David M

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Jackman, David M
Author's Publications: search.filters.isAuthorOfPublication.cc482cf6-fc17-498c-9555-91b36e34d872

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    Tumoral cavitation in patients with non-small-cell lung cancer treated with antiangiogenic therapy using bevacizumab
    (E-MED LTD, 2012) Nishinoa, Mizuki; Cryer, Sarah K.; Okajim, Yuka; Sholl, Lynette; Hatabu, Hiroto; Rabin, Michael; Jackman, David M; Johnson, Bruce
    Rationale and objectives: To investigate the frequency and radiographic patterns of tumoral cavitation in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab, and correlate the imaging findings with the pathology, clinical characteristics and outcome. Materials and methods: Seventy-two patients with NSCLC treated with bevacizumab therapy were identified retrospectively. Baseline and follow-up chest computed tomography scan were reviewed to identify tumoral cavitation and subsequent filling in of cavitation. Radiographic cavitation patterns were classified into 3 groups. The clinical and outcome data were correlated with cavity formation and patterns. Results: Out of 72 patients, 14 patients developed cavitation after the initiation of bevacizumab therapy (19%; median time to event, 1.5 months; range 1.0–24.8 months). Three radiographic patterns of tumoral cavitation were noted: (1) development of cavity within the dominant lung tumor (n = 8); (2) development of non-dominant cavitary nodules (n = 3); and (3) development of non-dominant cavitary nodules with adjacent interstitial abnormalities (n = 3). Eleven patients (79%) demonstrated subsequent filling in of cavitation (the time from the cavity formation to filling in; median 3.7 months; range 1.9–22.7 months). No significant difference was observed in the clinical characteristics, including smoking history, or in the survival between patients who developed cavitation and those who did not. Smoking history demonstrated a significant difference across 3 radiographic cavitation patterns (P = 0.006). Hemoptysis was noted in 1 patient with cavity formation and 4 patients without, with no significant difference between the 2 groups. Conclusion: Tumoral cavitation occurred in 19% in patients with NSCLC treated with bevacizumab and demonstrated 3 radiographic patterns. Subsequent filling in of cavitation was noted in the majority of cases.
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    EGFRMutation Is a Better Predictor of Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Carcinoma Than FISH, CISH, and Immunohistochemistry
    (Oxford University Press (OUP), 2010) Sholl, Lynette; Xiao, Yun; Joshi, Victoria; Yeap, Beow; Cioffredi, Leigh-Anne; Jackman, David M; Lee, Charles; Janne, Pasi; Lindeman, Neal
    About 10% of patients with non–small cell lung carcinoma (NSCLC) respond to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs). More than 75% of “responders” have activating mutations in EGFR. However, mutation analysis is not widely available, and proposed alternatives (in situ hybridization and immunohistochemical analysis) have shown inconsistent associations with outcome. Fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), immunohistochemical analysis, and DNA sequencing were compared in this study of 40 NSCLC samples from TKI-treated patients. Response rates were 12 of 19 in EGFR-mutant vs 1 of 20 EGFR wild-type tumors (P = .0001), 7 of 19 FISH+ vs 4 of 17 FISH– tumors (not significant [NS]), 5 of 16 CISH+ vs 6 of 21 CISH– tumors (NS), and 3 of 9 immunohistochemically positive vs 7 of 22 immunohistochemically negative tumors (NS). EGFR mutation was associated with improved progression-free survival (P = .0004). Increased copy number (FISH or CISH) and protein expression (immunohistochemical) did not independently predict outcome. Thus, EGFR sequence analysis was the only method useful for predicting response and progression-free survival following TKI therapy in NSCLC.
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    Advanced nodal stage predicts venous thromboembolism in patients with locally advanced non-small cell lung cancer
    (Elsevier BV, 2016) Li, Richard Jay; Hermann, Gretchen; Baldini, Elizabeth; Chen, Aileen; Jackman, David M; Kozono, David; Nguyen, Paul; Nohria, Anju; Powell, Graham; Mak, Raymond
    Objectives: Patients with non-small cell lung cancer (NSCLC) are known to be at high risk for venous thromboembolism (VTE), but previous studies have not specifically analyzed locally advanced disease. We performed a retrospective VTE risk analysis in a cohort of locally advanced NSCLC treated with definitive intent including radiation therapy. Materials and Methods: The cohort consisted of 629 patients with stage II-III NSCLC treated at a single institution from January 2003 to December 2012. All patients received treatment with curative intent, including radiation therapy. Fine and Gray’s competing-risks regression model, accounting for death and distant metastasis as competing risks, was used to identify significant predictors of VTE risk, and cumulative incidence estimates were generated using the competing-risks model. Results and Conclusion: At a median follow-up of 31 months, 127 patients developed a VTE, with 80% of events occurring in the first year after treatment initiation. 1-year and 3-year overall cumulative incidence estimates were 13.5% and 15.4%, respectively. On univariate analysis, stage IIIB and N3 nodal disease were associated with increased VTE risk. In the final multivariable model, N3 nodal disease was associated with increased VTE risk (Hazard ratio 1.64; 95% CI 1.06-2.54; p=0.027). In conclusion, patients with locally advanced NSCLC are at high risk for VTE, especially in the first year after treatment initiation, with a 1-year cumulative incidence of 13.5%. N3 nodal staging was associated with significantly higher VTE risk compared to N0-N2 staging.
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    Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival
    (Elsevier BV, 2014) Gray, Phillip; Mak, Raymond; Yeap, Beow; Cryer, Sarah K.; Pinnell, Nancy E.; Christianson, Laura W.; Sher, David J.; Arvold, Nils; Baldini, Elizabeth; Chen, Aileen; Kozono, David; Swanson, Scott; Jackman, David M; Alexander, Brian
    Objectives: Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation. Materials and Methods: We retrospectively analyzed NSCLC patients with 1-4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain. Results: Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p=0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p<0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p=0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p=0.032) and initial combined modality brain therapy (HR 0.34, p=0.046). Conclusion: Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively.
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    Pathologic Characteristics of NUT Midline Carcinoma Arising in the Mediastinum
    (Ovid Technologies (Wolters Kluwer Health), 2012) Evans, Andrew G.; French, Christopher; Cameron, Michael J.; Fletcher, Christopher; Jackman, David M; Lathan, Christopher; Sholl, Lynette
    NUT midline carcinomas (NMC) comprise a group of highly aggressive tumors that have been reported primarily in the head, neck, and mediastinum of younger individuals. These tumors overexpress the nuclear protein in testis (NUT), most commonly due to a chromosomal translocation that fuses the NUT gene on chromosome 15 with the BRD4 gene on chromosome 19. Although the earliest recognized cases were described in the thymus or mediastinum, an extensive survey for NMC among malignant thymic or other mediastinal neoplasms has not been reported. We examined NUT expression in 114 cases of poorly differentiated carcinomas or unclassified mediastinal malignancies using a clinically validated NUT-specific monoclonal antibody. Four of 114 (3.5%) cases showed nuclear NUT expression. A NUT translocation was confirmed by fluorescence in situ hybridization (FISH) in 3 of these cases. These tumors arose in two male and two female adults with a median age of 50 (range 28 to 68). Three of the tumors were originally diagnosed as undifferentiated epithelioid or round cell malignant neoplasms; one tumor contained focal squamous differentiation and was originally diagnosed as a poorly differentiated squamous carcinoma of probable thymic origin. We find that the incidence of NMC within the mediastinum, particularly amongst undifferentiated tumors, is similar to that reported at other anatomic sites. NMC should be considered in the differential diagnosis of any poorly-differentiated epithelioid mediastinal tumor, regardless of age.
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    MET Exon 14 Mutations in Non–Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression
    (American Society of Clinical Oncology (ASCO), 2016) Awad, Mark; Oxnard, Geoffrey; Jackman, David M; Savukoski, Daniel O.; Hall, Dimity; Shivdasani, Priyanka; Heng, Jennifer C.; Dahlberg, Suzanne; Janne, Pasi; Verma, Suman; Christensen, James; Hammerman, Peter S.; Sholl, Lynette
    Purpose Non–small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. Patients and Methods We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. Results MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14–mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14–mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14–mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14–wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. Conclusion MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.