Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression.

Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive non-Hodgkin's lymphoma, predominantly affecting young patients. We analyzed 45 primary PMBCL tumor biopsies and 3 PMBCL-derived cell lines for the presence of genetic alterations involving the major histocompatibility complex (MHC) class II transactivator CIITA and found frequent aberrations consisting of structural genomic rearrangements, missense, nonsense, and frame-shift mutations (53% of primary tumor biopsies and all cell lines). We also detected intron 1 mutations in 47% of the cases, and detailed sequence analysis strongly suggests AID-mediated aberrant somatic hypermutation as the mutational mechanism. Furthermore, we demonstrate that genomic lesions in CIITA result in decreased protein expression and reduction of MHC class II surface expression, creating an immune privilege phenotype in PMBCL. In summary, we establish CIITA alterations as a common mechanism of immune escape through reduction of MHC class II expression in PMBCL, with potential implications for future treatments targeting microenvironment-related biology.

Maintenance chemotherapy in advanced NSCLC: a population-based assessment of eligibility.

BACKGROUND: Maintenance chemotherapy has been incorporated into treatment paradigms for advanced NSCLC. Eligibility criteria include stable disease/partial response and PS 0-1 after a first line platinum doublet. In practice, maintenance can be difficult to deliver due to patient factors and preferences. We propose to examine the proportion of patients eligible for maintenance and factors associated with the delivery of subsequent lines of chemotherapy. METHODS: The BC Cancer Agency provides care to a population of 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in 2009 who received first line systemic therapy. Baseline characteristics, PS and response after first line and subsequent systemic therapy details were recorded. Patients were deemed potentially maintenance eligible or not based on clinical trial criteria; however maintenance therapy was not delivered to these patients as it was not yet available. RESULTS: 330 patients were identified; 98 were potentially maintenance eligible. The reason for maintenance ineligibility in n = 232; no upfront doublet (n = 41), PS ≥ 2 (n = 38), progressive disease (PD) (n = 53), PS ≥ 2 and PD (n = 62), PS ≥ 2 and unknown response (n = 35), PD and unknown PS (n = 3). Further chemotherapy (2nd line or beyond) was administered in maintenance eligible 68% vs ineligible 56%. Reasons for no further chemotherapy were predominantly decline in PS and brain metastasis. Median OS: 7 m for 1st line only versus 16.8m for ≥ 2 nd line (p < 0.001). CONCLUSIONS: In our population based study, 30% of advanced NSCLC patients were eligible to receive maintenance chemotherapy based on the clinical trial criteria. Despite a good initial PS and disease control only 68% of maintenance eligible patients received subsequent therapy. A clear survival benefit was seen with ≥ 2 nd line treatment. Maintenance therapy or initiation of early second line therapy should be considered for advanced NSCLC patients to improve survival outcomes.

Referral patterns in advanced non-small cell lung cancer: impact on delivery of treatment and survival in a contemporary population based cohort.

INTRODUCTION: Chemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes. METHODS: All referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan-Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment. RESULTS: 1373 patients were identified. Median age 70 years, 53% male, 37% ECOG ≥ 3. HISTOLOGY: 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0-2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p<0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59-0.78). CONCLUSIONS: In this population-based setting, 37% of patients had an ECOG ≥ 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated.