Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial.

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

CD117, BAP1, MTAP, and TdT Is a Useful Immunohistochemical Panel to Distinguish Thymoma from Thymic Carcinoma.

BACKGROUND: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. MATERIALS AND METHOD: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963-2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). RESULTS: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. CONCLUSION: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive.

Small-cell Lung Cancer in Very Elderly (≥ 80 Years) Patients.

BACKGROUND: This analysis was performed to describe the outcome of very elderly (≥ 80 years) patients with small-cell lung cancer (SCLC) as there is no published data regarding these patients. MATERIALS AND METHODS: One hundred forty-six very elderly patients with SCLC were identified from the Institutional Lung Cancer Database ranging in age from 80 to 92 years (median, 82 years). Of these, 47 (32%) patients had limited-stage SCLC (L-SCLC), and 99 (68%) had extensive-stage SCLC (E-SCLC). All were Caucasian, and the majority (64%) were female. Sixty-seven (46%) patients had Zubrod performance status (PS) of 0 to 1. RESULTS: Of the 146 patients, 44 (30%) received no therapy, 65 (45%) received chemotherapy alone, 27 (19%) received chemotherapy plus local therapy (thoracic radiotherapy [TRT] or surgery), and 10 (7%) received local therapy alone. The median survival was 5.4 months. On univariable analysis, age (P = .019), stage (L-SCLC vs. E-SCLC; P = .0002), PS (P < .0001), and treatment option (P < .0001) were associated with survival. On multivariable analysis, stage (P = .011), PS (P = .029), and treatment option (P < .0001) maintained significance. For entire cohort, the median survival was 1.3 months without active therapy, 6 months with local therapy alone, 7.2 months with chemotherapy alone, and 14.4 months with chemotherapy plus local therapy (P < .0001, univariable and multivariable). Similar survival findings in response to treatment were found when the L-SCLC and E-SCLC cohorts were separately analyzed. CONCLUSIONS: The survival of very elderly patients with SCLC was associated with stage (L-SCLC vs. E-SCLC), PS, and treatment option. Very elderly patients with SCLC often have limited functional reserve required to tolerate aggressive multimodality therapy but appeared to benefit from it. Geriatric assessments, careful monitoring, and extra support are warranted in elderly patients. Care should be individualized based on the desires and needs of each patient.

Efficacy of chest computed tomography prediction of the pathological TNM stage of thymic epithelial tumours.

OBJECTIVES: The aim of this study is to evaluate the efficacy of chest computed tomography (CT) to predict the pathological stage of thymic epithelial tumours (TET) using the recently introduced tumour, node and metastasis (TNM) staging with comparison to the modified Masaoka staging. METHODS: Preoperative chest CT examinations in cases of resected TET with sampled lymph nodes (2006-2016) were retrospectively reviewed by 2 thoracic radiologists and radiologically (r) staged using both staging systems. A thoracic pathologist reviewed all cases for the pathological (p) stage. Concordance between r-staging and p-staging was assessed by % agreement and unweighted kappa statistics. Associations between r-stage and p-stage with outcomes were assessed using the Cox proportional hazards regression. RESULTS: Sixty patients with TET were included (47 thymomas, 12 thymic carcinomas and 1 atypical carcinoid tumour). Sixteen patients (26.7%) had received neoadjuvant therapy. Fifty-four patients (90.0%) had complete resection. The overall agreement between the r-stage and p-stage was 66.7% (κ = 0.46) for TNM staging and 46.7% (κ = 0.30) for modified Masaoka staging. Agreement between r-assessment and p-assessment of the T, N and M components of the TNM stage was 61.7% (κ = 0.28), 86.7% (κ = 0.48) and 98.3% (κ = 0.88), respectively. CT overstaged 12 patients (20.0%) for TNM staging and 12 patients (20.0%) for modified Masaoka staging and understaged 8 (13.3%) and 20 (33.3%) patients for TNM staging modified Masaoka staging, respectively. The r-TNM staging accuracy was lower for patients with neoadjuvant therapy (50.0% with vs 72.7% without). During a median follow-up of 2.6 years (range 0.1-10.5 years), 12 patients had metastases and/or recurrence; 11 patients died (4 of disease). The r-TNM stage and modified Masaoka stage were associated with overall survival and progression-free survival (P < 0.001). CONCLUSIONS: Preoperative chest CT is able to accurately predict p-TNM stage in two-thirds of surgically resected TET, with an agreement between radiological staging and pathological staging superior to the modified Masaoka staging.

Extraskeletal Osteosarcoma: Outcomes and the Role of Chemotherapy.

OBJECTIVES: Extraskeletal osteosarcoma (EO) is a malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. Surgical resection is the mainstay of treatment; the role of chemotherapy is not well defined. Therefore, we evaluated the impact of chemotherapy in the survival of patients with EO. METHODS: All EO patients seen at Mayo Clinic between 1990 and 2014 were assessed. Forty-three patients were included after all archived pathology slides were reviewed to confirm the diagnosis of EO. RESULTS: Of 43 patients, 37 patients had localized disease and 6 patients had metastatic disease at diagnosis. Chemotherapy was used in 73% and 75% of patients, respectively. Chemotherapy was predominantly anthracycline based, and included platinum in 22 patients (84%).Median overall survival (OS) and progression-free survival (PFS) were 50 months (95% confidence interval, 25-99), and 21 months (95% confidence interval, 13-not reached), respectively. There was a trend towards longer OS and PFS in patients who received chemotherapy. Those who received platinum-based therapy had remarkably prolonged OS (median, 182 vs. 18 mo; 5-year, 61% vs. 0%; P=0.01) and PFS (median, not reached vs. 10 mo; 5-year, 56% vs. 0%; P=0.005). Baseline characteristics were similar in the platinum and nonplatinum group.In patients who received chemotherapy, relapse/recurrence rate was lower in the platinum-based group (41%) as opposed to the nonplatinum-based group (100%; P=0.02). In the neoadjuvant setting, the overall response rate of platinum-containing regimens was 27%. CONCLUSIONS: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of patients with EO. We plan to validate this further with an expanded multicenter analysis.

Management of Multifocal Lung Cancer: Results of a Survey.

INTRODUCTION: Multifocal lung cancer is an increasingly common clinical scenario, but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary International Association for the Study of Lung Cancer on their therapeutic approaches and analyzed the resultant practice patterns. METHODS: We described the clinical scenario of an otherwise healthy 60-year-old man with bilateral pulmonary nodules and asked the 6373 members of the International Association for the Study of Lung Cancer whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging and whether radiation therapy or chemotherapy would be suggested. RESULTS: We received 221 responses (response rate 3.5%) from multiple specialists. Most respondents (140 [63%]) recommended surgery for this scenario. Surgeons were significantly more likely to recommend surgery than were those in other specialties. Of those who recommended surgery, most would obtain a PET/CT scan to rule out distant metastases and a magnetic resonance imaging scan to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy before resection. When surgery was not recommended or declined, respondents commonly recommended radiation. CONCLUSIONS: This survey suggests that therapeutic recommendations for multifocal lung cancer are influenced to a large extent by physicians' specialty training, probably because of the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity.

Radiologic Response to Neoadjuvant Treatment Predicts Histologic Response in Thymic Epithelial Tumors.

INTRODUCTION: Neoadjuvant treatment might increase resectability of thymic epithelial tumors (TETs). No standardized pathologic grading scheme for tumor response is available. Also, it is unclear whether radiologic treatment response can predict pathologic response. METHODS: Patients with unresectable TETs who underwent neoadjuvant treatment before surgery at Mayo Clinic Rochester (1942-2014) were included. The pathologic tumor response grade (TRG) was based on Mandard grading (1994), ranging from TRG 1 (no viable tumor) to TRG 5 (no regression). TRG was compared with response by computed tomography, including with the Response Evaluation Criteria in Solid Tumors, version 1.1 (Byrne modification). RESULTS: A total of 49 patients, including 29 men, with a median age of 47.6 years and thymomas (n = 28) or thymic carcinomas (n = 21) were included. In five cases, pretreatment tumor type differed from posttreatment diagnosis. Thymic carcinomas had a greater morphologic response to neoadjuvant treatment than did thymomas with a lower percent viable tumor (p < 0.0001) and lower TRG (p<0.0001). Agreement for TRG by three reviewers was good (Krippendorff α = 0.838). By imaging (n = 24), partial response and larger reduction in tumor longest diameter and volume were associated with lower TRG (p = 0.0093, p = 0.0042, and p = 0.0021, respectively) and lower percent viable tumor (p = 0.0041, p = 0.0034, and p =0.0019). TRG correlated with radiologic change in tumor longest diameter and volume (Spearman correlation coefficient = 0.59 and 0.61, respectively). Radiologic change in tumor longest diameter and volume reasonably predicted pathologic TRG of 3 to 5 versus 1 or 2 (area under the curve 0.73 and 0.71, respectively). Sixty-seven percent of patients' tumors were completely resected. CONCLUSIONS: Our proposed histologic TRG for TETs appears easy and reproducible and correlates with radiologic response. Radiologic response is useful to predict pathologic response.

Risk factors for incident venous thromboembolism in active cancer patients: A population based case-control study.

BACKGROUND: Independent risk factors for cancer-associated incident venous thromboembolism (VTE) and their magnitude of risk are not fully characterized. AIM: To identify non-cancer and cancer-specific risk factors for cancer-associated incident VTE. METHODS: In a population-based retrospective case-control study, we used Rochester Epidemiology Project and Mayo Clinic Cancer Registry resources to identify all Olmsted County, MN residents with active cancer-associated incident VTE, 1973-2000 (cases; n=570) and 1-3 residents with active cancer matched to each case on age, sex, date and duration of active cancer (controls; n=604). Using conditional logistic regression, we tested cancer and non-cancer characteristics for an association with VTE, including a cancer site VTE risk score. RESULTS: In the multivariable model, higher cancer site VTE risk score (OR=1.4 per 2-fold increase), cancer stage≥2 (OR=2.2), liver metastasis (OR=2.7), chemotherapy (OR=1.8) and progesterone use (OR=2.1) were independently associated with VTE, as were BMI<18.5kg/m(2) (OR=1.9) or ≥35kg/m(2) (OR=4.0), hospitalization (OR=7.9), nursing home confinement (OR=4.7), central venous (CV) catheter (OR=8.5) and any recent infection (OR=1.7). In a subgroup analysis, platelet count≥350×10(9)/L at time of cancer diagnosis was marginally associated with VTE (OR=2.3, p=0.07). CONCLUSION: Cancer site, cancer stage≥2, liver metastasis, chemotherapy, progesterone, being underweight or obese, hospitalization/nursing home confinement, CV catheter, and infection are independent risk factors for incident VTE in active cancer patients.

Histopathologic and Cytogenetic Features of Pulmonary Adenoid Cystic Carcinoma.

INTRODUCTION: A significant portion of adenoid cystic carcinoma (ACC) cases are characterized by a t(6;9)(q22-23;p23-24) translocation that originates a MYB-NFIB fusion oncogene. The MYB-NFIB fusion oncoprotein activates transcription of MYB-mediated pathways that impact cell cycle control, DNA repair, and apoptosis. This translocation seems highly specific for ACC. Moreover, therapies targeting MYB-activated pathways to treat ACC are being explored. Pulmonary ACC (PACC) has not been thoroughly studied for rearrangements of the MYB gene. METHODS: Mayo Clinic Rochester surgical pathology archives (1972-2011) were searched for PACC. All cases were reviewed and classified according to the predominant histologic pattern (cribriform, solid, and tubular) by two surgical pathologists. Fluorescence in situ hybridization (FISH) was employed using a break-apart strategy to detect MYB rearrangement (at 6q23.3). Medical records were studied. RESULTS: Forty cases of PACC were studied; tissue blocks were available for FISH analysis in 35 cases. Six cases failed to hybridize. In 12 of 29 cases (41%), the MYB gene region was disrupted, whereas 17 cases (59%) showed no evidence of rearrangement. FISH studies performed on other histologic subtypes of lung cancer (10 squamous cell carcinomas, 10 adenocarcinomas, and 10 small-cell carcinomas) failed to show MYB rearrangement. There was no significant difference in MYB rearrangement status with respect to predominant histologic pattern, clinical features, or clinical outcome. CONCLUSIONS: A MYB rearrangement was identified in 41% of PACC and was 100% specific. FISH studies for MYB may be of diagnostic utility in PACC, particularly on small biopsy specimens. MYB rearrangement in PACC does not seem to be associated with clinical features or prognosis.

Reproducibility of 3 histologic classifications and 3 staging systems for thymic epithelial neoplasms and its effect on prognosis.

Data regarding the prognostic significance of the histopathologic classifications of thymic epithelial neoplasms are contradictory, perhaps reflecting issues in reproducibility. We studied the effect of reproducibility of 3 histopathologic classifications on prognosis and investigated the interobserver agreement on invasion and its effect on staging and prognosis. A total of 456 patients who underwent surgery for thymic epithelial neoplasm at Mayo Clinic Rochester (1942 to 2008) were staged (modified Masaoka, proposed Moran, proposed IASLC/ITMIG) and independently classified by 3 thoracic pathologists (World Health Organization, proposed Suster & Moran [S&M], and Bernatz). Interobserver agreement was moderate to substantial for all histopathologic classifications (κ values: 0.65, 0.52, 0.74 for World Health Organization, Bernatz, and S&M, respectively). All histopathologic classifications were significant for overall survival (OS) and disease-free survival (DFS) (all reviewers). If adjusted for Masaoka, only Bernatz classification for one reviewer and all histopathologic classifications for another reviewer were significant for OS. Interobserver agreement for invasion was substantial (κ=0.61) and almost perfect for Masaoka, Moran, and IASLC/ITMIG stage (κ values: 0.85, 0.81, and 0.92, respectively). The correlation coefficient for Masaoka and Moran staging was 0.93. Masaoka and IASLC/ITMIG staging were significant for OS and DFS (all reviewers). If adjusted for any histopathologic classification, Masaoka was significant for OS and DFS (all reviewers). In conclusion, reproducibility of histopathologic classifications has some effect on outcome. S&M is the most reproducible classification. Reproducibility of invasion has no effect on the prognostic value of staging. Masaoka, Moran, and IASLC/ITMIG staging are almost perfectly reproducible. The strong correlation between Masaoka and Moran staging suggests similar prognostic strength.

Modified Masaoka stage and size are independent prognostic predictors in thymoma and modified Masaoka stage is superior to histopathologic classifications.

INTRODUCTION: The prognostic value of histopathologic classifications of thymoma is debated. Problematic reproducibility might cause this controversy. We studied the prognostic significance of three histopathologic classifications of thymomas after three thoracic pathologists agreed upon thymoma subtype and invasion. We also compared the outcome to established prognostic parameters. METHODS: Patients, surgically treated for thymic epithelial neoplasm at Mayo Clinic (1942-2008), were staged according to the modified Masaoka staging and the recently proposed staging by Moran. Three thoracic pathologists independently classified all cases according to the World Health Organization, Bernatz, and proposed Suster and Moran classification. Only thymoma that all three pathologists diagnosed as the same histopathologic subtype and extent of invasion were included in outcome analysis. RESULTS: In 214 (proposed Suster and Moran classification), 145 (World Health Organization classification), and 120 cases (Bernatz classification), reviewers agreed upon subtype of thymoma and invasion and follow-up was available. Median follow-up time was 7.5-7.7 years (range between classifications). All histopathologic classifications were associated with overall survival (OS) and disease-free survival (p ≤ 0.0001 to p = 0.048); only Bernatz classification was independent of modified Masaoka staging associated with OS (p = 0.04). Modified Masaoka stage predicted outcome independent of all histopathologic classifications and resection status and strongly correlated with the proposed Moran stage (correlation coefficient, 0.95). Thymoma size and age were prognostic parameters for OS independent of any histopathologic classification. CONCLUSIONS: Histopathologic classifications of thymomas are associated with prognosis but are in general not independent predictors of outcome. Modified Masaoka stage and proposed Moran staging are independent prognostic parameters for thymoma and superior to histopathologic classifications.

Risk of site-specific cancer in incident venous thromboembolism: a population-based study.

BACKGROUND: The risk of venous thromboembolism (VTE) by cancer site is uncertain. OBJECTIVE: To estimate VTE risk by tumor site. METHODS: We enumerated observed active cancers by cancer site for Olmsted County, MN residents with incident VTE over the 13-year period, 1988-2000 (n = 345 of 1417). We used 1988-2000 Iowa State Surveillance, Epidemiology, and End Results (SEER) data to estimate the expected age-specific prevalence of cancer by cancer site for all VTE cases; standardized Morbidity Ratios (SMR) for each cancer site were estimated by dividing the observed number of cancers in the VTE incident cohort by the expected number. Relative risk regression was used to model the observed number of cancers of each site, adjusting for the expected value based on SEER prevalence data, using generalized linear regression with a Poisson error and the natural log of the age- and sex-group expected count as an offset. RESULTS: For men and women with VTE, all cancer sites had an increased SMR, ranging from 4.1 for head neck cancer to 47.3 for brain cancer. Among women, the SMR for breast, ovarian and other gynecologic cancers were 8.4, 13.0 and 8.4, respectively; for men, prostate cancer SMR was 7.9. Adjusting for age and sex, the relative risk (RR) of cancer in VTE cases was associated with cancer site in a multivariable model (p < 0.001). Adjusting for age and sex, pancreatic, brain, other digestive cancers, and lymphoma had significantly higher RRs than the grouped comparison cancers. CONCLUSIONS: Incident VTE risk can be stratified by cancer site.

Diagnostic significance of cell kinetic parameters in World Health Organization type A and B3 thymomas and thymic carcinomas.

The prognostic importance of histologic classifications of thymic epithelial neoplasms is controversial. Evidence suggests that difficulties in reproducibility affect prognostic studies. Two thoracic pathologists independently classified 80 cases of type A or B3 thymoma and thymic carcinoma according to World Health Organization (WHO) classification. Ki-67 labeling index (LI) was used to identify cutoff points between WHO types. Recursive partitioning (Rpart) and ad hoc methods separated the data points. The pathologists agreed on type A (n = 31), type B3 (n = 21), and thymic carcinoma (n = 14). Ki-67 LI differed between types A and B3 (P < .001) and between thymic carcinoma and type A (P < .001) or type B3 (P = .001). Mitotic activity differed between thymic carcinoma and type A (P < .001) or type B3 (P < .001). Rpart revealed Ki-67 LI greater than 14.0% only in thymic carcinoma; cases with Ki-67 LI less than 5.1% did not represent thymic carcinoma. Ad hoc analysis showed Ki-67 LI greater than or equal to 13.5% represents thymic carcinoma; only type A had Ki-67 LI less than 2%. The pathologists disagreed on histologic type in 14 cases. In 11 of 14 cases with available Ki-67, the Rpart method predicted the WHO type; in 7 of 14 cases, the ad hoc method predicted the WHO type. In conclusion, Ki-67 LI is helpful in differentiating thymic epithelial neoplasms, with Ki-67 LI less than 2% and greater than or equal to 13.5% distinguishing type A thymoma and thymic carcinoma, respectively.

Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study.

Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer-related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk.

Calibration of quality-adjusted life years for oncology clinical trials.

CONTEXT: Quality-adjusted life year (QALY) estimation is a well-known but little used technique to compare survival adjusted for complications. Lack of calibration and interpretation guidance hinders implementation of QALY analyses. OBJECTIVES: We conducted simulation studies to assess the impact of differences in survival, toxicity rates, and utility values on QALY results. METHODS: Survival comparisons used both log-rank and Wilcoxon testing. We examined power considerations for a North Central Cancer Treatment Group Phase III lung cancer clinical trial (89-20-52). RESULTS: Sample sizes of 100 events per treatment have low power to generate a statistically significant difference in QALYs unless the toxicity rate is 44% higher in one arm. For sample sizes of 200 per arm and equal survival times, toxicity needs to be at least 38% more in one arm for the result to be statistically significant, using a utility of 0.3 for days with toxicity. Sample sizes of 300 (500)/arm provide 80% power if there is a 31% (25%) toxicity difference. If the overall survival hazard ratio between the two treatment arms is 1.25, then samples of at least 150 patients and 13% increased toxicity are necessary to have 80% power to detect QALY differences. In study 89-20-52, there was only 56% power to determine the statistical significance of the observed QALY differences, clarifying the enigmatic conclusion of no statistically significant difference in QALY despite an observed 14.5% increase in toxicity between treatments. CONCLUSION: This calibration allows researchers to interpret the clinical significance of QALY analyses and facilitates QALY inclusion in clinical trials through improved study design.

Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.

To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung carcinoma (NSCLC), we conducted a consistency meta-analysis study using genome-wide association approaches for overall survival in 327 never smoker patients with NSCLC from The University of Texas MD Anderson Cancer Center (Houston, TX) and 293 cases from the Mayo Clinic (Rochester, MN). We then conducted a two-pronged validation of the top 25 variants that included additional validation in 1,256 patients with NSCLC from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a P value of 10(-6). Two variants of these 25 were also significant in the Taiwanese population: rs6901416 [HR, 1.44; 95% confidence interval (CI), 1.01-2.06] and rs10766739 (HR, 1.23; 95%CI, 1.00-1.51). These loci resulted in a reduction of median survival time of at least eight and five months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung tissue. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biologic mechanism for a subset of these observed associations.

NUT midline carcinoma: an aggressive intrathoracic neoplasm.

Nuclear protein in testis (NUT) midline carcinoma (NMC) is a poorly differentiated squamous cell carcinoma that is characterized by a balanced translocation between chromosomes 15 and 19 [t(15;19)(q14;p13.1)]. This genetic aberration results in the fusion of the NUT gene on chromosome 15 to the bromodomain containing 4 (BRD4) gene on chromosome 19. The resultant BRD4-NUT fusion oncogene leads to global hypoacetylation and transcriptional repression of genes required for differentiation." Although it was first reported in 1991 by Kubonishi et al., awareness of this condition remains low and the diagnosis is overlooked initially in a number of patients. A 36-year-old man complained of cough and right-sided chest pain for 3 weeks before presentation. Imaging studies revealed a right hilar mass, and a bronchoscopic biopsy was consistent with an aggressive poorly differentiated neoplasm. A combination of cisplatin, ifosfamide, and etoposide was administered for two cycles without any improvement. A repeat core biopsy showed focal squamous differentiation; and given the clinical presentation along with the histologic features, NMC was considered in the differential diagnosis. Immunohistochemical staining for NUT was positive, and dual-color break-apart fluorescence in situ hybridization demonstrated BRD4-NUT rearrangement, thereby confirming a diagnosis of NMC. Our patient was subsequently enrolled on a phase 1 clinical trial of a novel, orally bioavailable bromodomain and extra terminal inhibitor, GSK525762 (NCT01587703). This report illustrates the challenges in diagnosing this rare malignancy, and highlights new treatment options for these patients.