Assessing invasiveness of subsolid lung adenocarcinomas with combined attenuation and geometric feature models

The aim of this study was to develop and test multiclass predictive models for assessing the invasiveness of individual lung adenocarcinomas presenting as subsolid nodules on computed tomography (CT). 227 lung adenocarcinomas were included: 31 atypical adenomatous hyperplasia and adenocarcinomas in situ (class H1), 64 minimally invasive adenocarcinomas (class H2) and 132 invasive adenocarcinomas (class H3). Nodules were segmented, and geometric and CT attenuation features including functional principal component analysis features (FPC1 and FPC2) were extracted. After a feature selection step, two predictive models were built with ordinal regression: Model 1 based on volume (log) (logarithm of the nodule volume) and FPC1, and Model 2 based on volume (log) and Q.875 (CT attenuation value at the 87.5% percentile). Using the 200-repeats Monte-Carlo cross-validation method, these models provided a multiclass classification of invasiveness with discriminative power AUCs of 0.83 to 0.87 and predicted the class probabilities with less than a 10% average error. The predictive modelling approach adopted in this paper provides a detailed insight on how the value of the main predictors contribute to the probability of nodule invasiveness and underlines the role of nodule CT attenuation features in the nodule invasiveness classification

Software-based risk stratification of pulmonary adenocarcinomas manifesting as pure ground glass nodules on computed tomography

Objectives: To assess the performance of the “Computer-Aided Nodule Assessment and Risk Yield” (CANARY) software in the differentiation and risk assessment of histological subtypes of lung adenocarcinomas manifesting as pure ground glass nodules on computed tomography (CT). Methods: 64 surgically resected and histologically proven adenocarcinomas manifesting as pure ground-glass nodules on CT were assessed using CANARY software, which classifies voxel-densities into three risk components (low, intermediate, and high risk). Differences in risk components between histological adenocarcinoma subtypes were analysed. To determine the optimal threshold reflecting the presence of an invasive focus, sensitivity, specificity, negative predictive value, and positive predictive value were calculated. Results: 28/64 (44%) were adenocarcinomas in situ (AIS); 26/64 (41%) were minimally invasive adenocarcinomas (MIA); and 10/64 (16%) were invasive ACs (IAC). The software showed significant differences in risk components between histological subtypes (P<0.001–0.003). A relative volume of 45% or less of low-risk components was associated with histological invasiveness (specificity 100%, positive predictive value 100%). Conclusions: CANARY-based risk assessment of ACs manifesting as pure ground glass nodules on CT allows the differentiation of their histological subtypes. A threshold of 45% of low-risk components reflects invasiveness in these groups. Key points • CANARY-based risk assessment allows the differentiation of their histological subtypes. • 45% or less of low-risk component reflects histological invasiveness. • CANARY has potential role in suspected adenocarcinomas manifesting as pure ground-glass nodules. Electronic supplementary material The online version of this article (doi:10.1007/s00330-017-4937-2) contains supplementary material, which is available to authorized users

Utilization of ancillary studies in the cytologic diagnosis of respiratory lesions: The papanicolaou society of cytopathology consensus recommendations for respiratory cytology

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134863/1/dc23549.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134863/2/dc23549_am.pd

Rapidly fatal advanced EGFR -mutated lung cancers and the need for rapid tumor genotyping in clinical practice

Use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is associated with dramatic, durable, and tolerable responses and side effect profiles, respectively, when applied for palliation of advanced EGFR-mutated non-small-cell lung cancers (NSCLCs). Expert guidelines recommend that EGFR mutation testing results should be available within 10 working days of receipt of tumor specimen by the testing laboratory; in circumstances where the tumor specimen needs to be sent to an external laboratory for testing, the sample should be sent within 3 working days of receiving the request for testing. We report here 2 cases, out of 109 EGFR-mutated (exon 19 deletion or L858R) NSCLCs seen at our institution, experiencing rapid clinical deterioration and death within the window of time prescribed by consensus testing guidelines. We hypothesize that a faster turn-around time may have changed the clinical outcome. Improving rapid turnaround times for tumor genotyping may afford more optimal palliation vis-à-vis early initiation of oral targeted therapy in patients with advanced EGFR-mutated NSCLC

Offspring Production among the Extended Relatives of Samoan Men and Fa'afafine

Androphilia refers to sexual attraction to adult males, whereas gynephilia refers to sexual attraction to adult females. Male androphilia is an evolutionary paradox. Its development is at least partially influenced by genetic factors, yet male androphiles exhibit lower reproductive output, thus raising the question of how genetic factors underlying its development persist. The sexual antagonism hypothesis posits that the fitness costs associated with genetic factors underlying male androphilia are offset because these same factors lead to elevated reproduction on the part of the female relatives of androphilic males. Western samples drawn from low fertility populations have yielded inconsistent results when testing this hypothesis. Some studies documented elevated reproduction among the matrilineal female kin of androphilic males, whereas others found such effects in the paternal line. Samoa is a high-fertility population in which individuals reproduce closer to their maximum capacities. This study compared the reproductive output of the paternal and maternal line grandmothers, aunts, and uncles of 86 Samoan androphilic males, known locally as fa'afafine, and 86 Samoan gynephilic males. Reproductive output was elevated in the paternal and maternal line grandmothers, but not aunts or uncles, of fa'afafine. These findings are consistent with the sexual antagonism hypothesis and suggest that male androphilia is associated with elevated reproduction among extended relatives in both the maternal and paternal line. Discussion focuses on how this study, in conjunction with the broader literature, informs various models for the evolution of male androphilia via elevated reproduction on the part of female kin

Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer

Introduction—Identification of some somatic molecular alterations in non-small-cell lung cancer (NSCLC) has become evidence-based practice. The success and failure rate of using commercially-available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation, and ALK FISH in a cohort of lung cancers subjected to routine clinical tumor genotype. Methods—Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples. Results—From these 381 patients with lung cancer, the mean age was 65 years, 61.2% were women, 75.9% were white, 27.8% were never smokers, 73.8% had advanced NSCLC and 86.1% had adenocarcinoma histology. The tumor tissue was obtained from surgical specimens in 48.8%, core needle biopsies in 17.9%, and as cell blocks from aspirates or fluid in 33.3% of cases. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. The overall success rate for EGFR mutation analysis was 94.2%, for KRAS mutation 91.6% and for ALK FISH 91.6%. The highest failure rates were observed when the tissue was obtained from image-guided percutaneous transthoracic core-needle biopsies (31.8%, 27.3%, and 35.3% for EGFR, KRAS, and ALK tests, respectively) and bone specimens (23.1%, 15.4%, and 23.1%, respectively). In specimens obtained from bone, the failure rates were significantly higher for biopsies than resection specimens (40% vs 0%, p=0.024 for EGFR) and for decalcified compared to non-decalcified samples (60% vs 5.5%, p=0.021 for EGFR). Conclusions—Tumor genotype techniques are feasible in most samples, outside small imageguided percutaneous transthoracic core-needle biopsies and bone samples from core biopsies with decalcification, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation

CCAAT/Enhancer Binding Protein β Is Dispensable for Development of Lung Adenocarcinoma

Lung cancer is the leading cause of cancer death worldwide. Although disruption of normal proliferation and differentiation is a vital component of tumorigenesis, the mechanisms of this process in lung cancer are still unclear. A transcription factor, C/EBPβ is a critical regulator of proliferation and/or differentiation in multiple tissues. In lung, C/EBPβ is expressed in alveolar pneumocytes and bronchial epithelial cells; however, its roles on normal lung homeostasis and lung cancer development have not been well described. Here we investigated whether C/EBPβ is required for normal lung development and whether its aberrant expression and/or activity contribute to lung tumorigenesis. We showed that C/EBPβ was expressed in both human normal pneumocytes and lung adenocarcinoma cell lines. We found that overall lung architecture was maintained in Cebpb knockout mice. Neither overexpression of nuclear C/EBPβ nor suppression of CEBPB expression had significant effects on cell proliferation. C/EBPβ expression and activity remained unchanged upon EGF stimulation. Furthermore, deletion of Cebpb had no impact on lung tumor burden in a lung specific, conditional mutant EGFR lung cancer mouse model. Analyses of data from The Cancer Genome Atlas (TCGA) revealed that expression, promoter methylation, or copy number of CEBPB was not significantly altered in human lung adenocarcinoma. Taken together, our data suggest that C/EBPβ is dispensable for development of lung adenocarcinoma

Experience with targeted next generation sequencing for the care of lung cancer: Insights into promises and limitations of genomic oncology in day-to-day practice

Introduction Tumor genotyping using single gene assays (SGAs) is standard practice in advanced non-small-cell lung cancer (NSCLC). We evaluated how the introduction of next generation sequencing (NGS) into day-to-day clinical practice altered therapeutic decision-making. Methods Clinicopathologic data, tumor genotype, and clinical decisions were retrospectively compiled over 6 months following introduction of NGS assay use at our institution in 82 patient-tumor samples (7 by primary NGS, 22 by sequential SGAs followed by NGS, and 53 by SGAs). Results SGAs identified abnormalities in 34 samples, and all patients with advanced EGFR-mutated or ALK-rearranged tumors received approved tyrosine kinase inhibitors (TKIs) or were consented for clinical trials. NGS was more commonly requested for EGFR, ALK, and KRAS-negative tumors (p<0.0001). NGS was successful in 24/29 (82.7%) tumors. Of 17 adenocarcinomas (ACs), 11 (7 from patients with ≤15 pack-years of smoking) had abnormalities in a known driver oncogene. This led to a change in decision-making in 8 patients, trial consideration in 6, and off-label TKI use in 2. Of 7 squamous cell (SC) carcinomas, 1 had a driver aberration (FGFR1); 6 had other genomic events (all with TP53 mutations). In no cases were clinical decisions altered (p=0.0538 when compared to ACs). Conclusions Targeted NGS can identify a significant number of therapeutically-relevant driver events in lung ACs; particularly in never or light smokers. For SC lung cancers, NGS is less likely to alter current practice. Further research into the cost effectiveness and optimal use of NGS and improved provider training in genomic oncology are warranted

Brain metastases in patients with EGFR -mutated or ALK -rearranged non-small-cell lung cancers

Introduction—Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Methods—The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. Results—We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44–1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALKrearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. Conclusions—BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC