Molecular Subtypes and Tumor Microenvironment Characteristics of Small-Cell Lung Cancer Associated with Platinum-Resistance.

Although molecular subtypes of small-cell lung cancer (SCLC) have been proposed, their clinical relevance and therapeutic implications are not fully understood. Thus, we aimed to refine molecular subtypes and to uncover therapeutic targets. We classified the subtypes based on gene expression (n = 81) and validated them in our samples (n = 87). Non-SCLC samples were compared with SCLC subtypes to identify the early development stage of SCLC. Single-cell transcriptome analysis was applied to dissect the TME of bulk samples. Finally, to overcome platinum resistance, we performed drug screening of patient-derived cells and cell lines. Four subtypes were identified: the ASCL1+ (SCLC-A) subtype identified as TP53/RB-mutated non-SCLC representing the early development stage of SCLC; the immune activation (SCLC-I) subtype, showing high CD8+/PD-L1+ T-cell infiltration and endothelial-to-mesenchymal transition (EndMT); the NEUROD1 (SCLC-N) subtype, which showed neurotransmission process; and the POU2F3+ (SCLC-P) subtype with epithelial-to-mesenchymal transition (EMT). EndMT was associated with the worst prognosis. While SCLC-A/N exhibited platinum sensitivity, the EndMT signal of SCLC-I conferred platinum resistance. A BET inhibitor suppressed the aggressive angiogenesis phenotype of SCLC-I. We revealed that EndMT development contributed to a poor outcome in SCLC-I. Moreover, heterogenous TME development facilitated platinum resistance. BET inhibitors are novel candidates for overcoming platinum resistance.

Dynamics of disease progression during treatment with Osimertinib in patients with EGFR T790M-positive non-small cell lung cancer.

BACKGROUND: Patterns of treatment failure and subsequent treatment in non-small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies. METHODS: We identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed. RESULTS: Eighty-four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo-progressive disease (PD) and central nervous system (CNS)-sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM-free (46/49, 93.9%), and 60% of patients (21/35) with pre-existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M-loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M-loss (progression-free survival, 5.4 vs. 16.5 months, p = 0.02; overall survival, not reached, p = 0.03). CONCLUSION: PD during osimertinib treatment occurred preferentially in the thorax and pre-existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies for EGFR-mutated NSCLC with BM.

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation.

BACKGROUND: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. RESULTS: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. CONCLUSIONS: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. PLAIN LANGUAGE SUMMARY: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.

The Clinical Impact of Capmatinib in the Treatment of Advanced Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation or Gene Amplification.

PURPOSE: Capmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non-small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification. MATERIALS AND METHODS: Patients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients' clinical outcome were retrospectively reviewed. RESULTS: A total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123). CONCLUSION: Our data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

Phase II Study of Pemetrexed as a Salvage Chemotherapy for Thymidylate Synthase-Low Squamous Cell Lung Cancer.

PURPOSE: Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression. MATERIALS AND METHODS: In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate. RESULTS: Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2. CONCLUSION: Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.

Diagnostic Accuracy of Percutaneous Transthoracic Needle Lung Biopsies: A Multicenter Study.

OBJECTIVE: To measure the diagnostic accuracy of percutaneous transthoracic needle lung biopsies (PTNBs) on the basis of the intention-to-diagnose principle and identify risk factors for diagnostic failure of PTNBs in a multi-institutional setting. MATERIALS AND METHODS: A total of 9384 initial PTNBs performed in 9239 patients (mean patient age, 65 years [range, 20-99 years]) from January 2010 to December 2014 were included. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PTNBs for diagnosis of malignancy were measured. The proportion of diagnostic failures was measured, and their risk factors were identified. RESULTS: The overall accuracy, sensitivity, specificity, PPV, and NPV were 91.1% (95% confidence interval [CI], 90.6-91.7%), 92.5% (95% CI, 91.9-93.1%), 86.5% (95% CI, 85.0-87.9%), 99.2% (95% CI, 99.0-99.4%), and 84.3% (95% CI, 82.7-85.8%), respectively. The proportion of diagnostic failures was 8.9% (831 of 9384; 95% CI, 8.3-9.4%). The independent risk factors for diagnostic failures were lesions ≤ 1 cm in size (adjusted odds ratio [AOR], 1.86; 95% CI, 1.23-2.81), lesion size 1.1-2 cm (1.75; 1.45-2.11), subsolid lesions (1.81; 1.32-2.49), use of fine needle aspiration only (2.43; 1.80-3.28), final diagnosis of benign lesions (2.18; 1.84-2.58), and final diagnosis of lymphomas (10.66; 6.21-18.30). Use of cone-beam CT (AOR, 0.31; 95% CI, 0.13-0.75) and conventional CT-guidance (0.55; 0.32-0.94) reduced diagnostic failures. CONCLUSION: The accuracy of PTNB for diagnosis of malignancy was fairly high in our large-scale multi-institutional cohort. The identified risk factors for diagnostic failure may help reduce diagnostic failure and interpret the biopsy results.

Erratum: Analysis of Complications of Percutaneous Transthoracic Needle Biopsy Using CT-Guidance Modalities In a Multicenter Cohort of 10568 Biopsies.

This corrects the article on p. 323 in vol. 20, PMID: 30672172.

Analysis of Complications of Percutaneous Transthoracic Needle Biopsy Using CT-Guidance Modalities In a Multicenter Cohort of 10568 Biopsies.

OBJECTIVE: To analyze the complications of percutaneous transthoracic needle biopsy using CT-based imaging modalities for needle guidance in comparison with fluoroscopy in a large retrospective cohort. MATERIALS AND METHODS: This study was approved by multiple Institutional Review Boards and the requirement for informed consent was waived. We retrospectively included 10568 biopsies from eight referral hospitals from 2010 through 2014. In univariate and multivariate logistic analyses, 3 CT-based guidance modalities (CT, CT fluoroscopy, and cone-beam CT) were compared with fluoroscopy in terms of the risk of pneumothorax, pneumothorax requiring chest tube insertion, and hemoptysis, with adjustment for other risk factors. RESULTS: Pneumothorax occurred in 2298 of the 10568 biopsies (21.7%). Tube insertion was required after 316 biopsies (3.0%), and hemoptysis occurred in 550 cases (5.2%). In the multivariate analysis, pneumothorax was more frequently detected with CT {odds ratio (OR), 2.752 (95% confidence interval [CI], 2.325-3.258), p < 0.001}, CT fluoroscopy (OR, 1.440 [95% CI, 1.176-1.762], p < 0.001), and cone-beam CT (OR, 2.906 [95% CI, 2.235-3.779], p < 0.001), but no significant relationship was found for pneumothorax requiring chest tube insertion (p = 0.497, p = 0.222, and p = 0.216, respectively). The incidence of hemoptysis was significantly lower under CT (OR, 0.348 [95% CI, 0.247-0.491], p < 0.001), CT fluoroscopy (OR, 0.594 [95% CI, 0.419-0.843], p = 0.004), and cone-beam CT (OR, 0.479 [95% CI, 0.317-0.724], p < 0.001) guidance. CONCLUSION: Hemoptysis occurred less frequently with CT-based guidance modalities in comparison with fluoroscopy. Although pneumothorax requiring chest tube insertion showed a similar incidence, pneumothorax was more frequently detected using CT-based guidance modalities.

Development and Validation of Deep Learning-based Automatic Detection Algorithm for Malignant Pulmonary Nodules on Chest Radiographs.

Purpose To develop and validate a deep learning-based automatic detection algorithm (DLAD) for malignant pulmonary nodules on chest radiographs and to compare its performance with physicians including thoracic radiologists. Materials and Methods For this retrospective study, DLAD was developed by using 43 292 chest radiographs (normal radiograph-to-nodule radiograph ratio, 34 067:9225) in 34 676 patients (healthy-to-nodule ratio, 30 784:3892; 19 230 men [mean age, 52.8 years; age range, 18-99 years]; 15 446 women [mean age, 52.3 years; age range, 18-98 years]) obtained between 2010 and 2015, which were labeled and partially annotated by 13 board-certified radiologists, in a convolutional neural network. Radiograph classification and nodule detection performances of DLAD were validated by using one internal and four external data sets from three South Korean hospitals and one U.S. hospital. For internal and external validation, radiograph classification and nodule detection performances of DLAD were evaluated by using the area under the receiver operating characteristic curve (AUROC) and jackknife alternative free-response receiver-operating characteristic (JAFROC) figure of merit (FOM), respectively. An observer performance test involving 18 physicians, including nine board-certified radiologists, was conducted by using one of the four external validation data sets. Performances of DLAD, physicians, and physicians assisted with DLAD were evaluated and compared. Results According to one internal and four external validation data sets, radiograph classification and nodule detection performances of DLAD were a range of 0.92-0.99 (AUROC) and 0.831-0.924 (JAFROC FOM), respectively. DLAD showed a higher AUROC and JAFROC FOM at the observer performance test than 17 of 18 and 15 of 18 physicians, respectively (P < .05), and all physicians showed improved nodule detection performances with DLAD (mean JAFROC FOM improvement, 0.043; range, 0.006-0.190; P < .05). Conclusion This deep learning-based automatic detection algorithm outperformed physicians in radiograph classification and nodule detection performance for malignant pulmonary nodules on chest radiographs, and it enhanced physicians' performances when used as a second reader. © RSNA, 2018 Online supplemental material is available for this article.

Nondiagnostic Percutaneous Transthoracic Needle Biopsy of Lung Lesions: A Multicenter Study of Malignancy Risk.

Purpose To evaluate the malignancy risk of lung lesions that show nondiagnostic results at transthoracic needle biopsy (PTNB) of the lung and to identify any malignancy-associated risk factors in each nondiagnostic category. Materials and Methods In this retrospective study, 9384 initial PTNBs (9239 patients [mean age, 65 years; age range, 20-99 years] consisting of 5729 men [mean age, 66 years; age range, 20-99 years] and 3510 women [mean age, 63 years; age range, 20-94 years]) were performed in eight institutions between January 2010 and December 2014. PTNB results were categorized as diagnostic (malignant or specifically benign) or nondiagnostic (nonspecific benign pathologic findings, atypical cells, or insufficient specimen), and the proportion of final malignant diagnoses per nondiagnostic category was obtained. Malignancy-associated factors were determined by using multivariable analyses. Results Nondiagnostic results were present in 27.6% (2590 of 9384) of PTNBs. Proportions of final malignant diagnoses were 21.3% (339 of 1592) for nonspecific benignities, 90.1% (503 of 558) for atypical cells, and 46.6% (205 of 440) for insufficient specimens. In the nonspecific benign category, granulomatous inflammation (odds ratio [OR], 0.04; 95% confidence interval [CI]: 0.02, 0.12; P < .001), abscess (OR, 0.04; 95% CI: 0.01, 0.28; P = .001), and organizing pneumonia (OR, 0.05; 95% CI: 0.01, 0.23; P < .001) were demonstrated to be important factors negating malignancy. Atypical cells suspicious for malignancy were more associated with malignancy (OR, 6.3; 95% CI: 1.9, 21.0; P = .003) than were atypical cells of indeterminate malignancy. All 130 lesions with atypical cells suggestive of malignancy were finally malignant. Conclusion After nondiagnostic lung biopsies, lesions categorized as atypical cell lesions have a high likelihood of malignancy, with somewhat lower likelihood for lesions with insufficient specimens and nonspecific benign categories. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Elicker in this issue.

EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion.

Rearrangements of NRG1 have been identified in invasive mucinous adenocarcinoma of the lung (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma. NRG1 ligand signals through induction of HER2-HER3 heterodimers, thus leading to PI3K-AKT pathway activation. Therefore, targeting HER2, HER3 and the downstream pathway may be a hypothesis-driven strategy for IMA with NRG1 fusion. Herein we reported two patients who benefited from lumretuzumab, a monoclonal anti-HER3 antibody, in combination of erlotinib during a clinical trial (NCT01482377). At least sixteen weeks of progression-free survival were achieved without any unacceptable toxicity.

Development and Validation of Segmentation Method for Lung Cancer Volumetry on Chest CT.

The set of criteria called Response Evaluation Criteria In Solid Tumors (RECIST) is used to evaluate the remedial effects of lung cancer, whereby the size of a lesion can be measured in one dimension (diameter). Volumetric evaluation is desirable for estimating the size of a lesion accurately, but there are several constraints and limitations to calculating the volume in clinical trials. In this study, we developed a method to detect lesions automatically, with minimal intervention by the user, and calculate their volume. Our proposed method, called a spherical region-growing method (SPRG), uses segmentation that starts from a seed point set by the user. SPRG is a modification of an existing region-growing method that is based on a sphere instead of pixels. The SPRG method detects lesions while preventing leakage to neighboring tissues, because the sphere is grown, i.e., neighboring voxels are added, only when all the voxels meet the required conditions. In this study, two radiologists segmented lung tumors using a manual method and the proposed method, and the results of both methods were compared. The proposed method showed a high sensitivity of 81.68-84.81% and a high dice similarity coefficient (DSC) of 0.86-0.88 compared with the manual method. In addition, the SPRG intraclass correlation coefficient (ICC) was 0.998 (CI 0.997-0.999, p < 0.01), showing that the SPRG method is highly reliable. If our proposed method is used for segmentation and volumetric measurement of lesions, then objective and accurate results and shorter data analysis time are possible.

Lung Cancer Screening with Low-Dose CT in Female Never Smokers: Retrospective Cohort Study with Long-term National Data Follow-up.

PURPOSE: Because of growing concerns about lung cancer in female never smokers, chest low-dose computed tomography (LDCT) screening is often performed although it has never shown clinical benefits. We examinewhether or not female never smokers really need annual LDCT screening when the initial LDCT showed negative findings. MATERIALS AND METHODS: This retrospective cohort study included 4,365 female never smokers aged 40 to 79 years who performed initial LDCT from Aug 2002 to Dec 2007. Lung cancer diagnosis was identified from the Korea Central Cancer Registry Database registered until December 31, 2013. We calculated the incidence, cumulative probability, and standardized incidence ratio (SIR) of lung cancer by Lung Imaging Reporting and Data System (Lung-RADS) categories showed on initial LDCT. RESULTS: After median follow-up of 9.69 years, 22 (0.5%) had lung cancer. Lung cancer incidence for Lung-RADS category 4 was 1,848.4 (95% confidence interval [CI], 1,132.4 to 3,017.2) per 100,000 person-years and 16.4 (95% CI, 7.4 to 36.4) for categories 1, 2, and 3 combined. The cumulative probability of lung cancer for category 4 was 10.6% at 5 years and 14.8% at 10 years while they were 0.07% and 0.17% when categories 1, 2, and 3 were combined. The SIR for subjects with category 4 was 43.80 (95% CI, 25.03 to 71.14), which was much higher than 0.47 (95% CI, 0.17 to 1.02) for categories 1, 2, and 3 combined. CONCLUSION: Considering the low risk of lung cancer development in female never smokers, it seems unnecessary to repeat annual LDCT screening for at least 5 years or even longer unless the initial LDCT showed Lung-RADS category 4 findings.

Randomized Phase II Study of Afatinib Plus Simvastatin Versus Afatinib Alone in Previously Treated Patients with Advanced Nonadenocarcinomatous Non-small Cell Lung Cancer.

PURPOSE: This phase II study examined whether the addition of simvastatin to afatinib provides a clinical benefit compared with afatinib monotherapy in previously treated patients with nonadenocarcinomatous non-small cell lung cancer (NA-NSCLC). MATERIALS AND METHODS: Patients with advanced NA-NSCLC who progressed after one or two chemotherapy regimens were randomly assigned to a simvastatin (40 mg/day) plus afatinib (40 mg/day) (AS) arm or to an afatinib (A) arm. The primary endpoint was response rate (RR). RESULTS: Sixty-eight patients were enrolled (36 in the AS arm and 32 in the A arm). The RR was 5.7% (95% confidence interval [CI], 0.7 to 19.2) for AS and 9.4% (95% CI, 2.0 to 25.0) for A (p=0.440). In arms AS and A, the median progression-free survival (PFS) was 1.0 versus 3.6 months (p=0.240) and the overall survival was 10.0 months versus 7.0 months (p=0.930), respectively. Skin rash, stomatitis, and diarrhea were the most common adverse events in both arms. More grade 3 or 4 diarrhea was observed in arm A (18.8% vs. 5.6% in arm AS). In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976). However, skin rash severity was significantly related to the risk of progression for afatinib (hazard ratio for skin rash grade ≥ 2 vs. grade < 2, 0.44; 95% CI, 0.25 to 0.78; p=0.005). CONCLUSION: There were no significant differences in the efficacy between AS and A arms in patients with NA-NSCLC.

Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status. MATERIALS AND METHODS: Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D). RESULTS: Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities. CONCLUSION: Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.

ERCC1 Expression-Based Randomized Phase II Study of Gemcitabine/Cisplatin Versus Irinotecan/Cisplatin in Patients with Advanced Non-small Cell Lung Cancer.

PURPOSE: We evaluated the clinical utility of excision repair cross-complementation group 1 (ERCC1) expression as a predictive biomarker for platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligible patients were randomly assigned to the GP (gemcitabine 1,250 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1 every 3 weeks) or IP (irinotecan 65 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks) arm. The primary goal of this study was to compare the response rate (RR) of the GP and IP arms according to the ERCC1 expression level. RESULTS: A total of 279 patients were randomly assigned to the GP (n=139) and IP (n=140) arms, among which 63% were ERCC1-positive and 268 patients were assessable for the RR. The GP and IP arms did not differ significantly with respect to the RR (29.8% vs. 27.0%, respectively; p=0.082), median progression-free survival (PFS; 4.5 months vs. 3.9 months, respectively; p=0.117), and overall survival (OS; 16.5 months vs. 16.7 months, respectively; p=0.313). When comparing the efficacy between the ERCC1-positive and ERCC1-negative groups, there was no significant difference in the RR (GP, 28.2% vs. 32.6%, respectively, p=0.509; IP, 30.2% vs. 21.6%, respectively, p=0.536), median PFS (GP, 4.6 months vs. 5.0 months, respectively, p=0.506; IP, 3.9 months vs. 3.7 months, respectively, p=0.748), or median OS (GP, 18.6 months vs. 11.9 months, respectively, p=0.070; IP, 17.5 months vs. 14.0 months, respectively, p=0.821). CONCLUSION: Immunohistochemical analysis of the ERCC1 expression level did not differentiate the efficacy of platinum-based chemotherapy in advanced NSCLC.

A phase II study of nintedanib in patients with relapsed small cell lung cancer.

OBJECTIVES: Nintedanib is an oral triple angiokinase inhibitor. This study was conducted to evaluate the efficacy and safety of nintedanib in patients (pts) with relapsed/refractory small cell lung cancer (SCLC). PATIENTS AND METHODS: Pts with an ECOG PS from 0 to 2 who exhibited progression after one or two prior chemotherapy or chemo/radiotherapy were enrolled. Pts received nintedanib 200mg BID daily in a 4-week cycle until progression or intolerable toxicity. The primary end point was the objective response rate (ORR). A two-stage design was employed. To continue to stage 2, ≥2 responders out of 22 pts were required. RESULTS: From Dec 2011 to June 2014, 24 pts were enrolled. Twenty-two pts completed treatment and were evaluable for response. The median follow-up was 9.7 (0.5-19.8) months. The median age was 64 (46-77) years. Twenty-two pts were male. Six pts had sensitive relapse. Eight pts received one prior chemotherapy. A median of one (range 1-5) cycle was administered. One pt had a partial response, and seven pts exhibited stable disease. The ORR was 5% (95% confidence interval [CI], 0.1-22.8). Median progression-free survival was 1.0 (95% CI, 0.9-1.1) month, and overall survival was 9.8 (95% CI, 8.4-11.2) months. The response criteria to proceed to full accrual were not met. The most frequent drug-related adverse events (AE) included hepatic enzyme elevation (86%), anemia (73%), anorexia (59%), and nausea (50%). Most AEs were mild and manageable. Grade 3 hepatic enzyme elevation occurred in 5 pts (23%). CONCLUSIONS: Nintedanib exhibited only limited activity with a manageable AE profile in relapsed or refractory SCLC (NCT01441297).

A study of docetaxel and irinotecan in children and young adults with recurrent or refractory Ewing sarcoma family of tumors.

BACKGROUND: Patients with Ewing sarcoma family of tumors (ESFT) who are resistant even to salvage chemotherapy, have dismal prognoses and few therapeutic options. Because the docetaxel/irinotecan (DI) combination has not been previously evaluated in ESFT, we prospectively evaluated its use in patients with recurrent or refractory ESFT. METHODS: Patients aged <30 years with ESFT, who failed ≥ third-line therapy, were eligible. They received docetaxel 100 mg/m(2) intravenously on day 1, and irinotecan 80 mg/m(2) on days 1 and 8, of a 21-day cycle up to 15 cycles or until disease progressed. The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS) and safety. RESULTS: We enrolled nine patients (median age: 13 years); four were male. Two patients had recurrent disease and seven had progressive disease. This group had undergone a median of four prior chemotherapy regimens (range: 3-6), and received a total of 51 DI cycles (median: three cycles/per person; range: 1-15 cycles). The nine patients showed one complete response (CR), two partial responses (PRs), one stable disease, and five progressive diseases, for an ORR (CR + PR) of 3/9 (33.3%). Two patients with PR achieved CR with subsequent surgery. Overall median PFS was 2.2 months (range: 0.5-16.9 months). All nine patients had grade 4 neutropenia (100%); grade 3 diarrhea or grade 2/3 neuropathy each occurred in two patients (22%). All toxicities were manageable without serious morbidities or treatment-related mortality. CONCLUSIONS: The DI combination may be effective and tolerable for patients with heavily pre-treated ESFT. TRIAL REGISTRATION: NCT01380275. Registered June 21, 2011.

Missed pulmonary embolism on abdominal CT.

OBJECTIVE: The purpose of this study is to evaluate a series of missed pulmonary emboli (PE) identified on abdominal CT and to describe their characteristics and the clinical scenario. MATERIALS AND METHODS: All reports of chest CT scans performed during a 12-month period were searched for keywords indicative of PE. Among patients with PE, patients who also underwent an enhanced abdominal CT within 3 months were assessed for missed PE. Three radiologists reviewed the abdominal CT to confirm the presence of a missed PE. Missed PEs were classified as unknown or known. Each study was assessed for characteristics of the missed PE and the image quality of the PE study. The electronic medical record was used to document the clinical context in which the PE occurred. RESULTS: Eighteen patients (12 men and six women; average age, 58.8 years) were identified as having missed PE on abdominal CT. In seven patients (38.9%), the PE had not been previously diagnosed. Most of the missed PEs were segmental, but three missed PEs occurred in lobar vessels. In a slight majority of the cases, the reviewing radiologists judged the contrast bolus as good. The abdominal CT on which PE was overlooked was obtained for a variety of reasons, most commonly because of abdominal pain or to follow up a preexisting condition. CONCLUSION: This study shows that missed PE can occur on abdominal CT. It is recommended that interpretation include a careful search of the lower pulmonary arterial vasculature on contrast-enhanced abdominal CT scans.