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Purpose According to the lung cancer staging project, T1a (≤ 2 cm) non–small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. Methods We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer–specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. Results OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. Conclusion Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.

Objective To assess the feasibility of using MicroFil polymer perfusion to detect concomitant saccular aneurysms in an intracranial arterial dolichoectasia (IADE) model in mice, and to report detailed histomorphometric features of these aneurysms. Materials and methods IADE models were created in C57/BL6 mice via microsurgical injection of 25 mU elastase into the cisterna magna. The cerebral vasculature was perfused with MicroFil polymer and harvested at 1, 3, and 7 days, and 2 and 4 weeks (n=8 for each group). IADE was defined by a tortuosity index >10 combined with a 25% increase in diameter of the A1 segment of the anterior cerebral artery (ACA), internal carotid artery (ICA), or basilar artery compared with the baseline of controls, which received heat-inactivated elastase. Saccular aneurysm occurrence rate, location, and morphological parameters were investigated using macroscopic and microscopic analysis. Results IADE was present in 95% (36/38) of the subjects, with a mortality rate of 5% (2/40). Fifteen concomitant saccular aneurysms were detected in 8 (21%) of the 38 surviving mice, including 6 at the posterior communicating artery, 1 along the ACA, 2 along the anterior communicating artery complex, 3 along the ICA, and 3 along the middle cerebral artery. Rupture was confirmed in two aneurysms. Histological examination indicated that the aneurysms develop via arterial-wall remodelling, which is characterized by internal elastic lamina disruptions and muscular layer discontinuity in the media. Conclusions The proportion of subjects developing saccular aneurysms in addition to IADE in our mouse model is similar to the 15% of patients with IADE who have concomitant saccular aneurysms.

BACKGROUNDIn an ECOG‐ACRIN Cancer Research Group study (E1496), maintenance rituximab (MR) was reported to prolong progression‐free survival (PFS) in comparison with observation (OBS) alone in patients with indolent lymphoma after induction chemotherapy. Here the long‐term follow‐up of the same patient cohort is presented.METHODSPatients with indolent lymphoma received induction chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). Patients with stable disease or a better response were then randomized to weekly rituximab (375 mg/m2 × 4 doses) every 6 months for 2 years (MR) or to OBS. The primary endpoint was PFS; the secondary endpoints were overall survival (OS), response rate, and toxicities.RESULTSOf the 387 patients who initially received CVP induction, 158 were randomized to MR, and 153 were randomized to OBS. After a median follow‐up of 11.5 years, patients on MR had longer median PFS (4.8 years) than patients on OBS (1.3 years; hazard ratio [HR], 0.49; P < .0001). However, there was no difference in OS between MR and OBS (10‐year OS, 67% vs 59%; median OS, 13.5 years vs not reached; HR, 0.91; P = .69). Other than MR, only minimal residual disease after induction therapy was significantly associated with PFS on multivariate analysis (HR, 0.71; P = .02). A low initial tumor burden, minimal residual disease, follicular histology, a low Follicular Lymphoma International Prognostic Index score, and female sex were associated with longer OS. There was no increase in the rate of second primary malignancies with MR vs OBS.CONCLUSIONSWith long‐term follow‐up, MR did not influence OS. The PFS benefit was maintained. MR should be considered optional for patients with indolent B‐cell lymphoma. Cancer 2016;122:2996‐3004. © 2016 American Cancer Society.

AbstractObjectivesTo investigate whether Gianotti–Crosti syndrome (GCS) in children is associated with atopy.MethodsThe setting was two outpatient clinic. Diagnoses of asthma and atopic dermatitis (AD) were made according to internationally accepted diagnostic criteria. Allergic rhinitis, atopic urticaria, and allergic conjunctivitis were diagnosed clinically. Participants were children with GCS diagnosed over the previous 5 years. For any child with GCS, we extracted the record of the subsequent age and sex pair‐matched child seen for problems unrelated to the skin as controls.ResultsWe retrieved the records of 37 pairs of study and control subjects; 28 (76%) children with GCS and 9 (24%) controls had AD (risk ratio [RR] = 3.11[95% confidence interval {CI} 1.73, 5.73]), 31 (84%) children with GCS and 19 (51%) controls had at least one atopic condition (RR = 1.63 [95% CI 1.13, 2.18]) and 11 (30%) children with GCS and 2 (5%) controls had at least three atopic conditions (RR = 5.50 [95% CI 1.29, 35.35]).ConclusionGCS is significantly associated with AD and the presence of atopic conditions.

AbstractBackgroundThis study compared prucalopride, a selective, prokinetic, 5‐HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high‐amplitude propagating contractions (HAPCs) in patients with chronic constipation.MethodsThis randomized, cross‐over, reader‐blinded study was conducted at a single site in the USA. The study was open to men and women aged 18–75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co‐primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity.Key ResultsThirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12‐h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2) and mean AUC, force, and amplitude (HAPC3) compared with PEG3350. Adverse events were mild or moderate.Conclusions & InferencesPrucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation.ClinicalTrials.gov number NCT01707667.

Abstract Motivation: Prediction and prioritization of human non-coding regulatory variants is critical for understanding the regulatory mechanisms of disease pathogenesis and promoting personalized medicine. Existing tools utilize functional genomics data and evolutionary information to evaluate the pathogenicity or regulatory functions of non-coding variants. However, different algorithms lead to inconsistent and even conflicting predictions. Combining multiple methods may increase accuracy in regulatory variant prediction. Results: Here, we compiled an integrative resource for predictions from eight different tools on functional annotation of non-coding variants. We further developed a composite strategy to integrate multiple predictions and computed the composite likelihood of a given variant being regulatory variant. Benchmarked by multiple independent causal variants datasets, we demonstrated that our composite model significantly improves the prediction performance. Availability and Implementation: We implemented our model and scoring procedure as a tool, named PRVCS, which is freely available to academic and non-profit usage at http://jjwanglab.org/PRVCS. Contact: wang.junwen@mayo.edu, jliu@stat.harvard.edu, or limx54@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Abstract Introduction. For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. Materials and Methods. Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. Results. A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. Conclusion. Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.

Abstract Background: MRX34 is a liposomal nanoparticle formulation with an encapsulated mimic of the naturally occurring microRNA-34 (miR-34), which is lost or expressed at reduced levels in many tumors. miR-34 inhibits key oncogenic pathways by repressing multiple important oncogenes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ/β, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also represses the expression of PD-L1 and DGKζ, thereby possibly triggering an anti-tumor immune response and cancer cell death. A multicenter Phase 1 clinical trial of MRX34 is being conducted in patients with advanced malignancies. Methods: Eligible patients were enrolled in a standard 3 + 3 dose escalation study and were given a MRX34 starting dose of 10 mg/m2, administered intravenously (IV) twice weekly (BIW) for 3 weeks in 28-day cycles. Enrollment is ongoing into a second MRX34 dosing schedule, daily x 5 (QD x 5) in 21-day cycles. The primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for the two dosing schedules. Secondary objectives include assessments of safety, tolerability and the pharmacokinetic profile of MRX34 after intravenous dosing as well as to assess any biological and clinical activity. Results: As of July 2015, 75 patients with advanced solid tumors were enrolled and evaluable: 44 Caucasians, 47 males, a median age of 61 years and a median of 4 prior treatments. Histologies included 30 hepatocellular carcinoma (HCC), 7 pancreatic cancer, 4 cholangiocarcinoma, 3 each of bladder, breast, colorectal, cervix and lung. The remaining 19 patients represented various other malignancies &lt;3 patients each. The 110 mg/m2 was deemed to be the MTD for the BIW dosing schedule. The MTD has not been determined yet for the QD x 5 schedule and dose escalation is continuing. The current dose levels are 70 mg/m2 QD x 5 for HCC and 93 mg/m2 QD x 5 for other solid tumors. The following treatment-emergent, all-causality adverse events (AEs) were most frequent among 47 patients in BIW cohorts vs 28 patients in QD x 5 cohorts: fever (64% vs 61%), fatigue (57% vs 39%), chills (57% vs 36%), back pain (55% vs 36%), nausea (49% vs 39%), diarrhea (43% vs 11%), headache (34% vs 14%), vomiting (32% vs 11%), anorexia (26% vs 14%), abdominal pain (23% vs 21%), dyspnea (23% vs 14%), insomnia (23% vs 14%), and dehydration (23% vs 4%). Most frequent grade 3/4 laboratory abnormalities were: lymphopenia (36% vs 71%), neutropenia (26% vs 36%), hyponatremia (26% vs 7%), AST elevation (26% vs 29%), leukopenia (23% vs 36%), hyperglycemia (19% vs 36%), thrombocytopenia (17% vs 29%), anemia (11% vs 21%), alkaline phosphatase elevation (11% vs 21%), and ALT elevation (9% vs 21%). One patient with HCC and another patient with melanoma achieved confirmed partial responses per RECIST. Conclusions: MRX34 has a manageable safety profile with confirmed partial responses in two patients with advanced HCC and melanoma. Due to better tolerability, QD x 5 schedule has been chosen for further study. Following MTD determination, enrollment will soon begin into the QD x 5 expansion cohorts for selected tumors. Citation Format: Muhammad Shaalan Beg, Andrew Brenner, Jasgit Sachdev, Samuel Ejadi, Mitesh Borad, Yang-Kon Kang, Ho Lim, T-Y Kim, Andreas Bader, Jay Stoudemire, Susan Smith, Sinil Kim, David Hong. Safety, tolerability, and clinical activity of MRX34, the first-in-class liposomal miR-34 mimic, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C43.