A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer.

BACKGROUND: We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. RESULTS: A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (

Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC-a systematic review and meta-analysis.

BACKGROUND: The ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study. METHODS: A systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2). RESULTS: Information by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03). CONCLUSION: In advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

One-step lateral window approach for removal of benign minor sinus pathologies combined with transcrestal sinus floor elevation without bone grafts: a retrospective study.

The aim of this study was to evaluate the clinical and radiographic outcomes of a lateral window approach for removal of benign minor sinus pathologies combined with transcrestal sinus floor elevation. From 2014 to 2018, all patients who received sinus pathology removal via a lateral window approach combined with transcrestal sinus floor elevation were screened. The serous exudate or minor sinus pathology was drained or removed via lateral window approach. Subsequently, transcrestal sinus floor elevation without grafting and simultaneous implant placement were performed. Panoramic radiographs and cone-beam computed tomography were taken preoperatively, immediately after surgery, and after prosthesis delivery. Twelve patients were included in this study. The decrease in Schneiderian membrane thickness was statistically significant (P<0.001). Endo-sinus bone formation was observed on the buccal (1.35±2.31mm) and palatal (1.61±2.65mm) sites of the implant. The implant survival rate was 100%. All implants survived for an average of 21.83±11.11 months. Within the limitations of this study, we suggest that the lateral window approach for minor sinus pathology removal combined with transcrestal sinus floor elevation has several advantages including endo-sinus bone gain without bone graft, minimal patient discomfort, reduced postoperative complications and shorter treatment period.

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Usefulness of the Delay Alternating with Nutation for Tailored Excitation Pulse with T1-Weighted Sampling Perfection with Application-Optimized Contrasts Using Different Flip Angle Evolution in the Detection of Cerebral Metastases: Comparison with MPRAGE Imaging.

BACKGROUND AND PURPOSE: Contrast-enhanced T1-weighted sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) with the delay alternating with nutation for tailored excitation (DANTE) pulse could suppress the blood flow signal and provide a higher contrast-to-noise ratio of enhancing lesion-to-brain parenchyma than the MPRAGE sequence. The purpose of our study was to evaluate the usefulness of SPACE with DANTE compared with MPRAGE for detecting brain metastases. MATERIALS AND METHODS: Seventy-one patients who underwent contrast-enhanced SPACE with DANTE and MPRAGE sequences and who were suspected of having metastatic lesions were included. Two neuroradiologists determined the number of enhancing lesions, and diagnostic performance was evaluated using figure of merit, sensitivity, positive predictive value, interobserver agreement, and reading time. Contrast-to-noise ratiolesion/parenchyma and contrast-to-noise ratiowhite matter/gray matter were also assessed. RESULTS: SPACE with DANTE (observer one, 328; observer two, 324) revealed significantly more small (<5 mm) enhancing lesions than MPRAGE (observer one, 175; observer two, 150) (P < 0.001 for observer 1, P ≤ .0001 for observer 2). Furthermore, SPACE with DANTE showed significantly higher figure of merit and sensitivity and shorter reading time than MPRAGE for both observers. The mean contrast-to-noise ratiolesion/parenchyma of SPACE with DANTE (52.3 ± 43.1) was significantly higher than that of MPRAGE (17.5 ± 19.3) (P ≤ .0001), but the mean contrast-to-noise ratiowhite matter/gray matter of SPACE with DANTE (-0.65 ± 1.39) was significantly lower than that of MPRAGE (3.08 ± 1.39) (P ≤ .0001). CONCLUSIONS: Compared with MPRAGE, SPACE with DANTE significantly improves the detection of brain metastases.

Optimization of broth recovery for repair of heat-injured Salmonella enterica serovar Typhimurium and Escherichia coli O157:H7.

AIMS: The purpose of this research was to determine optimum conditions for broth recovery of heat-injured Salmonella Typhimurium and Escherichia coli O157:H7. METHODS AND RESULTS: Exposure to 55°C for 15 and 25 min, respectively, induced cellular injury to those pathogens. Comparison was made with the commonly used overlay method using selective medium for recovering sublethally injured cells of S. Typhimurium. For E. coli O157:H7, phenol red agar base with 1% sorbitol was used. After cell suspensions were heated at 55°C for selected time intervals, microbes were 10-fold diluted with brain heart infusion (BHI), tryptic soy broth (TSB) and TSB with 0·6% yeast extract (TSBYE) and incubated at 37°C for up to 3 h. At hourly intervals, diluents were plated onto selective medium for recovery. Simultaneously, diluents were plated onto tryptic soy agar (TSA) for recovery of sublethally injured cells. For overlays, diluents were plated onto TSA and overlaid with selective agar after a resuscitation interval. Broth recovery conditions for S. Typhimurium and E. coli O157:H7 were determined to be 1 h in any of the following broth media: BHI, TSB or TSBYE. When liquid resuscitation was applied to sublethally injured cells in food samples (milk), 1 h was also sufficient time for recovery. CONCLUSIONS: The broth recovery method is a convenient alternative to conventional recovery methods. SIGNIFICANCE AND IMPACT OF THE STUDY: Cells sublethally injured by control interventions might not grow on selective medium because they have no resistance to several selective compounds. However, injured cells can recuperate and multiply under conditions sufficient for recovery. To repair and detect heat-injured cells, the overlay method is commonly used but this method has some limitations. This study confirms the effectiveness of liquid resuscitation method on recovery of injured cells. The broth recovery can replace the overlay method due to greater convenience and timesaving.

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.

BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.

Graft Contrast-Induced Nephropathy Caused by Prerenal Transplant Computed Tomography: A Case Report.

BACKGROUND: We report a case of posttransplant contrast-induced nephropathy (CIN) that occurred after performing computed tomography (CT) scanning for pretransplant cardiac and vascular evaluation. CASE PRESENTATION: The patient had an 8-year history of hemodialysis and was admitted to the hospital for a kidney transplant from a deceased donor. Cardiac CT imaging and 3-dimensional low-extremity CT angiography were performed to confirm the patient's cardiac and iliac artery function. After successful transplantation surgery, the patient had a urine output of 250 mL and a reduced creatinine level from 8.8 to 2.3 mg/dL on postoperative day 4. However, urine output suddenly decreased to 30 mL and the creatinine level suddenly increased to 7.6 md/dL without any symptoms such as fever or graft tenderness. The patient tested negative for panel-reactive antibodies and donor-specific antibodies, and he was discharged 1 week later with an improvement in symptoms. Results of a graft biopsy indicated CIN, and the contrast-enhanced kidney was observed on noncontrast CT imaging that was performed immediately after transplantation to rule out vascular problems as well as other complications. CONCLUSIONS: There may be residual contrast present from pretransplant CT imaging, which could affect the functional kidney grafts after transplantation and can lead to CIN. This scenario could potentially lead to loss of graft function, suggesting that caution should be observed when ordering CT imaging in this patient population.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.

Long noncoding RNA GIHCG is a potential diagnostic and prognostic biomarker and therapeutic target for renal cell carcinoma.

OBJECTIVE: Long noncoding RNA (lncRNA) GIHCG has been reported as an oncogene in hepatocellular carcinoma. However, the expression, roles, and clinical values of GIHCG in renal cell carcinoma (RCC) remain unclear. The aim of this study was to investigate the expression, roles, diagnostic and prognostic values of GIHCG in RCC. PATIENTS AND METHODS: The expression of GIHCG in 46 pairs of RCC tissues and adjacent normal renal tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). GIHCG serum level in 46 RCC patients, 46 age- and sex-matched healthy controls, 20 pre- and post-surgery RCC patients was measured by qRT-PCR. The diagnostic values of serum GIHCG were evaluated by receiver operating characteristic (ROC) curves analysis. The effect of GIHCG on RCC cell proliferation was evaluated using Cell Count Kit-8 assay, and the effect of GIHCG on RCC cell migration was evaluated using transwell migration assay. RESULTS: GIHCG is upregulated in RCC tissues compared with adjacent normal renal tissues. Increased expression of GIHCG is positively correlated with advanced TNM stages, Fuhrman grades, and poor prognosis. Serum GIHCG level is also significantly upregulated in RCC patients and correlated with advanced TNM stages. Serum GIHCG could accurately discriminate RCC patients from healthy controls, and also early stage RCC patients from healthy controls. Furthermore, serum GIHCG level is positively correlated with GIHCG expression in RCC tissues. Serum GIHCG level is significantly reduced after radical resection of RCC. Functional assays showed that knockdown of GIHCG significantly represses proliferation and migration of RCC cells. CONCLUSIONS: Long noncoding RNA GIHCG would sever as a novel diagnostic and prognostic biomarker and therapeutic target for RCC.

Standardization of haematology critical results management in adults: an International Council for Standardization in Haematology, ICSH, survey and recommendations.

INTRODUCTION: These recommendations are intended to develop a consensus in the previously published papers as to which parameters and what values should be considered critical. A practical guide on the standardization of critical results management in haematology laboratories would be beneficial as part of good laboratory and clinical practice and for use by laboratory-accrediting agencies. METHODS: A working group with members from Europe, America, Australasia and Asia was formed by International Council for Standardization in Haematology. A pattern of practice survey of 21 questions was distributed in 2014, and the data were collected electronically by Survey Monkey. The mode, or most commonly occurring value, was selected as the threshold for the upper and lower alert limits for critical results reporting. RESULTS: A total of 666 laboratories submitted data to this study and, of these, 499 submitted complete responses. Full blood count critical results alert thresholds, morphology findings that trigger critical result notification, critical results alert list, notification process and maintenance of critical results management protocol are described. This international survey provided a snapshot of the current practice worldwide and has identified the existence of considerable heterogeneity of critical results management. CONCLUSION: The recommendations in this study represent a consensus of good laboratory practice. They are intended to encourage the implementation of a standardized critical results management protocol in the laboratory.

Whole-genome analysis of a patient with early-stage small-cell lung cancer.

We performed whole-genome sequencing (WGS) of a case of early-stage small-cell lung cancer (SCLC) to analyze the genomic features. WGS revealed a lot of single-nucleotide variations (SNVs), small insertion/deletions and chromosomal abnormality. Chromosomes 4p, 5q, 13q, 15q, 17p and 22q contained many block deletions. Especially, copy loss was observed in tumor suppressor genes RB1 and TP53, and copy gain in oncogene hTERT. Somatic mutations were found in TP53 and CREBBP. Novel nonsynonymous (ns) SNVs in C6ORF103 and SLC5A4 genes were also found. Sanger sequencing of the SLC5A4 gene in 23 independent SCLC samples showed another nsSNV in the SLC5A4 gene, indicating that nsSNVs in the SLC5A4 gene are recurrent in SCLC. WGS of an early-stage SCLC identified novel recurrent mutations and validated known variations, including copy number variations. These findings provide insight into the genomic landscape contributing to SCLC development.

A genome-wide association study of survival in small-cell lung cancer patients treated with irinotecan plus cisplatin chemotherapy.

We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) influencing overall survival (OS) of small-cell lung cancer (SCLC) patients. We prospectively collected blood samples from 139 SCLC patients who participated in phase II studies of irinotecan and cisplatin (IP) chemotherapy as first-line therapy. Among 334 127 SNPs, which passed quality control, seven showed significant association with OS. The rs16950650CT, rs7186128AG or GG, rs17574269AG, rs8020368CC, rs4655567CC, rs2166219TT or rs2018683TT showed shorter OS compared with control alleles. Among the seven SNPs, rs4655567, rs8020368 and rs2018683 were significantly associated with a resistant relapse (RR). In the multivariate analysis, rs8020368CC was significantly associated with higher risk of RR (odds ratio=16.7, P=0.007). In vitro and in silico analysis showed that SNPs in C14orf49 might be associated with epithelial-to-mesenchymal transition. This exploratory GWAS identified candidate SNPs that may be predictive of the clinical outcome of SCLC patients receiving IP.

Evaluation of 99mTc-peptide-ZHER2:342 Affibody® molecule for in vivo molecular imaging.

OBJECTIVE: The aim of this study was to develop an improved method for labelling ZHER2:342 with Technetium-99m ((99m)Tc) using Gly-(d) Ala-Gly-Gly as a chelator and to evaluate the feasibility of its use for visualization of HER2 expression in vivo. METHODS: The Affibody® molecule ZHER2:342 was synthesized by Fmoc/tBu solid phase synthesis. The chelator, Gly-(d) Ala-Gly-Gly, was introduced by manual synthesis as the N-terminal extensions of ZHER2:342. ZHER2:342 was labelled with (99m)Tc. The labelling efficiency, radiochemical purity and in vitro stability of the labelled molecular probe were analysed by reversed-phase high performance liquid chromatography. Biodistribution and molecular imaging using (99m)Tc-peptide-ZHER2:342 were performed. RESULTS: The molecular probe was successfully synthesized and labelled with (99m)Tc with the labelling efficiency of 98.10 ± 1.73% (n=5). The radiolabelled molecular probe remained highly stable in vitro. The molecular imaging showed high uptake in HER2-expressing SKOV-3 xenografts, whereas the MDA-MB-231 xenografts with low HER2 expression were not clearly imaged at any time after the injection of (99m)Tc-peptide-ZHER2:342. The predominant clearance pathway for (99m)Tc-peptide-ZHER2:342 was through the kidneys. Conculsion: (99m)Tc-peptide-ZHER2:342 using Gly-(d) Ala-Gly-Gly as a chelator is a promising tracer agent with favourable biodistribution and imaging properties that may be developed as a radiopharmaceutical for the detection of HER2-positive malignant tumours. ADVANCES IN KNOWLEDGE: The (99m)Tc-peptide-ZHER2:342 molecular probe is a promising tracer agent, and the results in this study provide a foundation for future development of protocols for earlier visual detection of cancer in the clinical setting.

Fetal and neonatal outcomes in women taking domperidone during pregnancy.

The safety of domperidone in pregnancy remains unknown. Therefore, the study aimed to prospectively evaluate the fetal outcomes of women who were taking domperidone during pregnancy. In a prospective cohort study design, 120 1st- trimester pregnant women who were taking domperidone for controlling gastrointestinal tract symptoms and 212 age-matched pregnant women not exposed to any potential teratogenic agent, were followed-up until delivery. In the case group, domperidone was indicated for control of functional gastrointestinal disorders in 59.2%, the maximum dose was 30 mg/day and exposure occurred between 2(+4) and 20 weeks' gestation. Fetal outcomes including gestational age at birth, birth weight and length, head circumference at birth, and 1- and 5-min Apgar score were similar in the two study groups. There were three babies born with malformations in each group (OR = 0.6; 95% CI 0.1, 2.8). In conclusion, domperidone does not appear to be a major human teratogen. However, our findings require further confirmation in larger studies.

A genome-wide association study for irinotecan-related severe toxicities in patients with advanced non-small-cell lung cancer.

The identification of patients who are at high risk for irinotecan-related severe diarrhea and neutropenia is clinically important. We conducted the first genome-wide association study (GWAS) to search for novel susceptibility genes for irinotecan-related severe toxicities, such as diarrhea and neutropenia, in non-small-cell lung cancer (NSCLC) patients treated with irinotecan chemotherapy. The GWAS putatively identified 49 single-nucleotide polymorphisms (SNPs) associated with grade 3 diarrhea (G3D) and 32 SNPs associated with grade 4 neutropenia (G4N). In the replication series, the SNPs rs1517114 (C8orf34), rs1661167 (FLJ41856) and rs2745761 (PLCB1) were confirmed as being associated with G3D, whereas rs11128347 (PDZRN3) and rs11979430 and rs7779029 (SEMAC3) were confirmed as being associated with G4N. The final imputation analysis of our GWAS and replication study showed significant overlaps of association signals within these novel variants. This GWAS screen, along with subsequent validation and imputation analysis, identified novel SNPs associated with irinotecan-related severe toxicities.

Homocysteine, folate and pregnancy outcomes.

The purpose of this study is to evaluate the relationship between maternal and/or cord blood folate/homocysteine concentrations and adverse pregnancy outcomes. The study population included a random sample of singleton pregnant women in whom we measured total homocysteine and folic acid in maternal or cord blood at deliveries. A total of 227 pregnant women were enrolled. The concentration of folate in maternal blood tended to be significantly lower in pre-term birth than in full-term delivery group (median (95% CI), 14.4 (3.6-73) vs 25 (7.3-105.5) p < 0.01). The total homocysteine in maternal and cord blood was significantly higher in the pre-eclampsia than in the normotensive group (7.9 (1.7-28.2) vs 5.9 (1.8-14.6) µmol/ml, p < 0.05; and 5.8 (2.6-14.4) vs 4.2 (0.7-7.9) ng/ml, p < 0.05, respectively). Lower maternal serum folate concentration is associated with pre-term delivery and higher maternal plasma homocysteine concentration with pre-eclampsia.