Osimertinib for Japanese patients with T790M-positive advanced non-small-cell lung cancer: A pooled subgroup analysis.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.

Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset.

BACKGROUND: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care. METHODS: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study. RESULTS: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient). CONCLUSIONS: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised. CLINICAL TRIAL REGISTRATION: NCT02296125 (ClinicalTrials.gov).

Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer.

Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells.

Effects of fasting on serial measurements of hyperpolarized [1-(13) C]pyruvate metabolism in tumors.

Imaging of the metabolism of hyperpolarized [1-(13) C]pyruvate has shown considerable promise in preclinical studies in oncology, particularly for the assessment of early treatment response. The repeatability of measurements of (13) C label exchange between pyruvate and lactate was determined in a murine lymphoma model in fasted and non-fasted animals. The fasted state showed lower intra-individual variability, although the [1-(13) C]lactate/[1-(13) C]pyruvate signal ratio was significantly greater in fasted than in non-fasted mice, which may be explained by the higher tumor lactate concentrations in fasted animals. These results indicate that the fasted state may be preferable for the measurement of (13) C label exchange between pyruvate and lactate, as it reduces the variability and therefore should make it easier to detect the effects of therapy. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression.

BACKGROUND AND AIMS: Although aberrant methylation of key genes in the progression of colorectal neoplasia has been reported, no model-based analysis of the incremental changes through the intermediate adenoma stage has been described. In addition, the biological drivers for these methylation changes have yet to be defined. Linear mixed-effects modelling was used in this study to understand the onset and patterns of the methylation changes of SFRP2, IGF2 DMR0, H19, LINE-1 and a CpG island methylator phenotype (CIMP) marker panel, and they were correlated with DNA methyltransferase 3B (DNMT3B) levels of expression in a sample set representative of colorectal neoplastic progression. METHODS: Methylation of the above CpG islands was measured using quantitative pyrosequencing assays in 261 tissue samples. This included a prospective collection of 44 colectomy specimens with concurrent normal mucosa, adenoma and invasive cancer tissues. Tissue microarrays from a subset of 64 cases were used for immunohistochemical analysis of DNMT3B expression. RESULTS: It is shown that the onset and pattern of methylation changes during colorectal neoplastic progression are locus dependent. The CIMP marker RUNX3 was the earliest CpG island showing significant change, followed by the CIMP markers NEUROG1 and CACNA1G at the hyperplastic polyp stage. SFRP2 and IGF2 DMR0 showed significant methylation changes at the adenomatous polyp stage, followed by the CIMP markers CDKN2A and hMLH1 at the adenocarcinoma stage. DNMT3B levels of immunohistochemical expression increased significantly (p < 0.001) from normal to hyperplastic and from adenomatous polyps to carcinoma samples. DNMT3B expression correlated positively with SFRP2 methylation (r = 0.42, p < 0.001, 95% CI 0.25 to 0.56), but correlated negatively with IGF2 DMR0 methylation (r = 0.26, p = 0.01, 95% CI -0.45 to -0.05). A subset of the CIMP panel (NEUROG1, CACNA1G and CDKN2A) positively correlated with DNMT3B levels of expression (p < 0.05). CONCLUSION: Hierarchical epigenetic alterations occur at transition points during colorectal neoplastic progression. These cumulative changes are closely correlated with a gain of DNMT3B expression, suggesting a causal relationship.

A 4-gene signature predicts survival of patients with resected adenocarcinoma of the esophagus, junction, and gastric cardia.

BACKGROUND & AIMS: The incidence of esophageal and junctional adenocarcinoma has increased 6-fold in the past 30 years and 5-year survival remains approximately 20%. Current staging is limited in its ability to predict survival which has ramifications for treatment choices. The aim of this study was to generate and validate a molecular prognostic signature for esophageal adenocarcinoma. METHODS: Gene expression profiling was performed and the resulting 42,000 gene signatures correlated with clinical and pathologic features for 75 snap-frozen esophageal and junctional resection specimens. External validation of selected targets was performed on 371 independent cases using immunohistochemistry to maximize clinical applicability. RESULTS: A total of 119 genes were associated significantly with survival and 270 genes with the number of involved lymph nodes. Filtering of these lists resulted in a shortlist of 10 genes taken forward to validation. Four genes proved to be prognostic at the protein level (deoxycytidine kinase [DCK], 3'-phosphoadenosine 5'-phosphosulfate synthase 2 [PAPSS2], sirtuin 2 [SIRT2], and tripartite motif-containing 44 [TRIM44]) and were combined to create a molecular prognostic signature. This 4-gene signature was highly predictive of survival in the independent external validation cohort (0/4 genes dysregulated 5-year survival, 58%; 95% confidence interval [CI], 36%-80%; 1-2/4 genes dysregulated 5-year survival, 26%; 95% CI, 20%-32%; and 3-4/4 genes dysregulated 5-year survival, 14%; 95% CI, 4%-24% (P = .001). Furthermore, this 4-gene signature was independently prognostic in a multivariable model together with the existing clinical TNM staging system (P = .013). CONCLUSIONS: This study has generated a clinically applicable prognostic gene signature that independently predicts survival in an external validation cohort and may inform management decisions.

Meta-analysis showing the beneficial effect of α-blockers on ureteric stent discomfort.

UNLABELLED: What's known on the subject? and What does the study add? Ureteric stents cause significant discomfort and this is probably related to ureteric smooth muscle spasm and trigonal irritation. Alpha-adrenoceptor antagonists reduce smooth muscle activity and are already widely used in medical expulsive therapy to aid passage of ureteric calculi. This meta-analysis incorporating five randomized controlled trials provides evidence that alpha-adrenoceptor antagonists reduce stent-related pain and storage symptoms as assessed by the Ureteric Stent Symptoms Questionnaire (USSQ). OBJECTIVES: • To evaluate the efficacy of α-blockers with respect to improving stent-related symptoms. • Ureteric stents remain a source of marked discomfort and their placement is often required after certain ureteroscopic procedures or in the acute setting. This analysis identifies and reviews the several studies that have investigated the role of α-blockers after stent placement. MATERIALS AND METHODS: • Pubmed/Medline, EMBASE, CINAHL and Cochrane Library databases were scrutinized using standard MeSH headings. • Randomized or controlled trials comparing α-blockers with control or standard therapy were included. • In all studies, patients completed the Ureteral Stent Symptom Questionnaire (USSQ). • The study data were independently reviewed by two assessors. RESULTS: • In total, five studies of varying quality were identified, including 461 patients receiving either tamsulosin or alfuzosin, or control. • On meta-analysis, all five studies showed a reduction in USSQ urinary symptom score and body pain scores. There was mean reduction of 8.4 (95% CI, 5.6-11.1) in the urinary symptom score and 7.2 (95% CI, 2.5-11.8) in the body pain score. • In three studies, the numbers of patients experiencing stent related pain were stated: 45% (51/114) of patients receiving an α-blocker experienced painful episodes within the follow-up period defined for that study compared to 76% (88/116) in the control groups, which is equivalent to a relative risk of pain of 0.59 (95% confidence interval, 0.47-0.71). • There were also reductions in other aspects of the USSQ, such as the general health score and sexual matters score, although these were not statistically significant or uniformly reported. CONCLUSION: • There is evidence that α-blockers provide an improvement in discomfort after placement of a ureteric stent.

CD4+ and CD8+ T-lymphocyte scores cannot reliably predict progression in patients with benign prostatic hyperplasia.

OBJECTIVE: To determine whether the density of CD4(+) and CD8(+) T-lymphocytes in a transrectal ultrasonography (TRUS) biopsy of the prostate can be used to predict the progression of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: In total, 100 patients were randomly selected from a pool of patients with histologically proven, benign TRUS biopsy specimens. There were seven full years of follow-up available. Clinical data were recorded, including prostate volume, International Prostate Symptom Score (IPSS), prostate-specific antigen, urine flow rate, postvoid residual urine volume and previous prostate surgery. Markers of disease progression included the subsequent development of acute urinary retention (AUR), ≥4 point rise in IPSS, prescription of medical therapy (α-blocker or 5-α-reductase inhibitor) and bladder outlet surgery. Four patients' specimens were unsuitable for analysis. Biopsy sections from 96 patients were immunohistochemically stained for the presence of CD4(+) and CD8(+) T-lymphocytes and the density of infiltrate was assessed using random field sampling and point counting. RESULTS: Some 29% of patients (28/96) did not have BPH at the time of biopsy. Of all patients, 41% (39/96) progressed, 10% of whom (4/39) did not have BPH at the time of biopsy. A further 10% (10/96) developed AUR, 7% (7/96) had a ≥4 point rise in IPSS, 33% (32/96) required medical therapy for BPH and 11% (11/96) required bladder outlet surgery. There was low correlation between CD4(+) and CD8(+) densities in paired sections. CD4(+) and CD8(+) densities did not provide any significant predictive function in the progression of BPH, nor was their any predictive association noted between CD4(+) and CD8(+) scores and the development of prostate cancer. Sub-analysis did show that a threshold mean of ≥1.35 CD8(+) cells per field predicted progression to AUR with a sensitivity of 60% (95% confidence interval, CI, 26.2-87.8), specificity of 73.3% (95% CI 62.6-82.2) but a positive predictive value of 20.6% (95% CI 8.0-39.7). CD4(+) infiltrate density suggested a trend to general progression but without statistical significance. CONCLUSION: The present study, despite certain trends, shows no evidence for an association between CD4(+) and CD8(+) T-lymphocytes and the progression of LUTS in BPH.

First 500 cases of robotic-assisted laparoscopic radical prostatectomy from a single UK centre: learning curves of two surgeons.

OBJECTIVE: • To study the outcomes and learning curve of robotic-assisted laparoscopic radical prostatectomy (RALP) in a single centre by two surgeons. PATIENTS AND METHODS: • In total, 500 consecutive patients underwent RALP between 2005 and 2009 carried out by two surgeons. Using an ethically-approved database, prospective data collection of demographic, surgical, oncological and functional outcomes (patient reported) was performed, with up to 4 years of follow-up. • The learning curves of both surgeons were analyzed and, in addition, the first 100 and last 100 patients were compared to determine the effect of surgeon experience. RESULTS: • The mean age of the patients was 61.5 years and mean preoperative prostate-specific antigen was 7.0 µg/L. Clinical stages were T1 in 63.2%, T2 in 33.8% and T3 in 3.0% of patients. Median (range) operating time was 170 (63-420) min and median (range) blood loss was 200 (20-3000) mL, with significant improvements for both surgeons with increasing experience (P < 0.001 and P= 0.029, respectively). • Pathological stages were pT2 in 53.4%, pT3a in 41.6%, pT3b in 4.0% and pT4 in 0.6% of patients. Overall, the positive margin rate (PMR) was 24.0% and stage-specific rates were 16.1%, 30.4%, 55.0% and 100.0% for pT2, pT3a, pT3b and pT4 disease, respectively. In the last 50 cases performed by each surgeon, the PMRs for pT2 and pT3a disease were 8.0% and 19.1% (surgeon 1) and 12.9% and 23.5% (surgeon 2). • At 12 months of follow-up, 91.3% of patients were continent and, by 48 months of follow-up, 75% of men with preoperative potency who underwent bilateral nerve-sparing RALP were potent. CONCLUSION: • This is the first report of two surgeons' learning curves in a single centre and shows that key learning curve outcomes continued to improve during the series, suggesting that the learning curve for RALP may be longer than has been previously suggested.

Show the data, don't conceal them.

Current standards of data presentation and analysis in biological journals often fall short of ideal. This is the first of a planned series of short articles, to be published in a number of journals, aiming to highlight the principles of clear data presentation and appropriate statistical analysis. This article considers the methods used to show data, in particular the value of the dot plot, and methods to summarise the distribution of values. The uses of measures such as standard deviation, standard error of the mean, and confidence intervals are contrasted.

Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer.

The imprinted insulin-like growth factor 2 (IGF2) gene is expressed predominantly from the paternal allele. Loss of imprinting (LOI) associated with hypomethylation at the promoter proximal sequence (DMR0) of the IGF2 gene was proposed as a predisposing constitutive risk biomarker for colorectal cancer. We used pyrosequencing to assess whether IGF2 DMR0 methylation is either present constitutively prior to cancer or whether it is acquired tissue-specifically after the onset of cancer. DNA samples from tumour tissues and matched non-tumour tissues from 22 breast and 42 colorectal cancer patients as well as peripheral blood samples obtained from colorectal cancer patients [SEARCH (n=case 192, controls 96)], breast cancer patients [ABC (n=case 364, controls 96)] and the European Prospective Investigation of Cancer [EPIC-Norfolk (n=breast 228, colorectal 225, controls 895)] were analysed. The EPIC samples were collected 2-5 years prior to diagnosis of breast or colorectal cancer. IGF2 DMR0 methylation levels in tumours were lower than matched non-tumour tissue. Hypomethylation of DMR0 was detected in breast (33%) and colorectal (80%) tumour tissues with a higher frequency than LOI indicating that methylation levels are a better indicator of cancer than LOI. In the EPIC population, the prevalence of IGF2 DMR0 hypomethylation was 9.5% and this correlated with increased age not cancer risk. Thus, IGF2 DMR0 hypomethylation occurs as an acquired tissue-specific somatic event rather than a constitutive innate epimutation. These results indicate that IGF2 DMR0 hypomethylation has diagnostic potential for colon cancer rather than value as a surrogate biomarker for constitutive LOI.

CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection.

BACKGROUND & AIMS: Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection. METHODS: Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome. RESULTS: Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p=0.003), independent of male sex (p=0.04), CMV positivity (p=0.003), previous HBV infection (p=0.007), and age (p=ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p<0.001), portal tract inflammatory grade (p=0.035), prothrombin time (p<0.001) and bilirubin (p=0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p=0.009) with an age-adjusted hazard ratio of 0.93 (0.90-0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p=0.001) independent of other factors. CONCLUSIONS: CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.

Tumor recurrence following liver transplantation for hepatocellular carcinoma: role of tumor proliferation status.

The selection of patients with hepatocellular carcinoma for liver transplantation is currently based on the size and number of tumors to minimize the risk of recurrence. These criteria measure tumor bulk but may not reflect tumor behavior accurately. A biological marker of tumor behavior could aid with patient selection further. The aims of this study were to determine factors associated with a higher risk of tumor recurrence and to assess the role of tumor proliferation status with respect to recurrence following transplantation. Pathological data on 67 patients who underwent transplantation for hepatocellular carcinoma were reviewed, and tumor proliferation was assessed by minichromosome maintenance protein-2 (MCM-2) and cyclin A expression. A Cox regression analysis of factors related to tumor recurrence and overall survival was carried out. Recurrence-free survival was assessed according to compatibility with selection criteria, vascular invasion, and proliferation status. Tumor size, vascular invasion, and highest MCM-2 expression were associated with tumor recurrence by multivariate analysis (P < 0.02). Recurrence-free survival was significantly better for those patients without vascular invasion, those who were within the Milan, University of California San Francisco (UCSF), or Up-to-Seven selection criteria, and those with lower expression of MCM-2. In conclusion, tumors meeting the Milan, UCSF, or Up-to-Seven selection criteria had a lower rate of recurrence following liver transplantation. Vascular invasion and tumor proliferation status were associated with the risk of recurrence independently of tumor size. Biopsy of larger tumors to assess proliferative activity could identify those at lower risk of recurrence who could also benefit from liver transplantation.

Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake.

BACKGROUND: The Chernobyl accident caused an unprecedented increase in papillary thyroid carcinoma (PTC) incidence with a surprisingly short latency and unusual morphology. We have investigated whether unexpected features of the PTC incidence after Chernobyl were radiation specific or influenced by iodine deficiency. METHODS: PTCs from children from Belarus, Ukraine, and the Russian Federation exposed to fallout from Chernobyl were compared with PTCs from children not exposed to radiation from the same countries, from England and Wales (E&W) and from Japan. The degree and type of differentiation, fibrosis, and invasion were quantified. RESULTS: There were no significant differences between PTCs from radiation-exposed children from Belarus, Ukraine, and the Russian Federation and PTCs from children from the same countries who were not exposed to radiation. Childhood PTCs from Japan were much more highly differentiated (p < 0.001), showed more papillary differentiation (p < 0.001) and were less invasive (p < 0.01) than "Chernobyl" tumors, while tumors from E&W generally showed intermediate levels of degree and type of differentiation and invasion. There was a marked difference between the sex ratios of children with PTCs who were radiation exposed and those who were not exposed (F:M exposed vs. unexposed 1.5:1 vs. 4.2:1; chi(2) = 7.90, p < or = 0.01005). CONCLUSIONS: The aggressiveness and morphological features of Chernobyl childhood PTCs are not associated with radiation exposure. The differences found between tumors from the Chernobyl area, E&W, and Japan could be influenced by many factors. We speculate that dietary iodine levels may have wide implications in radiation-induced thyroid carcinogenesis, and that iodine deficiency could increase incidence, reduce latency, and influence tumor morphology and aggressiveness.

Prevalence, characteristics and outcomes of people aged 65 years and over with an incidental rise in cardiac troponin I. An observational prospective cohort study.

BACKGROUND: Cardiac troponin I (cTnI) is a sensitive and specific marker of acute cardiac damage. We examined the prevalence, characteristics and outcome of incidental cTnI rises in older patients. METHODS: One hundred and eighty-seven consecutive patients aged 65 years or over with a raised cTnI on admission at least 8 h after symptom onset were categorised into: (1) ST-elevation myocardial infarction, (2) other acute coronary syndromes (ACS), (3) other recognised non-ACS causes of cTnI rise and (4) non-ACS with no other identifiable cause (an incidental finding). The number of readmissions and deaths for each group was measured at 30 and 90 days. RESULTS: Age range = 65-98 years. Male = 55.6%. Fifty-four percent had a raised cTnI due to non-ACS illnesses, whilst in 18% it was an incidental finding. The latter group was relatively older and had a significantly lower degree of cTnI rise (U = 1718.5, p = 0.002), but a higher readmission and mortality rate compared to the other groups (categories 1-3) for both follow-up periods. CONCLUSIONS: Incidental cTnI rise is common in older patients and is associated with a poorer prognosis compared to ACS or a recognised non-ACS condition. Future research should attempt to evaluate the significance of such incidental rises in elderly patients.