Long-term follow-up of the randomized trial of mesorectal excision with or without lateral lymph node dissection in rectal cancer (JCOG0212).

BACKGROUND: Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non-inferiority phase III trial of patients with clinical stage II-III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence-free survival (RFS). The planned primary analysis at 5 years failed to confirm the non-inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long-term follow-up data from JCOG0212. METHODS: Patients with clinical stage II-III rectal cancer below the peritoneal reflection and no lateral pelvic lymph node enlargement were included in this study. After surgeons confirmed R0 resection by ME, patients were randomized to receive ME alone or ME with LLND. The primary endpoint was RFS. RESULTS: A total of 701 patients from 33 institutions were assigned to ME with LLND (351) or ME alone (350) between June 2003 and August 2010. The 7-year RFS rate was 71.1 per cent for ME with LLND and 70·7 per cent for ME alone (hazard ratio (HR) 1·09, 95 per cent c.i. 0·84 to 1·42; non-inferiority P = 0·064). Subgroup analysis showed improved RFS among patients with clinical stage III disease who underwent ME with LLND compared with ME alone (HR 1·49, 1·02 to 2·17). CONCLUSION: Long-term follow-up data did not support the non-inferiority of ME alone compared with ME and LLND. ME with LLND is recommended for patients with clinical stage III disease, whereas LLND could be omitted in those with clinical stage II tumours.

ANTECEDENTES: El JCOG0212 (ClinicalTrials.gov: NCT00190541) fue un ensayo fase III de no inferioridad en pacientes con cáncer de recto en estadio clínico II/III sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. El ensayo comparó la escisión del mesorrecto (mesorectal excision, ME) con la ME con disección de los ganglios linfáticos laterales (lateral lymph node dissection, LLND), siendo el criterio de valoración principal la supervivencia libre de recidiva (recurrence free survival, RFS). El análisis primario planificado a los 5 años de seguimiento no pudo confirmar la no inferioridad de la ME frente a la ME con LLND. Este estudio tuvo como objetivo comparar la ME como procedimiento único y la ME con LLND utilizando datos de seguimiento a largo plazo del ensayo JCOG0212. MÉTODOS: En este estudio se incluyeron pacientes con cáncer de recto en estadio clínico II/III por debajo de la reflexión peritoneal sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. Después de que los cirujanos confirmaran la resección R0 mediante la ME, los pacientes fueron asignados al azar al brazo de ME sola o al brazo de ME con LLND. El criterio de valoración principal fue la supervivencia libre de recidiva (RFS). RESULTADOS: Un total de 701 pacientes de 33 instituciones fueron asignados al azar para ser tratados mediante una ME con LLND (n = 351) o EM sola (n = 350) entre junio de 2003 y agosto de 2010. Las tasas de RFS a 7 años fueron del 71,1% para ME con LLND y 70,7 % para ME sola (cociente de riesgos instantáneos, hazard ratio, HR: 1,09 (i.c. del 95% 0,84-1,42), no inferioridad P = 0,064)). El análisis de subgrupos mostró una mejor RFS entre los pacientes en estadio clínico III que se sometieron a ME con LLND en comparación con ME sola (HR: 1,49 (i.c. del 95%: 1,02-2,17)). CONCLUSIÓN: Los datos de seguimiento a largo plazo no justificaron la no inferioridad de la ME en comparación con la ME con LLND. Se recomienda la ME con LLND para pacientes en estadio clínico III, mientras que LLND podría omitirse para pacientes en estadio clínico II.

Independent Factors Contributing to Daytime and Nighttime Asthmatic Cough Refractory to Inhaled Corticosteroids.

BACKGROUND: Cough is a common feature of asthma, which is often resistant to inhaled corticosteroids (ICSs). The pathophysiology of this refractoriness may differ between daytime and nighttime asthmatic cough. We sought to identify factors contributing to ICS-refractory daytime and nighttime asthmatic cough. METHODS: Sixty-seven patients with asthma presenting solely or predominantly with chronic cough were prospectively enrolled from April 2012 to December 2014. At baseline and 12 weeks after ICS treatment, the capsaicin cough threshold (C2, C5) and methacholine airway sensitivity and reactivity were examined. A visual analog scale (VAS) and numeric scores were used to evaluate daytime and nighttime cough symptoms separately. The Japanese version of the Leicester Cough Questionnaire was also completed. When either the VAS or numeric scores showed an improvement of ≥50% or ≥2 points, patients were considered responders to ICS treatment. RESULTS: Fifty-five patients were eligible for evaluation. Subjective cough indices improved significantly at 12 weeks after ICS treatment (P<.001). Multivariate analysis revealed that lower C2 significantly contributed to residual daytime cough (P=.04). Meanwhile, methacholine hyperreactivity and lower IgE levels were predictors of the nighttime residual cough (P=.002 and P=.03, respectively). CONCLUSIONS: Heightened cough reflex sensitivity is an independent factor of daytime asthmatic cough that is refractory to ICSs. In contrast, airway hyperreactivity and less atopic status contribute to ICS-refractory nighttime cough.

IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.

BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness. METHODS: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations. RESULTS: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels. CONCLUSION: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment.

Mouth breathing, another risk factor for asthma: the Nagahama Study.

BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Smoking attenuates the age-related decrease in IgE levels and maintains eosinophilic inflammation.

BACKGROUND: Epidemiological studies have shown that smoking increases the propensity for atopy and asthma. However, the effects of smoking on atopy and eosinophilic inflammation in asthmatics, including the elderly, remain unknown. OBJECTIVE: To determine the effects of smoking on serum immunoglobulin E (IgE) levels and eosinophilic inflammation in asthmatics of all ages. METHODS: The associations of serum IgE levels, blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels with smoking and age in steroid-naive asthmatics were cross-sectionally assessed (n = 307). Levels of sputum eosinophil and thymic stromal lymphopoietin (TSLP) that promotes Th2 inflammation were also analysed. Current smokers were excluded when analysing contributing factors of FeNO. RESULTS: Levels of serum IgE, blood eosinophil and FeNO decreased with increasing age in never-smokers, whereas decrease in serum IgE levels with increasing age was not observed in current smokers. In addition, current smoking was associated with higher blood eosinophil counts. In atopic asthmatics, age-related declines in serum IgE levels were less steep in ex-smokers than in never-smokers, and atopic ex-smokers with asthma showed higher blood eosinophil counts and higher FeNO irrespective of age. Lastly, sputum TSLP levels were associated with sputum eosinophil proportions and pack-years. Current and ex-smokers had higher TSLP levels than never-smokers. CONCLUSIONS AND CLINICAL RELEVANCE: In steroid-naive asthmatics, smoking may attenuate the age-related decrease in IgE levels and maintain eosinophilic inflammation, in which TSLP may be involved.

Nomograms predicting survival and recurrence in colonic cancer in the era of complete mesocolic excision.

Background: More extensive lymphadenectomy may improve survival after resection of colonic cancer. Nomograms were created predicting overall survival and recurrence for patients who undergo D2-D3 lymph node dissection, and their validity determined. Methods: This was a multicentre study of patients with colonic cancer who underwent resection with D2-D3 lymph node dissection in Japan. Inclusion criteria included R0 resection. A training cohort of patients operated on from 2007 to 2008 was analysed to construct prognostic models predicting survival and recurrence. Discrimination and calibration were performed using an external validation cohort from the Japanese colorectal cancer registry (procedures in 2005-2006). Results: The training cohort consisted of 2746 patients. Predictors of survival were: age (hazard ratio (HR) 1·04), female sex (HR 0·71), depth of tumour invasion (HR 1·15, 1·22, 2·96 and 3·14 for T2, T3, T4a and T4b respectively versus T1), lymphatic invasion (HR 1·11, 1·15 and 2·95 for ly1, ly2 and ly3 versus ly0), preoperative carcinoembryonic antigen (CEA) level (HR 1·21, 1·59 and 1·99 for 5·1-10·0, 10·1-20·0 and 20·1 and over versus 0-5·0 ng/ml), number of metastatic lymph nodes (HR 1·07), number of lymph nodes examined (HR 0·98) and extent of lymphadenectomy (HR 0·23, 0·13 and 0·11 for D1, D2 and D3 versus D0). Predictors of recurrence were: female sex (HR 0·82), macroscopic type (HR 3·82, 4·56, 6·66, 7·74 and 3·22 for types I, II, III, IV and V versus type 0), depth of invasion (HR 1·25, 2·66, 5·32 and 6·43 for T2, T3, T4a and T4b versus T1), venous invasion (HR 1·43, 3·05 and 4·79 for v1, v2 and v3 versus v0), preoperative CEA level (HR 1·39, 1·43, 1·56 and 1·85 for 5·1-10·0, 10·1-20·0, 20·1-40·0 and 40·1 or more versus 0-5 ng/ml), number of metastatic lymph nodes (HR 1·07) and number of lymph nodes examined (HR 0·98). The validation cohort comprised 4446 patients. The internal and external validated Harrell's C-index values for the nomogram predicting survival were 0·75 and 0·74 respectively. Corresponding values for recurrence were 0·78 and 0·75. Conclusion: These nomograms could predict survival and recurrence after curative resection of colonic cancer.

Male sexual dysfunction after rectal cancer surgery: Results of a randomized trial comparing mesorectal excision with and without lateral lymph node dissection for patients with lower rectal cancer: Japan Clinical Oncology Group Study JCOG0212.

BACKGROUND: We conducted a randomized controlled trial (JCOG0212) to determine whether the outcome of mesorectal excision (ME) alone for rectal cancer is not inferior to that of ME with lateral lymph node dissection (LLND). The present study focused on male sexual dysfunction after surgery. METHODOLOGY: Eligibility criteria included clinical stage II/III rectal cancer, the lower margin of the lesion below the peritoneal reflection, the absence of lateral pelvic lymph node enlargement, and no preoperative radiotherapy. After confirmation of R0 resection by ME, patients were intraoperatively randomized. Questionnaires using the International Index of Erectile Function (IIEF-5) about the sexual function of men were collected before and 1 year after surgery. Sexual dysfunction incidence was defined as the ratio of patients showing sexual dysfunction after surgery relative to the number who had no erectile dysfunction before surgery. RESULTS: Among 701 patients enrolled between June 2003 and August 2010, 472 males were included. Among them, 343 (73%) completed preoperative and postoperative questionnaires. According to the study protocol, the incidences of sexual dysfunction in patients who underwent ME alone and ME with LLND were 68% (17/25; 95%CI, 47-85%) and 79% (23/29; 95%CI, 60-92%), respectively (p = 0.37). Incidences of sexual dysfunction in patients with no or only mild erectile dysfunction before surgery who underwent ME alone and ME with LLND were 59% (48/81) and 71% (67/95), respectively (p = 0.15). Multivariate analysis identified age as the only risk factor for sexual dysfunction after surgery (p = 0.02). CONCLUSIONS: LLND may not increase sexual dysfunction incidence after rectal cancer surgery. This incidence is associated with increased age. This trial is registered with ClinicalTrials.gov, number NCT00190541 and University Hospital Medical Information Network Clinical Trials Registry, number C000000034.

Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer.

Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.

Unconstrained detection of respiration rhythm and pulse rate with one under-pillow sensor during sleep.

A completely non-invasive and unconstrained method is proposed to detect respiration rhythm and pulse rate during sleep. By employing wavelet transformation (WT), waveforms corresponding to the respiration rhythm and pulse rate can be extracted from a pulsatile pressure signal acquired by a pressure sensor under a pillow. The respiration rhythm was obtained by an upward zero-crossing point detection algorithm from the respiration-related waveform reconstructed from the WT 2(6) scale approximation, and the pulse rate was estimated by a peak point detection algorithm from the pulse-related waveform reconstructed from the WT 2(4) and 2(5) scale details. The finger photo-electric plethysmogram (FPP) and nasal thermistor signals were recorded simultaneously as reference signals. The reference pulse rate and respiration rhythm were detected with the peak and upward zero-crossing point detection algorithm. This method was verified using about 24 h of data collected from 13 healthy subjects. The results showed that, compared with the reference data, the average error rates were 3.03% false negative and 1.47% false positive for pulse rate detection in the extracted pulse waveform. Similarly, 4.58% false negative and 3.07% false positive were obtained for respiration rhythm detection in the extracted respiration waveform. This study suggests that the proposed method is suitable, in sleep monitoring, for the diagnosis of sleep apnoea or sudden death syndrome.

[Treatment of solid tumor by a direct electric current].

This is a case report of a 37-year-old Japanese married female with laryngeal sarcoma, treated by direct electric current so as to obtain remission for more than 4 years without signs of recurrence. Due to her hoarseness and laryngeal numb feeling she underwent a laryngeal examination including a biopsy, resulting in a diagnosis of sarcoma. She refused a total laryngectomy and was given Cobalt treatment of 40 Grey. In the following several months, no improvement was observed, objectively or subjectively. In Nagoya University Hospital the patient then received direct electric current therapy of 36 Coulombs through two platinum electrodes inserted into the tumor under a CT guide, pericutaneously. Two months later, as the hoarseness remained in spite of some improvement, she underwent another session of direct electric current therapy of 14.4 Coulombs through the platinum electrodes by bronchoscope-guided direct insertion. Her hoarseness soon disappeared thereafter and there was a regression of the tumor in 6 months. She did well thereafter without any signs of recurrence for 4 years. Clinical treatment of solid tumors with electric treatment with direct electric current has been done in more than 8,000 cases with CR in 25% of all cases and PR in 50%. Its mechanism, however, remains unclear. In our experimental animal studies, apoptosis was observed. It is considered that this electric therapy using direct electric current will be recognized as one method to treat solid tumors.

[Quantitation of mRNA in micro-samples of the brain by competitive PCR: analysis of expression of interleukin-1 beta mRNA in rat hypothalamus and hippocampus after inflammatory or non-inflammatory stress].

Changes in the expressions of interleukin-1 beta (IL-1 beta) mRNA in the rat brain were investigated during inflammatory or non-inflammatory stress. We utilized competitive reverse transcription PCR (RT-PCR) to quantitate precisely the minute amount of IL-1 beta mRNA in small tissues which were micro-punched out from discrete sites in the brain. Intraperitoneal injection of lipopolysaccharide (100 micrograms/kg) caused a widespread and high elevation of IL-1 beta mRNA in the hypothalamus, hippocampus and cerebral cortex. Immobilization stress significantly increased IL-1 beta mRNA only in the hypothalamus, when examined in the brain block samples, which reached a peak 30 minutes after the start of stress. However, examination of the small tissues punched out from discrete sites in the brain revealed a profound elevation of IL-1 beta mRNA in the CA1 region of the hippocampus and in all the hypothalamic nuclei examined 30 minutes after the start of immobilization stress, but not in the CA3 region and the dentate gyrus or cerebral cortex. The method shown in this report proved to be useful and may be applied to quantify the low amount of mRNA in the small areas in the brain.