A prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged ≥ 80 years after curative resection of colorectal cancer, the HiSCO-03 study.

PURPOSE: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥ 80 years. We conducted a prospective multi-institutional phase II study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. PATIENTS AND METHODS: Patients with stage III CRC aged ≥ 80 years who underwent curative resection were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1-28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. RESULTS: Sixty-nine patients were enrolled between 2013 and 2021. Of the 69 patients, 65 were included in the analysis. There were 32 males and 33 females with a median age of 82 years (range 80-88 years). In the primary endpoint, administration completion rate was 67.3% (95% confidence interval 54.9-77.6%), and the lower limit of the 95% confidence interval was below the threshold of 60%. 21 patients discontinued treatment because of adverse events (AEs) and refused treatment. The median relative dose intensities were 84% (range 4-100%) for UFT, and 100% (range 4-100%) for LV. Incidence of grade three or higher AEs were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). CONCLUSIONS: The indications for adjuvant UFT/LV therapy for elderly CRC aged ≥ 80 years were considered limited. It is necessary to clarify the background of patients in whom drug administration is discontinued and investigate their impact on long-term prognosis.

The Conventional Technique Versus the No-touch Isolation Technique for Primary Tumor Resection in Patients With Colon Cancer (JCOG1006): A Multicenter, Open-label, Randomized, Phase III Trial.

OBJECTIVE: This phase III trial evaluated whether the no touch was superior to the conventional in patients with cT3/T4 colon cancer. BACKGROUND: No touch involves ligating blood vessels that feed the primary tumor to limit cancer cell spreading. However, previous studies did not confirm the efficacy of the no touch. METHODS: This open-label, randomized, phase III trial was conducted at 30 Japanese centers. The eligibility criteria were histologically proven colon cancer; clinical classification of T3-4, N0-2, andM0; and patients aged 20 to 80years. Patients were randomized (1:1) to undergo open surgery with conventional or the no touch. Patients with pathological stage III disease received adjuvant capecitabine chemotherapy. The primary endpoint was disease-free survival (DFS) according to the intention-to-treat principle. RESULTS: Between January 2011 and November 2015, 853 patients were randomized to the conventional group (427 patients) or the no touch group (426 patients). The 3-year DFS were 77.3% [95% confidence interval (CI) 73.1%-81.0%] and 76.2% (95% CI 71.9%-80.0%) in the conventional and no touch groups, respectively. The superiority of no touch was not confirmed: hazard ratio for DFS = 1.029 (95% CI 0.800- 1.324; 1-sided P = 0.59). Operative morbidity was observed in 31 of 427 conventional patients (7%) and 26 of 426 no touch patients (6%). All grade adverse events were similar between the conventional and no touch groups. No in-hospital mortality occurred in either group. CONCLUSION: The present study failed to confirm the superiority of the no touch.

Effectiveness and safety of oral direct factor Xa inhibitors for the treatment of venous thromboembolism in patients with cancer and/or older age.

Venous thromboembolism (VTE) is a multifactorial disease. Cancer and older age are risk factors for both recurrent VTE and bleeding under anticoagulant therapy. Oral direct factor Xa inhibitors (Xa inhibitors) have been widely used to treat VTE. However, their effectiveness and safety in cancer and elderly patients have not been fully elucidated. A total of 187 consecutive patients who started Xa inhibitors for VTE therapy between September 2014 and September 2016 were recruited. Patients' demographics, changes in VTE amount, VTE recurrence, clinically relevant bleeding, and death until February 2017 were compared between 92 cancer and 95 non-cancer patients, and 57 elderly (≥ 75 years) and 130 non-elderly patients. Compared with non-cancer patients, cancer patients had a significantly higher incidence of deep vein thrombosis (DVT) in the proximal legs, superior vena cava, and upper extremities (p = 0.034), although the patients' demographics and incidence of pulmonary thromboembolism (PE) were similar between the two groups. There were no significant differences in VTE recurrence (p = 0.328) and clinically relevant bleeding (p = 0.078) between the two groups. Death occurred in 29 cancer patients, 23 of whom died of cancer, while there were no deaths among the non-cancer patients. Elderly patients had a lower body weight and creatinine clearance than non-elderly patients. No significant differences between the two groups were found in relation to PE (p = 0.544), DVT site (p = 0.054), recurrent VTE (p = 0.194), clinically relevant bleeding (p = 0.130) and death (p = 0.241). In comparisons among the four groups (elderly and non-elderly patients with and without cancer), recurrent VTE and clinically relevant bleeding were comparable (p = 0.493 and 0.227, respectively), while death was more frequent in cancer patients regardless of age (p < 0.001). The efficacy and safety of Xa inhibitors as VTE treatment were comparable between cancer and non-cancer patients, and in elderly and non-elderly patients. This suggests that Xa inhibitors may be promising drugs for VTE treatment, irrespective of age and comorbid cancer.

Lower Circulating Omega-3 Polyunsaturated Fatty Acids Are Associated with Coronary Microvascular Dysfunction Evaluated by Hyperemic Microvascular Resistance in Patients with Stable Coronary Artery Disease.

The consumption of omega-3 polyunsaturated fatty acids (PUFAs) reduces the incidence of cardiovascular events and sudden cardiac death. Coronary microvascular dysfunction (CMD) is a predictor of cardiac mortality, but little information is known on the relationship between CMD and omega-3 PUFAs. This study aimed to identify the relationship between the serum levels of omega-3 PUFAs and the CMD evaluated by the hyperemic microvascular resistance index (hMVRI) to assess coronary microvascular function in patients with stable coronary artery disease (CAD).Intracoronary physiological variables (fractional flow reserve (FFR), hMVRI, mean distal coronary pressure (Pd), and average peak velocity (APV)) were measured in 108 patients. These parameters were evaluated in 150 coronary arteries with stenosis of intermediate severity and without significant ischemia (FFR > 0.80). The PUFA levels and atherosclerotic risk factors were also measured. Univariate analysis shows that hMVRI was negatively correlated with eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (ß = -0.31, P = 0.001) and EPA (ß = -0.25, P = 0.009) and was positively correlated with dihomo-γ-linolenic acid (ß = 0.26, P = 0.006). Multivariate regression analysis shows that the EPA/AA ratio was the only independent determinant of hMVRI (ß = -0.234, SE = 0.231, P = 0.024). Furthermore, hMVRI decreased significantly from the lowest to highest tertiles of the EPA/AA ratio (P = 0.007). The EPA/AA ratio was positively correlated with APV at hyperemia (ß = 0.26, P = 0.008) but not with Pd at hyperemia.A lower serum EPA/AA ratio may cause CMD in patients with stable CAD.

Neurofeedback Control of the Human GABAergic System Using Non-invasive Brain Stimulation.

Neurofeedback has been a powerful method for self-regulating brain activities to elicit potential ability of human mind. GABA is a major inhibitory neurotransmitter in the central nervous system. Transcranial magnetic stimulation (TMS) is a tool that can evaluate the GABAergic system within the primary motor cortex (M1) using paired-pulse stimuli, short intracortical inhibition (SICI). Herein we investigated whether neurofeedback learning using SICI enabled us to control the GABAergic system within the M1 area. Forty-five healthy subjects were randomly divided into two groups: those receiving SICI neurofeedback learning or those receiving no neurofeedback (control) learning. During both learning periods, subjects made attempts to change the size of a circle, which was altered according to the degree of SICI in the SICI neurofeedback learning group, and which was altered independent of the degree of SICI in the control learning group. Results demonstrated that the SICI neurofeedback learning group showed a significant enhancement in SICI. Moreover, this group showed a significant reduction in choice reaction time compared to the control group. Our findings indicate that humans can intrinsically control the intracortical GABAergic system within M1 and can thus improve motor behaviors by SICI neurofeedback learning. SICI neurofeedback learning is a novel and promising approach to control our neural system and potentially represents a new therapy for patients with abnormal motor symptoms caused by CNS disorders.

Combined effects of repeated sauna therapy and exercise training on cardiac function and physical activity in patients with chronic heart failure.

PURPOSE: We investigated the combined effects of repeated sauna therapy and exercise training on subjective symptoms, cardiac function, daily activities and ambulation capacity in patients with chronic heart failure. METHODS: Fifty four patients including 26 patients with repeated sauna therapy and exercise training (combined therapy group) and 28 patients with repeated sauna therapy (monotherapy group) participated in the study. Repeated sauna therapy and exercise training were performed once a day, 5 days a week. Clinical symptoms, brain natriuretic peptide concentration, cardiac functions evaluated by echocardiography, cardiac size on chest radiography, Barthel Index (BI) and ambulation capacity were examined and compared between the time of hospital admission and the time of discharge. RESULTS: Both the groups showed significantly improved New York Heart Association functional class, cardiothoracic ratio, brain natriuretic peptide concentration, left ventricular ejection fraction, BI score and ambulation capacity grade. The changes of New York Heart Association functional class, BI score and ambulation capacity in the combined therapy group were a higher level of statistical significance than those in monotherapy group. Notably, significant between group difference was observed in the changes of BI score. CONCLUSIONS: The addition of exercise training programs to repeated sauna therapy may be efficient and effective for improvement of cardiac function and daily activities for patients with chronic heart failure. IMPLICATIONS OF REHABILITATION: Repeated sauna therapy is an effective means of improving cardiac, vascular function and mental health in CHF patients. Exercise training is an effective means of improving exercise capacity, thus improving ADL. Combination of repeated sauna therapy and exercise training may be recommended as a comprehensive treatment to improve cardiac function, ambulation capacity, and ADL in CHF patients.

IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells.

Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4(+) and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4(+) T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6(+) subset of CCR2(+) γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6(+) cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner.

Safety and efficacy of adjuvant therapy with oxaliplatin, leucovorin and 5-fluorouracil after mesorectal excision with lateral pelvic lymph node dissection for stage iii lower rectal cancer.

BACKGROUND/AIM: Preoperative chemoradiotherapy followed by total mesorectal excision (TME) is the standard treatment for stage III lower rectal cancer worldwide. However, in Japan, the standard treatment is TME with lateral pelvic lymph node dissection (LPLD) followed by adjuvant chemotherapy. We examined the safety and efficacy of adjuvant therapy with oxaliplatin, leucovorin, and 5-fluorouracil (modified FOLFOX6) after TME with LPLD. PATIENTS AND METHODS: This retrospective study included 33 patients who received modified FOLFOX6 after TME with LPLD for stage III lower rectal cancer. RESULTS: The overall completion rate of 12 cycles of adjuvant modified FOLFOX6 was 76%. Grade 3 or 4 neutropenia was observed in eight patients (24%). Sensory neuropathy was observed in 32 patients (97%) with 4 (12%) having a grade 3 event. The disease-free survival (DFS) rate was 45% at 3 years. CONCLUSION: Adjuvant modified FOLFOX6 was feasible in patients with stage III lower rectal cancer after TME with LPLD.

Pharmacokinetics of docetaxel during hyperthermic intraperitoneal chemotherapy for peritoneal metastasis.

UNLABELLED: The purpose of this manuscript is to report the pharmacokinetics of docetaxel during hyperthermic intraperitoneal chemotherapy (HIPEC) after peritonectomy. MATERIALS AND METHODS: Eleven patients with peritoneal metastasis (PM) underwent peritonectomies combined with 40 min of HIPEC with 40 mg/body of docetaxel. The pharmacokinetics of docetaxel were studied by using high-performance liquid chromatography. RESULTS: The docetaxel concentration at the start of HIPEC (0 min) was 9.084 ± 0.972 mg/L. The concentration gradually decreased to 5.599 ± 0.458 mg/L 40 min after HIPEC. In contrast, serum docetaxel levels increased during HIPEC, reaching a maximum level of 0.1334 ± 0.0726 mg/L at 40 min. The clearance (CLp) was 3.164 ± 1.383 L/hr, and the area under the curve (AUC) ratio was 95.12 ± 87.32. The AUC ratio of less-extensive peritonectomies was significantly higher than that of extended peritonectomies. The docetaxel concentration in the tumor tissue increased at 40 min (4.45 mg/gr). The apparent permeability (Papp, 40 min) was 1.47 ± 0.67 mm/40 min. No severe adverse effects were observed after HIPEC. CONCLUSION: From these results, 40 mg is a safe dose for docetaxel combined with HIPEC, and the locoregional intensity of docetaxel is enough to control PM less than 1.47 mm in diameter.

The role of zinc in the treatment of taste disorders.

In the 1990s the number of patients diagnosed with taste disorders in the USA and Japan was over one million people each year, and the number is increasing annually. Taste disorders are caused by several factors such as genetic disease, head trauma, structural changes, glossodynia, cancer, change of lifestyle, and more. The role of zinc in the treatment of taste disorders has been studied since the oral administration of zinc by patients was reported to improve their taste disorders. Carbonic anhydrase (CA), a zinc metalloenzyme, has also been studied in association with taste disorders, since the regulation of serum CA levels was shown to influence the effect of orally administrated zinc in the treatment of taste disorders. Zinc is an essential trace element that contributes to the active center of approximately 300 enzymes. Studies have revealed that zinc is involved in various physiological functions. Moreover, some medications have been shown to induce a zinc deficiency, which has been associated with a variety of clinical conditions. Hence, since the relationship between taste disorder and serum zinc concentration has been discussed for long time, taste disorder may be useful in diagnosing zinc deficiency. Moreover, it appears that medicines of the zinc-containing supplement type contribute to the treatment of taste disorders caused by zinc deficiency. Orally administered zinc has been shown to directly stimulate food intake via neuropeptide in the hypothalamus. Therefore, zinc administration may potentially be used to treat taste disorders, as well as several other diseases by stimulating feeding. The article presents some promising patents on the role of zinc in the treatment of taste disorders.

The roles of salivary secretion, brain-gut peptides, and oral hygiene in obesity.

Obesity has a prevalence of 15-30% among European and American populations. It is an incurable chronic disease associated with considerable mortality and co-morbidity. The co-morbidity risk can be reduced substantially by a moderate weight loss of 5-15%. Notably, additional weight gain exacerbates the morbidity of any concurrent disease. Obesity is also recognized as the basis for metabolic syndrome. Recent research has shown that adipocytes secrete various hormones and cytokines that contribute to obesity. Leptin is an adipostatic hormone that acts on receptors in the hypothalamus to suppress food intake and increase energy consumption. Reduced sensitivity to this molecule can trigger the onset of obesity. Neuropeptides such as leptin also affect salivary secretion. Various neuropeptides have been identified in saliva; the associated receptors are located in the salivary glands or in the nerves innervating the salivary glands. Obesity is associated with hyposalivation and thereby related to several aspects of oral health, such as caries and periodontitis. Hyposalivation is a severe morbidity that can lead to a precipitous decline in oral hygiene, which further leads to multifocal dental caries and periodontitis, or even cardiac disorders. In this article, we review the relationship between salivary secretion and neuropeptides known to play a role in obesity.

[Current practices of perioperative nutritional therapy in colorectal surgery].

Earlier oral intake after colorectal surgery can be achieved effectively with laparoscopic procedures. "Fast track" or "enhanced recovery after surgery" programs have attempted to reduce the physiologic stress of surgery. Perioperative care in such programs includes drinking a carbohydrate-rich beverage 2 hours before surgery and oral liquid intake on the day of surgery. Early restoration of gastrointestinal function can reduce postoperative complications and the length of hospital stays.

Short-term effects of thermotherapy for spasticity on tibial nerve F-waves in post-stroke patients.

Thermotherapy is generally considered appropriate for post-stroke patients with spasticity, yet its acute antispastic effects have not been comprehensively investigated. F-wave parameters have been used to demonstrate changes in motor neuron excitability in spasticity and pharmacological antispastic therapy. The present study aimed to confirm the efficacy of thermotherapy for spasticity by evaluating alterations in F-wave parameters in ten male post-stroke patients with spastic hemiparesis (mean age: 49.0+/-15.0 years) and ten healthy male controls (mean age: 48.7+/-4.4 years). The subjects were immersed in water at 41 degrees C for 10 min. Recordings were made over the abductor hallucis muscle, and antidromic stimulation was performed on the tibial nerve at the ankle. Twenty F-waves were recorded before, immediately after, and 30 min following thermotherapy for each subject. F-wave amplitude and F-wave/M-response ratio were determined. Changes in body temperature and surface-skin temperature were monitored simultaneously. The mean and maximum values of both F-wave parameters were higher on the affected side before thermotherapy. In the post-stroke patients, the mean and maximum values of both parameters were significantly reduced after thermotherapy (P<0.01). Hence, the antispastic effects of thermotherapy were indicated by decreased F-wave parameters. Body temperature was significantly increased both immediately after and 30 min after thermotherapy in all subjects. This appeared to play an important role in decreased spasticity. Surface-skin temperature increased immediately after thermotherapy in both groups and returned to baseline 30 min later. These findings demonstrate that thermotherapy is an effective nonpharmacological antispastic treatment that might facilitate stroke rehabilitation.

Modulation of bone turnover by alfacalcidol and/or alendronate does not prevent glucocorticoid-induced osteoporosis in growing minipigs.

The study was performed to clarify the effects of active vitamin D (alfacalcidol) and/or alendronate (ALN) on bone tissue turnover in glucocorticoid (GC)-treated growing minipigs. Göttingen minipigs aged 8 months were divided into six groups (n = 5 each): group BC, killed for baseline control; group GC, injected subcutaneously with prednisolone (0.5 mg/kg body weight [BW] per day, 5 days/week for 24 weeks); group VC, treated with vehicle alone; group alf, treated with oral alfacalcidol at 0.1 microm/kg BW per day, 5 days/week; group ALN, treated with alendronate 1 mg/kg BW per day; and group alf* ALN, treated with both alf and ALN as above. Biochemical examinations dual-energy X-ray absorptiometry, micro-computed tomography, peripheral quantitative computed tomography, and histomorphometry were performed. In group GC, all bone chemical markers were lower than in group VC. GC treatment reduced the age-dependent augmentation of bone mass and structure by reducing the bone formation rate (BFR) and activation frequency (Ac.f) relative to VC in lumbar bone and femoral cortex. Trabecular and osteonal wall thickness values did not change by GC. Treatments with alf, ALN, and alf* ALN did not have substantial effects on bone mass or structure. Alf treatment maintained lumbar BFR and Ac.f, while ALN reduced osteoclasts. Femoral cortical Ac.f values were not affected by these treatments. GC caused reduced bone formation, leading to low tissue turnover and imbalance of bone formation and resorption. Modulation of bone tissue turnover by alfacalcidol and/or alendronate failed to maintain the growth-dependent increases in mass and structure in GC-treated young minipigs.

Regulation of mineral-to-matrix ratio of lumbar trabecular bone in ovariectomized rats treated with risedronate in combination with or without vitamin K2.

The relationship between bone turnover and bone tissue and material properties was examined in ovariectomized (OVX) rats treated with risedronate in combination with or without vitamin K2. Seventy female rats, 18 weeks of age, were assigned to 7 groups (n=10): sham-operated + vehicle control; OVX + vehicle control; OVX + risedronate 0.1, 0.5, or 2.5 mg/kg/day po; OVX + vitamin K2 approximately 30 mg/kg/day po; OVX + vitamin K2 (approximately 30 mg/kg/day) and risedronate (0.5 mg/kg/day). Treatments were given daily for 9 months. To assess bone turnover, we measured serum osteocalcin and urinary deoxypyridinoline at 0, 3, and 9 months. To assess vertebral and femoral tissue and material properties, bone mass, bone mineral density (BMD by DXA), trabecular bone structure (vertebra: 3D-microCT), cortical bone structure (femur: histomorphometry), biomechanical properties, and mineral properties (mineral-to-matrix and carbonate-to-phosphate ratios by Fourier transform infrared microspectroscopy) were measured ex vivo at 9 months. Ovariectomy increased bone turnover and induced significant loss of bone mass/density, structure, mineral properties (mineral-to-matrix ratio), and strength. Risedronate produced dose-dependent inhibition of the ovariectomy-induced increase in turnover and loss of bone mass/density, structure, mineral-to-matrix ratio, and strength, with a lowest effective dose of 0.1-0.5 mg/kg/day. High-dose risedronate (2.5 mg/kg/day) did not induce increases in any parameter above that of sham control. Vitamin K2 had no effects. In the OVX groups, urinary deoxypyridinoline at 3 and 9 months correlated significantly with vertebral BMD, trabecular bone volume, ultimate load, stiffness, and mineral-to-matrix ratio, and with femoral BMD, cortical area, and ultimate load. These results support the concept that changes in bone tissue and material properties can result directly from changes in bone turnover. Different effects among different drugs on material properties, including mineral-to-matrix ratio, may reflect differences in the relative rate and magnitude of osteoclastic bone resorption and osteoblastic primary bone mineralization.