Management of elderly patients with unresectable pancreatic cancer.

Systemic chemotherapy plays important role in pancreatic cancer not only for palliative treatment of unresectable disease, but also for neoadjuvant and adjuvant treatment of resectable disease. Most clinical trials of systemic chemotherapy have been conducted in non-elderly patients, and the results cannot always be extrapolated to elderly patients because of the uniqueness of this population. The number of elderly patients with pancreatic cancer has increased in an aging society; therefore, there is an urgent need to develop specific treatments for elderly patients with pancreatic cancer. Gemcitabine or S-1 monotherapy is generally considered appropriate even for vulnerable elderly patients. FOLFIRINOX is considered inapplicable based on its safety profile. Gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan with fluorouracil plus folinic acid can be administered to elderly patients, because the phase III trials have shown the efficacy and safety for patients including those who were 75 years or older. However, the feasibility of these therapies for elderly patients is still under debate since the number of elderly populations was relatively small in these studies. To determine the indication for these regimens in the elderly, the background of each patient should be considered. Geriatric assessment such as the Geriatric 8 and the Geriatric Nutritional Risk Index can identify vulnerabilities and are therefore recommended in daily clinical practice as well as in clinical studies of elderly patients. It is expected that geriatric assessment will elucidate the eligibility criteria for those regimens in elderly individuals. Randomized clinical trials are ongoing to establish a standard treatment in the vulnerable elderly with advanced pancreatic cancer, who cannot tolerate the same regimen as in the non-elderly patients.

Systemic therapy for hepatocellular carcinoma: current status and future perspectives.

Since sorafenib was established as the standard of care for patients with advanced hepatocellular carcinoma, various tyrosine kinase inhibitors, targeting vascular endothelial growth factor receptor and other molecular growth factors, have been developed. Lenvatinib demonstrated non-inferiority to sorafenib in terms of the overall survival, and it has also become confirmed as another standard of care for patients with advanced hepatocellular carcinoma. Recently, various immune checkpoint inhibitors have been investigated, either as monotherapy or in combination with another agent, and superiority of the combination of atezolizumab plus bevacizumab, in terms of the overall survival and progression-free survival, has been demonstrated over sorafenib, which is recognized as the treatment regimen of first choice for first-line systemic therapy of advanced hepatocellular carcinoma. Regorafenib, cabozantinib and ramucirumab have been demonstrated to show survival benefits as second-line treatment agents for progressive disease after first-line sorafenib treatment. There are still various medical requirements in systemic therapy for hepatocellular carcinoma. To date, no evidence has been established for the selection of sequential treatment after immune checkpoint inhibitor-containing treatments, especially atezolizumab plus bevacizumab. A promising treatment for Child-Pugh class B hepatocellular carcinoma patients is also an urgent medical need that has not yet been met. Although there are some difficulties in establishing the needed evidence, well-designed clinical trials are warranted.

Uptake of Metal (Zn, Y, Ti) Oxide Nanoparticles by Poaceae and Cucurbitaceae Plants Based On Metal Properties and Surface Conditions.

Metal nanoparticles (NPs) may serve as biomarkers, as the surfaces can be chemically modified to enable an analysis of several biosystems, including plant pathogenesis. We supplied metal oxide NPs including those of ZnO, TiO2, Y2O3, and Y2O3 doped with europium to plants of eight species of the Poaceae and Cucurbitaceae families. The plants were grown using hydroponics, where NPs were incorporated into the cultivation media. Energy-dispersive X-ray spectroscopy was used to detect the uptake of NPs by the plant in regions of the root, stem, and leaf. Results show that ZnO NPs were taken up more readily by the plants compared to other NPs. Unmodified NPs were only delivered up till the stems and not the leaves; however, when the surfaces were modified using photoinduced hydrophilization supplemented with poly(ethylene glycol), NPs were delivered to the leaves of plants. It is suggested that plants readily take up metals such as zinc that function as nutrients. Additionally, hydrophilization of NP surfaces using UV irradiation enhances uptake, where modified ZnO and TiO2 NPs may be delivered to the leaves. These findings may be used to design biomarker systems for detecting tissue damage and infections in various crops.

Integrated communication support program for oncologists, caregivers and patients with rapidly progressing advanced cancer to promote patient-centered communication: J-SUPPORT 1904 study protocol for a randomised controlled trial.

INTRODUCTION: Communication is an essential aspect of care for patients with progressive serious illnesses. This study aims to evaluate the efficacy of a new, integrated communication support program for oncologists, patients with rapidly progressing advanced cancer and their caregivers. METHODS AND ANALYSIS: The proposed integrated communication support programme is in the randomised control trial stage. It comprises a cluster of oncologists from comprehensive cancer centre hospitals in a metropolitan area in Japan. A total of 20 oncologists, 200 patients with advanced pancreatic cancer and the patients' caregivers are enrolled in this study as of the writing of this protocol report. Oncologists are randomly assigned to the intervention group (IG) or control group (CG). Patients and caregivers are allocated to the same group as their oncologists. The IG oncologists receive a 2.5-hour individual communication skills training, and patients and caregivers receive a half-hour coaching intervention to facilitate prioritising and discussing questions and concerns; the CG participants do not receive any training. Follow-up data will be collected quarterly for 6 months for a year and then annually for up to 3 years. The primary endpoint is the intergroup difference between before-intervention and after-intervention patient-centred communication behaviours during oncology visits. ETHICS AND DISSEMINATION: This study is conducted in accordance with the ethical guidelines for clinical studies published by Japan's Ministry of Education, Cultural, Sports, Science and Technology, the Ministry of Health, Labour and Welfare, and the ethical principles established for research on humans stipulated in the Declaration of Helsinki and further amendments thereto. The protocol was approved by the Institutional Review Board of National Cancer Center, Japan on 4 July 2018 (ID: 2017-474). TRIAL STATUS: This study is currently enrolling participants. Enrolment period ends 31 July 2020; estimated follow-up date is 31 March 2023. TRIAL REGISTRATION NUMBER: UMIN Clinical Trial Registry (UMIN000033612); pre-results.

Effects of concomitant neuromuscular electrical stimulation during repetitive transcranial magnetic stimulation before repetitive facilitation exercise on the hemiparetic hand.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) and Repetitive facilitative exercise (RFE) improves motor impairment after stroke. OBJECTIVE: To investigate whether neuromuscular electrical stimulation (NMES) can facilitate the effects of rTMS and RFE on the function of the hemiparetic hand in stroke patients. METHODS: This randomized double-blinded crossover study divided 20 patients with hemiparesis into two groups and provided treatment for 4 weeks at 5 days/week. NMES-before-sham group and NMES-following-sham group performed NMES sessions and sham NMES sessions for each 2 weeks. Patients received NMES or sham NMES for the affected extensor muscle concurrently with 1 Hz rTMS for the unaffected motor cortex for 10 min and performed RFE for 60 min. The Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), Box and Block Test (BBT) and Modified Ashworth Scale (MAS) were used for evaluation. RESULTS: FMA and ARAT improved significantly during both sessions. The gains in the BBT during an NMES session were significantly greater than those during a sham NMES session. MAS for the wrist and finger significantly decreased only during an NMES session. CONCLUSIONS: NMES combined with rTMS might facilitate, at least in part, the beneficial effects of RFE on motor function and spasticity of the affected upper limb.

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BACKGROUND: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. METHODS: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. TRIAL REGISTRATION: Registered at August 23, 2017. Registry number: UMIN000028801 .

TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial).

BACKGROUND: In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). PATIENTS AND METHODS: This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40-60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40-60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. RESULTS: A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82-1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67-0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. CONCLUSION: TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.

Inner ear hearing loss modulates ipsilateral temporal lobe activation by monaural speech stimuli.

We examined cortical activation by speech in patients with moderate inner ear hearing loss using PET to investigate the response of the language network to insufficient speech input. We made two word lists, well-perceived words and poorly-perceived words, and measured rCBF during monaural presentation of these words. Well-perceived words activated bilateral temporal lobes, bilateral inferior frontal gyri (IFG) and left angular gyrus (AG) regardless of the ear stimulated, Poorly-perceived words activated contralateral temporal lobe and bilateral IFG, while little or no activation was observed in the ipsilateral temporal lobe and left AG. Insufficient activation of the temporal lobe ipsilateral to the ear stimulated might correlated with less accurate word comprehension in patients with inner ear hearing loss.