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"Nakamura, Yoshio"
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Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget’s disease (EMPD-HER2DOC)
Abstract
Background
No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget’s disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD.
Methods
In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period.
Results
All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated.
Conclusion
The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).
This first prospective study provides new evidence for the treatment of metastatic extramammary Paget’s disease, which had no consensus on the optimal chemotherapy.
Journal Article
Mindfulness-Oriented Recovery Enhancement remediates anhedonia in chronic opioid use by enhancing neurophysiological responses during savoring of natural rewards
Neuropsychopharmacologic effects of long-term opioid therapy (LTOT) in the context of chronic pain may result in subjective anhedonia coupled with decreased attention to natural rewards. Yet, there are no known efficacious treatments for anhedonia and reward deficits associated with chronic opioid use. Mindfulness-Oriented Recovery Enhancement (MORE), a novel behavioral intervention combining training in mindfulness with savoring of natural rewards, may hold promise for treating anhedonia in LTOT.
Veterans receiving LTOT (
= 63) for chronic pain were randomized to 8 weeks of MORE or a supportive group (SG) psychotherapy control. Before and after the 8-week treatment groups, we assessed the effects of MORE on the late positive potential (LPP) of the electroencephalogram and skin conductance level (SCL) during viewing and up-regulating responses (i.e. savoring) to natural reward cues. We then examined whether these neurophysiological effects were associated with reductions in subjective anhedonia by 4-month follow-up.
Patients treated with MORE demonstrated significantly increased LPP and SCL to natural reward cues and greater decreases in subjective anhedonia relative to those in the SG. The effect of MORE on reducing anhedonia was statistically mediated by increases in LPP response during savoring.
MORE enhances motivated attention to natural reward cues among chronic pain patients on LTOT, as evidenced by increased electrocortical and sympathetic nervous system responses. Given neurophysiological evidence of clinical target engagement, MORE may be an efficacious treatment for anhedonia among chronic opioid users, people with chronic pain, and those at risk for opioid use disorder.
Journal Article
Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients
BackgroundCompletion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients.MethodsTotally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed.ResultsThe frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14–0.99; p = 0.047).ConclusionChanges in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient’s RFS while omitting immediate CLND had no significant negative influence on it.
Journal Article
Updates on the Systemic Treatment of Advanced Non-melanoma Skin Cancer
Non-melanoma skin cancers (NMSCs), which represent a diverse group of cutaneous malignancies, are the most common forms of human neoplasia. The incidence of these diseases is increasing due to a number of factors, including that of increasing human lifespans. The majority of NMSCs are basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC), with the remainder being various rare skin cancers, including extramammary Paget's disease (EMPD), Merkel cell carcinoma (MCC), and several skin adnexal carcinomas. Of these, MCC usually shows aggressive behavior with a high mortality rate. On the other hand, BCC, cSCC, EMPD, and skin adnexal tumors usually show an indolent clinical course and metastasize only rarely. Nevertheless, the metastatic forms of these tumors commonly lead to poor patient outcome. A definitive management strategy for the treatment of advanced NMSC has not been established, mainly due to their rarity and lack of reliable information based on well-controlled randomized trials. Chemotherapeutic regimens for treatment of these diseases have been mainly based on the observations of isolated, small case series or clinical trials with a limited numbers of patients. However, accumulating evidence regarding their pathobiological backgrounds as well as recent advances in molecular biotechnology have facilitated the development of novel drugs for treatment of these diseases. Over the past decade, the U.S. Food and Drug Administration has approved several molecular targeting therapies, including Hedgehog inhibitors for BCC, monoclonal antibodies targeting anti-programmed death ligand-1 and anti- programmed cell death 1 (PD-1) for MCC, and anti-PD-1 for cSCC. Here, we review their clinical utility and discuss updated systemic treatment strategies for advanced NMSC.
Journal Article
Nivolumab for unresectable cutaneous epithelial malignancies: an open-label, single-arm, multi-centre, phase II trial (NMSC-PD1)
Background
Data in East Asian patients and in other epithelial skin cancers, including extramammary Paget’s disease (EMPD) and adnexal carcinomas, are scarce. Therefore, we conducted a phase II trial of nivolumab in Japanese patients with advanced non-melanoma skin cancers (NMSCs).
Patients and methods
This multicentre, open-label, single-arm phase II study enrolled adults (≥ 20 years) with histologically confirmed unresectable or recurrent epithelial cutaneous malignancies, Eastern Cooperative Oncology Group performance status 0–1, and at least one measurable lesion (RECIST v1.1). Nivolumab 480 mg was administered intravenously every 4 weeks for up to 26 cycles. The primary endpoint was overall response rate (ORR), assessed by blinded independent central review (BICR; RECIST v1.1). Secondary endpoints included progression-free survival, overall survival, and safety.
Results
Thirty-one patients were enrolled (20 cSCC, 4 EMPD, 2 BCC, 5 other NMSCs); median age was 73 years (range 58–86), and 71% were male. ORR by BICR was 22.6% (7/31), and the disease control rate was 54.8% (17/31). Responses were durable, with a median duration of 21.3 months. In the cSCC cohort, median tumour mutational burden (TMB) was 9.0 mut/Mb, lower than in Western series; among three patients with TMB ≥ 30 mut/Mb, two achieved objective responses. Common adverse events included pyrexia, hypothyroidism, adrenal insufficiency, and pruritus.
Conclusions
Nivolumab showed durable antitumour activity with manageable toxicity in Japanese patients with advanced NMSCs, including rare non-cSCC. The lower ORR compared with Western trials may reflect intrinsic biological differences and support biomarker-driven, region-specific immunotherapy.
Clinical trial registration
jRCT2031190048; registered 2 July 2019.
Journal Article
The effect of interface roughness on the perpendicular exchange bias of NiO/CoPt/Pt stacking structure
An orthogonal coupling structure of NiO/CoPt/Pt/glass with perpendicular exchange bias effect has been prepared. The exchange bias is found to be strongly dependent on the interface roughness between NiO and CoPt layer. The conventional inverse proportionality of the exchange bias field with the ferromagnetic thickness is not applicable to this top-pinned stacking structure. Moreover, an anomalous ferromagnetic thickness dependence of blocking temperature is also observed. A simulation on the basis of a spin configuration model with defects at the interface agrees well with the experimental observations. These findings suggest considerable contribution of the interface roughness to the perpendicular exchange bias.
Journal Article
Complementary therapies for chronic knee pain: A placebo-controlled RCT of Reiki and mindfulness
Knee osteoarthritis (KOA) is a prevalent chronic pain condition that significantly impairs quality of life and is often treated with interventions that carry risks or provide limited relief. Reiki, a non-invasive complementary therapy, has shown early promise for pain management but lacks rigorous evaluation among American adults with KOA.
This study evaluated the specific efficacy of Reiki and mindfulness for adults with chronic KOA pain compared to sham and waitlist control conditions.
In this placebo-controlled randomized trial, 164 adults with physician-confirmed KOA were assigned to one of four groups: Reiki, sham Reiki (i.e., Feiki), mindfulness meditation, or a waitlist control. Active treatments were delivered in four weekly 30-minute sessions.
KOA symptom severity, assessed using the WOMAC at baseline, 1-month, and 2-month follow-ups, significantly improved in both the Reiki (p = .02) and mindfulness (p < .001) groups compared to waitlist controls. Mindfulness significantly outperformed Feiki (p = .004). Reiki demonstrated effects comparable to mindfulness (p = .22). Clinically meaningful reductions in symptoms (>30 %) were reported by 55 % of participants in the Reiki and mindfulness groups, compared to 20 % in the Feiki group and 13 % in the waitlist group. High retention (96 %) and successful blinding support the feasibility and internal validity of this approach.
These findings indicate that both Reiki and mindfulness may offer effective, well-tolerated, and time-efficient alternatives for managing KOA-related pain, with meaningful symptom improvement after just two hours of intervention. Larger trials are warranted to confirm efficacy and explore long-term outcomes and underlying mechanisms.
•Reiki and mindfulness reduced knee osteoarthritis symptoms after four short sessions.•Reiki effects were comparable to mindfulness and superior to waitlist controls.•Sham Reiki showed short-term benefit but symptoms rebounded by follow-up.•Over half of Reiki and mindfulness participants achieved clinically meaningful relief.•Reiki may offer a safe, accessible, non-pharmacologic option for chronic knee pain.
Journal Article
Psychological, social, and environmental factors to meeting physical activity recommendations among Japanese adults
Background
Although the benefits of the recommended level of physical activity on reducing chronic diseases are well-established, most of the Japanese population is not sufficiently active. Thus, examining correlates is an important prerequisite for designing relevant polices and effective programs. The present study investigated psychological, social, and environmental factors associated with meeting physical activity recommendations among Japanese adults.
Methods
Data were analyzed for 1,932 men and women (43.6 ± 13.0 years), who responded to an Internet-based cross-sectional survey. Self-reported measure of physical activity, psychological (self-efficacy, pros, and cons), social (social support, health professional advice), environmental (home fitness equipment, access to facilities, neighborhood safety, enjoyable scenery, frequently observing others exercising, residential area), and demographic (gender, age, marital status, educational level, household income level, employment status) variables were obtained. Based on the current national guidelines for exercise in Japan (23 METs·hour per week), respondents were divided into two categories–recommended and not recommended (insufficient and inactive)–according to their estimated weekly physical activity level. An adjusted logistic regression model was utilized.
Results
When adjusting for all other variables, self-efficacy (men: OR = 2.13; 95% CI: 1.55–2.94, women: OR = 2.72; 95% CI: 1.82–4.08) and possessing home fitness equipment (men: OR = 1.55; 95% CI: 1.14–2.10, women: OR = 1.41; 95% CI: 1.01–1.99) for both genders, social support (OR = 1.44; 95% CI: 1.06–1.97) for men, and enjoyable scenery (OR = 1.60; 95% CI: 1.09–2.36) for women were positively associated with attaining the recommended level of physical activity. In women, cons (OR = 0.47; 95% CI: 0.33–0.67) and living in rural areas (OR = 0.50; 95% CI: 0.25–0.97) were negatively associated with meeting the physical activity recommendations.
Conclusion
In the psychological, social, and environmental domains, significant correlates of attaining the recommended level of physical activity were observed. Men and women had different patterns of psychological, social, and environmental correlates. These findings suggest that an intervention design that accounts for those correlates may more effectively promote physical activity among Japanese adults.
Journal Article
artificial virus-like nano carrier system: enhanced endosomal escape of nanoparticles via synergistic action of pH-sensitive fusogenic peptide derivatives
We previously reported that transferrin (Tf)-modified liposomes (Tf-L) additionally modified with a cholesterylated pH-sensitive fusogenic peptide (Chol-GALA) can release an encapsulated aqueous phase marker to cytosol via endosomal membrane fusion. However, further obstacles need to be overcome to bring the Tf-L to the level of a viral-like gene delivery system. In this study, we developed a novel packaging method to encapsulate condensed plasmid DNA into PEgylated Tf-L (Tf-PEG-L) to form a core-shell-type nanoparticle. The most difficult challenge was to provide a mechanism of escape for the condensed core from endosome to cytosol in the presence of polyethylene glycol (PEG). We hypothesized that a membrane-introduced Chol-GALA and a PEgylated GALA would interact synergistically to induce membrane fusion between liposome and endosome. By simultaneously incorporating Chol-GALA into the membrane of Tf-PEG-L and GALA at tips of PEG chains, a condensed core was released into cytosol, and transfection acitivty increased 100-fold. We concluded that topological control was responsible for the synergistic effect of GALA derivatives introduced on Tf-PEG-L.
Journal Article