Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC).

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).

Identification of a rare MET variant in a familial case of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is an intraepithelial adenocarcinoma that primarily affects the genital and axillary areas in elderly individuals. A limited number of paired familial EMPD cases (i.e., parent-offspring, siblings) have been reported, whereas the genetics of these cases have not yet been adequately studied. We report the first familial case of EMPD involving three affected siblings. The tumour-only multi-gene panel testing using surgical specimens revealed a heterozygous c.2997A>C (p.Glu999Asp) nonsynonymous variant in the proto-oncogene MET (NM_000245.4) in the three affected siblings. The germline multi-gene panel testing using peripheral blood lymphocytes revealed the same missense MET variant in all five family members, including the two asymptomatic offspring (51 and 37 years of age). The MET variant we identified could be involved in EMPD carcinogenesis. Further genomic analyses of familial cases of EMPD are warranted to validate the pathogenic relevance of MET variants in EMPD development.

Mindfulness-Oriented Recovery Enhancement remediates anhedonia in chronic opioid use by enhancing neurophysiological responses during savoring of natural rewards.

BACKGROUND: 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. METHODS: Veterans receiving LTOT (N = 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. RESULTS: 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. CONCLUSIONS: 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.

Cutaneous eyelid melanoma with lacrimal sac metastasis: the potential role of lacrimal fluid as a metastatic pathway.

Here we present a patient with cutaneous eyelid melanoma patient with lacrimal sac metastasis. Clinicopathological findings in this case support the theory that lacrimal fluid can be a metastatic pathway for tumour cells. Dermatologists should be aware of the possibility that cutaneous eyelid melanoma may involve the nasolacrimal system and should examine it during the perioperative period and in postoperative follow-up.

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.

BACKGROUND: Completion 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. METHODS: Totally, 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. RESULTS: The 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). CONCLUSION: Changes 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.

Primary malignant melanoma of the uterine cervix or vagina which were successfully treated with nivolumab.

Primary malignant melanomas (MM) originating from the gynecological tract are rare. They respond poorly to immunotherapy when compared with cutaneous MM. This study reports two cases. The first is of a 54-year-old woman with a cervical amelanotic polypoid mass who was diagnosed as having stage IB1 cervical melanoma according to the International Federation of Gynecology and Obstetrics system. At 17 months post-surgery, a computed tomography examination revealed recurrence of a 68 mm pelvic tumor. The second case is of a 37-year-old woman with a 7 cm hemorrhagic mass on the vaginal wall. The patient was diagnosed as having stage IV vaginal melanoma according to the American Joint Committee on Cancer definition. Both patients received nivolumab therapy, programmed cell death receptor 1 monoclonal antibodies, and the tumors almost disappeared. These cases may add the possibility of using colposcopy with narrow-band imaging and positron-emission tomography to diagnose and evaluate primary MM.

Combination Cisplatin-Epirubicin-Paclitaxel Therapy for Metastatic Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required.In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane- and/or platinum-based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability.This is the first regimen to combine taxane and anthracycline. When treating breast cancer, anthracycline is regarded as the key cytotoxic agent, and anthracycline in combination with taxane constitutes a key chemotherapeutic regimen. Given our results, we speculate both drugs are critical chemotherapeutic agents for the treatment of metastatic EMPD.

Investigating Clinical Benefits of a Novel Sleep-Focused Mind-Body Program on Gulf War Illness Symptoms: A Randomized Controlled Trial.

OBJECTIVE: Mind-Body Bridging (MBB) has been shown to be effective for improving disturbed sleep. In this prospective randomized controlled trial, we evaluated the efficacy of sleep-focused MBB compared with sleep education control (SED) for improving sleep in previously deployed Gulf War veterans. METHODS: US military service members with sleep and physical health complaints who were deployed in 1990-1991 were randomized to receive three weekly sessions of either MBB (n = 33) or SED (n = 27) between 2012 and 2015. The primary outcome of Medical Outcomes Study Sleep Scale was completed at baseline, weekly during treatment, postintervention, and 3-month follow-up. Secondary outcome measures for posttraumatic stress disorder, depression, fatigue, quality of life, symptom severity, and mindfulness were completed at baseline, postintervention and 3-month follow-up. Salivary samples were collected at five time points per day at each visit for cortisol and α-amylase assessment. Clinician-administered assessments of sleep and co-occurring conditions were conducted at baseline and postintervention. RESULTS: MBB was significantly more efficacious than SED in reducing disturbed sleep at follow-up (F(1,180.54) = 4.04, p = .046). In addition, self-reported posttraumatic stress disorder (F(1,56.42) = 4.50, p = .038) for the treatment effect, depression (F(1,93.70) = 4.44, p = .038), and fatigue symptoms (F(1,68.58) = 3.90, p = .050) at follow-up improved in MBB compared with those in SED. Consistently higher percentages of veterans in MBB reported improvements of sleep, pain, and composite sleep/general co-occurring symptoms at the postclinical evaluation, as compared with veterans in SED. Finally, the mean waking level of salivary α-amylase in the MBB declined to a greater extent than that in the SED, at follow-up (F(1,88.99) = 3.78, p = .055), whereas no effects were found on cortisol. CONCLUSIONS: Sleep-focused MBB can improve sleep and possibly also co-occurring symptoms in Gulf War veterans. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01543997.

Randomized Controlled Trial of Brief Mindfulness Training and Hypnotic Suggestion for Acute Pain Relief in the Hospital Setting.

BACKGROUND: Medical management of acute pain among hospital inpatients may be enhanced by mind-body interventions. OBJECTIVE: We hypothesized that a single, scripted session of mindfulness training focused on acceptance of pain or hypnotic suggestion focused on changing pain sensations through imagery would significantly reduce acute pain intensity and unpleasantness compared to a psychoeducation pain coping control. We also hypothesized that mindfulness and suggestion would produce significant improvements in secondary outcomes including relaxation, pleasant body sensations, anxiety, and desire for opioids, compared to the control condition. METHODS: This three-arm, parallel-group randomized controlled trial conducted at a university-based hospital examined the acute effects of 15-min psychosocial interventions (mindfulness, hypnotic suggestion, psychoeducation) on adult inpatients reporting "intolerable pain" or "inadequate pain control." Participants (N = 244) were assigned to one of three intervention conditions: mindfulness (n = 86), suggestion (n = 73), or psychoeducation (n = 85). KEY RESULTS: Participants in the mind-body interventions reported significantly lower baseline-adjusted pain intensity post-intervention than those assigned to psychoeducation (p < 0.001, percentage pain reduction: mindfulness = 23%, suggestion = 29%, education = 9%), and lower baseline-adjusted pain unpleasantness (p < 0.001). Intervention conditions differed significantly with regard to relaxation (p < 0.001), pleasurable body sensations (p = 0.001), and desire for opioids (p = 0.015), but all three interventions were associated with a significant reduction in anxiety (p < 0.001). CONCLUSIONS: Brief, single-session mind-body interventions delivered by hospital social workers led to clinically significant improvements in pain and related outcomes, suggesting that such interventions may be useful adjuncts to medical pain management. TRIAL REGISTRATION: Trial Registry: ClinicalTrials.gov ; registration ID number: NCT02590029 URL: https://clinicaltrials.gov/ct2/show/NCT02590029.

Sources of strength-training information and strength-training behavior among Japanese older adults.

The promotion of strength training is now recognized as an important component of public health initiatives for older adults. To develop successful communication strategies to increase strength-training behavior among older adults, the identification of effective communication channels to reach older adults is necessary. This study aimed to identify the information sources about strength training that were associated with strength-training behaviors among Japanese older adults. The participants were 1144 adults (60-74 years old) randomly sampled from the registry of residential addresses. A cross-sectional questionnaire survey was conducted. The independent variables were sources of strength-training information (healthcare providers, friends, families, radio, television, newspapers, newsletters, posters, books, magazines, booklets, the Internet, lectures, other sources), and the dependent variable was regular strength-training behavior. Logistic regression analysis was used to identify potential relationships. After adjusting for demographic factors and all other information sources, strength-training information from healthcare providers, friends, books and the Internet were positively related to regular strength-training behavior. The findings of the present study contribute to a better understanding of strength-training behavior and the means of successful communication directed at increasing strength training among older adults. The results suggest that healthcare providers, friends, books and the Internet are effective methods of communication for increasing strength-training behaviors among older adults.

Dynamic reflexivity in action: an armchair walkthrough of a qualitatively driven mixed-method and multiple methods study of mindfulness training in schoolchildren.

Dynamic reflexivity is central to enabling flexible and emergent qualitatively driven inductive mixed-method and multiple methods research designs. Yet too often, such reflexivity, and how it is used at various points of a study, is absent when we write our research reports. Instead, reports of mixed-method and multiple methods research focus on what was done rather than how it came to be done. This article seeks to redress this absence of emphasis on the reflexive thinking underpinning the way that mixed- and multiple methods, qualitatively driven research approaches are thought about and subsequently used throughout a project. Using Morse's notion of an armchair walkthrough, we excavate and explore the layers of decisions we made about how, and why, to use qualitatively driven mixed-method and multiple methods research in a study of mindfulness training (MT) in schoolchildren.

Association of muscle-strengthening activity with knee and low back pain, falls, and health-related quality of life among Japanese older adults: a cross-sectional survey.

This study aimed to examine the association of muscle-strengthening activity with knee and low back pain, falls, and health-related quality of life among Japanese older adults. A cross-sectional survey targeted 3,000 people. The response rate was 52% and 208 respondents did not meet the inclusion criteria. Therefore, 1,351 individuals were analyzed. Muscle-strengthening activity (exercise using equipment and body weight, lifestyle activities), knee and low back pain, falls over the past year, health-related quality of life (SF-8), and potential confounders were assessed. Individuals engaging in exercise using body weight and lifestyle activity (≥ 2 days/week) were more likely to have knee pain. Engaging in exercise using equipment and body weight was associated with higher scores of general health. These results indicate that exercise using equipment and body weight might have a positive effect on health-related quality of life, but muscle-strengthening activities are associated with knee pain in older people.

Higher sika deer density is associated with higher local abundance of Haemaphysalis longicornis nymphs and adults but not larvae in central Japan.

Haemaphysalis longicornis (Acari: Ixodidae) is one of the most common and important arthropod disease vectors in Japan, carrying Japanese spotted fever and bovine theileriosis. The recent expansion of sika deer (Cervus nippon, Artiodactyla: Cervidae) populations, the most common wild host of H. longicornis, has also caused concern about increasing the risk of vector-borne diseases in Japan. We used generalized linear mixed model analysis to determine the relative contribution of deer density and other biological and abiotic factors on the abundance of H. longicornis ticks questing at each developmental stage. A total of 6223 H. longicornis adults, nymphs, and larvae were collected from 70 sites in three regions of central Japan. The abundance of questing adult and nymphal ticks was associated with deer density and other biotic and abiotic factors. However, the abundance of questing larvae showed no association with deer density but did show an association with other biotic and abiotic factors. These findings show that a high density of deer along with other biotic and abiotic factors is associated with increased risk of vector-borne diseases through amplified local abundance of questing nymphal and adult H. longicornis. Further, questing larvae abundance is likely regulated by environmental conditions and is likely correlated with survival potential or the distribution of other host species.

Low-volume walking program improves cardiovascular-related health in older adults.

Although numerous sources of evidence show that regular physical activity is beneficial to health, most individuals do not engage in a sufficient amount of physical activity to meet the guidelines set out by expert panels. In addition, the minimum amount of physical activity associated with reduced cardiovascular disease risk markers is not clear in older adults. The purpose of this study was to determine the effects of a 12-week walking program involving an exercise volume below the current minimum physical activity recommendation on cardiovascular disease risk markers in older adults. The participants were recruited from the following two groups separately: a walking group (n = 14) and a control group (n = 14). In the walking group, participants walked 30 to 60 minutes per session on 2 days per week for 12 weeks (average walking time, 49.4 ± 8.8 min/session). Plasma oxidised low-density lipoprotein concentrations tended to be lower than baseline values in the walking group after 12 weeks (paired t-test, p = 0.127). The ratio of oxidised low-density lipoprotein to high-density lipoprotein cholesterol was significantly lower than the baseline ratio in the walking group after 12 weeks (paired t-test, p = 0.035). Resting systolic blood pressure and diastolic blood pressure were significantly lower than baseline values in the walking group after 12 weeks (paired t-tests, p = 0.002, p < 0.0005, respectively). Our findings demonstrate that a 12-week walking program comprising a low volume of physical activity confers a benefit to cardiovascular-related health in older adults. Key PointsIt is important to consider baseline physical activity levels when evaluating physical activity program.Being physically active is important to reduce the potential risk marker of cardiovascular disease in older adults.These data imply that a small volume of 12-week walking program confers a benefit to cardiovascular-related health in older adults.

Spino-pelvic-rhythm with forward trunk bending in normal subjects without low back pain.

A strong correlation between low back pain and tight hamstrings has been reported. However, the effect of tight hamstrings on spinal biomechanics remains unclear. The purpose of the study was to investigate spino-pelvic-rhythm during forward bending of the trunk and to clarify the rhythm features with regard to hamstrings tightness. Eighteen healthy male adults with no history of low back pain volunteered to participate. First, we measured the finger-to-floor distance (FFD) in the upright position and set this parameter to 100 %. Using a spinal mouse, spinal alignment was measured in the following four positions: (1) upright posture­100 % FFD; (2) forward bending­50 % FFD; (3) forward bending­25 % FFD; and (4) forward bending­0 % FFD (fingers in contact with the floor). Changes of the angle of the thoracic and lumbar spine as well as the pelvis were calculated. As an indicator of tight hamstrings, we measured straight leg raising (SLR) angle. From positions 1­2 (phase I), the entire spino-pelvic angle moved in 104°. During this phase, the lumbar spine mainly moved. In the second phase (positions 2­3), it moved in 16°. Interestingly, all but 2 subjects showed a negative angle in the thoracic motion, meaning that the thoracic spine extended 4° during trunk flexion, thus exhibiting paradoxical motion. During this phase, lumbopelvic rhythm showed 2 patterns. In 7 subjects, pelvic motion was greater than lumbar motion, while the remaining subjects showed the opposite. In subjects without tight hamstrings, 83 % showed a pelvis-dominant pattern. Only 7 subjects were capable of position 4. During this phase, only slight motion was noted in the spine, and the majority of the motion occurred in the pelvis. Lumbar and pelvic motion correlated negatively in all phases. SLR angle and pelvic motion correlated strongly during phase III, indicating dominant pelvic movement in flexible subjects. The lumbo-pelvic-rhythm comprises 2 patterns­lumbar dominant and pelvis dominant. In flexible subjects, pelvis movement was dominant. In conclusion, improving tight hamstrings may reduce lumbar loading thereby reducing low back pain.

Spino-pelvic-rhythm with forward trunk bending in normal subjects without low back pain.

A strong correlation between low back pain and tight hamstrings has been reported. However, the effect of tight hamstrings on spinal biomechanics remains unclear. The purpose of the study was to investigate spino-pelvic-rhythm during forward bending of the trunk and to clarify the rhythm features with regard to hamstrings tightness. Eighteen healthy male adults with no history of low back pain volunteered to participate. First, we measured the finger-to-floor distance (FFD) in the upright position and set this parameter to 100 %. Using a spinal mouse, spinal alignment was measured in the following four positions: (1) upright posture-100 % FFD; (2) forward bending-50 % FFD; (3) forward bending-25 % FFD; and (4) forward bending-0 % FFD (fingers in contact with the floor). Changes of the angle of the thoracic and lumbar spine as well as the pelvis were calculated. As an indicator of tight hamstrings, we measured straight leg raising (SLR) angle. From positions 1-2 (phase I), the entire spino-pelvic angle moved in 104°. During this phase, the lumbar spine mainly moved. In the second phase (positions 2-3), it moved in 16°. Interestingly, all but 2 subjects showed a negative angle in the thoracic motion, meaning that the thoracic spine extended 4° during trunk flexion, thus exhibiting paradoxical motion. During this phase, lumbopelvic rhythm showed 2 patterns. In 7 subjects, pelvic motion was greater than lumbar motion, while the remaining subjects showed the opposite. In subjects without tight hamstrings, 83 % showed a pelvis-dominant pattern. Only 7 subjects were capable of position 4. During this phase, only slight motion was noted in the spine, and the majority of the motion occurred in the pelvis. Lumbar and pelvic motion correlated negatively in all phases. SLR angle and pelvic motion correlated strongly during phase III, indicating dominant pelvic movement in flexible subjects. The lumbo-pelvic-rhythm comprises 2 patterns-lumbar dominant and pelvis dominant. In flexible subjects, pelvis movement was dominant. In conclusion, improving tight hamstrings may reduce lumbar loading thereby reducing low back pain.