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 for Veterans and Military Personnel on Long-Term Opioid Therapy for Chronic Pain: A Randomized Clinical Trial.

OBJECTIVE: This randomized clinical trial evaluated the efficacy of Mindfulness-Oriented Recovery Enhancement (MORE) among past and present U.S. military personnel with prescriptions for long-term opioid therapy for chronic pain. METHODS: In this clinical trial, 230 past and present military personnel with prescriptions for long-term opioid therapy were randomized in a 1:1 ratio to MORE or supportive psychotherapy (initially delivered in person and then via videoconferencing after the onset of the COVID-19 pandemic). Primary outcomes were chronic pain, measured by the Brief Pain Inventory, and aberrant drug-related behaviors, measured by the Current Opioid Misuse Measure, through 8 months of follow-up. Opioid dose was a key secondary outcome. Other outcomes included psychiatric symptoms, catastrophizing, positive affect, ecological momentary assessments of opioid craving, and opioid attentional bias. RESULTS: MORE was superior to supportive psychotherapy through the 8-month follow-up in reducing pain-related functional interference, pain severity, and opioid dose. MORE reduced daily opioid dose by 20.7%, compared with a dose reduction of 3.9% with supportive psychotherapy. Although there was no overall between-group difference in opioid misuse, the in-person MORE intervention outperformed supportive psychotherapy for reducing opioid misuse. MORE reduced anhedonia, pain catastrophizing, craving, and opioid attentional bias and increased positive affect to a greater extent than supportive psychotherapy. MORE also modulated therapeutic processes, including mindful reinterpretation of pain sensations, nonreactivity, savoring, positive attention, and reappraisal. CONCLUSIONS: Among past and present U.S. military personnel, MORE led to sustained decreases in chronic pain, opioid use, craving, and opioid cue reactivity. MORE facilitated opioid dose reduction while preserving adequate pain control and preventing mood disturbances, suggesting its utility for safe opioid tapering.

Japanese Dermatological Association guidelines: Outlines of Japanese clinical guidelines for basal cell carcinoma 2021.

To summarize the current therapies for skin cancers, the Japanese Skin Cancer Society issued the first guidelines for skin cancers, including melanoma, squamous cell carcinoma, basal cell carcinoma (BCC), and extramammary Paget's disease, in 2007. These guidelines were revised in 2015. Herein, we present the English version of the 2021 edition of the Japanese clinical guidelines for BCC. In the latest edition, all procedures were performed according to the Grading of Recommendations, Assessment, Development and Evaluation systems. The clinical questions that could not be answered were selected for further analysis. A comprehensive literature search, systematic review, and recommendations for each clinical question were determined by a multidisciplinary expert panel comprising dermatologists, a plastic and reconstructive surgeon, and a pathologist. Surgical resection is the gold-standard therapy of BCC. Radiotherapy or topical treatments, other than surgical resection, have been used in some cases. Patients with unresectable or metastatic BCC require systemic therapy. Novel agents, such as immune response modifiers or hedgehog pathway inhibitors, are emerging worldwide for the treatment of BCC. Based on these viewpoints, four relevant clinical questions regarding, surgical resection, radiotherapy, topical treatment, and systemic therapy, were raised in this report that aims to help clinicians select suitable therapies for their patients.

Experiences of adults with opioid-treated chronic low back pain during the COVID-19 pandemic: A cross-sectional survey study.

This study aimed to evaluate the impact of the COVID-19 pandemic on adults with opioid-treated chronic low back pain (CLBP), an understudied area. Participants in a "parent" clinical trial of non-pharmacologic treatments for CLBP were invited to complete a one-time survey on the perceived pandemic impact across several CLBP- and opioid therapy-related domains. Participant clinical and other characteristics were derived from the parent study's data. Descriptive statistics and latent class analysis analyzed quantitative data; qualitative thematic analysis was applied to qualitative data. The survey was completed by 480 respondents from June 2020 to August 2021. The majority reported a negative pandemic impact on their life (84.8%), with worsened enjoyment of life (74.6%), mental health (74.4%), pain (53.8%), pain-coping skills (49.7%), and finances (45.3%). One-fifth (19.4%) of respondents noted increased use of prescribed opioids; at the same time, decreased access to medication and overall healthcare was reported by 11.3% and 61.6% of respondents, respectively. Latent class analysis of the COVID-19 survey responses revealed 2 patterns of pandemic-related impact; those with worse pandemic-associated harms (n = 106) had an overall worse health profile compared to those with a lesser pandemic impact. The pandemic substantially affected all domains of relevant health-related outcomes as well as healthcare access, general wellbeing, and financial stability among adults with opioid-treated CLBP. A more nuanced evaluation revealed a heterogeneity of experiences, underscoring the need for both increased overall support for this population and for an individualized approach to mitigate harms induced by pandemic or similar crises.

Role of androgen signaling in androgen receptor-positive extramammary Paget's disease: Establishment of organoids and their biological analysis as a novel therapeutic target.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that mainly affects the anogenital and axillary regions. Although its etiology has not been fully elucidated, there is evidence that androgen receptors (AR) are expressed in most cases of EMPD. However, the role of androgen signaling in the pathogenesis of EMPD remains unclear. OBJECTIVE: To evaluate the role of androgen signaling in tumor growth of AR-positive EMPD. METHODS: Patient-derived organoids were established and cultured from two AR-positive EMPD patients: one man and one woman. Cultured organoids were treated with androgen agonists and/or antagonists, then subjected to analysis of changes in organoid proliferation, as well as changes in androgen signaling pathway-specific genes. RESULTS: Organoid cultures were established from each EMPD sample. These organoids were immunohistologically and genetically identical to the original tumor. For each organoid sample, viable cell number increased in response to androgen exposure. The mRNA level of Fkbp5, a known AR target gene, increased in a concentration-dependent manner in organoids exposed to the synthetic androgen R1881. Conversely, the AR inhibitor darolutamide suppressed the viable cell number in a concentration-dependent manner. The mRNA expression levels of MKI67 and Fkbp5 were also suppressed by darolutamide. CONCLUSION: Our results indicate that androgen signaling is a key pathway involved in the growth of AR-positive EMPD. Therefore, androgen signaling inhibition may be a novel treatment option for EMPD patients who require systemic therapy.

Risk Factors for Self-Harm Ideation Among Persons Treated With Opioids for Chronic Low Back Pain.

OBJECTIVES: Chronic pain is a significant health concern that adversely affects all aspects of life, including emotional well-being. Opioids are prescribed for the management of refractory, severe chronic pain, although they have been associated with adverse effects, including addiction and overdose. The aim of this study was to examine factors that predict thoughts of self-harm among adults with chronic pain who are prescribed opioids. MATERIALS AND METHODS: Seven hundred sixty-five (N=765) persons with opioid-treated chronic lower back pain completed the Current Opioid Misuse Measure (COMM) and other validated questionnaires as part of a larger study. Response to 1 question from the COMM ("How often have you seriously thought about hurting yourself?") was used to assess suicide risk on a 5-point scale (0=never; 4=very often). RESULTS: Participants were categorized into 3 groups according to their responses to the self-harm question: never (N=628; 82.1%), seldom or sometimes (N=74; 9.7%), and often or very often (N=63; 8.2%). Multivariate adjusted odds ratio (aOR) analyses indicated that reports of alcohol or drug overuse within the past month (aOR=1.41,[95% CI 1.11-1.78]), posttraumatic stress (PTSD; aOR=1.24,[1.07 to 1.44]), pain catastrophizing (aOR=1.03,[1.01 to 1.05]), not loving oneself (aOR=0.99,[.98-1.00]) and poor perceived mental health (aOR=0.94,[.92 to 97]) were most associated with thoughts of self-harm. Importantly, the ideation frequency of self-harm was highest among individuals treated with higher daily doses of opioids. DISCUSSION: These results support the need for continued monitoring of adults treated with opioids for chronic pain, particularly among those on high-dose opioids who present with increased negative affect and concerns of substance misuse.

Negative differential resistance based on phase transformation.

The negative differential resistance (NDR) device is attracting attention because of its broad potential application in neuromorphic computing and non-volatile memory. However, only a limited range of materials show NDR and, therefore, there is less choice in material selection for NDR devices. Considering this issue, we here demonstrate a novel current controlled NDR device based on phase transformation. To the best of our knowledge, this report is the first experimental demonstration that NDR can be induced by phase transformation. We believe that the impact of this demonstration is very large, as phase transformation is the most common phenomenon in materials and consequently most materials can be reconsidered as possible candidates for NDR devices. The prototype NDR device is constructed using hydrogen absorbing metal palladium (Pd) thin-wire and the phase transformation from metal-hydride to metal is employed for the demonstration. The observed NDR property shows a strong dependence on the current sweep speed. Also, it exhibits no current polarity dependence. Therefore, the NDR device based on phase transformation is significantly different from typical NDR devices such as tunnel diodes and memristors. The prototype NDR device has been found to be very useful for evaluating the hydrogen storage properties of metals. The advantage of this analysis method is that the storage properties can be acquired just by sweeping the applied current. This demonstration offers novel directions for both the development and utilization of NDR devices.

Clinicopathological significance of androgen receptor expression in extramammary Paget disease: An analysis of 92 patients.

Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm arising in apocrine gland-rich areas. Although - like normal apocrine glands - EMPD frequently expresses androgen receptor (AR), the clinical significance of AR expression remains unclear. The present study investigated the clinicopathological impact of AR expression in EMPD. Immunohistochemistry for AR was performed in a retrospective cohort of 92 EMPD patients with 108 EMPD lesions, including 102 primary lesions, five lymph node [LN] metastases and one local recurrence. The total AR staining score was calculated as staining intensity score (IS 0-3) × positive-cell percentage score (PS 1-4). Expression levels were graded as Grade 1 (scores 0 and 1), Grade 2 (scores 2-4), and Grade 3 (scores 6-12). Higher expression grade was correlated with tumor thickness (P = 0.011), LN metastasis (P = 0.008), and higher EMPD stage (P = 0.023). Grade 1 EMPDs did not invade into the dermis and did not generate metastatic and/or recurrent lesions, whereas only Grade 2 or 3 EMPDs did so. AR expression in invasive components was significantly higher (P = 0.023) than in non-invasive components remaining within the epidermis. AR expression was further elevated in metastatic and/or recurrent lesions relative to locally invasive lesions (P = 0.014). These results clearly indicate that increased AR expression is associated with malignant progression of EMPD and that androgen blockade might be an effective therapy. Furthermore, AR expression assessed by immunohistochemistry may have potential for prediction of LN metastasis and local recurrence in EMPD.

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.

To be aware, or to accept, that is the question: Differential roles of awareness of automaticity and pain acceptance in opioid misuse.

BACKGROUND: Individuals with chronic low back pain (CLBP) are commonly prescribed long-term opioid therapy (LTOT) for analgesia, placing this population at increased risk for opioid misuse and opioid use disorder. Acceptance of aversive experiences (e.g., chronic pain) and awareness of automatic thoughts and behaviors (i.e., automaticity) are two facets of dispositional mindfulness that may serve as protective mechanisms against opioid misuse risk. Therefore, the aim of the current study was to examine the differential contributions of these constructs to opioid misuse risk among adults with CLBP receiving LTOT. METHODS: Data were obtained from a sample of 770 adults with opioid-treated CLBP. Bivariate correlations and hierarchical linear regression analyses were used to determine whether chronic pain acceptance and awareness of automatic thoughts and behaviors explained a statistically significant portion of variance in opioid misuse risk after accounting for the effects of other relevant confounders. RESULTS: Hierarchical regression results revealed that chronic pain acceptance and awareness of automatic thoughts and behaviors contributed a significant portion in the variance of opioid misuse risk. Awareness of automatic thoughts and behaviors was negatively associated with opioid misuse risk, such that individuals with lower levels of awareness of automaticity were at higher risk of opioid misuse. By contrast, pain acceptance was not associated with opioid misuse. CONCLUSIONS: Findings suggest that awareness of automaticity may buffer against opioid misuse risk. Interventions designed to strengthen awareness of automaticity (e.g., mindfulness-based interventions) might be especially efficacious among this population.

Path of intuitive compassion to transform conflicts into enduring peace and prosperity: Symmetry across domains of reiterated prisoner's dilemma, dyadic active inference, and Mahayana Buddhism.

Conflicts are increasingly intensified among the members of the community, making it almost impossible to extend compassion-defined as a wish to relieve others from suffering-from one side to the other, especially when both sides believe that "life is a battle of us the good vs. them the evil." Is compassion even relevant to conflicts? The answer depends on how a conflict is framed in one's perception. If a conflict is perceived in a frame of zero-sum competition, then compassion is meaningless in such a "tug-of-war" mindset. Conversely, if perceived in a non-zero-sum frame-as demonstrated in reiterated prisoner's dilemma (rPD) in which two players may interdependently render win-win, lose-lose, win-lose, or lose-win scenarios by their actions-then compassion can help achieve the most preferable outcomes for all in a "dyadic dance" mindset. In this article, we present a path of intuitive compassion by pointing to symmetry across three distinct domains of rPD, dyadic active inference, and Mahayana Buddhism. In each of these domains, conflicts serve as points of bifurcation on a bidirectional path, and compassion as a conflict-proof commitment to carrying out the best strategies-even if assessed for one's own sake only-that consistently produce optimal payoffs in rPD, minimal stress in dyadic active inference, and limitless joy of ultimate enlightenment in Mahayana Buddhism. Conversely, a lack of compassion is caused by invalid beliefs that obscure the nature of reality in these domains, causing conflicts to produce even more conflicts. These invalid beliefs are produced by mistakes of over-reduction, over-separation, and over-compression in the mind, and therefore, a person's mindset is overly compressed from a multidimensional frame to a one-dimensional frame. Taken together, intuitive compassion is not about how to balance one's self-serving goals with altruistic ones. Rather, it is a conflict-proof commitment to transforming conflicts into enduring peace and prosperity according to the ultimate nature of reality. The work presented here may serve as a preliminary science-informed introduction to a genre of time-tested compassion meditations, i.e., lojong mind training, for the world laden with conflicts, starting from the conflicts in close relationships to those in geopolitics.

Mindfulness-induced endogenous theta stimulation occasions self-transcendence and inhibits addictive behavior.

Self-regulation is instantiated by theta oscillations (4 to 8 Hz) in neurons of frontal midline brain regions. Frontal midline theta (FMΘ) is inversely associated with default mode network (DMN) activation, which subserves self-referential processing. Addiction involves impaired self-regulation and DMN dysfunction. Mindfulness is an efficacious self-regulatory practice for treating addiction, but little is known about the mechanisms by which mindfulness reduces addictive behavior. In this mechanistic study of long-term opioid users (N = 165), we assessed meditation-induced FMΘ as a mediator of changes in opioid misuse. Relative to a supportive psychotherapy control, participants treated with Mindfulness-Oriented Recovery Enhancement (MORE) exhibited increased FMΘ during a laboratory-based meditation session. FMΘ during meditation was associated with self-transcendent experiences characterized by ego dissolution, nondual awareness, and bliss. MORE's effects on decreasing opioid misuse were mediated by increased FMΘ. Given the role of aberrant self-referential processing in addiction, mindfulness-induced endogenous theta stimulation might "reset" DMN dysfunction to inhibit addictive behavior.

Intersubjectivity as an antidote to stress: Using dyadic active inference model of intersubjectivity to predict the efficacy of parenting interventions in reducing stress-through the lens of dependent origination in Buddhist Madhyamaka philosophy.

Intersubjectivity refers to one person's awareness in relation to another person's awareness. It is key to well-being and human development. From infancy to adulthood, human interactions ceaselessly contribute to the flourishing or impairment of intersubjectivity. In this work, we first describe intersubjectivity as a hallmark of quality dyadic processes. Then, using parent-child relationship as an example, we propose a dyadic active inference model to elucidate an inverse relation between stress and intersubjectivity. We postulate that impaired intersubjectivity is a manifestation of underlying problems of deficient relational benevolence, misattributing another person's intentions (over-mentalizing), and neglecting the effects of one's own actions on the other person (under-coupling). These problems can exacerbate stress due to excessive variational free energy in a person's active inference engine when that person feels threatened and holds on to his/her invalid (mis)beliefs. In support of this dyadic model, we briefly describe relevant neuroimaging literature to elucidate brain networks underlying the effects of an intersubjectivity-oriented parenting intervention on parenting stress. Using the active inference dyadic model, we identified critical interventional strategies necessary to rectify these problems and hereby developed a coding system in reference to these strategies. In a theory-guided quantitative review, we used this coding system to code 35 clinical trials of parenting interventions published between 2016 and 2020, based on PubMed database, to predict their efficacy for reducing parenting stress. The results of this theory-guided analysis corroborated our hypothesis that parenting intervention can effectively reduce parenting stress if the intervention is designed to mitigate the problems of deficient relational benevolence, under-coupling, and over-mentalizing. We integrated our work with several dyadic concepts identified in the literature. Finally, inspired by Arya Nagarjuna's Buddhist Madhyamaka Philosophy, we described abstract expressions of Dependent Origination as a relational worldview to reflect on the normality, impairment, and rehabilitation of intersubjectivity.

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.

Concordance in judgment of clinical borders of basal cell carcinomas in Japanese patients: A preliminary study of JCOG2005 (J-BASE-MARGIN).

Basal cell carcinoma is the most common type of skin cancer, and surgical excision with clear margins is the standard of care. Surgical margins are determined based on risk factors (high or low risk) for recurrence according to the National Comprehensive Cancer Network and Japanese basal cell carcinoma guidelines. The clarity of the clinical tumor border (well-defined or poorly defined) is considered a risk factor, and significant discrepancies in the judgment of clinical tumor borders among dermato-oncologists may occur. Therefore, we analyzed the dermato-oncologists' concordance in judging the clinical tumor border of basal cell carcinoma. Forty-seven dermato-oncologists (experts: 37; young trainees: 10) participated in this study. The datasets of clinical and dermoscopic photographs of 79 Japanese cases of head and neck basal cell carcinoma were used to determine the concordance in the judgment of clinical tumor border. The probability of the border that was selected more often was used to calculate the rater agreement rate for each dataset. Correct judgment was defined as a more frequently selected border, and the concordance rate of clarity of clinical tumor border for each dermato-oncologist was calculated based on the definition of the correct judgment. A median concordance rate of 85% or higher for all dermato-oncologists was predefined as an acceptable rate for clinical use. Of the 79 datasets, rater agreement rates were 80-100%, 60-79%, and 51-59% for 55, 19, and five datasets, respectively. The median concordance rate for all dermato-oncologists was 86% (interquartile range: 82-89%). There was no significant difference in the concordance rate between the experts and the trainees (median, 87% vs. 85.5%; p = 0.58). The concordance rates of dermato-oncologists for all datasets were relatively high and acceptable for clinical use.

Management and outcomes of hydronephrosis in patients with metastatic extramammary Paget's disease: A retrospective analysis.

Hydronephrosis in extramammary Paget's disease (EMPD) with distant metastasis (metastatic EMPD) has been observed in medical practice; however, its prognosis remains unclear. Retrospective analyses were performed to assess the management and outcomes of hydronephrosis in metastatic EMPD. During a follow-up of 44 patients with metastatic EMPD, 13 (30%) developed hydronephrosis. Ten (77%) of the 13 patients with hydronephrosis had impaired renal function (estimated glomerular filtration rate: <60 ml/min/1.73 m2 ), and ureteral stents were placed in every patient with impaired renal function. The stent was placed successfully in all 10 patients, and their renal function recovered within a median period of 7 days. Importantly, each of these patients continued chemotherapy, and none of them experienced stent failure. The median overall survival time (OS) in patients with metastatic EMPD and hydronephrosis (n = 13) was 7.8 months. Treatment for hydronephrosis was not a significant factor for OS, and median OS in patients who underwent ureteral stent replacement (n = 10) was 14.7 months. Collectively, our results indicate that hydronephrosis is relatively common, and ureteral stent placement should be considered in cases of metastatic EMPD with hydronephrosis to maintain renal function and continue chemotherapy toward a better prognosis.