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).

Diagnostic utility of the basophil activation test in natto-induced hypersensitivity.

BACKGROUND: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. METHODS: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. RESULTS: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. CONCLUSIONS: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

Clinical effectiveness and adverse events associated with tolvaptan in patients above 90 years of age with acute decompensated heart failure.

With the aging society, the number of very-elderly (VE) patients with acute decompensated heart failure (ADHF) is increasing. Although tolvaptan is recommended for patients with ADHF in whom conventional diuretic therapy is ineffective, few reports exist on VE patients over 90 years of age. Therefore, we aimed to evaluate the clinical effectiveness and adverse events associated with tolvaptan in VE patients with ADHF. From January 2011 to December 2018, we retrospectively studied 180 patients with ADHF who were first administered tolvaptan during hospitalization. Patients were divided into two groups, namely, VE patients who were ≥ 90 years of age (n = 32) and not-VE patients (NVE) who were < 90 years of age (n = 148). The primary effective endpoints were the total urine volume and change in body weight. The safety endpoints evaluated were the incidence of hypernatremia (≥ 150 mEq/L) and worsening renal function (WRF) at any time during hospitalization. The median [interquartile range] patient age was 93 [91-94] years in the VE group and 80 [69-85] years in the NVE group. The mean dose of tolvaptan for the first week of administration was similar between groups (7.9 ± 5.0 mg, VE group; 7.3 ± 3.7 mg, NVE group; p = 0.52). There were no significant differences between the two groups in the total urine volume at 24 h (1901 ± 666 mL, VE group; 2101 ± 1167 mL, NVE group; p = 0.33) and that at 48 h (3707 ± 1274 mL, VE group; 4195 ± 1990 mL, NVE group; p = 0.19) and in the mean change in body weight (- 2.5 ± 2.0 kg, VE group; -2.7 ± 2.4 kg, NVE group; p = 0.70). The median duration of hospitalization was 24 [20-9] and 31 [20-42] days in the VE and NVE groups, respectively (p = 0.67). The incidence of hypernatremia (6.3% (2/32), VE group; 3.4% (5/148), NVE group; p = 0.61) and WRF (25.0% (8/32) VE group; 19.6% (29/148), NVE group; p = 0.31) was similar between the groups. In conclusion, tolvaptan has similar clinical effectiveness in increasing urine volume and decreasing body weight, without increased adverse events, in VE patients with ADHF who were ≥ 90 years of age compared to NVE patients with ADHF.

[Spontaneous remission of relapsed skin lesions of ALK-positive anaplastic large cell lymphoma after autologous stem cell transplantation].

A 44-year-old woman was diagnosed with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) with clinical stage IVA (nodal and bladder involvement). Complete response (CR) was achieved after the CHOP chemotherapy; however, 12 months after the last course of chemotherapy, ALCL relapsed in the form of skin lesions without nodal involvement. After achieving a second CR with chemotherapy, autologous stem cell transplantation was performed. Two months after transplantation, the disease again relapsed as multiple skin lesions. Electron beam irradiation was performed; however, other skin lesions appeared thereafter and spontaneously disappeared. At present, 3.4 years after the transplantation, the patient is free from disease. ALK-positive ALCL relapsing as skin lesions may behave differently from the nodal relapse. An accumulation of cases is required to elucidate ALCL characteristics relapsing as skin lesions.

Clinical severity scores as a guide for prediction of initial treatment responses in pemphigus and pemphigoid patients.

Pemphigus and pemphigoid are autoimmune blistering diseases that affect mucosa and skin. Several clinical scoring systems, including the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), have been validated for managing disease activity and severity. Current guidelines recommend that treatment response be evaluated with clinical scores and that additional second-line therapies be considered if initial treatment is insufficient for disease control. However, there have been few studies analyzing correlations between PDAI/BPDAI transitions and initial treatment effects. To investigate whether PDAI/BPDAI transitions during the treatment initiation phase correlate with initial treatment responses and whether such information can be used as a guide for necessary additional treatment, we retrospectively analyzed 67 pemphigus patients and 47 pemphigoid patients who received initial treatment at Keio University between 2012 and 2018. The clinical symptoms were evaluated weekly with PDAI/BPDAI. The patients were divided into two groups: in group A, disease was controlled only with oral corticosteroids and immunosuppressants (initial treatment), whereas in group B additional therapies were required due to insufficient responses. In pemphigus, the PDAI ratio of day 7/day 0 was significantly reduced in group A compared to group B (0.548 vs 0.761, P < 0.01) after initial treatment had started. In pemphigoid, the ratios of day 7/day 0 of BPDAI (erosion/blister) and BPDAI (urticaria/erythema) significantly decreased in group A compared to group B (0.565 vs 0.901 and 0.350 vs 0.760, respectively, P < 0.05). Receiver operating characteristic analyses on PDAI, BPDAI (erosion/blister) and BPDAI (urticaria/erythema) revealed that the cut-off values in the ratios of day 7/day 0 were 0.762, 0.675, and 0.568, respectively. Our results suggest that PDAI/BPDAI transitions during the initial phase of the treatments may be useful to predict the outcome of the treatment provided and the necessity of additional therapies to achieve disease control.

A case of blastomycosis-like pyoderma caused by mixed infection of Staphylococcus epidermidis and Trichophyton rubrum.

Blastomycosis-like pyoderma (BLP) is a type of chronic pyoderma characterized histologically by specific epidermal changes namely: pseudoepitheliomatous hyperplasia and intraepithelial abscesses. These epidermal changes are also seen in blastomycosis (referred to as deep dermatophytosis in North America). Here, we describe the case of a 53-year-old male with prurigo nodularis, diabetes, and chronic lymphocytic leukemia who presented with multiple yellowish-red colored papules that coalesced to form a vegetating plaque. In addition to the typical features of BLP, spores with budding were seen histopathologically in a biopsy specimen. Cultures of a skin specimen grew Staphylococcus epidermidis and Trichophyton rubrum. Antibiotic therapy was effective but failed to eliminate the lesion until antifungal therapy using terbinafine was administered concurrently. Past reports suggest that BLP is mainly caused by bacterial infection, but our case suggests that fungal infection can also be involved as the causative organism in BLP.

EpCAM (CD326) Regulates Intestinal Epithelial Integrity and Stem Cells via Rho-Associated Kinase.

Humans with biallelic inactivating mutations in Epithelial Cell Adhesion Molecule (EpCAM) develop congenital tufting enteropathy (CTE). To gain mechanistic insights regarding EpCAM function in this disorder, we prepared intestinal epithelial cell (IEC) organoids and spheroids. IEC organoids and spheroids were generated from ROSA-CreERT2 EpCAMfl/fl mice. Proliferation, tight junctions, cell polarity and epithelial integrity were assessed in tamoxifen-induced EpCAM-deficient organoids via confocal immunofluorescence microscopy and Western blotting. Olfm4-expressing stem cells were assessed in IEC cells in vitro and in vivo via fluorescence in situ hybridization. To determine if existing drugs could ameliorate effects of EpCAM deficiency in IEC cells, a variety of pharmacologic inhibitors were screened. Deletion of EpCAM resulted in increased apoptosis and attenuated growth of organoids and spheroids. Selected claudins were destabilized and epithelial integrity was severely compromised. Epithelial integrity was improved by treatment with Rho-associated coiled-coil kinase (ROCK) inhibitors without restoration of claudin expression. Correspondingly, enhanced phosphorylation of myosin light chain, a serine/threonine ROCK substrate, was observed in EpCAM-deficient organoids. Strikingly, frequencies of Olfm4-expressing stem cells in EpCAM-deficient IEC cells in vitro and in vivo were decreased. Treatment with ROCK inhibitors increased numbers of stem cells in EpCAM-deficient organoids and spheroids. Thus, EpCAM regulates intestinal epithelial homeostasis via a signaling pathway that includes ROCK.

Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient.

A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain.

Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex.

Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31.

Patient voice on management of facial dermatological adverse events with targeted therapies: a qualitative study.

BACKGROUND: With the increased use of targeted therapies in oncology, dermatological adverse events (dAEs) have drawn attention. Because the face is crucial for human identity and social interactions, facial dAEs have significant impact on a patient's quality of life. This study aimed to explore patients' experience with regard to the management of targeted oncological therapy-induced facial dAEs. METHODS: In this qualitative study, 20 patients at a university hospital in Japan with advanced/metastatic cancer and targeted therapy-induced facial dAEs were individually interviewed to collect data. Thematic analysis was used to analyze the data. RESULTS: Patients with cancer and targeted oncological therapy-induced facial dAEs who were referred to the Department of Dermatology had certain expectations from specialist services. Three key themes were identified: professional input and advice, empathetic commitment to individual management, and integrated care across specialties. CONCLUSIONS: The referred patients with cancer and facial dAEs needed more in-depth information and advice from dermatological services and were reassured by the empathetic commitment to individual management in integrated care across specialties. These findings suggest that attention to the patient's perspective with a "sick person first" attitude and a collaborative effort across different specialties is important to minimize the effects of facial dAEs on the quality of life of patients with cancer.

[Case of cutaneous Pseudallescheria boydii infection caused by trauma].

Pseudallescheria boydii is a ubiquitous filamentous fungus. We report a case of cutaneous P. boydii infection of the left knee in a 79-year-old Japanese man who was receiving oral predonisolone (25 mg/day) for radiation pneumonitis after radiation therapy on left breast cancer. He presented with a 2-week-history of a lesion on the left knee. A biopsy specimen from the skin lesion revealed granulomatous inflammation with hyphae. Culture of the pus from the skin specimen confirmed the diagnosis of cutaneous P. boydii infection. rDNA ITS sequence was analyzed to confirm the mycological diagnosis. The patient was treated orally with 200 mg/day of itraconazole. The lesion was gradually cured and left a hypertrophic scar. Cutaneous injury may be responsible for an incidence of localized infection. Such rare fungus infection in immunocompromised patients who have a persistent traumatic skin ulcer needs to be ruled out. An opportunistic infection in immunocompromised patients can be life-threatening and prompt treatment based on accurate diagnosis is important.

Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome.

The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.

Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells.

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

Granuloma caused by subcutaneous injection of leuprorelin acetate product: case report and histopathological findings.

Leuprorelin acetate is a luteinizing hormone-releasing hormone (LH-RH) analog, which is used for chemical castration. Chemical castration treatment has an especially important role for prostate cancer. To ensure ongoing chemical castration, a novel sustained-action injection system using spherical microcapsules has been developed. We report a patient who had granuloma caused by administration of the 11.25 mg leuprorelin acetate product. Histological examination revealed many giant cells with vacuoles. On the basis of reported cases, these vacuoles are characteristic for the granuloma caused by leuprorelin acetate product. The vacuoles in the granuloma are the same size as the microcapsules, and their shape is almost spherical. We assume that the vacuoles in the granuloma are actually the microcapsules. We expect that there will be investigations regarding the procatarctic cause of granuloma formation.

EpCAM Expressed by Murine Epidermal Langerhans Cells Modulates Immunization to an Epicutaneously Applied Protein Antigen.

Langerhans cells (LCs) induce type 2 antibodies reactive with protein antigens that are applied to murine skin in the absence of adjuvant after extending their dendrites through tight junctions to acquire antigens and migrating to regional lymph nodes. In response to contact sensitizers, epithelial cell adhesion molecule (EpCAM) on LCs promotes LC dendrite mobility and LC migration. In epithelial cells, EpCAM regulates expression and distribution of selected tight junctions-associated claudins. To determine if EpCAM regulates claudins in LC and immune responses to externally applied proteins, we studied conditional knockout mice with EpCAM-deficient LCs. Although LC claudin-1 levels were dramatically reduced in the absence of EpCAM, conditional knockout mice with EpCAM-deficient LCs and control LC dendrites docked with epidermal tight junctions with equal efficiencies and ingested surface proteins. Topical immunization of conditional knockout mice with EpCAM-deficient LCs with ovalbumin led to increased induction of type 2 Ova-specific antibodies and enhanced proliferation of ovalbumin-reactive T cells associated with increased accumulation of LCs in lymph nodes. These results suggest that, in the absence of strong adjuvants, EpCAM-deficient LCs exhibit increased migration to regional lymph nodes. EpCAM appears to differentially regulate LC mobility/migration in the setting of limited inflammation as compared with the intense inflammation triggered by contact sensitizers.

Trichophyton tonsurans infection manifesting as multiple concentric annular erythemas.

We report a case of dermatophytosis in a Judo wrestler caused by Trichophyton tonsurans (T. tonsurans) with clinical features that mimicked the concentric rings of tinea imbricata. Tinea imbricata is a unique dermatophytosis caused by Trichophyton concentricum (T. concentricum), observed endemically in subtropical to torrid zones and characterized by impressive concentric rings. We found three similar cases of the dermatophytosis in the literature that were reported as tinea pseudoimbricata or tinea indecisiva. All of these cases were associated with systemic or local immunosuppression, perhaps simulating the mechanism of tinea imbricata, which is known to involve the lack of delayed type hypersensitivity to T. concentricum. These cases imply that iatrogenic immunosuppression may perhaps play an important role in the development of the unique clinical features mimicking tinea imbricata. Furthermore, three of the four cases, including the presented case, were caused by T. tonsurans. It may be necessary to consider T. tonsurans infection when multiple concentric erythemas are encountered.

Identification of Trichophyton rubrum by nested PCR analysis from paraffin embedded specimen in trichophytia profunda acuta of the glabrous skin.

Trichophytia profunda acuta of the glabrous skin (TPAGS) arose in a 67-year-old Japanese man. The patient presented indurated erythematous plaques and nodules on his left forearm. Direct microscopic examination of the scale in KOH preparation was negative for fungal elements, and culture for dermatophytes was also negative. Although fungal infection could not be proven in hematoxillin-eosin stained sections, deep-cut sections of the biopsied skin lesion with PAS stain revealed the ectothrix presence of fungal elements. Nested PCR was done with Trichophyton specific primers directed to internal transcribed spacer gene 1 (ITS1), using template DNA obtained from formalin fixed, paraffin embedded skin sections. A single band corresponding to T. rubrum was obtained, and the etiological agent was thus identified. KOH tests and cultures may often turn out unsuccessful, perhaps reflecting the hair follicle dominant fungus growth in TPAGS. Although these tests are most important for diagnosis of TPAGS, nested PCR using paraffin embedded skin sections may be an alternative method to identify the etiological agent.