Merkel cell carcinoma: A systematic review of the demographic and clinical characteristics of 847 cases in Japan.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin associated with Merkel cell polyomavirus and immunosuppression. Although MCC incidence is rising worldwide, MCC has not been sufficiently investigated in Japan. This study aimed to determine MCC demographics in Japan, including incidence, age, sex, location, spontaneous regression, and pure/combined MCC. Using PubMed and Igaku Chuo Zasshi, 847 MCC cases between 1985 and 2015 were extracted, and the main epidemiological characteristics were described. The mean age of all patients was 77.5 years. Regarding the characterized lesions, 63.0% were located on the head and neck, 5.2% on the trunk, 12.6% on the upper limb, 15.1% on the lower limb, 3.5% on the buttocks, and 0.6% on the genitals. Histopathological information regarding the presence of other malignancies could be retrieved in 611 cases, and a coexisting malignancy, mainly squamous cell carcinoma and Bowen's disease, was present in 14.2%. Subcutaneous MCC was observed in 31 patients with a male : female ratio of 1.07 (16 men/15 women). Nodal lesions with unknown primary tumor location were described in 19 patients with a male : female ratio of 0.9 (nine men/10 women) and a mean age of 77.7 years. Of 640 evaluable cases, spontaneous regression developed in 9.1%. Among those 58 patients, the male : female ratio was 1:2.1 in 56 evaluable cases (18 men/38 women). Merkel cell polyomavirus was assessed in 180 patients, and the virus was detected in 31.1% and not detected in 68.9% of the patients. MCC is a rare disease in Japan, with incidence rates and male : female ratios differing from those in the USA and European countries. Besides, this study reveals the high frequency of subcutaneous MCC and MCC with divergent differentiation patterns and spontaneous regression in Japan compared to other countries.

Dermal and Intraepidermal Merkel Cell Carcinoma With Squamous Cell Carcinoma: A Report of a Rare Case With Special Reference to the Touch Dome.

ABSTRACT: In skin containing hair follicles, specialized epithelial structures known as "touch domes (TDs)" are located where the Merkel cells are clustered. We explored the histogenetic relationship between intraepidermal and dermal Merkel cell carcinomas (MCCs) and investigated which transformed progenitor cells can develop into intraepidermal MCC. We encountered an association between an extremely rare case of dermal and intraepidermal MCC with squamous cell carcinoma, which was examined using standard immunohistochemical methods with various epithelial, neuroendocrine, and TD markers including several immunohistochemical markers. Differential expression levels of CK20 and CD56 were found between intraepidermal and dermal MCCs, indicating molecularly distinct MCC populations. CK15 and CK17, expressed in TDs, were partially expressed in the intraepidermal neuroendocrine component at the tumor periphery in intraepidermal MCC with squamous cell carcinoma. These differences may suggest that the origin of dermal and intraepidermal MCCs is different under pathological conditions. We hypothesize that intraepidermal MCC is derived from tissue-specific stem cells localized within TDs.

Association of Genetic Polymorphisms With Afatinib-induced Diarrhoea.

BACKGROUND/AIM: Afatinib, a 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of non-small cell lung cancer (NSCLC), causes diarrhoea in over 90% of patients. The association of genetic background with diarrhoea is poorly understood. PATIENTS AND METHODS: We evaluated the roles of four single nucleotide polymorphisms (SNPs) in ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2) genes-ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T, and ABCG2 421 C>A-on treatment-induced diarrhoea in 38 patients with NSCLC treated with afatinib. RESULTS: Diarrhoea occurred more frequently in patients with ABCB1 2677 T(A)/T(A) (14/16, 87.5%) than in patients with non-T(A)/T(A) alleles (8/22, 36.4%) (p=0.003). ABCB1 2677 T(A)/T(A) was significantly predictive of diarrhoea (p=0.002) by multivariable regression analysis. CONCLUSION: Afatinib-induced diarrhoea is associated with the SNP ABCB1 2677 T(A)/T(A).

Development of an application for management of drug holidays in perioperative periods.

Before surgery and other invasive treatments, decisions must be made on whether to discontinue drugs and provide appropriate drug holidays especially for antithrombotic drugs, and this is made difficult by the large number of available drugs and associated guidelines. We have therefore developed an online application for perioperative drug discontinuation and resumption management, named Saga Application for Management of Drug Holidays in PeriOperative Periods (SAMPOP).Multidisciplinary medical staff at Saga University Hospital (SUH) worked together to build an evidence-based Perioperative Drug Discontinuation Management Database (PDDMD) and developed the user-friendly SAMPOP online application via preliminary verification at SUH. From September 2018 to February 2020, 420 medical staff at SUH, including physicians, nurses, and pharmacists, installed and tested SAMPOP.Rate per surgical procedure for forgetting to discontinue antithrombotic drugs preoperatively decreased from 0.18% to 0.09% as of August 2019, 12 months after the introduction of SAMPOP (P = .1359). In addition, six months later, it decreased further to 0.03% as of February 2020 (P = .0436). Forgetting to resume antithrombotic drugs postoperatively decreased from 0.20% to 0.02% as of August 2019, 12 months after the introduction of SAMPOP (P = .0008). There was no case of forgetting to resume the medication in the last 6 months.SAMPOP may be useful for management of drug holidays in the clinic and warrants further evaluation of its safety and efficacy.

Immunohistochemical localization of afatinib in male rat intestines and skin after its oral administration.

Afatinib, a second-generation tyrosine kinase inhibitor, was designed to bind covalently to and irreversibly inhibit active ErbB family receptors. The major metabolites of afatinib in human plasma are adducts of afatinib covalently bound to plasma proteins via. the Michael addition reaction. These findings suggest that afatinib may form covalent bonds with proteins in tissue and be localized in tissue. However, there is no method for the specific detection of afatinib-protein conjugates localized in tissue. In this paper, we aimed to develop an immunohistochemical protocol to detect afatinib-protein conjugates. Immunostainings were performed with male rat intestinal tract and skin at 24 h after an oral administration of afatinib. In the intestinal tract, strong staining was observed in the ileum and colon, but only slight staining was observed in the duodenum and jejunum. In the skin, strong staining was observed in the epidermis, sebaceous glands and hair follicles. Immunohistochemistry for afatinib-protein conjugates could be a useful tool to detect the localization of such conjugates. This study is the first to elucidate the localization of afatinib-protein conjugates in the rat intestinal tract and skin and is expected to be of great use in efforts to clarify the mechanism underlying afatinib-induced diarrhoea or skin toxicities.

Development of a sandwich enzyme-linked immunosorbent assay for the quantification of ponatinib in serum.

The tyrosine kinase inhibitor ponatinib is extensively metabolized in the body, and consequently the development of specific immunoassays for pharmacokinetic studies and therapeutic drug monitoring of ponatinib is challenging. If two antibodies simultaneously recognize the entire structure of ponatinib, they could be utilized to establish an ultra-specific sandwich immunoassay for ponatinib, free of any interference from ponatinib metabolites. In this study, we created two types of anti-ponatinib polyclonal antibodies that recognize two different ponatinib epitopes, and sandwiched almost all structural components of ponatinib in these two antibodies in order to develop an enzyme-linked immunosorbent assay (ELISA) technique not affected by any ponatinib metabolites. After optimization, this sandwich ELISA showed a linear detection range of 640 pg/mL to 2000 ng/mL and a limit of quantification of 640 pg/mL. This sandwich ELISA was specific to ponatinib and showed no cross-reactivity with the major metabolite M14. Comparison between the sandwich ELISA and HPLC, using serum samples from 15 rats orally administered a single dose of 15 mg/kg ponatinib, showed a linear regression (y = 0.9662x + 3.5354, r = 0.9683). Thus, in this study, we successfully developed the first ultra-specific sandwich ELISA for ponatinib in serum.

Development of a competitive enzyme-linked immunosorbent assay for therapeutic drug monitoring of afatinib.

Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for treating advanced non-small cell lung cancer. It is necessary to develop a simple quantification method for TKIs in order to facilitate therapeutic drug monitoring (TDM) in clinical settings. This study sought to develop a simple and sensitive competitive enzyme-linked immunosorbent assay (ELISA) to quantify afatinib in plasma for routine pharmacokinetic applications. An anti-afatinib antibody was obtained using (S)-N-4-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diamine (CTQD), which has the same substructure as afatinib, as a hapten. Enzyme labeling of afatinib with horseradish peroxidase was similarly performed using CTQD. A simple competitive ELISA for afatinib was developed based on the principle of direct competition between afatinib and the enzyme marker for the anti-afatinib antibody, which had been immobilized on the plastic surface of a microtiter plate. Plasma afatinib concentrations below the limit of quantification of 30 pg/mL were reproducibly measurable. Also, the values of plasma afatinib levels measured from 20 patients were comparable with those measured by high-performance liquid chromatography, and there was a strong correlation between the values determined by both methods (Y = 0.976X - 0.207, r = 0.975). As indicated by its specificity and sensitivity, this newly developed ELISA for afatinib is an important tool for TDM and studies of the pharmacokinetics of afatinib.

Cross-sectional multicenter observational study of psoriatic arthritis in Japanese patients: Relationship between skin and joint symptoms and results of treatment with tumor necrosis factor-α inhibitors.

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross-sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P < 0.01). Biologic agents were used in 206 patients (72.3%), anti-tumor necrosis factor (TNF)-α antibodies being prescribed first to 157 of them. Anti-TNF-α antibodies were continued by 105 participants and discontinued by 47, the remaining five patients being lost to follow up. Patients who discontinued anti-TNF-α antibodies were significantly older than those who continued (55 vs 51 years, P = 0.04) and significantly older at onset of joint manifestations (50 vs 44 years, P = 0.01). Multivariate analysis revealed that patients over 50 years significantly more frequently terminated anti-TNF-α antibodies (P < 0.01). In conclusion, patients with PsA and severe skin manifestations have earlier onset and axial disease, which seriously impacts on quality of life. Anti-TNF-α antibodies were generally effective enough to continue but less so in patients aged over 50 years. Further detailed research is needed.

Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma.

The cellular origin of Merkel cell carcinoma (MCC) is controversial. We previously hypothesized that MCC originates from hair follicle stem cells or Merkel cell (MC) progenitors residing within the hair follicle bulge. Examination of three cases of combined MCC led to the unexpected discovery that numerous keratin 20 (CK20)-positive MCs within the squamous cell carcinoma (SCC) component of combined MCC appeared morphologically normal with dendritic and oval shapes. Moreover, one extremely rare case of combined SCC and MCC showed both intra-epidermal and dermal MCCs. These three cases represent the first documentation of MC hyperplasia in MCC, besides various benign follicular neoplasms associated with MC hyperplasia. Therefore, to elucidate the proliferating potential of MCs and their histogenetic relationship with MCCs, we further investigated these cases based on pathological observations. We identified numerous cells co-expressing CK20 and the proliferation marker Ki-67, identical to the morphological and immunohistochemical features of normal MCs. This finding indicated that MCs can no longer be considered as pure post-mitotic cells. Instead, they have proliferative potential under specific conditions in the diseased or wounded skin, or adjacent to various skin tumors, including MCC. Intimate co-existence of two malignant cell components composed of intradermal and intra-epidermal MCCs, with the proliferation of normal-appearing MCs in the same lesion, lends support to the hypothesis that MCs and MCC cells are derived from MC progenitors residing within the hair follicle bulge. Specifically, MCCs are derived from transformed MC progenitors with potential for dual-directional differentiation towards neuroendocrine and epithelial lineages.

Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus-negative and combined Merkel cell carcinoma: A retrospective study.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin that is associated with Merkel cell polyomavirus (MCPyV). The clinical appearance and demographic characteristics of this tumor have been described using the mnemonic AEIOU: asymptomatic, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed fair skin. In addition, MCC can be categorized based on morphology as pure MCC or combined MCC that exhibits neuroendocrine and other phenotypic elements. There is limited information regarding the clinical characteristics and prognosis of combined MCC. This retrospective study aimed to identify factors, such as ulceration or hyperkeratosis, that could predict MCPyV status and morphological variants. Twenty patients with MCC were divided into groups based on MCPyV status and morphology: MCPyV-positive or MCPyV-negative MCC and pure or combined MCC. The patients' MCPyV status was immunohistochemically determined using the CM2B4 antibody to the MCPyV large T-antigen. The patients' clinicopathological characteristics were evaluated to identify predictors of MCPyV-negative MCC and combined MCC. The presence of ulceration/hyperkeratosis predicted the presence of MCPyV-negative MCC (80% of cases) and combined MCC (50% of cases). None of the 10 patients with MCPyV-positive MCC had ulceration/hyperkeratosis. The clinical presence of ulceration/hyperkeratosis may help guide the diagnosis of MCPyV-negative MCC and combined MCC.

Immunotherapy for Merkel Cell Carcinoma.

OPINION STATEMENT: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin, with frequent recurrences, metastasis, and a high mortality rate. For primary or locoregional MCC, a wide local excision followed by radiation therapy is the basic treatment modality for preventing recurrence at the primary site and involved lymph nodes. Cytotoxic chemotherapy has been commonly used to treat patients with metastatic MCC, but not as an adjuvant therapy for high-risk resected MCC. Although MCC is often chemotherapy-sensitive in the first-line setting, responses are rarely durable and most patients subsequently relapse and develop metastasis. Treatment with checkpoint inhibitors (CPIs) has shown a major advancement in the treatment of advanced MCC. Systemic therapy against programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) is associated with a high objective response rate (ORR), prolonged durable responses, and good tolerability in advanced-stage MCC. CPIs are now included in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with metastatic MCC. Multiple clinical trials of CPIs administered as monotherapy or in combination with other agents or modalities, including the adjuvant setting, are ongoing. Immunotherapy offers a promising future for patients with MCC. In this review, we present an overview of emerging data on immunotherapy, especially CPIs of the PD-1/PD-L1 pathway, for patients with advanced MCC.

Anxiety and depression associated with tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia.

BACKGROUND: ABL tyrosine kinase inhibitors (TKIs) significantly changed the prognosis of patients with chronic myeloid leukemia (CML), and clinical trials demonstrated that TKIs can be discontinued in approximately 50% of patients after a period of deep molecular response (DMR). However, in some patients, TKI discontinuation leads to anxiety and depression. Here, we analysed the incidence of anxiety and depression in patients who stop TKI therapy. METHODS: Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS) in 32 patients with CML. The survey periods were at TKI discontinuation, at 1, 6, 12, and 24 months and at reintroduction of TKIs. The HADS score at the initial TKI discontinuation was compared between patients within and outside clinical trials. Treatment-free remission (TFR) rates outside clinical trials were evaluated. RESULTS: The HADS scores were significantly higher at TKI reintroduction after molecular relapse than at the initial TKI discontinuation (at the initiation of stopping TKIs vs. at reintroduction of TKIs, 8.47 ± 5.53 vs. 1.67 ± 2.26; p = 0.0003). The TFR rate at 12 months after stopping TKIs outside clinical trials was 55.6%. The HADS score at the initial TKI discontinuation did not differ between patients within and outside clinical trials. CONCLUSION: Stopping TKIs outside clinical trials is feasible if the guidelines for stopping are followed and an adequate monitoring system is available. Discontinuation of TKIs requires adequate management of anxiety and depression.

Case of probable spontaneous regression of Merkel cell carcinoma combined with squamous cell carcinoma without surgical intervention.

Merkel cell carcinoma (MCC) is a rare but more lethal cutaneous cancer than melanoma. However, spontaneous regression of a number of MCC has been reported, although the cause of this regression remains unclear. In most cases, MCC regresses after a surgical procedure, for example, biopsy. Herein, we report a case of Merkel cell polyomavirus-negative MCC coincident with squamous cell carcinoma (SCC) that underwent true spontaneous regression without biopsy. One month after the patient's first visit, clinical examination revealed that the tumor had not grown, but its surface showed changes in texture and color. Histopathologically, the excised specimen was indicative of MCC coincident with SCC and showed extensive necrosis in the upper portion of the tumor, numerous caspase-3-positive apoptotic cells, an accumulation of CD68-positive foam cells and vascular invasion. These findings suggested that the tumor had regressed. We hypothesize that extensive coagulative necrosis resulting from an insufficient local blood supply triggered the shedding of some products or components of MCC and SCC, which in turn induced antitumor immunity against both lesions.

Hyperuricemia is an independent risk factor for psoriatic arthritis in psoriatic patients.

Psoriatic arthritis (PsA) is a spondyloarthritic condition mainly seen in patients with psoriasis. Psoriatic patients with plaques on the scalp, gluteal fold or nail lesions are known to develop PsA more frequently, but other markers for PsA have not yet been identified. To determine which psoriatic patients are at greatest risk of developing PsA, psoriasis vulgaris (PsV) patients who visited the Department of Dermatology, Fukuoka University Hospital in 2015 were enrolled. Patients with and without PsA were statistically compared with respect to age, sex, age at onset, body mass index (BMI), smoking and drinking habits, familial history of psoriasis and comorbidities. Of 331 patients (237 men, 94 women), 55 had PsA (17%; 39 men, 16 women). PsA patients had significantly higher frequencies of nail lesions (PsA vs PsV-only, 62% vs 29%; P < 0.0001) and hyperuricemia (PsA vs PsV-only, 22% vs 9%; P = 0.01). These were confirmed as independent risk factors for PsA by logistic regression analysis, with odds ratios of 5.05 for nail lesions (P < 0.0001) and 4.18 for hyperuricemia (P < 0.01). There was no difference in age at onset, sex, BMI and incidence of diabetes mellitus, hypertension or dyslipidemia. Hyperuricemia is also known to be more frequent in psoriatic subjects than the normal population. Uric acid crystals are a strong stimulator of innate immunity. Considering that none of our cohort had gouty arthritis, hyperuricemia may increase uric acid crystallization in and around joints, thereby inducing PsA in psoriatic subjects. Hyperuricemia appears to be an independent risk factor for PsA.

An ultra-specific and sensitive sandwich ELISA for imatinib using two anti-imatinib antibodies.

The development of an immunoassay for a low-molecular-weight drug first requires the identification of specific antibodies that do not cross-react with the drug's metabolites. If two antibodies can simultaneously recognize the entire structure of the drug, we can then utilize them to establish an ultra-specific sandwich ELISA, free from interference due to the metabolic products of the drug. This paper reports an ultra-specific and sensitive sandwich ELISA for determination of the tyrosine kinase inhibitor imatinib using two anti-imatinib antibodies. The anti-imatinib antibodies were obtained by two partial structures of imatinib as haptens (2-(5-amino-2-methylanilino)-4-(3-pyridyl)pyrimidine and 4-{(4-methyl-1-piperazinyl)-methyl}-benzoate). Under optimized conditions, this sandwich ELISA shows a linear detection range from 64 pg mL-1 to 8 ng mL-1, and a limit of detection of approximately 64 pg mL-1 for 100-µL samples. The ELISA is specific to imatinib and while there was no cross-reactivity with the major metabolite N-desmethyl-imatinib, slight cross-reactivity was found with metabolite pyridine-N-oxide-imatinib. This assay demonstrated significantly lower cross-reactivity with metabolites than competitive ELISAs. Using this assay, drug levels were easily measured in rat blood after oral administration of imatinib via a single dose of 30 mg kg-1 or 100 mg kg-1. The levels in rat serum measured by this ELISA were comparable with those measured by HPLC, and there was a strong correlation between the values determined by the two methods (y = 0.983x + 0.081, R2 = 0.948). Thus, we have successfully developed the first specific and sensitive sandwich ELISA for imatinib using two anti-imatinib antibodies. This sandwich ELISA will be a valuable tool for therapeutic drug monitoring and pharmacokinetic studies of imatinib.