Current Management and Treatment of Extramammary Paget's Disease.

OPINION STATEMENT: Extramammary Paget's disease (EMPD) is a rare neoplastic disease affecting areas rich in apocrine glands in the elderly. EMPD clinically resembles a benign inflammatory skin disease, and ill-defined tumor borders can lead to misdiagnosis and incomplete excision. Several prognostic factors have been reported, including nodule formation, tumor thickness, tumor invasion, lymphovascular invasion, and a perianal location, which are characteristic of primary tumors. EMPD typically presents as an in situ tumor spreading horizontally within the epidermis and then invading into the dermis as it transitions to a vertical growth phase. For this reason, tumor thickness, rather than tumor size, is correlated with patient prognosis. The best treatment for resectable EMPD is complete surgical removal of the tumor. EMPD sometimes has unclear tumor borders, and it can unexpectedly spread beyond its clinical boundaries. Surgical resection in such cases is often associated with tumor-positive margins, which can result in recurrence. However, surgical excision with wide margins may deteriorate patients' organ functions and quality of life. Mohs micrographic surgery may be ideal for controlling the surgical margins and minimizing the sacrifice of normal tissue, but this technique is not always feasible because of constraints associated with the medical environment. No standard treatment for unresectable or metastatic EMPD has been established. Although conventional chemotherapy has been used as the first-line treatment, it frequently causes adverse events, and consequently, targeted therapy will become more valuable in the near future.

Nectin-4: a Novel Therapeutic Target for Skin Cancers.

OPINION STATEMENT: Nectin-4 is a tumor-associated antigen that is highly expressed on various cancer cells, and it has been further proposed to have roles in tumor development and propagation ranging from cellular proliferation to motility and invasion. Nectin-4 blockade reduces tumor proliferation and induces apoptosis in several malignancies. Nectin-4 has been used as a potential target in antibody-drug conjugate (ADC) development. Enfortumab vedotin, an ADC against Nectin-4, has demonstrated efficacy against solid tumor malignancies. Enfortumab vedotin has received US Food and Drug Administration approval for treating urothelial cancer. Furthermore, the efficacy of ADCs against Nectin-4 against solid tumors other than urothelial cancer has been demonstrated in preclinical studies, and clinical trials examining the effects of enfortumab vedotin are ongoing. Recently, Nectin-4 was reported to be highly expressed in several skin cancers, including malignant melanoma, cutaneous squamous cell carcinoma, and extramammary Paget's disease, and involved in tumor progression and survival in retrospective studies. Nectin-4-targeted therapies and ADCs against Nectin-4 could therefore be novel therapeutic options for skin cancers. This review highlights current knowledge on Nectin-4 in malignant tumors, the efficacy of enfortumab vedotin in clinical trials, and the prospects of Nectin-4-targeted agents against skin cancers.

Automated radiosynthesis of [11 C]MTP38-a phosphodiesterase 7 imaging tracer-using [11 C]hydrogen cyanide for clinical applications.

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[11 C]carbonitrile ([11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [11 C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [11 C]MTP38 using [11 C]hydrogen cyanide ([11 C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [11 C]MTP38 was performed using an automated 11 C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [11 C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [11 C]CO2 at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/µmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [11 C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [11 C]MTP38 for clinical applications using an 11 C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [11 C]MTP38 suitable for clinical applications.

Radiosynthesis and quality control testing of the tau imaging positron emission tomography tracer [18 F]PM-PBB3 for clinical applications.

Recently, we produced 11 C-labeled 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([11 C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half-life) of [11 C]PBB3, we further synthesized 18 F-labeled 1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([18 F]PM-PBB3). [18 F]PM-PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [18 F]PM-PBB3 for clinical applications. [18 F]PM-PBB3 was synthesized by direct 18 F-fluorination of the tosylated derivative, followed by removal of the protecting group. [18 F]PM-PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay-corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/µmol at EOS; n = 53). Moreover, [18 F]PM-PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV-cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [18 F]PM-PBB3 injection complied with our in-house quality control and quality assurance specifications. We have accomplished >200 production runs of [18 F]PM-PBB3 in our facility for various research purposes.

Trop2 Expression in Extramammary Paget's Disease and Normal Skin.

Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.

[Effect of Increased Use of a Closed System Drug Transfer Device and Simplification of Personal Protective Equipment on the Cost of Medical Materials].

As a preventive measure for occupational exposure to anticancer drugs, the use of a closed system drug transfer device (CSTD)is not widespread. The main reason for this is the high cost of the equipment. For inpatient chemotherapy(Ⅳ)at our hospital, CSTD was used for the following 3 drugs, cyclophosphamide, ifosfamide, and bendamustine; however, from Nov. 2018, CSTD was used for all chemotherapy drugs. Meanwhile, the personal protective equipment (PPE) for ward nurses was simplified. The purpose of this study was to determine the effects of increased CSTD use and simplification of PPE on the cost of medical materials. Information collected between Apr. and Sep. 2019 was extracted from health records. The total number of inpatient chemotherapy treatments during the study period was 970. The increase in the cost of drug administration equipment due to expansion of CSTD use was ¥1.74 million per half a year. However, the cost savings from simplifying PPE was approximately ¥290,000 per half a year, which is about 16.8% of the increase in cost. We hope that the amount of reimbursement will increase and that device prices will decrease as CSTD use becomes more widespread.

Dynamic Changes in Striatal mGluR1 But Not mGluR5 during Pathological Progression of Parkinson's Disease in Human Alpha-Synuclein A53T Transgenic Rats: A Multi-PET Imaging Study.

Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by resting tremor and movement deficits. Group I metabotropic glutamate receptor subtypes 1 and 5 (mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated the in vivo roles of mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging in A53T transgenic (A53T-Tg) rats expressing an abnormal human α-synuclein (ASN) gene. A53T-Tg rats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [(11)C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]methylbenzamide), a selective PET ligand for mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPND values for (E)-[(11)C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[(11)C]methyloxime], a specific PET ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal mGluR1 BPND values also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in mGluR1 BPND values were correlated with decreases in BPND values for [(18)F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2ß-carbo-[(18)F]fluoroethoxy-3ß-(4-methylphenyl) nortropane], a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model. SIGNIFICANCE STATEMENT: Synaptic signaling by glutamate, the principal excitatory neurotransmitter in the brain, is modulated by group I metabotropic glutamate receptors, including the mGluR1 and mGluR5 subtypes. In the brain, mGluR1 and mGluR5 have distinct functional roles and regional distributions. Their roles in brain pathology, however, are not well characterized. Using longitudinal PET imaging in a chronic rat model of PD, we demonstrated that expression of mGluR1, but not mGluR5, dynamically changed in the striatum accompanying pathological PD progression. These findings imply that monitoring mGluR1 in vivo may provide beneficial information to further understand central nervous system disorders.

[Development of a Drug Cost Calculation Tool for Breast Cancer Therapy].

Drug cost is considered an important factor in treatment compliance for cancer patients. However, it is difficult to calculate individual drug costs. We were previously unable to provide sufficient information on costs to cancer patients starting drug therapy. Therefore, we developed a tool, in the form of a spreadsheet, which calculates drug costs for breast cancer treatment. This software tool runs on every terminal for electronic medical charts in our hospital. To evaluate the tool, we created 10 fictional breast cancer patient sets. Five pharmacists calculated the drug costs for a single regimen using method A (without software) and method B (with software). The pharmacists then calculated the drug costs for 3 regimens in the same way. We compared the time taken to calculate costs using method A and method B. For the single regimen, the mean time for method B (22.6±6.9 s) was 6.4-times shorter than that for method A (145.2±28.3 s, p<0.0001). For the 3 regimens, the mean time for method B (35.5±5.0 s) was 8.9-times shorter than that for method A (315.8±43.1 s, p<0.0001). The differences observed were statistically significant. By using the software, we were able to shorten the calculation time for drug costs, and therefore, alleviate the burden on medical staff.

Sonication-induced formation of size-controlled self-assemblies of amphiphilic Janus-type polymers as optical tumor-imaging agents.

In this study, amphiphilic Janus-type polymers were synthesized via ring-opening metathesis polymerization (ROMP), multiple vicinal diol formation, and grafting of poly(ethylene glycol) monomethyl ether (mPEG). These amphiphilic polymers formed self-assemblies, which were a mixture of micelles and multimicellar aggregates, in water. By choosing suitable Janus-type polymers and irradiating an aqueous solution of polymers using a sonicator, either small micelles or large multimicellar aggregates were obtained selectively. Hydrophobic substituents controlled the aggregation-disaggregation behavior, leading to the formation of metastable self-assemblies by sonication. The formation of self-assemblies with a uniform size was affected by ultrasonic frequency, rather than power. In vivo optical tumor imaging revealed that the large-size multimicellar aggregates persisting for a long time in blood circulation slowly accumulated in tumor tissues. In contrast, the tumor site was rapidly, clearly visualized using the small-size micelles.

Effectiveness of palonosetron for preventing delayed chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy in patients with gastrointestinal cancer.

PURPOSE: Patients with gastrointestinal cancer who were receiving moderately emetogenic chemotherapy (MEC) were switched from granisetron, a first-generation 5-hydroxytryptamine-3 receptor antagonist, to palonosetron at our hospital. In the present study, we compared effectiveness before and after switching antiemetic treatment. METHODS: Among patients who were receiving MEC for gastrointestinal cancer, we prospectively observed 46 patients given granisetron and 46 given palonosetron. To allow adverse reactions to be graded in accordance with the Common Terminology Criteria for Adverse Events, version 4.0, a questionnaire designed at our hospital was used to compare the occurrence of delayed nausea and vomiting between patients who received granisetron (GRA group) and those who received palonosetron (PAL group). RESULTS: The incidence of delayed nausea was significantly lower in the PAL group (8.7%, 4/46; p < 0.01) than in the GRA group (37%, 17/46). Delayed vomiting developed in five patients (10.9%) in the GRA group, but did not occur in the PAL group. On the basis of the results of multivariate analysis, young age, female gender, and the use of granisetron were significant risk factors for delayed nausea. CONCLUSION: Our survey showed that palonosetron effectively controls delayed nausea caused by MEC for gastrointestinal cancer.

A first-in-man study of [18F] FEDAC: a novel PET tracer for the 18-kDa translocator protein.

PURPOSE: N-benzyl-N-methyl-2-[7, 8-dihydro-7-(2-[18F] fluoroethyl) -8-oxo-2-phenyl-9H-purin-9-yl] acetamide ([18F] FEDAC) is a novel positron emission tomography (PET) tracer that targets the translocator protein (TSPO; 18 kDa) in the mitochondrial outer membrane, which is known to be upregulated in various diseases such as malignant tumors, neurodegenerative diseases, and neuroinflammation. This study presents the first attempt to use [18F]FEDAC PET/CT and evaluate its biodistribution as well as the systemic radiation exposure to the radiotracer in humans. MATERIALS AND METHODS: Seventeen whole-body [18F]FEDAC PET/CT (injected dose, 209.1 ± 6.2 MBq) scans with a dynamic scan of the upper abdomen were performed in seven participants. Volumes of interest were assigned to each organ, and a time-activity curve was created to evaluate the biodistribution of the radiotracer. The effective dose was calculated using IDAC-Dose 2.1. RESULTS: Immediately after the intravenous injection, the radiotracer accumulated significantly in the liver and was subsequently excreted into the gastrointestinal tract through the biliary tract. It also showed high levels of accumulation in the kidneys, but showed minimal migration to the urinary bladder. Thus, the liver was the principal organ that eliminated [18F] FEDAC. Accumulation in the normal brain tissue was minimal. The effective dose estimated from biodistribution in humans was 19.47 ± 1.08 µSv/MBq, and was 3.60 mSV for 185 MBq dose. CONCLUSION: [18F]FEDAC PET/CT provided adequate image quality at an acceptable effective dose with no adverse effects. Therefore, [18F]FEDAC may be useful in human TSPO-PET imaging.

Carbon-11 radiolabeling of an oligopeptide containing tryptophan hydrochloride via a Pictet-Spengler reaction using carbon-11 formaldehyde.

A procedure for the synthesis of a(11)C-labeled oligopeptide containing [1-(11)C]1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid ([1-(11)C]Tpi) from the corresponding Trp•HCl-containing peptides has been developed involving a Pictet-Spengler reaction with [(11) C]formaldehyde. The synthesis of [1-(11)C]Tpi from Trp and [(11)C]formaldehyde was examined as a model reaction with the aim of developing a facile and effective method for the labeling of peptides with carbon-11. The Pictet-Spengler reaction of Trp and [(11)C]formaldehyde in acidic media (TsOH or HCl) afforded the desired [1-(11)C]Tpi in a moderate radiochemical yield. Herein, the application of a Pictet-Spengler reaction to an aqueous solution of Trp•HCl gave the desired product with a radiochemical yield of 45.2%. The RGD peptide cyclo[Arg-Gly-Asp-D-Tyr-Lys] was then selected as a substrate for the labeling reaction with [(11)C]formaldehyde. The radiolabeling of a Trp•HCl-containing RGD peptide using the Pictet-Spengler reaction was successful. Furthermore, the remote-controlled synthesis of a [1-(11)C]Tpi-containing RGD peptide was attempted by using an automatic production system to generate [(11)C]CH3 I. The radiochemical yield of the [1-(11) C]Tpi-containing RGD at the end of synthesis (EOS) was 5.9 ± 1.9% (n = 4), for a total synthesis time of about 35 min. The specific activity was 85.7 ± 9.4 GBq/µmol at the EOS.

Fully automated reagent peak-free liquid chromatography fluorescence analysis of highly polar carboxylic acids using a column-switching system and fluorous scavenging derivatization.

In this study, we combined a column-switching system with a fluorous scavenging derivatization method to develop a fully automated reagent peak-free LC fluorescence detection protocol for the analysis of highly polar carboxylic acids. In this method, highly polar carboxylic acids were derivatized with fluorescent 1-pyrenemethylamine in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-1H-benzotriazole. Residual excess of the unreacted reagent was tagged with 2-(perfluorooctyl)ethyl isocyanate and then removed selectively using a fluorous column-switching system placed in front of an analytical reversed-phase column. The signal of the fluorous-tagged unreacted reagent was completely absent in the resulting chromatograms; therefore, it did not interfere with the quantification of each acid especially those eluted before 20 min. The detection limits (S/N = 3) for the examined acids were in the range from 4.0 to 22 fmol per injection. We have applied this method to comparative analysis of highly polar carboxylic acids in urine samples obtained from diabetes mellitus type-II model mice and their control.

The use of tetrabutylammonium fluoride to promote N- and O-(11) C-methylation reactions with iodo[(11) C]methane in dimethyl sulfoxide.

The N- or O-methylation reactions of compounds bearing amide, aniline, or phenol moieties using iodo[(11) C]methane (1) with the aid of a base are frequently applied to the preparation of (11) C-labeled radiopharmaceuticals. Although sodium hydride and alkaline metal hydroxides are commonly employed as bases in these reactions, their poor solubility properties in organic solvents and hydrolytic activities have sometimes limited their application and made the associated (11) C-methylation reactions difficult. In contrast to these bases, tetrabutylammonium fluoride (TBAF) is moderately basic, highly soluble in organic solvents, and weakly nucleophilic. Although it was envisaged that TBAF could be used as the preferred base for (11) C-methylation reactions using 1, studies concerning the use of TBAF to promote (11) C-methylation reactions are scarce. Herein, we have evaluated the efficiency of the (11) C-methylation reactions of 13 model compounds using TBAF and 1. In most cases, the N-(11) C-methylations were efficiently promoted by TBAF in dimethyl sulfoxide at ambient temperature, whereas the O-(11) C-methylations required heating in some cases. Comparison studies revealed that the efficiencies of the (11) C-methylation reactions with TBAF were comparable or sometimes greater than those conducted with sodium hydride. Based on these results, TBAF should be considered as the preferred base for (11) C-methylation reactions using 1.

Nail Apparatus Melanoma: Current Management and Future Perspectives.

Nail apparatus melanoma (NAM) is a rare type of cutaneous melanoma that belongs to the acral melanoma subtype. NAM is managed principally in accordance with the general treatment for cutaneous melanoma, but there is scarce evidence in support of this in the literature. Acral melanoma is genetically different from non-acral cutaneous melanoma, while recently accumulated data suggest that NAM also has a different genetic background from acral melanoma. In this review, we focus on recent advances in the management of NAM. Localized NAM should be surgically removed; amputation of the digit and digit-preserving surgery have been reported. Sentinel lymph node biopsy can be considered for invasive NAM for the purpose of accurate staging. However, it is yet to be clarified whether patients with metastatic sentinel lymph nodes can be safely spared completion lymph node dissection. Similar to cutaneous melanoma, immune checkpoint inhibitors and BRAF/MEK inhibitors are used as the first-line treatment for metastatic NAM, but data on the efficacy of these therapies remain scarce. The therapeutic effects of immune checkpoint inhibitors could be lower for NAM than for cutaneous melanoma. This review highlights the urgent need to accumulate data to better define the optimal management of this rare melanoma.

Site-specific dose conversion factors for radon progeny based on ambient aerosol characteristics in an outdoor environment and a tourist cave.

Site-specific Dose Conversion Factors (DCFs) for radon progeny were estimated based on the aerosol measurement results in an outdoor environment and a tourist cave. The Activity Median Diameter (AMD) and unattached fraction were measured and used to calculate the effective dose per unit intake of radon progeny. The AMDs in the outdoor environment was in the range of 0.24-0.71 µm with the unattached fraction of 0.17. In the tourist cave, two peaks were found in the aerosol size distribution at nucleation and accumulation modes and the unattached fraction was measured to be 0.69 with a range of 0.36-0.85. The DCFs at the outdoor environment did not differ from those from the publication of the International Commission on Radiological Protection; however, the DCF in the tourist cave was significantly higher due to the discrepancy in the unattached fraction and the aerosol size distribution. It was found that these two factors would significantly affect the DCF so that we should be aware of it.

Design and implementation of a hybrid cloud system for large-scale human genomic research.

In the field of genomic medical research, the amount of large-scale information continues to increase due to advances in measurement technologies, such as high-performance sequencing and spatial omics, as well as the progress made in genomic cohort studies involving more than one million individuals. Therefore, researchers require more computational resources to analyze this information. Here, we introduce a hybrid cloud system consisting of an on-premise supercomputer, science cloud, and public cloud at the Kyoto University Center for Genomic Medicine in Japan as a solution. This system can flexibly handle various heterogeneous computational resource-demanding bioinformatics tools while scaling the computational capacity. In the hybrid cloud system, we demonstrate the way to properly perform joint genotyping of whole-genome sequencing data for a large population of 11,238, which can be a bottleneck in sequencing data analysis. This system can be one of the reference implementations when dealing with large amounts of genomic medical data in research centers and organizations.

Calibration experiments for radon in drinking water measurements using portable-type electrostatic-collection radon monitors.

Portable-type electrostatic-collection radon monitors (RAD7) are often used for in-situ measurements of radon in water. In this study, we evaluated the calibration factors and their uncertainties for two RAD7 monitors based on comparative measurements with the liquid scintillation counting method. In the first experiment, we found that both RAD7 monitors had relatively large uncertainties due to leakage of radon gas that bubbled from the gaps between the lids of the desiccant container and the glass vial. Therefore, for the second experiment, these gaps were closed as much as possible using parafilm and clay, respectively. As a result, the relative uncertainties for both RAD7 monitors were significantly decreased. Furthermore, we collected spring water samples to confirm the reliability of radon concentrations. After closing the leakage point, the uncertainty of radon concentrations in spring water we measured using the typical protocol of the RAD7 were significantly lower, which improves the measurement.