Cancer-associated point mutations within the extracellular domain of PTPRD affect protein stability and HSPG interaction.

PTPRD, a well-established tumor suppressor gene, encodes the protein tyrosine phosphatase-type D. This protein consists of three immunoglobulin-like (Ig) domains, four to eight fibronectin type 3 (FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer-associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer-associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan-binding pocket enhanced PTPRD's binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG-mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.

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.

Two cases of Hailey-Hailey disease effectively treated with apremilast and a review of reported cases.

Hailey-Hailey disease (HHD) is an autosomal dominant genetic disease caused by a mutation of the ATP2C1 gene. Corticosteroids, antibiotics or cyclosporine have been administered to reduce inflammation and prevent flare-ups, but the efficacy is not always sufficient. We herein report two cases of HHD effectively treated with apremilast and review the previous literature. Patient 1 was a 28-year-old male and patient 2 was a 35-year-old female. Both patients were diagnosed with HHD based on histological and genetic analyses. Both patients were treated with oral antibiotics or topical corticosteroids, but their symptoms were refractory, therefore apremilast was administered to both patients. Two weeks later, the skin lesion of both patients was improved. No adverse reaction was observed except for mild headache in patient 2. There have been 13 reported cases of HHD treated with apremilast, including our cases. Eight cases showed a good response to apremilast, whereas five cases showed no response. There seems to be no association between the disease severity and efficacy of apremilast, although the reason remains unknown. Interestingly, an early improvement of the HHD lesion was observed in all good response cases. Although digestive symptoms, headache, and myalgia were observed as adverse events, the treatment was well-tolerated. The accumulation of a greater number of similar cases and further research will be required. We hypothesize that apremilast may be a useful therapeutic option for skin lesions of HHD.

Observation policy for sentinel node metastasis of melanoma: Comparative study with completion lymph node dissection in Japanese patients.

Based on the results of international multicenter randomized trials, completion lymph node dissection for patients with sentinel lymph node-positive melanoma is no longer routinely recommended. However, clinicians should take into consideration racial and medical resource differences when applying this evidence to clinical practice in Japan. To evaluate the clinical validity of the observation policy of omitting completion lymph node dissection, we retrospectively surveyed patients with sentinel lymph node-positive melanoma between 2002 and 2020 at Niigata Cancer Center Hospital. A total of 59 patients were categorized into the observation group (n = 19) and completion lymph node dissection group (n = 40). Newly developed anticancer agents, including targeted therapy and immunotherapy, were more commonly used in the observation group than in the completion lymph node dissection group as either adjuvant therapy (31.6% vs. 5.0%) or post-recurrence therapy (100% vs. 34.8%). The median overall survival in the observation group (not reached) was significantly longer than that in the completion lymph node dissection group (95.0 months; p = 0.02), which was mainly attributed to the difference in post-recurrence overall survival. There was no significant difference in recurrence-free survival between the two groups (p = 0.63). Although the use of new anticancer agents leads to bias, this study demonstrates that observation without prompt completion lymph node dissection provides a favorable overall survival without increasing the risk of recurrence compared with completion lymph node dissection. The observation policy for patients with sentinel lymph node-positive melanoma patients is considered to be clinically valid in real-world medical practice.

Dermatologist's role in a cancer hospital: An overview of in-hospital consultations.

As cancer treatment advances, the need for dermatologists in the treatment process is increasing. Cancer patients often experience cutaneous manifestations of internal diseases and dermatological adverse events from chemotherapy, radiation, surgery, and stem cell transplants. These diminish patients' health-related quality of life and negatively affect cancer treatment adherence. To identify the dermatologist's role, we analyzed 893 cases of in-hospital dermatology consultations at the Niigata Cancer Center Hospital during 2019. The number of dermatology consultations was the second highest among all hospital departments. Malignant tumors accounted for 91.7% of the underlying diseases, including hematological, gastrointestinal, and lung cancer as the top three primary cancers. The most common consultation category was inflammatory skin disorders (29.2%), followed by chemotherapy-related skin disorders (23.5%), cutaneous infections (11.5%), skin tumors (9.5%), and continued treatment of pre-existing skin disorders (8.8%). The average intervention time was the longest for continued treatment of existing skin disorders (229 ± 60.6 days), followed by malignant wound management (126 ± 60.6 days) and chemotherapy-related skin disorders (122 ± 60.6 days). The median overall survival time of the 27 patients in the malignant wound management group was 5 months (95% confidence interval, 1.8-8.2 months) from the initial dermatology consultation. Our results show an increasing demand for dermatologists in cancer management. However, the number of full-time dermatologists is insufficient in some Japanese cancer hospitals. There is a need to consider increasing the number of adequately trained dermatologists in cancer medical settings.

Trends in the prognosis of metastatic melanoma in the era of targeted therapy and immunotherapy: A single-institution survey in Japan.

Advances in anticancer therapy, including the development of targeted therapy and immunotherapy, have drastically changed treatment options for metastatic melanoma. However, to date, only a few studies have been published that directly compare overall survival (OS) before and after introduction of these new therapeutic options in Japan. We retrospectively surveyed patients with metastatic melanoma treated in our hospital between 1989 and 2019 to investigate the OS benefit of the new therapies. A total of 115 patients with metastatic melanoma (cutaneous origin, 92; mucosal, 14; uveal, two) were included in the study. Kaplan-Meier analysis showed that the patient group receiving targeted therapy/immunotherapy (TT/IT) (n = 47) had a median OS of 19.0 months, which was longer than that in patients receiving conventional chemotherapy (n = 42, 8.0 months) or no treatment (n = 26, 6.0 months) (P < 0.001). In the subgroup analysis performed for the TT/IT group, patients of younger age and with the BRAF mutation had significantly improved OS. As the number of treatment lines increased, the median OS tended to become longer. Our real-world data confirmed an improvement of median OS upon the introduction of the new therapies for metastatic melanoma. However, the long-term OS benefit was limited, possibly because of racial differences in some of the clinical characteristics. To improve the overall melanoma prognosis, the entire treatment strategy, including perioperative therapy needs strengthening.

Photocatalytic Giese-Type Reaction with Alkylsilicates Bearing C,O-Bidentate Ligands.

Herein, a photocatalytic Giese-type reaction with alkylsilicates bearing C,O-bidentate ligands as stable alkyl radical precursors has been reported. The alkylsilicates were prepared in one step from organometallic reagents. Not only primary, secondary, and tertiary alkyl radicals, but also elusive methyl radicals, could be generated by using the present reaction system. The generated radicals were trapped by electron-deficient olefins bearing various functional groups to give the desired alkyl adducts. The silicon byproduct can be recovered after the photoreaction. The radical generation process was investigated by theoretical calculations, which provided an insight into the facile generation of methyl radicals from methylsilicate bearing C,O-bidentate ligands.

Suzuki Coupling Reactions Catalyzed by PdO Dispersed on Dealuminated Y Zeolite in Air under Ambient Conditions.

Suzuki coupling reactions are performed using PdO loaded on dealuminated Y (USY) zeolite. The reaction between bromobenzene and phenylboronic acid is complete in 15 min at room temperature in air, with a turnover number of 1300. The reaction can be repeated at least five times by using 1 wt % Pd. Inductively coupled plasma analysis does not reveal the dissolution of Pd from products, even if the reaction is repeated up to four times. Pd K-edge extended X-ray absorption fine structure analysis reveals the presence of molecular-like PdO and a mixture of Pd(0) -PdO before and after the reaction, respectively. This is probably because Pd stabilized by Al sites is present at the II sites of the Y-type zeolite, as estimated using first-principles calculations. Conversely, Pd species change to PdO clusters after repeated reactions in air using the thermally treated sample.