Activated Akt expression is associated with the recurrence of primary melanomas and further refines the prognostic and predictive values for relapse in acral melanomas.

A PTEN deficiency leads to the activation of phospho-Akt at serine 473 (p-Akt) and promotes the tumorigenesis of melanomas by coupling with NUAK2 amplification. We tested the prognostic impact of p-Akt and/or NUAK2 expression on the relapse-free survival (RFS) and overall survival (OS) of melanoma patients. Primary tumors from patients with acral melanomas (112), Low-cumulative sun damage (CSD) melanomas (38), and High-CSD melanomas (18) were examined using immunohistochemistry and their prognostic significance was analyzed statistically. The expression of p-Akt was found in 32.1%, 68.4%, and 55.6% of acral, Low-CSD, and High-CSD melanomas, while NUAK2 expression was found in 46.4%, 76.3%, and 50.0%, respectively. Either p-Akt or NUAK2 expression was inversely correlated with the RFS of primary melanoma patients and acral melanoma patients (p-Akt: p < .0001, p < .0001; NUAK2; p = .0005, p < .0001, respectively). Strikingly, multivariate analyses revealed that p-Akt had a significant impact on RFS (Hazard ratio = 4.454; p < .0001), while NUAK2 did not. Further subset analyses revealed that p-Akt expression had an inferior RFS of patients with acral melanomas (Hazard ratio = 4.036; p = .0005). We conclude that the expression of p-Akt has a significant impact on RFS of patients with primary melanomas and can predict the relapse of patients with acral melanomas.

A single-center retrospective analysis of prognoses in patients with melanoma brain metastases and effectiveness of treatment in Japan.

BACKGROUND: Melanoma brain metastasis (MBM) has a poor prognosis, although recent treatments, including immune checkpoint inhibitors and targeted therapy, have improved the prognosis. However, these systemic therapies have been reported to be less efficient for Asian patients. We investigated the survival of Asian patients with MBM and the effectiveness of systemic therapies. METHODS: We retrospectively reviewed the survival rates of patients diagnosed with MBM between January 2011 and December 2021 at the National Cancer Center Hospital in Tokyo, Japan. In addition, we identified factors associated with survival using Cox regression analysis. RESULTS: A total of 135 patients were included. The median overall survival (OS) after an MBM diagnosis was 7.8 months (95% confidence interval [CI] 6.1-9.6). The 6-month and 1-year survival rates were 60.7% and 34.8%, respectively. We identified the prognostic factors of MBM, including non-acral primary location, low serum LDH levels, systemic therapy of single-agent immune checkpoint inhibitors (ICIs) or targeted therapies (TTs), and radiotherapy of stereotactic irradiation (STI). We found no significant difference in effectiveness between single-agent ICIs, the combination of Nivolumab and Ipilimumab (COMBI-ICI), and TTs (COMBI-ICI vs. single-agent ICI, hazard ratio 0.71, 95% confidence interval 0.27-1.88, p = 0.49; COMBI-ICI vs. TT: hazard ratio 0.46, 95% confidence interval 0.14-1.55, p = 0.21). CONCLUSIONS: Systemic therapy and radiotherapy have improved the survival of MBM patients, but the survival of Asian patients remains poor. Our findings suggest that COMBI-ICIs are not significantly more effective than single-agent ICI or TT in treating MBM.

A retrospective study of sentinel lymph node biopsy for skin cancer in Japan: Comparison with breast cancer and evaluation of factors related to its use.

BACKGROUND: Sentinel lymph node biopsy (SLNB) underuse has been reported for skin cancers; however, actual performance rates have not been compared. The objective of this study was to investigate the SLNB performance rate in skin cancers covered by health insurance in Japan and compare it with that in breast cancer. METHODS: This was a retrospective study of the SLNB performance rate in SLNB-eligible patients with breast or skin cancer from 2018 to 2019, utilizing a database linked to the Hospital-Based Cancer Registry and Diagnosis Procedure Combination survey. Demographic and tumor characteristics were analyzed using logistic regression. RESULTS: A total of 71,652 patients were included in this study. SLNB was performed in 86.4% (57,904/67,036) of the patients with breast cancer, 44.7% (694/1552) with melanomas, 3.1% (89/2849) with squamous cell carcinomas (SCCs), and 13.5% (29/215) with Merkel cell carcinomas (MCCs). The performance rate of SLNB was significantly lower for skin cancers than for breast cancers (odds ratio [OR], 0.03; p < 0.001). In addition, the performance rates of SLNB were significantly lower for SCCs and MCCs than for melanomas (SCC: OR, 0.04; p < 0.001; MCC: OR, 0.19; p < 0.001). Factors associated with SLNB performance included age, sex, year of incidence, primary tumor site, T stage, and number of hospital beds. CONCLUSIONS: SLNB is underutilized for skin cancer. Further investigation is required to explore the reasons for its underutilization so that it may be implemented more universally.

Prognostic factors in cutaneous apocrine carcinoma: a single-institution retrospective study of 32 patients.

BACKGROUND: Cutaneous apocrine carcinoma (CAC) is a rare adnexal carcinoma. Limited data exists on the demographics and overall survival (OS) of patients with CAC; thus, there is no consensus on surgical management. This study aimed to examine demographic and survival data of patients with CAC to determine optimal surgical management. METHODS: A single-center retrospective cohort study was conducted at the National Cancer Center Hospital in Tokyo between 2005 and 2022. Patients with a histologically-confirmed CAC diagnosis were identified and data on patient demographics, OS, and lymph node (LN) status were gathered. RESULTS: Thirty-two patients were included (median age, 65.5 years; male-female ratio, 15:1). The most common involvement site was the axilla (87.5%). Of the nine patients in the clinical local stage, pathological LN metastases were found in five patients. Either pathological LN or distant metastases were present in 75% of the patients at initial diagnosis. The most common initial surgical treatments included wide local excision and complete LN dissection. Across cohorts, the median OS was 39 months. Patients with ≥ 4 LN metastases had reduced recurrence-free survival and OS compared to those with ≤ 3 LN metastases (p = 0.042, p = 0.041, respectively). The OS was not remarkably different between patients who did and did not receive postoperative radiation therapy. CONCLUSIONS: Since CAC has a high rate of LN metastasis-and the number of LN metastases is a significant prognostic factor-LN evaluation should be considered for patients with CAC as initial treatment. Nonetheless, ≥ 4 LN metastases can be a poor prognostic factor for CAC.

Efficacy of chemotherapies for unresectable extramammary Paget disease: a single-centre retrospective study.

BACKGROUND: Extramammary Paget disease (EMPD) is a cutaneous neoplasm that can metastasize to the lymph nodes and distant organs, resulting in a poor prognosis. For unresectable distant metastases of EMPD, no consensus has been reached regarding optimal chemotherapy owing to a lack of data. OBJECTIVES: To evaluate the efficacy of three regimens: docetaxel (DTX) monotherapy; combination therapy with 5-fluorouracil, epirubicin, carboplatin, vincristine and mitomycin C (FECOM); and tegafur (S-1) monotherapy. METHODS: This single-centre retrospective study included 32 patients diagnosed with unresectable EMPD and treated with chemotherapy between 2002 and 2022 at the National Cancer Center Hospital in Japan. Patient characteristics, responses to treatment and survival data were evaluated for each of the first-line therapies. RESULTS: Among the 17 patients who received DTX monotherapy, the response rate (RR) and disease control rate (DCR) were 47% and 77%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 12.3 months [95% confidence interval (CI) 6.1-26.6] and 19.2 months (95% CI 8.5-not reached), respectively. Among the 11 patients who received combination FECOM chemotherapy, the RR and DCR were 55% and 64%, respectively. The median PFS and OS were 6.8 months (95% CI 3.5-not reached) and 13.4 months (95% CI 8.6-21.3), respectively. Among the four patients who received S-1 monotherapy, the RR and DCR were 0% and 25%, respectively. The median PFS and OS were 5.4 months (95% CI 2.3-not reached) and 12.5 (95% CI 2.3-not reached) months, respectively. CONCLUSIONS: Further investigations with prospective analysis are required to confirm these findings.

The potential value of thallium-201 scintigraphy in the diagnosis of squamous cell carcinoma arising from extensive pyoderma.

Squamous cell carcinoma (SCC) arises from a variety of premalignant conditions, including pyoderma. However, an accurate diagnosis of SCC is sometimes challenging due to indistinguishable inflammatory lesions. Here, we present a case of SCC arising from extensive pyoderma, which was successfully diagnosed by taking advantage of thallium-201 scintigraphy. A 49-year-old man presented with an elevated tumor on his right buttock. Computed tomography (CT) and enhanced magnetic resonance imaging (MRI) identified the tumor, but many indistinguishable lesions were also found around the tumor. Histopathology revealed an atypical proliferation of keratinocytes with cancer pearls inside the tumor nests, while histopathology of nodules around the tumor revealed inflammatory tissues. Positron emission tomography CT (PET/CT) revealed an accumulation of 2-deoxy-2-[18 F]-D-glucose at the axillae and inguinal nodes, and at subcutaneous tissues in addition to the tumor. From the CT, enhanced MRI, and PET/CT analyses it was impossible to differentiate many scattered subcutaneous nodules on the trunk from SCCs. However, thallium-201 scintigraphy identified only the tumor and found no accumulation in other nodules. This finding suggests that thallium-201 scintigraphy is useful for the diagnosis of SCC by excluding false-positive signals detected by other imaging technologies.

Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element-binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.

Folliculin promotes substrate-selective mTORC1 activity by activating RagC to recruit TFE3.

Mechanistic target of rapamycin complex I (mTORC1) is central to cellular metabolic regulation. mTORC1 phosphorylates a myriad of substrates, but how different substrate specificity is conferred on mTORC1 by different conditions remains poorly defined. Here, we show how loss of the mTORC1 regulator folliculin (FLCN) renders mTORC1 specifically incompetent to phosphorylate TFE3, a master regulator of lysosome biogenesis, without affecting phosphorylation of other canonical mTORC1 substrates, such as S6 kinase. FLCN is a GTPase-activating protein (GAP) for RagC, a component of the mTORC1 amino acid (AA) sensing pathway, and we show that active RagC is necessary and sufficient to recruit TFE3 onto the lysosomal surface, allowing subsequent phosphorylation of TFE3 by mTORC1. Active mutants of RagC, but not of RagA, rescue both phosphorylation and lysosomal recruitment of TFE3 in the absence of FLCN. These data thus advance the paradigm that mTORC1 substrate specificity is in part conferred by direct recruitment of substrates to the subcellular compartments where mTORC1 resides and identify potential targets for specific modulation of specific branches of the mTOR pathway.

Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.

Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure. Rather, it was induced by the excessive loss of lipids through the skin as sebum. TSLP and T cells regulated sebum release and sebum-associated antimicrobial peptide expression in the steady state. In human skin, TSLP expression correlated directly with sebum-associated gene expression. Thus, we establish a paradigm in which adipose loss can be achieved by means of sebum hypersecretion and uncover a role for adaptive immunity in skin barrier function through sebum secretion.

Noncanonical WNT Activation in Human Right Ventricular Heart Failure.

Background: No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35). Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P < 0.05). ROR2 protein expression correlated linearly to mRNA expression (R 2 = 0.41, P = 8.1 × 10-18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R 2 = 0.40, P = 3.0 × 10-5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-µ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-µ (R 2 = 0.25), total FLNA (R 2 = 0.67), calpain cleaved FLNA (R 2 = 0.32) and FLNA phosphorylation (R 2 = 0.62, P < 0.05 for all). Conclusion: We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.