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Primary squamous cell carcinoma of the thyroid (PSCCT) is a rare disease with a poor prognosis. Because of its rarity, there is no established therapeutic regimen in unresectable cases. We report a case of PSCCT treated with weekly paclitaxel (wPTX) for more than 2 years. A 59-year-old woman presented to our hospital with a progressively enlarging neck mass. CT and MRI scans showed a tumor arising from the right lobe of the thyroid, invading the esophagus and trachea, as well as partially surrounding and invading the right common carotid artery. It was deemed unresectable. Biopsy revealed poorly differentiated squamous cell carcinoma. wPTX therapy was initiated. The patient achieved a partial response and is still undergoing treatment 28 months later. Adverse events included grade 3 neutropenia and grade 2 peripheral sensory neuropathy, which were manageable. Long-term wPTX therapy has been effective in this case of unresectable PSCCT.

We previously reported that regulatory T (Treg) cells expressing CTLA-4 on the cell surface are abundant in head and neck squamous cell carcinoma (HNSCC). The role of expanded Treg cells in the tumor microenvironment of HNSCC remains unclear. In this study, we revealed that the tumor microenvironment of HNSCC is characterized by the high expression of genes related to Treg cells, dendritic cells (DCs), and interleukin (IL)-17-related molecules. Increased expression of IL17A, IL17F, or IL23A contributes to a favorable prognosis of HNSCC. In the tumor microenvironment of HNSCC, IL23A and IL12B are expressed in mature dendritic cells enriched in regulatory molecules (mregDCs). The mregDCs in HNSCC are a migratory and mature phenotype; their signature genes strongly correlate with Treg signature genes in HNSCC. We also observed that IL17A was highly expressed in Th17 cells and exhausted CD8

Contains fulltext : 229418.pdf (Publisher’s version ) (Open Access) BACKGROUND: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare disease, which is commonly classified with the modified Pittsburgh classification. Our aim was to evaluate the predictive performance of this classification in relation to disease-free survival (DFS). METHODS: We examined retrospective data from a nationwide Dutch cohort study including patients with primary EAC SCC. These data were combined with individual patient data from the literature. Using the combined data, the predictive performances were calculated using the c-index. RESULTS: A total of 381 patients were included, 294 for clinical and 281 for the pathological classification analyses. The c-indices of the clinical and the pathological modified Pittsburgh classification predicting DFS were 0.725 (0.668-0.782) and 0.729 (0.672-0.786), respectively. CONCLUSION: The predictive performance of the modified Pittsburgh classification system as such appears to be acceptable to predict the DFS of EAC SCC. Other factors need to be added to a future model to improve the predicted performance.

Owing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified. In this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy. A higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

FOXP3+ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4+ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface-CTLA-4+ and surface-CTLA-4- Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4+ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4+ Treg cells were PD-1+ , actively proliferated and associated with CD45RA- FOXP3high Treg cells with strong suppressive function. Thus, surface-CTLA-4+ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4+ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer.

Summary Ezh2, a well-established epigenetic repressor, can down-regulate leukocyte inflammatory responses, but its role in cutaneous health remains elusive. Here we demonstrate that Ezh2 controls cutaneous tolerance by regulating Langerhans cell (LC) transmigration across the epidermal basement membrane directly via Talin1 methylation. Ezh2 deficiency impaired disassembly of adhesion structures in LCs, leading to their defective integrin-dependent emigration from the epidermis and failure in tolerance induction. Moreover, mobilization of Ezh2-deficient Langerin– dermal dendritic cells (dDCs) via high-dose treatment with a weak allergen restored tolerance, which is associated with an increased tolerogenic potential of Langerin– dDCs likely due to epigenetic de-repression of Aldh in the absence of Ezh2. Our data reveal novel roles for Ezh2 in governing LC- and dDC-mediated host protection against cutaneous allergen via distinct mechanisms., Graphical Abstract, Highlights • Ezh2 regulates LC transmigration across basement membrane via Talin1 methylation • Ezh2-mediated LC migration is required for cutaneous tolerance induction • Ezh2 represses Aldh epigenetically in dermal DCs • Ezh2-deficient dermal DCs exhibit increased tolerogenicity, Dermatology; Biological Sciences; Immunology

Foxp3+CD25+CD4+ regulatory T (Treg) cells constitute about 10% of peripheral CD4+ T cells and suppress a variety of immune responses in mice and humans (1). Our recent report (2) shows that proenkephalin (PENK)-expressing Treg cells expanded by ultraviolet B (UVB) exposure promoted wound healing. The Letter from Slominski et al. (3) points out that skin-resident cells produce enkephalins and other neuropeptides and that skin neuroendocrine activity exerted by keratinocytes, fibroblasts, and melanocytes was detected early after UVB irradiation within a day (3⇓⇓–6), although they did not address possible roles of PENK produced by skin T cells (3⇓⇓– … [↵][1]2To whom correspondence may be addressed. Email: yamazas{at}med.nagoya-cu.ac.jp. [1]: #xref-corresp-1-1

Regulatory T (Treg) cells, expressing CD25 (interleukin-2 receptor α chain) and Foxp3 transcription factor, maintain immunological self-tolerance and suppress various immune responses. Here we report a feature of skin Treg cells expanded by ultraviolet B (UVB) exposure. We found that skin Treg cells possessing a healing function are expanded by UVB exposure with the expression of an endogenous opioid precursor, proenkephalin (PENK). Upon UVB exposure, skin Treg cells were expanded with a unique TCR repertoire. Also, they highly expressed a distinctive set of genes enriched in “wound healing involved in inflammatory responses” and the “neuropeptide signaling pathway,” as indicated by the high expression of Penk. We found that not only was PENK expression at the protein level detected in the UVB-expanded skin Treg (UVB-skin Treg) cells, but that a PENK-derived neuropeptide, methionine enkephalin (Met-ENK), from Treg cells promoted the outgrowth of epidermal keratinocytes in an ex vivo skin explant assay. Notably, UVB-skin Treg cells also promoted wound healing in an in vivo wound closure assay. In addition, UVB-skin Treg cells produced amphiregulin (AREG), which plays a key role in Treg-mediated tissue repair. Identification of a unique function of PENK(+) UVB-skin Treg cells provides a mechanism for maintaining skin homeostasis.

Carcinoma of the external and middle ear is a very rare disease. Despite the various treatment modalities available, its prognosis is still poor. We aimed to analyze the treatment modalities, outcomes, and validity of surgical approaches, especially in advanced tumors in the ear. Twenty-five patients with carcinoma of the external and middle ear were retrospectively analyzed. The modified Pittsburgh staging system was used for staging of the patients. Overall and disease-free survival was estimated using of Kaplan-Meier method. In our cohort of 25 patients, the majority (76%) had tumor located in external auditory meatus. The most common histologic subtype was squamous cell carcinoma (80%). More than half of patients (56%) had tumor stage IV. In the stage IV group, five patients underwent subtotal temporal bone resection and ipsilateral neck dissection. Seven patients underwent definitive radiotherapy. The remaining two patients underwent palliative chemotherapy. The 2-year overall and disease-free survival for patients with tumor stage IV was 67.7% and 57.8%, respectively. In patients with tumor stage IV, the 2-year overall survival for patients who underwent surgery was 80.0% versus 53.6% for those who underwent radiotherapy (P = 0.16). The 2-year disease-free survival for patients who underwent surgery was 80.0% versus 28.6% for those who underwent radiotherapy (P = 0.15). In the present study, the outcome of patients who received surgical treatment tended to be better than that of patients who received radiation therapy. Our results suggest that en bloc resection could be the first choice even in the advanced disease stage.

The present study aimed to clarify the incidence and clinical outcomes of nasopharyngeal carcinoma (NPC) in the Chubu region of Japan from 2006 to 2015, compared with previous reports. A retrospective analysis was conducted based on medical records from 40 hospitals located in the Chubu region in the central Japanese main island, with a population of around 22.66 million individuals. This study was designed in line with to two previous clinical studies into NPC conducted in the same area of Japan. We recruited NPC patients diagnosed in hospitals across this area over a 10-year period (2006&ndash, 2015) using a questionnaire about sex, age, primary site, clinical symptoms, pathology, Union for International Cancer Control (UICC) staging, serological exam, treatment, and survival. A total of 620 NPC patients were identified. The age-standardized incidence of NPC from 2006 to 2015 was 0.27 per 100,000 individuals per year. There were no significant differences between this study and the previous two studies conducted in the same area of Japan. The five-year overall survival rate for all patients was 75.9%, while those for patients with stages I, II, III, and IVA were 97%, 91%, 79%, and 68%, respectively. The age-standardized annual incidence of NPC in the present study was 0.27 per 100,000 individuals per year, which was relatively low and stable. The five-year overall survival rate for all NPC patients was significantly improved in this decade compared with previous studies. The smoking rates in male and female NPC patients were 64.5% and 18.8%, respectively, thereby suggesting the involvement of smoking in the incidence of NPC.

平成30年度

Background Induction chemotherapy for patients with head and neck cancer is widely performed, and several advantages of induction chemotherapy have been reported. However, there is currently insufficient evidence to strongly recommend induction chemotherapy. In this study, we analyzed the outcomes for patients treated with induction chemotherapy and subsequent definitive treatments. Methods Operable patients with untreated oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma treated with induction chemotherapy were included in this retrospective study. We conducted induction chemotherapy using docetaxel, cisplatin and 5-fluorouracil and performed subsequent surgical treatment or radiotherapy according to the response to induction chemotherapy. Results A total of 65 patients were included in this study, and 50 patients (76.9%) had Stage IV tumors. The response to induction chemotherapy was CR in two patients, PR in 55 patients, and SD in eight patients. The subsequent definitive treatment was radiotherapy in 60 patients, and surgery in five patients. The 3-year overall survival rates for patients who received radiotherapy and surgery were 88.4% and 75.0%, respectively (P = 0.30). The 3-year disease-free survival rates for patients who received radiotherapy and surgery were 68.0% and 0%, respectively (P = 0.01). The 3-year laryngeal dysfunction free survival rates for patients who received RT and surgery were 77.8% and 0%, respectively (P < 0.01). Conclusions We achieved favorable survival outcomes and high larynx preservation rates. Our results suggest that induction chemotherapy using TPF regimen is one of the optimal treatment strategies when treating head and neck cancers. Further prospective studies with a larger cohort are required to confirm our findings.

The lymph node density (LND) has been reported to be a significant prognostic factor in various types of carcinoma. This study investigated whether the LND is associated with survival in patients with hypopharyngeal squamous cell carcinoma (HPSCC) who have positive lymph nodes without distant metastasis. Forty-six patients who were pathologically diagnosed with HPSCC with positive lymph nodes and without distant metastasis were enrolled in this study. The LND was defined as the ratio of positive lymph nodes to the total number of lymph nodes. An LND of ≥0.09 was found to be significantly correlated with a shorter overall (p = 0.044) and disease-specific (p = 0.019) survival according to a log-rank test. In a multivariate survival analysis using a Cox proportional hazards model adjusted for the pathological T category (pT3-4/pT1-2), pathological N category (pN2/pN1) and positive surgical margin and/or extracapsular spread (presence/absence), both an LND of ≥0.09 and pT3-4 category were associated with significantly shorter overall survival (p