Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Bilateral multiple pulmonary metastases in a patient with double advanced cancer of the head and neck.

A case of advanced gingival cancer is described. The cancer invaded into the mandible and skin of the cheek and was associated with cervical lymph node metastases, mediastinal lymph node metastases, and bilateral multiple pulmonary metastases. The patient received neoadjuvant chemoradiotherapy and local immunotherapy, followed by curative surgery for the primary and neck lesions. Histopathological examination of the primary cancer and the upper and middle cervical nodes (n = 7) indicated a diagnosis of squamous cell carcinoma. Sections of the lower cervical nodes (n = 5) revealed well-differentiated thyroid carcinoma, suggesting that the mediastinal and pulmonary lesions were of thyroid origin. After total thyroidectomy and mediastinal dissection followed by treatment with radioiodine, the multiple pulmonary nodules disappeared. There has been no evidence of recurrent tumour for 5 years.

[Retrospective analysis of facial fractures related to falls in 260 Japanese patients]. / Retrospektive Analyse von Frakturen des Viszerokraniums nach Sturztraumen in einem japanischen Patientenkollektiv.

OBJECTIVE: Numerous epidemiological studies concerning fall-related injuries have been performed in the geriatric and orthopedic field to clarify the relation between the type of fall and fracture patterns. Although falls are a common cause of facial fractures, there is no study describing these relations. This study thus investigates the relationship between the type of fall and fracture pattern. MATERIALS AND METHODS: We analyzed 260 patients with fall-related facial fractures treated between 1995 and 2000 at the First Department of Oral and Maxillofacial Surgery, Osaka University Dental Hospital, Japan. These patients were classified into two groups: (1) those who suffered fractures by a fall from a standing position or lower and (2) those who suffered fractures by a fall from a level higher than the standing position. RESULTS: Fractures caused by falling from a standing position or lower was more common in older patients, especially in women beyond 70 years. The localization of mandibular fractures was not significantly different between the two groups. However, a high incidence of midface fractures was observed in the patients who fell from a higher position. These patients tended to suffer from central midface or dislocated fractures. CONCLUSION: The results were consistent with recent orthopedic studies, which suggest a relation between fractures in old patients and osteoporosis. A strong force caused by falls from a high position tends to act on the high portion of the midface. Our classification based on the height of the falls was able to demonstrate clearly the relation between etiological factors and fracture patterns. Therefore, it seemed reasonable to analyze patients treated in the Department of Oral and Maxillofacial Surgery, Heidelberg University, Germany, according to the same classification in order to compare both collectives.

Retrospective analysis of 1502 patients with facial fractures.

A total of 1502 patients with facial fractures treated between 1981 and 1996 were retrospectively analysed. The male: female ratio was 2.8:1 and the largest subgroup of patients was between 10 and 29 years of age. The most common cause of injury was traffic accidents (52%) involving motorcycles, bicycles or automobiles. Other common causes included, in descending order, falls (16.6%), assaults (15.5%) and sports (9.7%). Isolated mandibular fractures were most common (56.9%), followed by isolated midface fractures (25.9%). The percentage of fractures involving both the midface and mandible was 6.7, and that of isolated alveolar fractures was 10.5.

Plunging ranula as a complication of intraoral removal of a submandibular sialolith.

Mucous cysts in the submandibular region--so-called 'plunging' ranula--are relatively uncommon. We report a case of a plunging ranula that complicated excision of an intraductal sialolith of the submandibular gland.

Incidence of cleft lip or palate in 303738 Japanese babies born between 1994 and 1995.

To investigate the incidence of cleft lip or palate or both (CLP) in Japan, 303738 babies born in 1532 institutions between 1994 and 1995 were examined and 437 (0.14%) were found to have abnormalities. Of these babies, 32.1% had cleft lip, 43.3% had cleft lip and palate, and 24.8% had cleft palate (Table 2). These results show that the incidence of cleft lip and palate has declined compared with the period from 1981 to 1982.

Migration of a dental implant into the maxillary sinus. A case report.

This article reports a rare case of a displaced dental implant that migrated into the maxillary sinus.

Small cell undifferentiated carcinoma of the submandibular gland: immunohistochemical evidence of myoepithelial, basal and luminal cell features.

A primary small cell undifferentiated carcinoma of the submandibular gland is reported. Histological studies revealed that the major part of this tumor was composed of cells slightly larger (10-14 microm) than lymphocytes. These tumor cells showed myoepithelial-cell differentiation, which was confirmed by the immunohistochemical and ultrastructural findings. Furthermore, some of them showed luminal-cell and basal-cell differentiation immunohistochemically. However, there was no evidence of neuroendocrine differentiation. These findings demonstrated that the tumor had the features of all the salivary ductal components (myoepithelial, basal, and luminal cells) and supported that the tumor might arise from the salivary duct. Furthermore, it supports the hypothesis of multipotential stem cells as the origin for small cell undifferentiated carcinomas in salivary glands.

Mouse semaphorin H induces PC12 cell neurite outgrowth activating Ras-mitogen-activated protein kinase signaling pathway via Ca(2+) influx.

We recently showed that mouse semaphorin H (MSH), a secreted semaphorin molecule, acts as a chemorepulsive factor on sensory neurites. In this study, we found for the first time that MSH induces neurite outgrowth in PC12 cells in a dose-dependent manner. Comparison of Ras-mitogen-activated protein kinase (MAPK) signaling pathways between MSH and nerve growth factor (NGF) revealed that these pathways are crucial for MSH action as well as NGF. K-252a, an inhibitor of tyrosine autophosphorylation of tyrosine kinase receptors (Trks), did not inhibit the action of MSH, suggesting that MSH action occurs via a different receptor than NGF. L- and N-types of voltage-dependent Ca(2+) channel blockers, diltiazem and omega-conotoxin, inhibited MSH-induced neurite outgrowth and MAPK phosphorylation in a Ca(2+)-dependent manner. A transient elevation in intracellular Ca(2+) level was observed upon MSH stimulation. These findings suggest that extracellular Ca(2+) influx, followed by activation of the Ras-MAPK signaling pathway, is required for MSH induced PC12 cell neurite outgrowth.

Changes of arterial oxygen saturation (SpO2) following push-back operation.

This study showed the influence of the push-back operation on the occurrence of sleep-related apnea in cleft-palate patients with an analysis of arterial oxygen saturation (SpO2) during sleep, polygraphic analysis of nasal air flow, and chest wall movements. The postoperative SpO2 was lower than that of the presurgical period in all cases, requiring from five to nine days to recover to presurgical levels. According to polygraphic analysis this depression of SpO2 was caused by peripheral obstructive apnea, while, in spite of the cessation of nasal airflow, chest wall movement continued.

Diagnostic imaging in two cases of recurrent maxillary ameloblastoma: comparative evaluation of plain radiographs, CT and MR images.

We report detailed clinical and imaging findings of two patients with recurrent maxillary ameloblastoma. In one patient the recurrent tumour presented at follow-up examination 5 years after the initial operation. The other patients had a far advanced recurrent tumour with maxillary destruction extending into the adjacent normal structures including the infratemporal fossa, infraorbital fissure, masticator space and the left ethmoid sinus. The findings on conventional radiography including panoramic, posteroanterior and Waters' projection, and the findings of computed tomography (CT) and magnetic resonance (MR) imaging were evaluated using the following three variables: artefact degradation, lesion detectability, and conspicuity. The results suggested that MR imaging was the best imaging method for visualization of the tumours, followed by contrast enhanced CT. These two cases show that maxillary ameloblastoma can be difficult to control when it extends to the adjacent normal structures after destroying the maxilla. MR imaging was essential to establish the exact extent of the advanced maxillary ameloblastoma.

Induction chemotherapy is associated with an increase in the incidence of locoregional recurrence in patients with carcinoma of the oral cavity: results from a single institution.

BACKGROUND: This study was conducted to determine long term survival rates and the pattern of failure in patients with carcinoma of the oral cavity treated with induction chemotherapy or preoperative radiotherapy followed by surgery. METHODS: A retrospective analysis was performed of 141 eligible patients with Stage II-IV International Union Against Cancer (UICC) staging system squamous cell carcinoma of the oral cavity at the study department between 1985 and 1994. These patients received one of three treatments: surgery with or without peplomycin chemotherapy (Group A; n = 49); preoperative radiotherapy with or without concomitant peplomycin chemotherapy followed by surgery (Group B; n = 59); and induction chemotherapy followed by surgery (Group C; n = 33). Induction chemotherapy was comprised of two cycles of cisplatin, vincristine, peplomycin, with or without mitomycin C. RESULTS: When all 141 patients were analyzed, there was no significant difference in overall survival or disease free survival. However, a statistically significant increase in the incidence of neck recurrence in Group C was observed compared with Group A (P = 0.002). Within 79 patients with N0 disease, a statistically significant disadvantage was detected for Group C in terms of disease free survival compared with Group A (P = 0.038). In patients with Stage II disease (50 patients), there was a significant difference in disease free survival, with Group C inferior to both Group A (P = 0.04) and Group B (P = 0.066). CONCLUSIONS: Induction chemotherapy was associated with a significant increase in regional failure for patients with carcinoma of the oral cavity with N0 disease and those with Stage II disease.

Effects of human fibroblasts on invasiveness of oral cancer cells in vitro: isolation of a chemotactic factor from human fibroblasts.

Oral fibroblasts stimulated invasion of oral-carcinoma cells into the collagen matrix. The mechanisms of the fibroblast-induced stimulation of invasiveness was further investigated by examining cell motility and proteolytic activity of tumor cells, using mainly an adenoid-cystic-carcinoma cell line (ACCS) and normal fibroblasts from gingival tissues. Conditioned medium from the fibroblasts grown in serum-free medium was fractionated on a Superdex 200 pg column, and Peak 1 eluted at 200 to 300 kDa and Peak 2 eluted at 50 to 100 kDa were found to contain different specific activity. Treatment of ACCS cells with Peak 1 resulted in an increase in the production of proteolytic enzymes. Peak 2 stimulated both chemotaxis and chemokinesis of ACCS cells. A chemotactic factor was purified from the heparin-unbound fraction of Peak 2 by anion exchange and hydrophobic chromatography, and was named "fibroblast-derived motility factor (FDMF)". At 1 microg/ml, FDMF stimulated chemotaxis of ACCS cells by 4-fold compared with unstimulated controls. Characterization of the physicochemical properties of FDMF suggested that it might be different from any known motility factors. Exposure of ACCS cells to FDMF resulted in reduced amounts of actin stress fiber in the cytoplasm and induction of tyrosine phosphorylation of several cellular proteins detectable 30 to 60 min after treatment. These FDMF-induced changes were blocked by pre-treatment either with genistein or with pertussis toxin. These findings suggest that FDMF may be a novel protein which stimulates cell motility via a signaling pathway mediated by a pertussis-toxin-sensitive G protein and tyrosine phosphorylation.

Effect of dexamethasone on invasion of human squamous cell carcinoma cells into collagen gel.

The effect of dexamethasone (Dex) on the ability to invade type I collagen gel was investigated in two cell lines of oral squamous cell carcinoma (SCC). At concentrations higher than 10(-8) M, Dex significantly suppressed the invasive growth of SCC cells into the gel. The same concentrations of Dex led to a decrease in urokinase type plasminogen activator (u-PA) synthesis and an increase in plasminogen activator inhibitor type 1 (PAI-1) synthesis by SCC cells. These findings suggest that Dex inhibits the invasiveness of SCC cells by decreasing their proteolytic activity.

Expression of S-100 protein and glial fibrillary acidic protein in cultured submandibular gland epithelial cells and salivary gland tissues. Histogenetic implication for salivary gland tumors.

S-100 protein and glial fibrillary acidic protein (GFAP) were studied in human salivary gland tissues and human cultured submandibular gland epithelial cells. Immunohistochemically, ductal cells in normal salivary gland tissues were positive for S-100 protein and GFAP, but myoepithelial cells were uniformly negative. Immunocytochemically, cultured submandibular gland ductal cells were positive for S-100 protein and GFAP. By immunoblotting analysis of the cultured cell lysates, a 6.5-kd S-100 protein was detected. This band corresponded to S-100 protein purified from bovine brain. The cultured submandibular gland cells expressed 49- and 54-kd GFAP polypeptides. These results have important implications for the histogenesis of salivary gland tumors.

Establishment of bone morphogenetic protein 2 responsive chondrogenic cell line.

A clonal cell line named RMD-1 was established from the skeletal muscle of a 20-day fetal rat. RMD-1 represents a morphologically homogeneous population of undifferentiated mesenchymal cells, expressing alpha-smooth muscle actin and type I collagen, but no cartilage-associated genes. When cultured in agarose gel containing 100 ng/ml of recombinant human bone morphogenetic protein 2 (rhBMP-2; BMP-2), RMD-1 cells formed colonies and showed chondrocyte-like features as assessed by their ultrastructure, metachromatic staining with toluidine blue, and the production of large hydrodynamic-size proteoglycans. RMD-1 cells also differentiated into chondrocytes when the cells were plated at high density (over 2.5 x 10(5) cells/cm2) on type I collagen and incubated in medium containing 0.5% fetal bovine serum and 100 ng/ml of BMP-2. This chondrogenic differentiation was evidenced by a distinct morphological change into spherical cells, an increase in the levels of sulfated glycosaminoglycans, a decrease in type I collagen mRNA and the expression of cartilage-associated genes, including type II collagen, type IX collagen, aggrecan and alkaline phosphatase. In the presence of ascorbic acid and 10% serum, RMD-1 cells increased in size and expressed type X collagen as well as high alkaline phosphatase activity, then induced matrix mineralization. Thus, RMD-1 is a unique cell line that can differentiate from undifferentiated mesenchymal cells into hypertrophic chondrocytes.

Treatment of recurrent temporomandibular joint dislocation after failed Dautrey operation: a case report.

A patient with recurrent unilateral dislocation of the temporomandibular joint for seven years had been treated by the Dautrey procedure. A subsequent condylar dislocation recurred 26 months after the surgical treatment. The condyle head was held in front of the operated eminence without any resorption of the eminence, producing re-dislocation. An articular emineplasty, oblique resection of the posterior eminence, was performed as a salvage operation. This emineplasty shifted the top of the eminence anterior to the condyle, producing effective results.