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.

Effect of serotonin (5-HT) on trigeminal rhythmic activities generated in in vitro brainstem block preparations.

We used rat isolated brainstem block preparations to analyze the functional roles of serotonin receptors in the generation of trigeminal rhythmic activities. We previously reported that trigeminal rhythmic activities could be induced by some pharmacological applications in an isolated brainstem preparation with a rostral boundary at the border between the inferior and superior colliculus, and a caudal border at the level of the rostral facial nucleus. However, the same stimulation did not induce trigeminal rhythmic activities in a whole brainstem block preparation with the same rostral boundary and a caudal border at the obex level. In the present study, both the 5-HT(1A) phthalimido-butyl-piperazine, and the 5-HT(2C) agonist, 1-2,5-dimethoxy-4-iodophenyl-2-aminopropane, combined with N-methyl-D,L-aspartate and bicuculline, elicited trigeminal rhythmic activities in a whole brainstem block preparation. Our results suggest that serotonin has both facilitation and inhibition effects on the generation of trigeminal rhythmic activities in an isolated brainstem block preparation in vitro.

IL-12 plays a pivotal role in LFA-1-mediated T cell adhesiveness by up-regulation of CCR5 expression.

The chemokine receptor CCR5 has been implicated in the recruitment of T cells to inflammatory sites. However, the regulation of CCR5 induction on T cells and its contribution to T cell adhesiveness are poorly understood. Using a Th1 clone, 2D6, that can be maintained with interleukin (IL)-12 or IL-2 alone (designated 2D6(IL-12) or 2D6(IL-2), respectively), we investigated how CCR5 is induced on T cells and whether CCR5 is responsible for up-regulating the function of adhesion molecules. 2D6(IL-12) grew, forming cell aggregates, in culture containing IL-12. This was due to lymphocyte function-associated antigen (LFA)-1-intercellular adhesion molecule (ICAM)-1 interaction, because 2D6(IL-12) expressed both LFA-1 and ICAM-1 and cell aggregation was inhibited by anti-ICAM-1 monoclonal antibody. Despite comparable levels of LFA-1 and ICAM-1 expression, 2D6(IL-2) cells did not aggregate in culture with IL-2. It is important that there was a critical difference in CCR5 expression between 2D6(IL-12) and 2D6(IL-2); the former expressed high levels of CCR5, and the latter expressed only marginal levels. Both types of cells expressed detectable albeit low levels of RANTES (regulated on activation, normal T expressed and secreted) mRNA. Unlike IL-12 or IL-2, IL-18 induced high levels of RANTES mRNA expression without modulating CCR5 expression. Therefore, combined stimulation with IL-12 and IL-18 strikingly up-regulated 2D6 cell aggregation. Notably, LFA-1-mediated aggregation of 2D6(IL-12) cells was suppressed by anti-CCR5 antibody. These results indicate that IL-12 plays a critical role in CCR5 expression on Th1 cells and consequently contributes to CCR5-mediated activation of LFA-1 molecules.

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.

Velopharyngeal closure pattern exerted by contraction of the pharyngeal constrictor muscle in dogs.

OBJECTIVE: This study was performed to investigate aspects of velopharyngeal closure demonstrated by movements of the parapharyngeal wall under various physiological conditions and especially the stimulation of several intrapneumonal receptors. MATERIALS AND METHODS: Fifteen mongrel dogs were anesthetized and a nasopharyngeal fiberscope was inserted from the oronasal fistula at the center of the hard palate, with the tip fixed around the choana. Mechanical and chemical stimulation was applied, and ongoing velopharyngeal movements were observed. In each case examined, the muscle nerve located under the bilateral levator veli palatini (LVP) was severed. RESULTS: Two different closure patterns were recognized between rebreathing and deglutition. Chemical stimulation of the pulmonary irritant receptor and type-J receptor induced a sphincteric tight closure of the velopharynx but only a weak inward movement of the lateral pharyngeal wall at lung inflation. CONCLUSION: The movements of the parapharyngeal wall, mainly represented by the pharyngeal constrictor muscle's contraction, are facilitated as a sphincteric velopharyngeal closure under reflexive movements such as deglutition or gagging.

Effect of norepinephrine receptors on trigeminal rhythm generation in newborn rats.

N-methyl-D,L-aspartate acid and bicuculline are required to enhance the trigeminal rhythmic activities in an in vitro isolated brainstem block preparation. In this study, we analyzed the effect of norepinephrine on the trigeminal neural circuit underlying rhythmic jaw movements. Rhythmic trigeminal activity is observed in brainstem preparations (inferior colliculus to obex) only following blockade of alpha(2)-adrenoceptors with idazoxan. This observation, combined with the inhibition of rhythm by alpha(2)-adrenoceptor agonists suggests endogenous alpha(2)-adrenoceptor mediated inhibition of trigeminal networks. A complex noradrenergic modulation of trigeminal systems is further supported by the prazosin-sensitive potentiation of rhythm by bath application of the alpha(1)-adrenoceptor agonist phenylephrine.

Hedgehog proteins stimulate chondrogenic cell differentiation and cartilage formation.

Sonic hedgehog (Shh) and Indian hedgehog (Ihh) are important regulators of skeletogenesis, but their roles in this complex multistep process are not fully understood. Recent studies have suggested that the proteins participate in the differentiation of chondrogenic precursor cells into chondrocytes. In the present study, we have tested this possibility more directly. We found that implantation of dermal fibroblasts expressing hedgehog proteins into nude mice induces ectopic cartilage and bone formation. Immunohistological and reverse-transcription polymerase chain reaction (RT-PCR) analyses revealed that the ectopic tissues derived largely if not exclusively from host cells. We found also that treatment of clonal prechondrogenic RMD-1 and ATDC5 cells in culture with Ihh or recombinant amino half of Shh (recombinant N-terminal portion of Shh [rShh-N]) induced their differentiation into chondrocytes, as revealed by cytoarchitectural changes, Alcian blue staining and proteoglycan synthesis. Induction of RMD-1 cell differentiation by Ihh or rShh-N was synergistically enhanced by cotreatment with bone morphogenetic protein 2 (BMP-2) but was blocked by cotreatment with fibroblast growth factor 2 (FGF-2). Our findings indicate that hedgehog proteins have the ability to promote differentiation of chondrogenic precursor cells and that their action in this process can be influenced and modified by synergistic or antagonist cofactors.

Role of the superior pharyngeal constrictor muscle in forced breathing in dogs.

OBJECTIVE: Respiratory-related electromyographic (EMG) activity of the superior pharyngeal constrictor (SPC) muscle was analyzed during the early stage of forced breathing. DESIGN: Four adult dogs anesthetized with sodium pentobarbital were used. In the first part of the study, oral and nasal breathing tubes were placed into the respective cavities, and a tracheotomy tube was placed in the second part of the study. Two conditions, the presence (oral-nasal tube breathing) and absence (tracheotomy breathing) of airflow in the upper airway, were achieved in each dog. Following quiet breathing, animals were connected to a closed breathing system, first by an oral-nasal tube and then by a tracheotomy tube. We proposed to induce a forced breathing condition mechanically by using this system for 1 minute. We increased resistance to airflow during forced breathing by means of connecting tubes and a bag. Our aim was not to produce chemical drive but to produce a forced respiration by increasing the resistance to airflow. Tidal volume, breathing frequency, minute volume, chest wall movement, and EMG activity of the SPC muscle were measured and analyzed. RESULTS: During quiet breathing through an oral-nasal or tracheotomy tube, low-amplitude EMG activity of the SPC muscle corresponding to the expiratory cycle of the respiration was observed. In both study conditions, phasic expiratory EMG activity increased immediately after the advent of the breathing from the closed system. Tidal volumes and frequencies also increased rapidly during forced breathing. CONCLUSIONS: An increase in the resistance to airflow increased the activity of the SPC muscle. This augmented respiratory activity probably assists the patency of the upper airway. The augmented respiratory activity was independent of the local reflex pathways. Respiratory-related activity of the SPC muscle may help dilate and stiffen the pharyngeal airway, promoting airway patency.

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.

Temporal patterns of trigeminal respiratory activity in rat brainstem-spinal cord in vitro.

Respiratory activity in trigeminal (V) motoneurons was studied in rhythmically active en bloc brainstem-spinal cord preparations isolated from neonatal rats (P0-P3). In the majority of preparations (83%), the temporal pattern of V activity consisted of spontaneous inspiratory phasic discharge with onset delayed or coincident with onset of phrenic motoneuron discharge. Blockade of alpha-2 noradrenergic receptor activation shifted onset of V respiratory discharges earlier than phrenic discharges, while elevation of extracellular potassium concentration or blockade of GABAergic and glycinergic inhibitory synaptic transmission had little effect on temporary pattern of V respiratory discharges. We conclude V motoneurons in the in vitro preparation generate respiratory activity during inspiratory phase, and their temporal patterns are modulated by inhibitory noradrenergic synaptic transmission.

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.