Phase II trial of combination treatment with S-1/cetuximab in patients with platinum-ineligible recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab. METHODS: Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m2/day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). RESULTS: Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49-82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22-66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0-18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1-8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%). CONCLUSIONS: Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123.

Carcinoma ex pleomorphic adenoma of the parotid gland: a multi-institutional retrospective analysis in the Northern Japan Head and Neck Cancer Society.

CONCLUSION: The 3-year progression-free survival rate of non-invasive salivary duct carcinoma (SDC) or adenocarcinoma not otherwise specified (NOS) was significantly better than that of invasive SDC or adenocarcinoma NOS in Carcinoma ex pleomorphic adenoma (CXPA). The presence of invasion is an important prognostic factor for SDC and adenocarcinoma NOS in CXPA. OBJECTIVES: CXPA is a rare parotid gland malignant tumor for which therapy is not yet standardized. The purpose of this study was to review the characteristics of CXPA patients and to analyze their outcomes in the Northern Japan Head and Neck Cancer Society. METHOD: The medical records of 33 patients who had been provided initial treatment in 12 institutes of northern Japan from 2002-2011 were reviewed as a multi-institutional retrospective study. RESULTS: The 3-year overall and progression-free survival rate of all patients was 79.9% and 76.8%, respectively. Both the 3-year overall and progression-free survival rates were 87.5% for patients with non-invasive SDC or adenocarcinoma NOS. The 3-year overall and progression-free survival rates for patients with invasive SDC or adenocarcinoma NOS were 60.4% and 30.5%, respectively. The progression-free survival rates for patients with invasive SDC or adenocarcinoma NOS was significantly poor (p < 0.05).

Laryngeal neuroma in multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia (MEN) type 2 syndrome is an autosomal dominant inherited disease caused by mutations of the RET proto-oncogene, and is clinically divided into three phenotypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma. Although multiple mucosal neuromas are commonly observed in patients with MEN2B, there are only a few reports of laryngeal neuroma. We present here a rare case of laryngeal mucosal neuromas with MEN2B.

Effects of cholesterol alterations are mediated via G-protein-related pathways in outer hair cells.

Cholesterol is an essential component of cell membranes, and determines their rigidity and fluidity. Alterations in membrane cholesterol by MßCD or water-soluble cholesterol affect the stiffness, capacitance, motility, and cell length of outer hair cells (OHCs). This suggests that reconstruction of the cytoskeleton may be induced by cholesterol alterations. In this study, we investigated intracellular signaling pathways involving G proteins to determine whether they modulate the changes in voltage-dependent capacitance caused by cholesterol alterations. Membrane capacitance of isolated guinea pig OHCs were assessed using a two-sine voltage stimulus protocol superimposed onto a voltage ramp (200 ms duration) from -150 to +140 mV. One group of OHCs was treated with 100 µM guanosine 5'-O-(3-thiotriphosphate) tetralithium salt (GTPγS), the GTP analog, administrated into individual cells via patch pipettes. Another group of OHCs was internally perfused with 600 µM guanosine 5'-(ß-thio) diphosphate trilithium salt (GDPßS), the GDP analog. A third group was perfused with internal solution only as a control. Application of 1 mM MßCD shifted non-linear capacitance curves to the depolarized direction of the control group with reduction of the peak capacitance (C mpeak). After the 10-min application of MßCD, shifts of voltage at C mpeak (V cmpeak) and reduction of C mpeak were 73.32 ± 11.09 mV and 9.09 ± 2.10 pF, respectively (n = 4). On the other hand, in the GTPγS-treated group, the shift of V cmpeak and reduction of C mpeak were attenuated remarkably. The shift of V cmpeak and reduction of C mpeak in the 10-min application of MßCD were 9.73 ± 10.92 mV and 3.08 ± 1.91 pF, respectively (n = 7). MßCD decreased the cell length by 16.53 ± 4.27 % in the control group and by 6.45 ± 6.22 % in the GTPγS group. In addition, we investigated the effects of GDPßS on cholesterol-treated OHCs. One millimolar cholesterol was externally applied after the 4-min application of 1 mM MßCD because the shift of V-C m function caused by cholesterol alone was small. Application of cholesterol shifted V-C m curves of the control group to the hyperpolarized direction with increase of the C mpeak. After the 10-min application of cholesterol, changes of V cmpeak and C mpeak were -9.19 ± 6.68 mV and 2.14 ± 0.44 pF, respectively (n = 4). On the other hand, in the GDPßS-treated OHCs, the shift of V cmpeak and increase of C mpeak were attenuated markedly. The shift of V cmpeak and increase of C mpeak after 10 min were 5.13 ± 10.46 mV and -0.55 ± 1.39 pF, respectively (n = 6). This study demonstrated that internally perfused GTPγS inhibited the MßCD effects and GDPßS inhibited the cholesterol effects, raising the possibility that G proteins may be involved in outer hair cell homeostasis as well as the possibility that cholesterol response may be G protein mediated. More study is required to clarify the detailed role of G proteins in the relation between cholesterol and the OHC cytoskeleton.

The role of periostin in eosinophilic otitis media.

CONCLUSION: We investigated the localization of periostin in middle ear specimens from patients with eosinophilic otitis media (EOM) and from a newly constructed animal model for EOM. Periostin-positive immunostaining was observed in the middle ear sections obtained from the EOM patients. Immunoreactivity for periostin was also seen in the animal model. These results suggest that periostin plays an important role in subepithelial fibrosis in the middle ear in EOM. OBJECTIVE: The purpose of the present study was to investigate the role of periostin in the middle ear of EOM patients and an animal model. METHODS: Histological and immunohistochemical analyses for periostin were carried out in the middle ear specimens of six EOM patients with/without asthma. An animal model of EOM was constructed by intraperitoneal and topical sensitization with ovalbumin (OVA). Histological and immunocytochemical analyses for periostin were also performed in this model. RESULTS: Immunoreactivities for periostin were observed in the basement membrane and extracellular matrix of the middle ear sections obtained from all EOM patients with/without asthma. In the animal model, eosinophil infiltration and middle ear mucosa thickness were observed. Moreover, periostin-positive immunostaining was shown in the extracellular matrix of the middle ear mucosa on the side topically boosted by OVA.

Developmental expression of the outer hair cell motor prestin in the mouse.

The development of motor protein activity in the lateral membrane of the mouse outer hair cell (OHC) from postnatal day 5 (P5) to P18 was investigated under whole-cell voltage clamp. Voltage-dependent, nonlinear capacitance (C (v)), which represents the conformational fluctuations of the motor molecule, progressively increased during development. At P12, the onset of hearing in the mouse, C (v) was about 70% of the mature level. C (v) saturated at P18 when hearing shows full maturation. On the other hand, C (lin), which represents the membrane area of the OHC, showed a relatively small increase with development, reaching steady state at P10. This early maturation of linear capacitance is further supported by morphological estimates of surface area during development. These results, in light of recent prestin knockout experiments and our results with quantitative polymerase chain reaction, suggest that, rather than the incorporation of new motors into the lateral membrane after P10, molecular motors mature to augment nonlinear capacitance. Thus, current estimates of motor protein density based on charge movement may be exaggerated. A corresponding indicator of motor maturation, the motor's operating voltage midpoint, V (pkcm), tended to shift to depolarized potentials during postnatal development, although it was unstable prior to P10. However, after P14, V (pkcm) reached a steady-state level near -67 mV, suggesting that intrinsic membrane tension or intracellular chloride, each of which can modulate V (pkcm), may mature at P14. These developmental data significantly alter our understanding of the cellular mechanisms that control cochlear amplification and provide a foundation for future analysis of genetic modifications of mouse auditory development.