Yuichiro Tojima

NAK is an IκB kinase-activating kinase

Phosphorylation of IκB by the IκB kinase (IKK) complex is a critical step leading to IκB degradation and activation of transcription factor NF-κB. The IKK complex contains two catalytic subunits, IKKα and IKKβ, the latter being indispensable for NF-κB activation by pro-inflammatory cytokines. Although IKK is activated by phosphorylation of the IKKβ activation loop, the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure. Here we describe an IKK-related kinase, named NAK (NF-κB-activating kinase), that can activate IKK through direct phosphorylation. NAK induces IκB degradation and NF-κB activity through IKKβ. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-κB by protein kinase C-ε (PKCε). Thus, NAK is an IKK kinase that may mediate IKK and NF-κB activation in response to growth factors that stimulate PKCε activity.

NAK is an IkappaB kinase-activating kinase.

Phosphorylation of IκB by the IκB kinase (IKK) complex is a critical step leading to IκB degradation and activation of transcription factor NF-κB. The IKK complex contains two catalytic subunits, IKKα and IKKβ, the latter being indispensable for NF-κB activation by pro-inflammatory cytokines. Although IKK is activated by phosphorylation of the IKKβ activation loop, the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure. Here we describe an IKK-related kinase, named NAK (NF-κB-activating kinase), that can activate IKK through direct phosphorylation. NAK induces IκB degradation and NF-κB activity through IKKβ. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-κB by protein kinase C-ε (PKCε). Thus, NAK is an IKK kinase that may mediate IKK and NF-κB activation in response to growth factors that stimulate PKCε activity.

Neoadjuvant Oxaliplatin and Capecitabine and Bevacizumab without Radiotherapy for Poor-risk Rectal Cancer: N-SOG 03 Phase II Trial

OBJECTIVE This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. METHODS Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. RESULTS Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. CONCLUSIONS Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).

Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with otherwise node-negative hilar cholangiocarcinoma

ObjectiveTo investigate whether immunohistochemically demonstrated lymph node micrometastasis has prognostic significance in patients with histologically node-negative (pN0) hilar cholangiocarcinoma. Summary Background DataThe clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, no reports have addressed this issue with regard to hilar cholangiocarcinoma. MethodsA total of 954 lymph nodes from surgical specimens of 45 patients with histologically node-negative hilar cholangiocarcinoma who underwent macroscopically curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were examined for relationships with clinical and pathologic features and with patient survival. ResultsLymph node micrometastases were detected immunohistochemically in 11 (24.4%) of the 45 patients, being found in 13 (1.4%) of 954 lymph nodes examined. Of the 13 nodal micrometastases, 11 (84.6%) were found in the N2 regional lymph node group rather than N1. Clinicopathologic features showed no associations with lymph node micrometastases. Survival curves were essentially similar between patients with and without micrometastasis. In addition, the grade of micrometastasis showed no effect on survival. The Cox proportional hazard model identified microscopic venous invasion, microscopic resection margin status, and histologic differentiation as significant prognostic factors in patients with pN0 disease. ConclusionsLymph node micrometastasis has no survival impact in patients with otherwise node-negative hilar cholangiocarcinoma. The authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostic evaluation.

Phase II trial of neoadjuvant chemotherapy with XELOX plus bevacizumab for locally advanced rectal cancer.

In Western countries, the standard treatment for locally advanced rectal cancer is preoperative chemoradiotherapy followed by total mesorectal excision. On the other hand, in Japan, treatment results without radiotherapy are by no means inferior; therefore, extrapolation of results of preoperative treatment in Western countries to Japan is controversial. We consider that survival may be improved by preoperative treatment with new anticancer agents as they are expected not only to decrease the local recurrence rate but also to prevent distant metastases. We are conducting a multicentre Phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy using XELOX plus bevacizumab without radiotherapy in patients with locally advanced rectal cancer. The primary endpoint of the study is treatment compliance. Secondary endpoints are overall survival, disease-free survival, local recurrence-free survival, objective response rate, R0 resection rate and adverse events. Thirty patients are required for this study.

NAK is an I|[kappa]|B kinase-activating kinase

Phosphorylation of IκB by the IκB kinase (IKK) complex is a critical step leading to IκB degradation and activation of transcription factor NF-κB. The IKK complex contains two catalytic subunits, IKKα and IKKβ, the latter being indispensable for NF-κB activation by pro-inflammatory cytokines. Although IKK is activated by phosphorylation of the IKKβ activation loop, the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure. Here we describe an IKK-related kinase, named NAK (NF-κB-activating kinase), that can activate IKK through direct phosphorylation. NAK induces IκB degradation and NF-κB activity through IKKβ. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-κB by protein kinase C-ε (PKCε). Thus, NAK is an IKK kinase that may mediate IKK and NF-κB activation in response to growth factors that stimulate PKCε activity.

Optimal schedule of adjuvant chemotherapy with S-1 for stage III colon cancer: study protocol for a randomized controlled trial

BackgroundAlthough, in Western countries, oxaliplatin-based regimens have been established as a gold standard treatment for patients with stage III or high risk stage II colon cancer after curative resection, in Japan fluorouracil-based regimens have been widely accepted and recommended in the guidelines for adjuvant settings in patients with stage III colon cancer. S-1, an oral preparation evolved from uracil and tegafur, has equivalent efficacy to uracil and tegafur/leucovorin for treating patients with advanced colorectal cancer and might be a suitable regimen in an adjuvant setting. However, the completion rate of the standard six-week cycle of the S-1 regimen is poor and the establishment of an optimal treatment schedule is critical. Therefore, we will conduct a multicenter randomized phase II trial to compare six-week and three-week cycles to establish the optimal schedule of S-1 adjuvant therapy for patients with stage III colon cancer after curative resection.Methods/DesignThe study is an open-label, multicenter randomized phase II trial. The primary endpoint of this study is three-year disease-free survival rate. Secondary endpoints are the completion rate of the treatment, relative dose intensity, overall survival, disease-free survival, and incidence of adverse events. The sample size was 200, determined with a significance level of 0.20, power of 0.80, and non-inferiority margin of a 10% absolute difference in the primary endpoint.DiscussionAlthough S-1 has not been approved yet as a standard treatment of colon cancer in an adjuvant setting, it is a promising option. Moreover, in Japan S-1 is a standard treatment for patients with stage II/III gastric cancer after curative resection and a promising option for patients with colorectal liver metastases in an adjuvant setting. However, a six-week cycle of treatment is not considered to be the best schedule, and some clinicians use a modified schedule, such as a three-week cycle to keep a sufficient dose intensity with few adverse events. Therefore, it will be useful to determine whether a three-week cycle has an equal or greater efficacy and tolerance to side-effects compared with the standard six-week cycle schedule, and thus may be the most suitable treatment schedule for S-1 treatment.Trial registrationThe University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000006750.