The major heat shock protein, Hsp70, can protect against cell death by directly interfering with mitochondrial apoptosis pathways. However, Hsp70 also sensitizes cells to certain apoptotic stimuli like TNF. Little is known about how Hsp70 enhances apoptosis. We demonstrate here that Hsp70 promotes TNF killing by specifically binding the coiled-coil domain of IB kinase ␥ (IKK␥) to inhibit IKK activity and consequently inhibit NF-B-dependent antiapoptotic gene induction. An IKK␥ mutant, which interacts with Hsp70, competitively inhibits the Hsp70-IKK␥ interaction and relieves heat-mediated NF-B suppression. Depletion of Hsp70 expression with RNA interference rescues TNF-mediated cell death. Although TNF may or may not be sufficient to trigger apoptosis on its own, TNF-triggered apoptosis was initiated or made worse when Hsp70 expression increased to high levels to disrupt NF-B signaling. These results provide significant novel insights into the molecular mechanism for the pro-apoptotic behavior of Hsp70 in death-receptor-mediated cell death.

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Abstract.Postoperative radiotherapy has shown positive efficacy in lowering the recurrence rate and improving the survival rate in cases involving lymph node (LN) metastasis. However, the radiotherapy target volume remains controversial. Certain published studies have paid more attention to LNs found to be affected during surgery, while little effort has been made to study the LN metastatic pattern following surgery and its influence on the determination of the target volume of postoperative radiotherapy. In this study, the locoregional recurrence of esophageal squamous cell cancer was examined in 134 patients receiving radical surgery with two-field lymph node dissection from 2004 to 2009. In the 134 cases of recurrence, LN metastasis occurred in 126 patients (94.0%) while 13 patients (9.7%) developed anastomotic recurrence and 5 patients (3.7%) experienced tumor bed recurrence. The difference among the groups was statistically significant (P= 0.000). In the 126 cases with lymph node metastasis, the mediastinal metastasis rate (80.2%) was significantly higher compared with the rate of supraclavicular metastasis and abdominal metastasis (P= 0.000). A significant difference was identified between right and left supraclavicular LN metastasis (31.7% vs 16.7%, P= 0.005). Furthermore, the difference between the metastatic rates in the upper (73.8%), middle (39.7%) and lower mediastinum (1.6%) was statistically significant (P= 0.000). Nevertheless, no significant correlation between the rate of LN metastasis was observed in the supraclavicular, mediastinal and abdominal regions for upper, middle and lower thoracic carcinomas (P= 0.404, P= 0.718 and P= 0.169, respectively). Based on our data, LN metastasis is the major locoregional recurrence pattern for esophageal squamous cell cancer following radical surgery. The high-risk lymphatic drainage areas include the supraclavicular nodes, recurrent laryngeal nerve nodes, azygos nodes and subcarinal nodes. IntroductionSurgery is the mainstay treatment for resectable esophageal cancer. Although the long-term survival rate associated with esophageal cancer remains at approximately 15% worldwide (1), certain recent studies have described an increase in the overall 5-year survival rate of 40% or more following esophagectomy with three-field lymphadenectomy (2), but with more complications. Postoperative radiotherapy has shown positive efficacy in lowering the recurrence rate and improving the survival rate in cases involving lymph node (LN) metastasis (3-5), although it remains unknown whether postoperative radiotherapy improves survival in all cases (3,6). Reasons for this controversy may be the undetermined target volume or insensitivity of the tissue to radiotherapy due to ischemia and hypoxia following surgery. A large T-shaped field was first used which encompassed the bilateral supraclavicular fossi, mediastinum and left gastric nodes. In recent years, the large T-shaped field was modified into a smaller T-shaped field to reduce unacceptable complication rates by omitting...

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Background and purpose: To evaluate the safety profile and efficacy of high-dose (60 Gy) concurrent chemoradiotherapy (CCRT) compared with standard-dose (50.4-54 Gy) CCRT. Materials and methods: Patients with oesophageal squamous cell carcinoma (OSCC) undergoing CCRT were eligible for a propensity score matched cohort (1:1 for high dose versus standard dose). Adverse events, local control (LC) and overall survival (OS) were assessed. Results: A total of 380 patients with good balance in observed co-variables were enrolled. OS and LC rates of patients receiving high-dose CCRT were significantly higher than those receiving standard-dose CCRT, with the 10-year OS at 24% versus 13.3%, respectively. In contrast, there was a trend towards increased grades 2-3 acute oesophagitis toxicity among patients receiving high-dose versus standard-dose CCRT (37.4% versus 27.9%, respectively). None experienced grade 5 acute oesophagitis and grade 4 acute toxicities were rare. Similar rates of late radiation oesophagitis, radiation pneumonitis, gastrointestinal reactions and haematological toxicities were observed between patients receiving high-dose versus standard-dose CCRT. Six patients (3.2%) receiving high-dose CCRT experienced >grade 3 leucocytopaenia, and two (1.1%) received standard-dose CCRT, whereas none experienced >grade 3 thrombocytopaenia or anaemia. Three patients (2.3%) receiving high-dose CCRT died of infections caused by myelosuppression. Multivariate analysis showed that anaemia is a significant independent predictor of poor prognosis. Conclusions: Compared with standard-dose CCRT, high-dose CCRT yielded more favourable local control and survival outcomes for patients with OSCC. Grades 2-3 acute oesophagitis toxicity in patients undergoing high-dose CCRT increased, whereas severe, life-threatening toxicities (>grade 3) did not.