Zhengfei Zhu

Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes.

Peripheral inflammation induces central sensitization characterized by the development of allodynia and hyperalgesia to thermal stimuli. Recent evidence suggests that activation of glial cells and a subsequent increase in proinflammatory cytokines contribute to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous agonist of the N/OFQ peptide receptor (ORL1 receptor), has been demonstrated to play an important role in modulation of nociceptive signals. In the present study, we investigated: (1) astrocyte activation and proinflammatory cytokine expression at the lumbar spinal cord following intraplantar administration of complete Freunds adjuvant (CFA) in rats; (2) the mechanism of N/OFQ on nociception modulation, the relationship between N/OFQ and cytokines in the rat CNS in vivo and in vitro. The results showed: (1) CFA-induced peripheral inflammation evoked robust astrocyte activation and proinflammatory cytokines spinally; (2) down-regulation of cytokine mRNA transcripts by intrathecal administration of N/OFQ, the effects produced by N/OFQ were abolished by combination with ORL1 receptor-specific antagonist [Nphe(1)]N/OFQ(1-13)NH2; (3) ORL1 receptor was expressed on astrocytes of rat spinal cord; (4) cytokine gene expression was inhibited in astrocyte cultures exposed to N/OFQ, the inhibiting effects of N/OFQ were significantly blocked by [Nphe(1)]N/OFQ(1-13)NH2. The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway.

Stereotactic ablative radiotherapy

Surgical resection has been the standard treatment for early stage multiple primary lung cancer (MPLC). However, a significant proportion of patients with MPLC cannot undergo surgery. For this report, the authors explored the role of stereotactic ablative radiotherapy (SABR) for patients with MPLC.

A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer

PURPOSE The aim of this study is to evaluate the safety and efficacy of accelerated hypofractionated radiotherapy (HypoRT) combined with sequential chemotherapy in locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS A total of 34 patients with stage III NSCLC were enrolled. All patients received accelerated HypoRT (initially 50Gy/20 fractions, then a fraction dose of 3Gy) using three-dimensional conformal radiation therapy (3D-CRT), omitting elective nodal irradiation (ENI), to a total dose of 65-68Gy. All patients received two cycles of induction chemotherapy; 1-2 cycles of consolidation chemotherapy were given to 31 patients. The primary outcome measure was a profile of radiation toxicity. The secondary endpoints included overall survival (OS), progression-free survival (PFS), locoregional PFS (LR-PFS) and the pattern of initial failure. RESULTS Radiation toxicity was minimal. The median and 3-year OS, PFS were 19.0 months, 32.1%; 10.0 months, 29.8%, respectively. The 1-, 2-, and 3-year LR-PFS were 69.6%, 60.9% and 60.9%, respectively. No patient experienced isolated elective nodal failure as the first site of failure. CONCLUSION This study suggests that accelerated HypoRT using 3D-CRT omitting ENI can be used in combination with sequential chemotherapy in locally advanced NSCLC.

Phosphorylated AKT1 is associated with poor prognosis in esophageal squamous cell carcinoma.

BackgroundThe epidermal growth factor receptor (EGFR) signaling pathway is important in regulating biological behaviors in many malignancies. We explored whether expression and activation of EGFR and several components on its downstream pathways have prognostic significance in patients with esophageal squamous cell carcinoma (ESCC).MethodsExpression of EGFR, phosphorylated (p)-EGFR, AKT1, p-AKT1, AKT2, p-AKT2, ERK1, ERK2, p-ERK1/2, STAT3, and p-STAT3 was assessed by immunohistochemical analysis of tissue microarrays for 275 ESCC patients who had undergone complete three-field lymphadenectomy. Spearman rank correlation tests were used to determine the relationships among protein expression, and Cox regression analyses were performed to determine the prognostic factors on overall survival (OS).Resultsp-EGFR expression was correlated statistically with all of the other phosphorylated markers. Gender, N stage, and p-AKT1 expression were found to be independent prognostic factors for OS. Increased expression of p-AKT1 was associated with decreased patient survival. EGFR and p-EGFR expression was not significantly associated with patient survival.ConclusionActivation of AKT1 was associated with poor prognosis in ESCC.

Phase 2 Study of Accelerated Hypofractionated Thoracic Radiation Therapy and Concurrent Chemotherapy in Patients With Limited-Stage Small-Cell Lung Cancer

PURPOSE To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. METHODS AND MATERIALS Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. RESULTS Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. CONCLUSION Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

Radiation recall with vinorelbine and cisplatin.

Background: Radiation recall dermatitis (RRD) is an inflammatory skin reaction in a previously irradiated field in response to certain pharmacological agents. Little is known about the potential risk of RRD in response to the use of vinorelbine and cisplatin. Case Report: Herein, we report a case of RRD following the combination treatment of vinorelbine and cisplatin in a lung cancer patient with lymph node metastasis. We describe the timing and doses of radiation exposure and chemotherapy, the features of the skin reactions, the clinical management, and the outcome. We also review previous reports on RRD to explain the characteristics of the reaction and the potential mechanisms. Conclusion: Clinical health care professionals should be aware of the possibility of a recall reaction whenever vinorelbine and cisplatin are used, although the frequency is probably low.

Full-dose pemetrexed plus cisplatin combined with concurrent thoracic radiotherapy for previously untreated advanced nonsquamous non-small cell lung cancer.

Compared with other platinum-based doublet chemotherapy, pemetrexed plus platinum is more effective and tolerable as the first-line treatment for nonsquamous non-small cell lung cancer (NSCLC). Thus, we examined the feasibility of using thoracic radiotherapy combined with concurrent full-dose pemetrexed as the first-line treatment for advanced nonsquamous NSCLC patients. From January 2009 to July 2012, 41 patients with stage IIIB or IV nonsquamous NSCLC were treated with full-dose pemetrexed plus cisplatin as the first-line chemotherapy combined with concurrent thoracic radiotherapy, with or without radiotherapy for metastases. The status of mutations in the epidermal growth factor receptor was unknown before the treatment, and no tyrosine-kinase inhibitor and cytotoxic drug maintenance therapy were administered to the patients after the chemotherapy. The median follow-up duration was 26.3 months (range, 5.8–57.5 months). Twenty-one patients had stage IIIB disease (19 with stage N3-IIIB). Of the 20 patients with stage IV disease, 16 had oligometastases (⩽5) and four had polymetastases. The median number of chemotherapy cycles was 4. The median radiation dose was 60 Gy. Thirty-six patients received radical doses of radiotherapy. Toxicities were highly tolerated. The median progression-free survival was 12 months and the median overall survival was 32 months. The 1-, 2-, and 3-year overall survival rates were 87.5, 67.1, and 43.4%, respectively. As the first-line treatment for selected patients with advanced nonsquamous NSCLC, thoracic radiotherapy combined with concurrent full-dose pemetrexed plus cisplatin was safe and highly tolerable. In addition, the survival rate was encouraging. Prospective clinical trials are needed to verify the results.

Prognostic value of EGFR family expression in lymph node-negative esophageal squamous cell carcinoma patients

The human epidermal growth factor receptor (EGFR) family has been widely studied in cancer, however, the prognostic role of EGFR family expression in lymph node-negative esophageal squamous cell carcinoma (ESCC) patients have not been invalidated. This study was designed to determine the prognostic value of EGFR family expression in a population of lymph node-negative ESCC patients treated with curative resection. EGFR family protein expression was examined by immunohistochemical analysis of tissue microarrays of 94 patients with lymph node-negative ESCC after radical esophagectomy with three-field lymphadenectomy. Survival differences were compared using Kaplan-Meier analysis. Cox regression analyses were performed to determine the prognostic factors for overall survival and disease-free survival (DFS). ErbB4 expression was found to be an independent prognostic factor for DFS in patients without lymph node metastasis; increased ErbB4 expression was associated with decreased DFS. Additionally, patients with high ErbB4 expression tended to have worse overall survival. EGFR, ErbB2 and ErbB3 expression were not significantly associated with survival in lymph node-negative ESCC patients. Increased ErbB4 immunohistochemical expression was associated with poor prognosis in lymph node-negative ESCC patients.

Comparison of paclitaxel in combination with cisplatin (TP), carboplatin (TC) or fluorouracil (TF) concurrent with radiotherapy for patients with local advanced oesophageal squamous cell carcinoma: a three-arm phase III randomized trial (ESO-Shanghai 2)

Introduction Concurrent chemoradiation is the standard therapy for patients with local advanced oesophageal carcinoma unsuitable for surgery. Paclitaxel is an active agent against oesophageal cancer and it has been proved as a potent radiation sensitiser. There have been multiple studies evaluating paclitaxel-based chemoradiation in oesophageal cancer, of which the results are inspiring. However, which regimen, among cisplatin (TP), carboplatin (TC) or fluorouracil (TF) in combination with paclitaxel concurrent with radiotherapy, provides best prognosis with minimum adverse events is still unknown and very few studies focus on this field. The purpose of this study is to confirm the priority of TF to TP or TF to TC concurrent with radiotherapy in terms of overall survival and propose a feasible and effective plan for patients with local advanced oesophageal cancer. Methods and analysis ESO-Shanghai 2 is a three-arm, multicenter, open-labelled, randomised phase III clinical trial. The study was initiated in July 2015 and the duration of inclusion is expected to be 4 years. The study compares two pairs of regimen: TF versus TP and TF versus TC concurrent with definitive radiotherapy for patients with oesophageal squamous cell carcinoma (OSCC). Patients with histologically confirmed OSCC (clinical stage II, III or IVa based on the sixth Union for International Cancer Control-tumour, node, metastasis classification) and without any prior treatment of chemotherapy, radiotherapy or surgery against oesophageal cancer will be eligible. A total of 321 patients will be randomised and allocated in a 1:1:1 ratio to the three treatment groups. Patients are stratified by lymph node status (N0, N1, M1a). The primary endpoint is overall survival and the secondary endpoint is progression-free survival and adverse events. Ethics and dissemination This trial has been approved by the Fudan University Shanghai Cancer Centre Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. Trial status The trial was initiated in July 2015 and is currently recruiting patients in all of the participating institutions above. Trial registration number NCT02459457.

Is a clinical target volume (CTV) necessary for locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy? —a dosimetric evaluation of three different treatment plans

Background The aim of this study was to determine the feasibility of omitting the clinical target volume (CTV) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT) by comparing dosimetric characteristics of three different IMRT plans with or without CTV implementation. Methods Thirteen patients with stage III NSCLC were reviewed. Target volumes were contoured such that the planning target volume (PTV) derived from the gross tumor volume (GTV) directly was named PTV_g and that from GTV plus CTV margin was named PTV_c. The PTV margin to generate PTV_g or PTV_c was the same within each case. Three IMRT plans were retrospectively generated to deliver: (I) 60 Gy to PTV_g in plan_routine; (II) 60 Gy to PTV_c in plan_CTV, and (III) 50 Gy to PTV_c while the dose was simultaneously escalated to 60 Gy to PTV_g in plan_SIB, achieved using the simultaneous integrated boost (SIB) technique. Optimization was performed to minimize the dose volumes of the irradiated normal lung, heart, esophagus, and spinal cord. Dose distributions and dosimetric indexes for the target volumes and critical structures in the three plans were computed and compared. Results In plan_routine, the 50-Gy isodose line covered at least 95% of the GTV plus CTV margins in all 13 patients. The statistics showed better sparing of the organs at risk (OAR) in plan_routine than in plan_CTV, and the best OAR sparing in plan_SIB. Conclusions In patients with locally advanced lung cancer, IMRT planning without CTV implementation provides sufficient dose coverage of subclinical disease while reducing the dose to normal tissues. The omission of CTV was feasible in our cohort of patients. However, when CTV was implemented, IMRT planning that included the SIB technique had further dosimetric benefits to the patients. This strategy thus merits further evaluation in clinical trials.