In vitro and in vivo evaluation of the safety and efficacy of a novel liquid fiducial marker for image-guided radiotherapy.

The true extent of a tumor is difficult to visualize, during radiotherapy, using current modalities. In the present study, the safety and feasibility of a mixture of N-butyl cyanoacrylate and lipiodol (NBCA/Lip) was evaluated in order to investigate the optimal combination for application as a fiducial marker for radiotherapy. Four combinations of NBCA/Lip injection (1:1-0.1, 1:1-0.15, 1:3-0.1 and 1:3-0.15 ml) were injected into the subcutaneous tissue of BALB/c mice. The changes in gross histopathology, body weight, skin score, marker volume, neutrophil and macrophage counts were observed to analyze the effects of the different mixing ratios and injection volumes, in order to identify the best combination. Evaluation according to the International Organization for Standardization criteria was further conducted in order to test the biocompatibility of the mixture, including an acute systematic assay with mice, cytotoxicity with L929 fibroblasts and delayed-type hypersensitivity tests with guinea pigs and an intradermal test with rabbits. The results revealed that at the seventh week, 42 markers (42/48; 87.5%) were still visible using computed tomography (CT) imaging. No serious adverse effects were observed throughout the study period; however, the combination of 1:1-0.1 ml had the lowest body weight and worst skin score. A review of the histopathological reaction to NBCA/Lip revealed a combination of acute inflammation, chronic inflammation, granulation tissue, foreign-body reaction and fibrous capsule formation. The 1:1 NBCA combination ratio resulted in the most intense tissue repair reaction and a slower degradation rate of markers. In general, the combination of 1:3-0.15 ml had a better fusion with local tissue, maintained a stable imaging nodule on CT images for 7 weeks and the final biocompatibility test demonstrated its safety. Overall, the findings of the present study demonstrated NBCA/Lip as a safe and feasible fiducial marker, when using the 1:3-0.15 ml combination.

Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review.

Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer (PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage IV, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo. All drug-related side effects were well controlled with medication. To the best of our knowledge, this is the first case of PC which responded to apatinib. Considering this remarkable response, apatinib may be a promising agent in the treatment of PC. We also reviewed the literature on chemotherapy and targeted therapy, especially the anti-angiogenesis therapy for patients with PC, and investigated the effect of apatinib in other solid tumors as well.

Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma: A Case Report and Literatures Review.

Malignant pleural mesothelioma (MPM) is a lethal disease with poor prognosis. The combination of cisplatin and pemetrexed has been confirmed as the standard of care for nonoperable MPM. Data have shown that the adoption of pemetrexed maintenance therapy (PMT) following first-line treatment appears extremely promising.We describe a 57-year-old man diagnosed as advanced MPM. We treated this patient with PMT after first-line cisplatin-based bevacizumab-containing chemotherapy and residual tumor disappeared after 6 course of PMT. A perfect response and a long progression-free survival (PFS) were reached with tumor mass disappearing and 14 months duration of PFS.This case suggests that adding bevacizumab to standard first-line chemotherapy is feasible and that PMT could be promising and useful for treating advanced MPM. We further entail a review of the literature on the first-line treatment, continuation maintenance therapy, switch maintenance therapy, and second-line treatment of patients with advanced MPM.

Effect of celecoxib on inhibiting tumor repopulation during radiotherapy in human FaDu squamous cell carcinoma.

AIM OF THE STUDY: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrated accelerated tumor repopulation during fractionated irradiation with pathological validation in a xenograft model system. Previous studies showed that the selective cyclooxygenase (COX)-2 inhibitor celecoxib can enhance the tumor response to radiotherapy. So we aimed to explore the effect of celecoxib in inducing apoptosis and inhibiting repopulation of FaDu tumors in nude mice during fractionated radiotherapy. MATERIAL AND METHODS: FaDu-hSCC was transplanted into the right hind leg of BALB/C nude mice. Mice were treated with celecoxib and/or fractionated irradiation. Celecoxib (100 mg/kg/day) was administered by daily gavage. Irradiation was delivered with 12 to 18 fractions of 3.0 Gy daily or every second day based on Petersen's repopulation model. At different time points, tumors were excised for immunohistochemistry staining. RESULTS: Significant tumor repopulation occurred after about 18 days of radiotherapy. On average, Ki-67 and bromodeoxyuridine (BrdUrd) labeling indices (LI) decreased with daily irradiation (both p < 0.05) and increased with every-second-day irradiation (both p > 0.05), suggesting accelerated repopulation. Ki-67 LI decreased in celecoxib concurrent with radiotherapy for 12 fractions in 24 days and 18 fractions in 36 days compared with irradiated alone (p = 0.004 and 0.042, respectively). BrdUrd LI values were lower in the concurrent groups than irradiated alone (p = 0.001 and 0.006, respectively). Epithelial growth factor receptor (EGFR) expression score decreased in the concurrent groups than irradiated alone (p = 0.037 and 0.031, respectively). Caspase-3 expression scores were higher in the concurrent groups than irradiated alone (p = 0.05 and 0.006, respectively). CONCLUSIONS: Celecoxib concurrent radiotherapy could inhibit tumor repopulation and increase tumor apoptosis during the treatment in FaDu squamous cell carcinoma.

Histopathologic validation of 3'-deoxy-3'-18F-fluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude mice.

BACKGROUND AND PURPOSE: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrates accelerated tumor repopulation during fractionated irradiation with pathological validation (Ki-67 and BrdUrd makers) in a xenograft model system. However, these and other functional assays must be performed ex vivo and post hoc. We propose a novel, in vivo, real-time assay utilizing (18)F-FLT PET. MATERIAL AND METHODS: Nude mice with FaDu-hSCC were irradiated with 12 or 18 fractions of 1.8 Gy ([Dm]=3.0 Gy), either daily or every second day. (18)F-FLT micro-PET scans were performed at different time points, FLT parameters (SUVmax, SUVmean, and T/NT) were measured. Tumor sections were stained for Ki-67 and BrdUrd, a labeling index (LI) was calculated. Imaging-pathology correlation was determined by comparing FLT parameters and immunohistochemical results. RESULTS: Measured SUVmax, SUVmean and T/NT decreased significantly after daily irradiation with 12 fractions in 12 days (P<0.05) and 18 fractions in 18 days (P<0.05). In contrast, these parameters increased in mice treated with 12 fractions in 24 days (P>0.05) and 18 fractions in 36 days (P>0.05), suggesting accelerated repopulation. Similarly, Ki-67 and BrdUrd LIs demonstrated significant decreases with daily irradiation (P<0.05), and increases with every-second-day irradiation (P>0.05). (18)F-FLT parameters correlated strongly with proliferation markers (r(2): 0.679-0.879, P<0.001). CONCLUSIONS: (18)F-FLT parameters were in good agreement with Ki-67 and BrdUrd Li. These results may support a potential role for (18)F-FLT PET in real-time detection of tumor repopulation during fractionated radiotherapy.

New strategy for monitoring targeted therapy: molecular imaging.

Targeted therapy is becoming an increasingly important component in the treatment of cancer. How to accurately monitor targeted therapy has been crucial in clinical practice. The traditional approach to monitor treatment through imaging has relied on assessing the change of tumor size by refined World Health Organization criteria, or more recently, by the Response Evaluation Criteria in Solid Tumors. However, these criteria, which are based on the change of tumor size, show some limitations for evaluating targeted therapy. Currently, genetic alterations are identified with prognostic as well as predictive potential concerning the use of molecularly targeted drugs. Conversely, considering the limitations of invasiveness and the issue of expression heterogeneity, molecular imaging is better able to assay in vivo biologic processes noninvasively and quantitatively, and has been a particularly attractive tool for monitoring treatment in clinical cancer practice. This review focuses on the applications of different kinds of molecular imaging including positron emission tomography-, magnetic resonance imaging-, ultrasonography-, and computed tomography-based imaging strategies on monitoring targeted therapy. In addition, the key challenges of molecular imaging are addressed to successfully translate these promising techniques in the future.

[Prognostic value of CYFRA 21-1 and CEA in patients with undifferentiated nasopharyngeal carcinoma before and after radiotherapy].

OBJECTIVE: The purpose of this study was to evaluate the potential of CYFRA 21-1 (CYFRA) and CEA as a prognostic marker in patients with undifferentiated nasopharyngeal carcinoma (NPC). METHODS: From March 2004 to February 2008, 62 patients with newly diagnosed, undifferentiated NPC were treated in our department. Their clinocopathological data were analyzed retrospectively. All patients received intensity-modulated radiotherapy using 6 MV X-rays, and serum CYFRA and CEA before and after radiotherapy were assayed. The association among the long-term follow-up results and age, sex, smoke, TNM stage, chemotherapy, CEA, CYFRA and the changes in any direction of serum CYFRA and CEA were determined. RESULTS: Patients with low pre-RT level (≤ 2.49 µg/L) of CYFRA had a significantly better overall survival (OS) than patients with high level (> 2.49 µg/L,OR = 8.555, P = 0.029). N classification and T classification were positively associated with the prediction of progression free survival (OR = 4.054, P = 0.001;OR = 3.873, P = 0.001). But there was no significant association between the rest predictors (age, sex, CEA, post-RT CYFRA, chemotherapy and a radiation-induced decrease in serum markers) and the survival or recurrence rate by multivariate analysis. CONCLUSIONS: The results of the present study show that pre-RT serum CYFRA level is a valuable factor for predicting long-term survival in patients with undifferentiated nasopharyngeal carcinoma. More aggressive treatment may be given to those patients with a high serum CYFRA level.

Serum CYFRA21-1 as a prognostic marker for patients with undifferentiated nasopharyngeal carcinoma.

The purpose of this study was to evaluate the potential of serum CYFRA21-1 and carcinoembryonic antigen (CEA) as prognostic markers in patients with undifferentiated nasopharyngeal carcinoma. Sixty-one patients who received definitive radiotherapy/chemoradiotherapy were analysed retrospectively. We investigated the association of the follow-up results with pretreatment level, post-treatment level and change of serum CYFRA21-1 and CEA, respectively. Patients with low pretreatment CYFRA21-1 had a significantly better overall survival. There were no significant associations among the remaining serum markers, and the survival and recurrence rates on multivariate analysis. The present study shows that pretreatment CYFRA21-1 level is a potential factor for predicting long-term survival.

Prognostic value of 18F-FDG PET-CT metabolic index for nasopharyngeal carcinoma.

PURPOSE: The purpose of this study was to evaluate the prognostic value of metabolic tumor volume (MTV) and metabolic index (MI) from fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in patients with nasopharyngeal carcinoma (NPC). METHODS: From October 2002 to July 2004, 41 patients with NPC who underwent (18)F-FDG PET-CT scan before and after radiotherapy were reviewed retrospectively. All patients received intensity-modulated radiotherapy using 6MV X-rays. We examined the association of MTV and the results of long-term follow-up of the patients. RESULTS: Patients having tumors with an MTV below 30 cm(3) had significantly better 5-year overall survival (OS) (84.6:46.7%, P = 0.006) and disease-free survival (DFS) (73.1:40.0%, P = 0.014) than patients with an MTV of 30 cm(3) or greater. And the patients with MI below 130 had significantly higher 5-year OS (88.0:43.8%, P = 0.002) and DFS (76.0:37.5%, P = 0.005) than other patients. In the Cox multivariate analysis, MI and metabolic response (MR) were predictive of DFS, and we did not find a significant relationship between standard uptake value (SUV) and OS or DFS. CONCLUSIONS: The present study shows that tumor volume parameters, especially the combination of MTV and SUV in the "metabolic index", are valuable for predicting long-term survival. High MI may be useful for identifying patients requiring more aggressive treatment.

[Prognostic value of 9mTc-HL91 SPECT hypoxia imaging in patients with advanced NSCLC].

OBJECTIVE: Tumor hypoxia can influence response to radiotherapy and other treatment modalities. Oxygenation status is proved to be an independent prognostic factor. 99mTc-HL91 (99mTc labeled 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime) is a potential noninvasive marker of tumor hypoxia. It has been reported that 99mTc-HL91 has certain validity for hypoxia imaging. But its clinical study had not been reported widely. This study was carried out to evaluate the relationship between the T/N ratio of HL91 SPECT hypoxia imaging and the radiotherapeutic outcome. METHODS: 32 patients with pathologically proven non-small cell lung cancer received three-dimensional conformal radiotherapy were enrolled into the study. 99mTc-HL91 SPECT scanning was performed in all patients at one or two days before radiotherapy. It was also performed in 18 patients at one or two days after the onset of radiotherapy, when they received a dose of 30 - 40 Gy already. Anterior, posterior and lateral planar images were collected at 2, 4 and 6 hours, respectively, after intravenous injection of approximately 740 MBq 99mTc-HL91. Regions of interest (ROIs) were drawn in the tumor and the contralateral normal lung tissue, and the radioactivity ratio of tumor to normal tissue (T/N) was calculated. To assess whether the tumor uptake of 99mTc-HL91 is predictive of treatment response, the SPECT results were correlated with the results of clinical follow-up. RESULTS: The relationship between T/N ratios at 4 h images after injection was shown to be the best of three acquired images before radiotherapy. The response and overall survival to radiotherapy were analyzed for all 32 patients. The results of 9mTc-HL91 correlated well with radiotherapy response (P = 0. 002) and also patients' survival (P = 0.043). The average T/N values of 18 patients who received serial scanning were 1.57 +/- 0.18, 1.44 +/- 0.19 and 1.30 +/- 0.14, respectively. There was a significant difference between those three groups (P = 0. 000). The T/N changes during radiotherapy were not associated with the treatment outcome. CONCLUSION: HL91 SPECT imaging can identify the hypoxia status and changes during radiotherapy in lung cancer. Hypoxia SPECT imaging with HL91 before treatment may predict radiotherapy response and patients' survival. Longer follow up in more patients is planned to confirm this result.

[Involved-field three-dimensional conformal radiation treatment for stage III non-small-cell lung].

OBJECTIVE: To investigate the feasibility of involved-field irradiation (IFI ) for stage III non-small cell lung cancer (NSCLC). METHODS: From September 1997 to November 2001, 200 stage-III NSCLC patients were randomly divided into two groups-- IFI and ENI (elective node irradiation). The IFI group was irradiated by 3DCR to a dose of 68-74 Gy/34-37f/7-9 w including the primary tumor and the lymph nodes of > or = 10 mm in short axis. The ENI group was irradiated to a dose of 60-64 Gy/30-32f/6-7.5 w including the primary tumor, ipsilateral hilum, subcarinal and mediastinal lymph nodes, even the supraclavicular area when the lymph nodes of superior mediastinum were involved. RESULTS: The overall response (CR + PR) rates were 90.0% in IFI group and 79.0% in ENI group. Radiation pneumonitis developed in 29.0% of the patients in ENI group and 17.0% in IFI group (P = 0.04). The 1-year primary tumor failure rate in IFI group (13.0%) was lower than that (23.0%) in ENI group. The 1-year involved nodal failure rate was 20.0% in ENI group and 10.0% in IFI group (P = 0.048). The 1-year elective node failure rate was 16.0% in ENI group versus 21.0% in IFI group (P = 0.39). The 1-, 2-and 3-year overall survival rate was 67.2% , 38.7% , 27.3% , respectively, in IFI group; versus 59.7% , 25.6% , 19.2% in ENI group, with a difference significant in the 2-year overall survival rate between IFI and ENI group (P = 0.048). CONCLUSION: Involved-field 3D-CRT for stage-III non-small cell lung cancer is well tolerated. It does not increase the rate of lymph node failure in the elective node irradiation field, and may improve the survival due to dose escalation.

[Randomized clinical study of surgery versus radiotherapy alone in the treatment of resectable esophageal cancer in the chest].

OBJECTIVE: To compare the treatment results between radical surgery and late course accelerated hyperfractionated radiotherapy (LCAHFR) for patients with resectable esophageal cancer in the chest. METHODS: From June 1998 to September 2002, 269 patients with resectable esophageal cancer in the chest were randomized into two groups: 135 in surgery group and 134 in radiotherapy. The surgery group received esophagectomy including resection of the lesion and 5 cm margin at both ends from the lesion as well as surrounding lymph nodes > or = 5 mm and fatty tissue. In the radiotherapy group: irradiation field for the lesion in the upper esophageal cancer included the gross lesion, bilateral supraclavicular nodes and 4 cm of normal esophagus from lower margin of the gross disease; for the esophageal cancer at the middle segment, it included the gross disease with 4 cm normal esophagus from both ends of the lesion; for the lesion in the lower esophageal cancer, it included 4 cm of normal esophagus and the gross lesion as well as the draining gastric lymph nodes. The width of the irradiation field was 5-6 cm. The 90% isodose volume was covered by the entire CTV with 3-5 beams, in a conventionally fractionated RT at 1.8-2.0 Gy/d for the first two thirds of treatment course to a dose of about 50-50.4 Gy followed by LCAHFR using reduced fields (2 cm extended margin at both ends of the lesion) , twice daily at 1.5 Gy per fraction ( with aminimal interval of 6 h between fractions) to a dose of 18-21 Gy. The total dose whole radiotherapy was 68.4-71.0 Gy. RESULTS: The 1-, 3- and 5-year overall survival rate was 93.3%, 61.5% and 36.9% in the surgery group versus 88.6%, 56.2% and 34.7% in the radiotherapy group without statistical difference between the two groups. The 1-, 3- and 5-year progression free survival rate was 75.9%, 43.7% and 23.1% in the surgery group and 73.3%, 39.7% and 20.6%, respectively, in the radiotherapy group without statistical difference between the two groups either. CONCLUSION: The results treated by late course accelerated hyperfractionated conformal radiotherapy alone may be comparable to that by radical surgery for patient with resectable esophageal cancer in the chest.