c.1439delA frameshift deletion mutation in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a rare autosomal dominant genetic disease related to germline mutations of the APC gene. The clinical features of this disease most commonly include hundreds of adenomas or polyps. If not treated in a timely fashion, FAP can eventually result in colorectal carcinoma. In this report, clinical manifestations, family history, relevant auxiliary examinations and gene detection from patient blood led us to discover a novel frameshift mutation in exon 12 of the APC gene. The deletion of adenine in c.1439 resulted in the formation of codon 480. The occurrence of this frameshift deletion may lead to inexpressibility of the main functional regions in APC and may affect gene function. In addition, colonoscopy and histopathology showed malignant changes in the colon and rectum. There have been no reports of this frameshift mutation, but it can be considered in case of APC mutations and FAP in patients with clinical manifestations; auxiliary examination may be related, and it may be used as a reference for preventive clinical treatment in the future.

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.

Repopulation of tumor cells during fractionated radiotherapy and detection methods (Review).

Repopulation of tumor cells during radiotherapy is believed to be a significant cause for treatment failure. The phenomenon of tumor repopulation during fractionated radiotherapy was found from clinical observations that identified that the local control rate decreased with a prolonged treatment time. A series of animal experiments with varied overall treatment time and fractionated doses were performed to demonstrate tumor cell repopulation during radiotherapy in various mouse xenograft models. However, conventional detection methods are challenging, as it is difficult to separate viable cells from those destined for apoptosis during fractionated radiotherapy. In essence, the mechanism of tumor repopulation involves the continuing proliferation of clonogenic tumor cells. In vivo imaging, tracking and targeting of the repopulation of these cells has been of clinical interest so as to administer a higher dose to the tumor repopulation regions. Currently, functional imaging methods, including 3'-deoxy-3'-18F-fluorothymidine positron emission tomography (18F-FLT PET), are showing promise in assessing the proliferation activity of tumors in vivo. This review mainly focuses on the phenomenon of tumor repopulation during radiotherapy and its conventional and novel detection methods, particularly on the feasibility of 18F-FLT PET for the detection of tumor-cell repopulation.

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.

Prognostic value of serial [18F]fluorodeoxyglucose PET-CT uptake in stage III patients with non-small cell lung cancer treated by concurrent chemoradiotherapy.

OBJECTIVE: To evaluate (18)FDG PET-CT for the assessment of therapy response and prediction of patient outcome after concurrent chemoradiotherapy (CCRT) for non-small cell lung cancer (NSCLC). METHODS: Forty-six patients with pathologically proven stage III NSCLC had 2 serial FDG PET-CT scans, before and during CCRT. The maximum standardized uptake value (SUV(max)) of the primary lung lesion was calculated. The value changes of SUV(max) before and during treatment were calculated according to the following equation: SUV=(SUV(before)-SUV(during))100%/SUV(before). The relationship between changes of the SUV(max) and the therapy response as well as long-term survival was studied in the responsive and non-responsive groups after CCRT. RESULTS: Of the 46 enrolled patients, after a medicine follow-up of 2 years, the initial SUV(max) in the responsive and non-responsive groups was 7.59±3.14 and 14.72±4.67, respectively. The SUV(max) during treatment in the two groups was 2.89±1.39 and 9.82±3.31, respectively. Significant difference (P=0.001; P=0.001) in SUV(max) was observed either before or during treatment. Furthermore, the percent change of SUV(max) before and during treatment was 61.91±86.69 and 33.56±90.37, respectively. There was significant difference between these two groups (P=0.007). In addition, the 1-year survival rate in the responsive and non-responsive group was 73% and 69%, respectively. The 2-year survival rate in the two groups was 40% and 37%, respectively. There was significant difference between these two groups (P=0.001). CONCLUSIONS: (18)FDG PET-CT is an effective method in the prediction of therapy response in patients with stage III NSCLC. The analysis of percent change of SUV(max) provides additional value in early prediction of therapy response and patient outcome.

[Prognostic value of (18)F-fluorodeoxyglucose uptake in patients with non-small cell lung cancer treated by concurrent chemoradiotherapy].

OBJECTIVE: To evaluate the value of (18)F-FDG PET-CT for assessment of therapeutic response and prediction of patient outcome after concurrent chemoradiotherapy (CCRT) of non-small cell lung cancer (NSCLC). METHODS: Forty six patients with histologically proven stage III NSCLC had two repeated (18)F-FDG PET-CT scans either one week before therapy and at the dose of 40 ∼ 50 Gy. The SUV(max) and changes of the two groups were compared with (1) the therapeutic response and (2) treatment results and long-term survival. RESULTS: Of the 46 eligible cases, the pretreatment SUV(max) of the responding and non-responding groups was 7.59 ± 3.14 and 14.72 ± 4.67, respectively. The midtreatment SUV(max) of the two groups was 2.89 ± 1.39 and 9.82 ± 3.31, respectively. Significant difference(t = 4.74, P = 0.001;t = 7.23, P = 0.001) in SUV(max) was observed both before and during treatment. Furthermore, the percentage change of pretreatment and midtreatment SUV(max) was ΔSUV(max) = 61.9% ± 8.7% and ΔSUV(max) = 33.6% ± 9.0%, also with a significant difference between the two groups (t = 2.83, P = 0.007). In addition, the 1-year survival rate of the the responding and non-responding groups was 68.0% and 38.1%, respectively. The 2-year survival rate of the two groups was 64.0% and 33.3%, respectively, with a significant difference between the two groups (P = 0.043, P = 0.038). CONCLUSION: (18)F-FDG PET-CT is highly effective in detecting therapeutic response in stage III NSCLC patients. The analysis of percentage change of SUV(max) provides incremental value in early prediction of therapeutic response and patient outcome.

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.