A predator-prey model with genetic differentiation both in the predator and prey.

In this paper, we propose a predator-prey model with genetic differentiation both in the predator and prey. First, we analyze two special cases: a model without the predators and a model with one genotype in both the predator and prey, and for each model show that the positive equilibria are always globally stable when they exist, while the boundary equilibria are always unstable. Then, for the newly proposed model, we give the results that the positive equilibrium is always local stable when it exists, the boundary equilibrium at the origin is always unstable, and the stability of another boundary equilibrium is determined by the existence of the positive equilibrium. Moreover, our discussions show the existence of local center manifolds near the equilibria. Finally, we give some examples to illustrate our results.

Clinical and molecular characterization of POU3F4 mutations in multiple DFNX2 Chinese families.

BACKGROUND: Many X-linked non-syndromic hearing loss (HL) cases are caused by various mutations in the POU domain class 3 transcription factor 4 (POU3F4) gene. This study aimed to identify allelic variants of this gene in two Chinese families displaying X-linked inheritance deafness-2 (DFNX2) and one sporadic case with indefinite inheritance pattern. METHODS: Direct DNA sequencing of the POU3F4 gene was performed in these families and in 100 Chinese individuals with normal hearing. RESULTS: There are characteristic imaging findings in DFNX2 Chinese families with POU3F4 mutations. The temporal bone computed tomography (CT) images of patients with DFNX2 are characterized by a thickened stapes footplate, hypoplasia of the cochlear base, absence of the bony modiolus, and dilated internal acoustic meatus (IAM) as well as by abnormally wide communication between the IAM and the basal turn of the cochlea. We identified three causative mutations in POU3F4 for three probands and their extended families. In family 1468, we observed a novel deletion mutation, c.973delT, which is predicted to result in a p.Trp325Gly amino acid frameshift. In family 2741, the mutation c.927delCTC was identified, which is predicted to result in the deletion of serine at position 310. In both families, the mutations were located in the POU homeodomain and are predicted to truncate the C-terminus of the POU domain. In the third family, a novel de novo transversion mutation (c.669 T > A) was identified in a 5-year-old boy that resulted in a nonsense mutation (p.Tyr223*). The mutation created a new stop codon and is predicted to result in a truncated POU3F4 protein. CONCLUSIONS: Based on characteristic radiological findings and clinical features, POU3F4 gene mutation analysis will increase the success rate of stapes operations and cochlear implantations, and improve molecular diagnosis, genetic counseling, and knowledge of the molecular epidemiology of HL among patients with DFNX2.

Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair.

Recent evidences have demonstrated the potential of metformin as a novel agent for cancer prevention and treatment. Here, we investigated its ability of radiosensitization and the underlying mechanisms in human pancreatic cancer cells. In this study, we found that metformin at 5 mM concentration enhanced the radiosensitivity of MIA PaCa-2 and PANC-1 cells, with sensitization enhancement ratios of 1.39 and 1.27, respectively. Mechanistically, metformin caused abrogation of the G2 checkpoint and increase of mitotic catastrophe, associated with suppression of Wee1 kinase and in turn CDK1 Tyr15 phosphorylation. Furthermore, metformin inhibited both expression and irradiation-induced foci formation of Rad51, a key player in homologous recombination repair, ultimately leading to persistent DNA damage, as reflected by γ-H2AX and 53BP1 signaling. Finally, metformin-mediated AMPK/mTOR/p70S6K was identified as a possible upstream pathway controlling translational regulation of Wee1 and Rad51. Our data suggest that metformin radiosensitizes pancreatic cancer cells in vitro via abrogation of the G2 checkpoint and inhibition of DNA damage repair. However, the in vivo study is needed to further confirm the findings from the in vitro study.

Intensity modulated radiotherapy for locally advanced and metastatic pancreatic cancer: a mono-institutional retrospective analysis.

BACKGROUND: To evaluate the role of intensity modulated radiotherapy (IMRT) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC), and the prognostic factors in the setting of multidisciplinary approach strategies. METHODS: 63 patients with LAPC and MPC receiving IMRT in our institution were retrospectively identified. Information on patient baseline, treatment characteristics and overall survival (OS) time were collected. Data of pain relief and toxicity were evaluated. Univariate and multivariate analyses were conducted to investigate the prognostic factors. RESULTS: All patients received IMRT with a median dose of 46.0 Gy. The median OS for LAPC and MPC patients were 15.7 months and 8.0 months, respectively (p = 0.029). Symptomatic improvements were observed in the 44 patients with abdominal/back pain after radiotherapy (RT) or concurrent chemoradiotherapy (CCRT), particularly in those with severe pain. Only 13.9% and 14.8% cases presented Grade ≥ 3 hematologic toxicities in RT and CCRT group, while no cases developed Grade ≥ 3 non-hematologic toxicities in both groups. Multivariate analysis indicated that tumors located in pancreas body/tail (HR 0.28, p = 0.008), pretreatment CA19-9 < 1000 U/mL (HR 0.36, p = 0.029) and concurrent chemotherapy (HR 0.37, p = 0.016) were independent favorable predictors for OS. CONCLUSIONS: CCRT further improved OS for LAPC and MPC with acceptable toxicities, and use of RT markedly alleviated pain. Tumors located in pancreas body/tail, pretreatment CA19-9 level of < 1000 U/mL and CCRT were associated with better OS. However, regional intra-arterial chemotherapy did not show any survival benefit in our study.

Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

AIMS: Recent epidemiological studies indicated that use of metformin might decrease the risk of various cancers among patients with type 2 diabetes mellitus (T2DM). However, its influence on pancreatic cancer was controversial. Therefore, we did a meta-analysis of currently available observational studies on the issue. METHODS: We did a PubMed and ISI Web of Science search for observational articles. The pooled relative risk (RR) was estimated using a random-effect model. Heterogeneity was evaluated using I(2) statistic. Subgroup analysis was performed to explore the source of heterogeneity and confirm the overall estimates. Publication bias was also examined. RESULTS: The analysis included 11 articles (13 studies) comprising 10 cohort studies and 3 case-control studies. Use of metformin was associated with a significant lower risk of pancreatic cancer [RR 0.63, 95% confidence internal (CI) 0.46-0.86, p=0.003]. In a total 11 subgroup analyses, 5 provided the consistent result with pooled effect estimates of overall analysis. No publication bias was detected by Begg's (Z=-0.79, p=0.428) and Egger's test (t=-0.92, p=0.378). CONCLUSIONS: From present observational studies, use of metformin appears to be associated with a reduced risk of pancreatic cancer in patients with T2DM. Further investigation is needed.

A novel mutation in the TECTA gene in a Chinese family with autosomal dominant nonsyndromic hearing loss.

TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257-262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.

Expressions of nuclear factor-kappa B p50 and p65 and their significance in the up-regulation of intercellular cell adhesion molecule-1 mRNA in the nasal mucosa of allergic rhinitis patients.

The purpose of the study was to investigate expressions of nuclear factor-kappa B (NF-κB) and intercellular cell adhesion molecule-1 mRNA (ICAM-1 mRNA) in the nasal mucosa of allergic rhinitis (AR) patients. Expressions of NF-κB and ICAM-1 mRNA were studied using immunohistochemistry and reverse transcription-PCR (RT-PCR) in AR tissues and corresponding normal nasal mucosa. The correlation between NF-κB and ICAM-1 mRNA was studied using linear correlation analysis. The results of immunohistochemistry showed that expression of NF-κB was significantly up-regulated in the nasal mucosa of AR compared with that in normal tissue (P < 0.01), over-expression of NF-κB p50 was found in the cytoplasm and nucleus (P < 0.01), and NF-κB p65 was mainly expressed in the cytoplasm (P < 0.01). ICAM-1 mRNA was strongly expressed in the nasal mucosa of AR compared with that in normal tissue as shown by RT-PCR (P < 0.01). Up-regulation of ICAM-1 mRNA was significantly correlated with over-expressions of NF-κB p50 and NF-κB p65 (r = 0.8995, P < 0.01; r = 0.7601, P < 0.01). In conclusion, NF-κB plays a key role in AR. Excessively activated NF-κB promotes the transcription of ICAM-1 mRNA. ICAM-1 is related to the pathogenesis and development of AR.

[Surgical treatment of carotid body tumor: a report of 36 cases].

OBJECTIVE: To study surgical methods and techniques to reduce complications in carotid body tumors (CBT). METHODS: A total of 36 patients with CBT treated by the same surgeon between 2004 and 2012 was reviewed. Clinical presentation, imaging, surgery techniques, postoperative complications and outcomes as well as follow-up evaluations were analyzed. RESULTS: Of 36 patients, 13 males and 23 females, with a median age of 42 years (range 9-61 years). Nineteen patients had a CBT on the left side, 14 on the right side and 3 on both sides. All patients (36 patients with 38 tumors) received surgical treatment. Twenty nine tumors were excised completely. Kudo clamp was used in 6 cases with solid firm tumors and potentially high risks of intracranial complications, with common carotid artery compression exercise before tumor excision. Blood loss in operation were less than 80 ml(n = 17), 100-550 ml(n = 18), 800 ml (n = 1), 1000 ml(n = 1) and 1500 ml(n = 1) respectively. There were more blood loss in cases used embolization (median of 200 ml) than in those without embolization (median of 60 ml) . Post-operative local nerve impairment occurred in 10 patients (26.3%) including persistence of preexisting deficits (n = 8) and newly developed deficits (n = 2). Twenty-seven patients were followed up for 10 month to 6 years with a mean period of 24 months and 9 patients lost of follow-up. One patient with malignant CBT survived with tumor and other 26 patients were alive with no recurrence. CONCLUSIONS: Surgery is the first choice of treatment for CBT. Soft CBT often can be excised completely with preservation of the internal carotid artery (ICA), whereas solid firm CBT encasing the ICA should be evaluated with DSA preoperatively to determine the presence of communicating branches of cerebral vessels, due to the high risk of major vessel compromise. Two-stage operation is often required, in which the ICA is gradually closed following ligation of the external carotid to establish collateral circulation, followed by excision of the tumor and IAC, so that serious intracranial complications can be avoided.

[Diagnosis and treatment of the primary parapharyngeal space tumors].

OBJECTIVE: To study the clinical characteristics, diagnosis and surgical managements of the parapharyngeal space tumors. METHODS: A retrospective study of 40 patients with primary parapharyngeal space tumors treated from January 2006 to December 2008 in Chinese PLA General Hospital was performed. Among the 40 patients, there were male 22 patients, female 18 (45%), age ranged from 1 - 77, median 42 years old. CT scan combined with MRI was helpful to diagnose the parapharyngeal space tumor and make surgical plan. The surgical approaches include: trans-oral in 1 patient, trans-cervical approach in 22, transcervical-parotid approach in 8, vertical ramus osteotomy approach in 1, transcervical-partial bone resection in the angle of mandible in 4, transparotid approach in 2, and transcervical in combination with post auricle craniotomy approach in 2. RESULTS: All 40 patients had undergone surgical treatment. Postoperative histopathology showed benign in 28 patients and malignant in 12 patients. The tumors originating from salivary glands were in 15 patients, neurogenic tumors in 12 patients and tumors originating from other tissues were in 13 patients.Among 28 patients with benign tumors, 23 had been cured with one operation, without recurrence during following-up of 13 - 47 months, with a median of 39 months. Among 12 patients with malignant tumors, 6 patients alive (with following-up of 24 - 50 months and a median of 36 months), 3 patients died in half year after operation and 3 patients lost. The post-operative complication included Cerebrospinal fluid leak in one patient, operative field infection in 2 patients, and vagus nerve injury in 3 patients. CONCLUSIONS: Surgery is the first choice for parapharyngeal space tumors. Transcervical approach alone can apply to most tumors and a broader approach is indicated for malignant or large benign tumors. The prognosis is good for the benign lesions, but poor for the malignant tumors.

Use of combined maximum and minimum intensity projections to determine internal target volume in 4-dimensional CT scans for hepatic malignancies.

BACKGROUND: To evaluate the accuracy of the combined maximum and minimum intensity projection-based internal target volume (ITV) delineation in 4-dimensional (4D) CT scans for liver malignancies. METHODS: 4D CT with synchronized IV contrast data were acquired from 15 liver cancer patients (4 hepatocellular carcinomas; 11 hepatic metastases). We used five approaches to determine ITVs: (1). ITVAllPhases: contouring gross tumor volume (GTV) on each of 10 respiratory phases of 4D CT data set and combining these GTVs; (2). ITV2Phase: contouring GTV on CT of the peak inhale phase (0% phase) and the peak exhale phase (50%) and then combining the two; (3). ITVMIP: contouring GTV on MIP with modifications based on physician's visual verification of contours in each respiratory phase; (4). ITVMinIP: contouring GTV on MinIP with modification by physician; (5). ITV2M: combining ITVMIP and ITVMinIP. ITVAllPhases was taken as the reference ITV, and the metrics used for comparison were: matching index (MI), under- and over-estimated volume (Vunder and Vover). RESULTS: 4D CT images were successfully acquired from 15 patients and tumor margins were clearly discernable in all patients. There were 9 cases of low density and 6, mixed on CT images. After comparisons of metrics, the tool of ITV2M was the most appropriate to contour ITV for liver malignancies with the highest MI of 0.93 ± 0.04 and the lowest proportion of Vunder (0.07 ± 0.04). Moreover, tumor volume, target motion three-dimensionally and ratio of tumor vertical diameter over tumor motion magnitude in cranio-caudal direction did not significantly influence the values of MI and proportion of Vunder. CONCLUSION: The tool of ITV2M is recommended as a reliable method for generating ITVs from 4D CT data sets in liver cancer.

Is involved-field radiotherapy based on CT safe for patients with limited-stage small-cell lung cancer?

PURPOSE: To examine the pattern of failures in patients with limited-stage small-cell lung cancer (LS-SCLC) treated with involved-field radiotherapy (IFRT) and chemotherapy, with the aim of investigating the safety of IFRT. METHODS AND MATERIALS: Two consecutive clinical phase II trials in patients with LS-SCLC conducted in our center from 1997 to 2010 were reviewed retrospectively. Both trials had the same inclusion criteria. All patients (n=108) received combined chemotherapy and thoracic radiotherapy. Only the primary tumor and involved lymphatic regions based on computed tomography (CT) scan were irradiated. Isolated nodal failure (INF) was defined as a failure in an initially uninvolved lymph node region in the absence of local recurrence or distant metastasis. RESULTS: With a median follow-up of 21 months, 78 patients experienced treatment failures. Out of 28 patients with local-regional recurrences, 16 in-field, 10 out-of-field, and 2 both in-field and out-of-field recurrences were observed. INF occurred in 5 patients (4.6%), all in the ipsilateral supraclavicular area. Four patients developed simultaneously supraclavicular nodal failures and distant metastases. The median overall survival was 27 months (95% confidence interval, 24-30 months) and the median progression-free survival was 16 months (95% confidence interval, 12-21 months). For the 5 patients with INF, the median time to INF from the end of thoracic radiotherapy was 5 months (range, 1-18 months). CONCLUSIONS: IFRT based on CT scan in our patients resulted in a low rate of INF (4.6%), all in the ipsilateral supraclavicular area; but another four supraclavicular nodal failures with simultaneously distant metastases were also observed. The modern imaging with higher diagnostic capabilities of lymph node especially for supraclavicular area should be incorporated in the assessment of LS-SCLC when IFRT is being contemplated.

Hepatic proliferation after partial liver irradiation in Sprague-Dawley rats.

The liver has powerful capability to proliferate in response to various injuries, but little is known as to liver proliferation after irradiation (IR) injury. This study investigated whether liver proliferation could be stimulated in low-dose irradiated liver by partial liver IR injury with high dose radiation. Sprague-Dawley rats were irradiated by 6-MV X-ray with single dose of 25 Gy to the right-half liver, while the left-half liver was shielded (0.7 Gy) or irradiated with single doses of 3.2, 5.6, and 8.0 Gy, respectively. Hepatic proliferation in the shielded and low-dose irradiated left-half liver was evaluated by serum hepatic growth factor (HGF), proliferating cell nuclei antigen (PCNA), liver proliferation index (PI), hepatocyte mitosis index (MI). The observation time was 0 day (before IR), 30, 60, 90, and 120 days after IR. Our results showed that serum HGF and hepatocyte HGF mRNA increased after IR with HGF mRNA peak on day 30 in the shielded and low-dose irradiated left-half livers, and their values increased as the dose increased to the left-half liver. Liver PI and PCNA mRNA peaked on day 60 with stronger expressions in higher doses-irradiated livers. MI increased after IR, with the peak noted on day 60 in the shielded and on day 90 in the low-dose irradiated left-half livers. There was a 30 day delay between MI peaks in the shielded and low-dose irradiated livers. In conclusion, 25 Gy partial liver IR injury could stimulate the shielded liver and low-dose irradiated liver to proliferate. In the livers receiving a dose range of 3.2-8.0 Gy, the proliferation was stronger in higher doses-irradiated liver than the low-dose irradiated. However, IR delayed hepatocyte mitosis.

Hepatic regeneration after sublethal partial liver irradiation in cirrhotic rats.

Our previous animal study had demonstrated that partial liver irradiation (IR) could stimulate regeneration in the protected liver, which supported the measurements adopted in radiotherapy planning for hepatocellular carcinoma. The purpose of this present study is to investigate whether cirrhotic liver repopulation could be triggered by partial liver IR. The cirrhosis was induced by thioacetamide (TAA) in rats. After cirrhosis establishment, TAA was withdrawn. In Experiment 1, only right-half liver was irradiated with single doses of 5 Gy, 10 Gy and 15 Gy, respectively. In Experiment 2, right-half liver was irradiated to 15 Gy, and the left-half to 2.5 Gy, 5 Gy and 7.5 Gy, respectively. The regeneration endpoints, including liver index (LI); mitotic index (MI); liver proliferation index (LPI); PCNA-labeling index (PCNA-LI); serum HGF, VEGF, TGF-α and IL-6, were evaluated on 0 day, 30-day, 60-day, 90-day, 120-day and 150-day after IR. Serum and in situ TGF-ß1 were also measured. In both experimental groups, the IR injuries were sublethal, inducing no more than 9% animal deaths. Upon TAA withdrawal, hepatic regeneration decelerated in the controls. In Experiment 1 except for LI, all other regeneration parameters were significantly higher than those in controls for both right-half and left-half livers. In Experiment 2 all regeneration parameters were also higher compared with those in controls for both half livers. Serum HGF and VEGF were increased compared with that of controls. Both unirradiated and low dose-irradiated cirrhotic liver were able to regenerate triggered by sublethal partial liver IR and higher doses and IR to both halves liver triggered a more enhanced regeneration.

The effect of bioequivalent radiation dose on survival of patients with limited-stage small-cell lung cancer.

BACKGROUND: To investigate the biological radiation dose-response for patients of limited-stage small-cell lung cancer (LS-SCLC) treated with high radiation dose. METHODS: Two hundred and five patients of LS-SCLC treated with sequential chemotherapy and thoracic radiotherapy with involved-field between 1997 and 2006 were reviewed retrospectively. Biologically effective dose (BED) was calculated for dose homogenization and was corrected with the factor of overall radiation time. Patients were divided into low BED group (n = 70) and high BED group (n = 135) with a cut-off of BED 57 Gy (equivalent to 60 Gy in 30 fractions over 40 days). Outcomes of the two groups were compared. RESULTS: Median follow-up was 20.7 months for all analyzable patients and 50.8 months for surviving patients. Considering all patients, median survival was 22.9 months (95% confidence interval, 20.6-25.2 months); 2- and 5-year survival rates were 47.2% and 22.3%, respectively. Patients in high BED group had a significantly better local control (p = 0.024), progression-free survival (p = 0.006) and overall survival (p = 0.005), with a trend toward improved distant-metastasis free survival (p = 0.196). Multivariable Cox regression demonstrated that age (p = 0.003), KPS (p = 0.009), weight loss (p = 0.023), and BED (p = 0.004) were significant predictors of overall survival. CONCLUSIONS: Our data showed that a high BED was significantly associated with favourable outcomes in the Chinese LS-SCLC population, indicating that a positive BED-response relationship still existed even in a relatively high radiation dose range.

A natural process of cirrhosis resolution and deceleration of liver regeneration after thioacetamide withdrawal in a rat model.

Characteristics of thioacetamide (TAA)-induced liver cirrhosis in rat was observed for 120 days after TAA withdrawal as part of the radiobiological study of partial liver irradiation on TAA-induced cirrhotic rats. The natural process focused on cirrhosis and regeneration was recorded as a baseline condition for the interpretation of the outcome of the partial liver irradiation study. Cirrhosis in rats was successfully induced by drinking 0.03% TAA water orally for 29 weeks with a modeling rate of 96%. After establishment of the cirrhosis model, the rats were observed for 120 days upon TAA withdrawal to investigate the dynamic changes of cirrhosis and regeneration. The following characteristics were observed: (1) Histological changes; (2) Liver functions; (3) Cirrhosis: trichrome stain, quantification of hydroxyproline in hydrolysed liver tissue and TGF-ß1; (4) Liver regeneration: liver index, hepatocyte mitotic index (MI), hepatocyte proliferation index (PI) by flow cytometry, PCNA labeling index (LI) by IHC and expression of PCNA mRNA; and (5) Growth factors: serum HGF, VEGF, TGF-α, and IL-6. After TAA withdrawal, gradual improvement in liver functions was noted with decreases of ALT, AST, and ALP, and increase of PA. The resolution of cirrhosis was evident by histological improvement with attenuation of collagen fiber and decrease of TGF-ß1 IHC index, and also decrease of trichrome stain and hydroxyproline content. However, cirrhosis was still existed on 120 days after TAA withdrawal. Significant deceleration of liver regeneration was demonstrated with TAA withdrawal, evidenced by decrease of MI and PI, reduced expression of PCNA mRNA and PCNA LI. In conclusion, upon TAA withdrawal hepatic cirrhosis was continuously resolved, but persisted up to 120 days, and liver regeneration was significantly decelerated.

Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma: an irradiation dose escalation study.

PURPOSE: To determine the maximum tolerated dose (MTD) of three-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT) combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma. METHODS AND MATERIALS: Patients were assigned to two subgroups based on tumor diameter: Group 1 had tumors <10 cm; Group II had tumors ≥10 cm. Escalation was achieved by increments of 4.0 Gy for each cohort in both groups. Dose-limiting toxicity (DLT) was defined as a grade of ≥3 acute liver or gastrointestinal toxicity or any grade 5 acute toxicity in other organs at risk or radiation-induced liver disease. The dose escalation would be terminated when ≥2 of 8 patients in a cohort experienced DLT. RESULTS: From April 2005 to May 2008, 40 patients were enrolled. In Group I, 11 patients had grade ≤2 acute treatment-related toxicities, and no patient experienced DLT; and in Group II, 10 patients had grade ≤2 acute toxicity, and 1 patient in the group receiving 52 Gy developed radiation-induced liver disease. MTD was 62 Gy for Group I and 52 Gy for Group II. In-field progression-free and local progression-free rates were 100% and 69% at 1 year, and 93% and 44% at 2 years, respectively. Distant metastasis rates were 6% at 1 year and 15% at 2 years. Overall survival rates for 1-year and 2-years were 72% and 62%, respectively. CONCLUSIONS: The irradiation dose was safely escalated in hepatocellular carcinoma patients by using 3DCRT/IMRT with an active breathing coordinator. MTD was 62 Gy and 52 Gy for patients with tumor diameters of <10 cm and ≥10 cm, respectively.

Maintenance of Sorafenib following combined therapy of three-dimensional conformal radiation therapy/intensity-modulated radiation therapy and transcatheter arterial chemoembolization in patients with locally advanced hepatocellular carcinoma: a phase I/II study.

BACKGROUND: Three-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT) combined with or without transcatheter arterial chemoembolization (TACE) for locally advanced hepatocellular carcinoma (HCC) has shown favorable outcomes in local control and survival of locally advanced HCC. However, intra-hepatic spreading and metastasis are still the predominant treatment failure patterns. Sorafenib is a multikinase inhibitor with effects against tumor proliferation and angiogenesis. Maintenance Sorafenib would probably prevent or delay the intrahepatic and extrahepatic spread of HCC after radiotherapy, which provides the rationale for the combination of these treatment modalities. METHODS AND DESIGN: Patients with solitary lesion (bigger than 5 cm in diameter) histologically or cytologically confirmed HCC receive TACE (1-3 cycles) plus 3DCRT/IMRT 4-6 weeks later. Maintenance Sorafenib will be administered only for the patients with non-progression disease 4 to 6 weeks after the completion of radiotherapy. The dose will be 400 mg, p.o., twice a day. Sorafenib will be continuously given for 12 months unless intolerable toxicities and/or tumor progression. If no more than 3 patients discontinue Sorafenib treatment who experience dose-limiting toxicity after necessary dose modification and delay and/or radiation-induced liver disease in the first 15 enrolled patients, the study will recruit second fifteen patients for further evaluating safety and efficacy of treatment. Hypothesis of the current study is that Sorafenib as a maintenance therapy after combined therapy of 3DCRT/IMRT and TACE is safe and superior to radiotherapy combined with TACE alone in terms of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) in comparison to historical data. DISCUSSION: A recent meta-analysis showed TACE in combination with radiotherapy, improved the survival and the tumor response of patients, and was thus more therapeutically beneficial. In this study, local therapy for HCC is the combination of TACE and radiotherapy. Radiation exposure as a kind of stress might induce the compensatory activations of multiple intracellular signaling pathway mediators, such as PI3K, MAPK, JNK and NF-kB. Vascular endothelial growth factor (VEGF) was identified as one factor that was increased in a time- and dose-dependent manner after sublethal irradiation of HCC cells in vitro, translating to enhanced intratumor angiogenesis in vivo. Therefore, Sorafenib-mediated blockade of the Raf/MAPK and VEGFR pathways might enhance the efficacy of radiation, when Sorafenib is followed sequentially as a maintenance modality. (ClinicalTrials.gov number, NCT00999843.).

Hepatocyte regeneration after partial liver irradiation in rats.

Liver has a strong potential for regeneration after physical, biological or chemical injury, but no data have been reported so far on liver regeneration in response to irradiation injury. The present experiment in rats was designed to clarify whether partial liver irradiation could induce and stimulate the unirradiated part of liver to regenerate. The left-half of rat liver was irradiated with a single dose of 25Gy. Liver tissues from the irradiated and unirradiated liver, and blood sample were collected at different time points after irradiation. Radiation injury was evaluated by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, histopathologic features and trichrome stain. The hepatic regeneration was assessed by serum hepatic growth factor (HGF), mitotic index and proliferation cell nuclear antigen (PCNA) immunohistochemical stain. Expression of transforming growth factor-beta1 (TGF-beta1) by immunohistochemistry assay was also performed. Results showed that 25Gy of single-dose irradiation produced severe hepatic injury in the irradiated liver, and the unirradiated liver had been stimulated to regenerate, demonstrated by significant increases of serum HGF 30 days after irradiation, and increase of mitotic index and the number of PCNA-positive hepatocytes 60 days after irradiation. TGF-beta1 was strongly and uniformly expressed in the irradiated liver 90-day-post-irradiation, and it was also expressed slightly in unirradiated liver region. In summary, partial liver irradiation could stimulate the unirradiated liver to regenerate, and the role of TGF-beta1 in hepatic injury and proliferation needs further investigation.

Application of active breathing control in 3-dimensional conformal radiation therapy for hepatocellular carcinoma: the feasibility and benefit.

BACKGROUND AND PURPOSE: To investigate the feasibility and effectiveness of utilizing active breathing coordinator (ABC) in 3DCRT for HCC. MATERIALS AND METHODS: A dosimetric comparison between the free-breathing (FB) plan and ABC plan in HCC 3DCRT was performed. Set-up errors and reproducibility of diaphragm position using ABC were measured, and patients' acceptance was also recorded. RESULTS: From April 2005 to February 2007, 28 HCC were irradiated with ABC and they tolerated ABC well. The mean dose to normal liver was reduced from 16.9Gy in FB plan to 14.3Gy in ABC plan. PTV for ABC and FB plans were 529cm(3) and 781cm(3), respectively, and V(23) were reduced from 45% to 30%. The predicted incidences of radiation-induced liver disease by Lyman model were 1% and 2.5%, respectively, in favor of ABC plan. The systematic and random errors for the ABC and FB plans were 1.2mm vs. 4.7mm, 1.6mm vs. 3.5mm, and 1.8mm vs. 2.7mm, respectively, in cranio-caudal, anterior-posterior, and left-right directions. The average intrafraction reproducibility of diaphragm position in cranio-caudal direction was 1.6mm, and the interfraction, 6.7mm. CONCLUSIONS: The utilization of ABC in HCC 3DCRT is feasible, and can reduce liver irradiation.