Large cell/anaplastic medulloblastoma is associated with poor prognosis-a retrospective analysis at a single institute.

PURPOSE: Medulloblastoma (MB) is the most commonly occurring malignant pediatric brain tumor worldwide. However, a recent study found that the treatment outcomes in those with high-risk disease receiving conventional treatment were suboptimal. This study aimed to assess outcomes and treatment strategies for specific histologic subtypes of pediatric MB. METHODS: A total of 114 pediatric patients (age < 20 years) diagnosed with MB between March 1998 and August 2011 were retrospectively reviewed; 52 that were treated with surgery followed by adjuvant radiotherapy (RT) and chemotherapy (CHT) were included. RESULTS: The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 73 and 69%, respectively. Median time to relapse was 17 months with a median survival time of 6 months after relapse. Patients of average risk had a better 5-year OS rate compared with high-risk patients (p = 0.027). The 5-year RFS of high-risk patients was lower compared with average risk (p = 0.038). A greater proportion of patients with large cell/anaplastic (LC/A) MB had recurrence than classic MB with 5-year RFS rate of 34 and 76%, respectively (p = 0.001), and OS rate of 56 and 76%, respectively (p = 0.04). CONCLUSION: High-risk group and histology of LC/A were the most significant factors associated with worse OS and RFS. Patients with LC/A-MB had higher relapse rates and worse survival than those with classic MB. LC/A-MB carries a high risk for recurrence and should be treated with the more aggressive strategies.

Targeted antitumor prodrug therapy using CNGRC-yCD fusion protein in combination with 5-fluorocytosine.

BACKGROUND: The enzyme-prodrug system is considered a promising tool for tumor treatment when conjugated with a targeting molecule. The asparagine-glycine-arginine (NGR) motif is a developing and interesting targeting peptide that could specifically bind to aminopeptidase N (APN), which is an NGR receptor expressed on the cell membrane of angiogenic endothelial cells and a number of tumor cells within the tumor tissues. The objective of this study was to develop a novel targeted enzyme-prodrug system using 5-fluorocytosine (5-FC) and an NGR-containing peptide fused with yeast cytosine deaminase (yCD), i.e. CNGRC-yCD fusion protein, to target APN-expressing cells within the tumor tissues and to convert 5-FC into 5-fluorouracil (5-FU) to kill tumors. RESULTS: Both yCD and CNGRC-yCD proteins were cloned into the pET28a vector and expressed by an Escherichia coli host. Both yCD and CNGRC-yCD proteins were purified and the yields were approximately 20 mg/L with over 95 % purity. The binding assay demonstrated that the CNGRC-yCD fusion protein had specific binding affinity toward purified APN recombinant protein and high-APN-expressing cells, including human endothelial cells (HUVECs) and various types of human tumor cell lines, but not low-APN-expressing tumor cell lines. Moreover, the enzyme activity and cell viability assay showed that the CNGRC-yCD fusion protein could effectively convert 5-FC into 5-FU and resulted in significant cell death in both high-APN-expressing tumor cells and HUVECs. CONCLUSIONS: This study successfully constructs a new targeting enzyme-prodrug system, CNGRC-yCD fusion protein/5-FC. Systematic experiments demonstrated that the CNGRC-yCD protein retained both the APN-binding affinity of NGR and the enzyme activity of yCD to convert 5-FC into 5-FU. The combined treatment of the CNGRC-yCD protein with 5-FC resulted in the significantly increased cell death of high-APN-expressing cells as compared to that of low-APN-expressing cells.

Radiotherapy-related intracranial aneurysm: case presentation of a 17-year male and a meta-analysis based on individual patient data.

PURPOSE: The aim of this study was to investigate the incidence, clinical profiles, latency, and outcomes of radiotherapy (RT)-related intracranial aneurysms, rare but often fatal complications of cranial irradiation. METHODS: We reviewed all published individual patient data regardless of language, using survival analysis to make statistical inferences. RESULTS: We examined a total of 58 patients with RT-related intracranial aneurysms, including one unpublished case presented here, of whom 74.1 % presented with rupture. In the study, 29.3 % were younger than 18 years. The mean age at which patients received the first course of RT was 34.8 ± 22.8 years old. The mean latency between initiating RT and presenting with aneurysm was 10.4 ± 8.5 years. Rapid death ensured in 24 % shortly after presentation. The only significant predictor of death was rupture. In those with a single aneurysm, 43.1 % were located at the internal carotid artery, while 15.5 % of patients had multiple aneurysms. A male-to-female ratio of 1.87, 0.5, and 1.32 was found in patients younger than age 52, 52 years of age or older, and all 58 patients, respectively. Older age when receiving RT and presentation with ruptured aneurysm were significantly associated with shorter latency. CONCLUSIONS: RT-related intracranial aneurysms presented differently from classical ones based on age, sex, site, multiplicity, and type. Sex ratios differed with age. The younger age group showed a longer latency of occurrence of an aneurysm. Older patients and those who develop ruptured aneurysms presented earlier. Since rupture may affect outcome, early detection of aneurysms before rupture may save lives.

Clinical considerations and surgical approaches for low-grade gliomas in deep hemispheric locations: thalamic lesions.

BACKGROUND: Tumors with epicenter in the thalamus occur in about 4 % of pediatric brain tumors. The histological diagnosis is mainly gliomas. Among them, low-grade glioma (LGG) constituted of a significant entity of the tumors (Cuccia et al., Childs Nerv Syst 13:514-521, 1997; Puget et al., J Neurosurg 106:354-362, 2007; Bernstein et al., J Neurosurg 61:649-656, 1984; Bilginer et al., Childs Nerv Syst 30:1493-1498, 2014). Since Kelly's report in 1989, >90 % resection of thalamic tumors were achieved in reported series (Ozek and Ture, Childs Nerv Syst 18:450-6, 2002; Villarejo et al., Childs Nerv Syst 10:111-114, 1994; Moshel et al., Neurosurgery 61:66-75, 2007; Albright, J Neurosurg 100(5 Suppl Pediatrics): 468-472, 2004; Kelly, Neurosurgery 25:185-195, 1989; Drake et al., Neurosurgery 29: 27-33, 1991). MATERIALS AND METHODS: Sixty-nine cases of thalamic tumors in children were retrospectively reviewed. There were 25 cases of LGGs. We analyzed our experience and correlated it with reported series. RESULTS: Summing up of 4 reported series and the present series, there were 267 cases of thalamic tumors in children. Among these tumors, 107 (40.1 %) were LGGs and 91 (34.1 %) were low-grade astrocytomas (LGAs). In the present series, all of the 25 LGGs were LGAs that consisted of 11 pilocytic astrocytomas (PAs) and 14 diffuse astrocytomas (DAs). Six cases received biopsy sampling only. The remaining 19 cases received different degrees of surgical resection via several approaches. Radical (>90 %) resection was achieved better in PAs comparing with DAs. There was no operative mortality. Two patients had increased neurological deficits. In a mean follow-up period of 11.9 years, three patients died of tumor progression and one patient died of anaplastic change. The 5- and 10-year overall survival (OS) was 87.1 and 87.1 %, respectively. CONCLUSION: Thalamic LGGs are mainly LGAs and are indolent. The rate of >90 % resection was relatively low in the present series. By applying contemporary diagnostic MRI studies, surgical facilities, and appropriate approaches in selective cases, we may try maximum neuroprotective radical (>90 %) resection.

Development and Characterization of the Recombinant Human VEGF-EGF Dual-Targeting Fusion Protein as a Drug Delivery System.

The design, preparation, as well as structural and functional characterizations of the recombinant fusion protein hVEGF-EGF as a dual-functional agent that may target both EGFR (R: receptor) and angiogenesis are reported. hVEGF-EGF was found to bind to EGFR more strongly than did EGF, and to bind to VEGFR similarly to VEGF. Mass spectrometry measurements showed that the sites of DTPA (diethylenetriaminepentaacetic acid) conjugated hVEGF-EGF (for radiolabeling) were the same as those of its parent hEGF and hVEGF proteins. All DTPA-conjugated proteins retained similar binding capacities to their respective receptors as compared to their respective parent proteins. In vitro cell binding studies using BAEC (a bovine aortic endothelial cell) and MDA-MB-231 (a human breast cancer) cells expressing both EGFR and VEGFR confirmed similar results. Treating BAEC cells with hVEGF-EGF induced remarkable phosphorylation of EGFR, VEGFR, and their downstream targets ERK1/2. Nevertheless, the radiolabeled (111)In-DTPA-hVEGF-EGF showed cytotoxicity against MDA-MB-231 cells. Pharmacokinetic studies using (111)In-DTPA-hVEGF-EGF in BALB/c nude mice showed that appreciable tracer activities were accumulated in liver and spleen. In all, this study demonstrated that the fusion protein hVEGF-EGF maintained the biological specificity toward both EGFR and VEGFR and may be a potential candidate as a dual-targeting moiety in developing anticancer drugs.

Treatment results and prognostic factors for intracranial nongerminomatous germ cell tumors: single institute experience.

PURPOSE: This study aimed to evaluate the treatment of intracranial nongerminomatous germ cell tumors (NGGCT) and to identify the prognostic factors for survival. METHODS: Thirty-nine patients with nondisseminated NGGCTs, excluding those with pure mature teratomas, were treated between January 1985 and December 2010. Twenty-four patients received gross total or partial removal, 11 had excision biopsies, and 4 had no surgery. Radiotherapy was given postoperatively or definitively with a median tumor bed dose of 54 Gy (range 30-54) with or without craniospinal irradiation. All patients received ten cycles of adjuvant chemotherapy, vinblastine, bleomycin, etoposide, and cisplatin after radiotherapy, except for one with mixed anaplastic astrocytoma component who received oral temozolomide. Survival and prognostic factors were estimated by the Kaplan-Meier method and log-rank tests, respectively. RESULTS: After a median follow-up of 77.7 months (range 14-336), the 6-year overall survival (OS) and progression-free survival (PFS) were 74.4 and 79.5 %, respectively. Inferior PFS was associated with lesions in the suprasellar region (p = 0.017), poor pathological features (p = 0.048), and with poor image (p < 0.0001) and tumor marker (TM) response (p = 0.003) to irradiation. Decreased OS was associated with lesions in the suprasellar region (p = 0.026) and with poor image (p < 0.0001) and TM response (p = 0.027) to irradiation. Neither the extent of surgery nor the radiation field was found to significantly influence survival. CONCLUSIONS: By our multimodality approach, patients achieved comparable outcomes. Other than poor pathological features, patients with poor responses to radiotherapy are prone to early recurrence and inferior survival. These patients should be focused for more intensive adjuvant treatment.

Factors affecting survival of medulloblastoma in children: the changing concept of management.

Medulloblastoma (MB) is a type of malignant tumor arising only in the cerebellum that was first defined by Cushing and Bailey in 1920s. In this review paper, we trace the evolution of risk stratification and the correlated changing concept of management in the past years. Outcome analysis of the hospital series of the Taipei Veterans General Hospital, Cheng Hsin General Hospital, and Taipei Medical University Hospital was performed to correlate prognostic indicators with reported studies. The purpose is to provide clues for age-specific and risk-adjusted optimal, effective, but beneficial and protective treatment strategies of these tumors in children.

External beam radiation therapy with or without concurrent chemotherapy for patients with unresectable locally advanced hilar cholangiocarcinoma.

BACKGROUND/AIMS: To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) compared to radiotherapy (RT) for unresectable, locally advanced hilar cholangiocarcinoma (HCCA). METHODOLOGY: Between 2001 and 2010, 34 patients with unresectable locally advanced HCCA at our institute were reviewed. Eighteen patients received RT and 16 patients received CCRT. Survivals and multivariate analyses were performed to explore potential variables affecting survivals. RESULTS: There were 18 males and 16 females, with a median age of 72 years and median follow-up time 9.4 months. The median overall survival (OS) was 10.4 months (95% CI, 6.7-13.5) with the 1-year survival rates of 41%. The median OS and progression-free survival (PFS) were 13.5 months and 8.8 months for patients receiving CCRT as compared to 6.7 months and 4.4 months for patients receiving RT alone (p = 0.003 and p = 0.005, respectively). On multivariate analysis demonstrated that Karnofsky performance status (KPS) ≥ 80 (p = 0.001), pretreatment carbohydrate antigen 19-9 (CA 19-9) 200 U/ml (p = 0.045) and CCRT were prognostic factors for OS and PFS. CONCLUSIONS: As compared with RT, CCRT provides longer OS and PFS for patients with unresectable HCCA. The efficacy of adding novel chemotherapeutic to RT needs to be further investigated.

Feasibility estimation of injected hydrodissection before definitive radiotherapy of pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma is often not diagnosed until an advanced stage, and so most patients are not eligible for resection. For patients who are inoperable, definitive radiotherapy is crucial for local disease control. However, the pancreas is located close to other vulnerable gastrointestinal organs, making it challenging to deliver an adequate radiation dose. The surgical insertion of spacers or injection of fluids such as hydrogel before radiotherapy has been proposed, however, no study has discussed which patients are suitable for the procedure. METHODS: In this study, we reviewed 50 consecutive patients who received definitive radiotherapy at our institute to determine how many could have benefitted from hydrodissection to separate the pancreatic tumor from the adjacent gastrointestinal tract. By hypothetically injecting a substance using either computed tomography (CT)-guided or endoscopic methods, we aimed to increase the distance between the pancreatic tumor and surrounding hollow organs, as this would reduce the radiation dose delivered to the organs at risk. RESULTS: An interventional radiologist considered that hydrodissection was feasible in 23 (46%) patients with a CT-guided injection, while a gastroenterologist considered that hydrodissection was feasible in 31 (62%) patients with an endoscopic injection. Overall, we found 14 (28%) discrepancies among the 50 patients reviewed. Except for 1 patient who had no available trajectory with a CT-guided approach but in whom hydrodissection was considered feasible with an endoscopic injection, the other 13 patients had different interpretations of whether direct invasion was present in the CT images. CONCLUSION: Our results suggested that about half of the patients could have benefited from hydrodissection before radiotherapy. This finding could allow for a higher radiation dose and potentially better disease control.

A DNA vaccine against cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) prevents tumor growth.

Co-stimulatory signaling pathway triggered by the binding of B7.1/B7.2 (CD80/86) of antigen-presenting cells (APCs) to CD28 of T cells is required for optimal T-cell activation. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2 binding with a greater affinity. Ipilimumab, a monoclonal antibody against CTLA-4, has shown positive efficacy in a pivotal clinical trial for the treatment of metastatic melanoma and was approved by FDA. However, the cost of monoclonal antibody-based therapeutics might limit the number of patients treated. To develop a novel therapeutics specifically targeting CTLA-4, we constructed a DNA vaccine by cloning the sequence of CTLA-4 fused with a transmembrane domain sequence of placental alkaline phosphatase (PLAP) into a mammalian expression plasmid, pVAC-1. Immunization with the resulting construct, pVAC-1-hCTLA-4, elicited antibody specific to human CTLA-4 with cross reactivity to murine CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4 could break tolerance to self-antigen in BALB/c mice and induce potent immunity against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma (Renca).

Efficacy of therapeutic play for pediatric brain tumor patients during external beam radiotherapy.

OBJECTIVE: External beam radiotherapy (EBRT) is frequently used to improve disease control for pediatric brain tumor patients. However, to facilitate the radiotherapy (RT) procedure, "forced" type interventions including conscious sedation or general anesthesia are frequently used to manage patients' fear and anxiety. The aim of this study was to investigate the effects of therapeutic play (TP) in reducing anxiety for pediatric brain tumor patients treated by EBRT. METHODS: Between April 1st and September 30th, 2009, 19 young brain tumor patients, aged 3-15 years and recommended for RT, were recruited: ten to a control group and nine to the study intervention group. The study group was introduced with TP during EBRT. The Beck Youth Anxiety Inventory and the Faces Anxiety Scale were used to evaluate patients' psychological levels of anxiety. The heart rate variability and salivary cortisol concentrations were used to indicate the patients' physical levels of anxiety. Both the psychological and physiological tests were administered to all subjects before and after the RT procedure. RESULTS: The study group had significantly lower anxiety scores and expressed fewer negative emotions than did the control group before EBRT. CONCLUSIONS: TP can not only improve the quality of medical services but can also reduce costs and staffing demands. In addition, it can help lower young patients' anxiety and fear during medical procedures. As a result, it further decreases the potential negative impacts of hospitalization on these young patients.

Combined modality therapy for patients with esophageal squamous cell carcinoma: Radiation dose and survival analyses.

BACKGROUND: We aimed to analyze the radiation dose and compare survival among combined modality therapy using modern radiation techniques for patients with esophageal squamous cell carcinoma (ESCC). METHODS: This retrospective study included patients with clinically staged T1-4N0-3M0 ESCC from 2014 to 2018. Patients who received combined modality therapies with curative intent were enrolled. The overall survival (OS) rates among combined modality therapy were compared. The clinical variables and impacts of radiation dose on survival were analyzed by the Kaplan-Meier method and Cox regression model. RESULTS: Of the 259 patients, 141 (54.4%) received definitive concurrent chemoradiotherapy (DCCRT); 67 (25.9%) underwent neoadjuvant chemoradiotherapy followed by surgery (NCRT+S); 51 (19.7%) obtained surgery followed by adjuvant chemoradiotherapy (S+ACRT). Two-year OS rates of the DCCRT, NCRT+S and S+ACRT group were 48.9, 61.5 and 51.2%. In the subgroup analysis of DCCRT group, the 2-year OS of patients receiving radiation dose 55-60 Gy was 57.1%. Multivariate analyses showed that clinical stage (p = 0.004), DCCRT with 55-60 Gy (p = 0.043) and NCRT+S with pathological complete response (pCR) (p = 0.014) were significant prognostic factors for better OS. The radiation dose-survival curve demonstrated a highly positive correlation between higher radiation dose and better survival. CONCLUSION: Our results suggest that NCRT+S can provide a favorable survival for patients with ESCC, especially in patients who achieved pCR. The optimal radiation dose might be 55-60 Gy for patients receiving DCCRT via modern radiation techniques. Further randomized clinical studies are required to confirm the survival benefits between NCRT+S and DCCRT with escalated dose.

Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

BACKGROUND: This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). METHODS: BNCT was administered using an intravenous boronophenylalanine-fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. RESULTS: This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. CONCLUSION: Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

Personalized cancer avatars for patients with thymic malignancies: A pilot study with circulating tumor cell-derived organoids.

BACKGROUND: Systemic therapy is the primary treatment for advanced thymic malignancies. However, there is an urgent need to improve clinical outcome. Personalized treatment based on predictive biomarkers is a potential approach to address this requirement. In this study, we aimed to show the correlation between drug sensitivity tests on CTCs-derived organoids and clinical response in patients with thymic malignancies. This approach carries the potential to create personalized cancer avatars and improve treatment outcome for patients. METHODS: We previously reported potential treatment outcome prediction with patient-derived organoids (cancer avatars) in patients with pancreatic ductal adenocarcinoma. To further investigate the feasibility of this approach in advanced thymic malignancies, we conducted a study in which 12 patients were enrolled and 21 liquid biopsies were performed. RESULTS: Cancer avatars were successfully derived in 16 out of 21 samples (success rate 76.2%). We found a sensitivity of 1.0 and specificity of 0.6 for drug sensitivity tests on the cancer avatars, and a two-tailed Fisher's exact test revealed a significant correlation between drug sensitivity tests and clinical responses (p = 0.0275). CONCLUSION: This study supports the potential of circulating tumor cell-derived organoids to inform personalized treatment for advanced thymic malignancies. Further validation of this proof of concept finding is ongoing.

Old age and EGFR mutation status in inoperable early-stage non-small cell lung cancer patients receiving stereotactic ablative radiotherapy: A single institute experience of 71 patients in Taiwan.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is now the standard of care for patients with inoperable early-stage lung cancer. Many of these patients are elderly. EGFR (epidermal growth factor receptor) mutation is also common in the Asian population. METHODS: To evaluate the effects of old age and EGFR mutation on treatment outcomes and toxicity, we reviewed the medical records of 71 consecutive patients with inoperable early-stage non-small cell lung cancer (NSCLC) who received SABR at Taipei Veterans General Hospital between 2015 and 2021. RESULTS: The study revealed that median age, follow-up, Charlson comorbidity index, and ECOG score were 80 years, 2.48 years, 3, and 1, respectively. Of these patients, 37 (52.1%) were 80 years or older, and 50 (70.4%) and 21 (29.6%) had T1 and T2 diseases, respectively. EGFR mutation status was available for 33 (46.5%) patients, of whom 16 (51.5%) had a mutation. The overall survival rates at 1, 3, and 5 years were 97.2, 74.9, and 58.3%, respectively. The local control rate at 1, 3, and 5 years was 97.1, 92.5, and 92.5%, respectively. Using Cox proportional hazards regression we found that male sex was a risk factor for overall survival (p = 0.036, 95% CI: 1.118-26.188). Two patients had grade 2 pneumonitis, but no other grade 2 or higher toxicity was observed. We did not find any significant differences in treatment outcomes or toxicity between patients aged 80 or older and those with EGFR mutations in this cohort. CONCLUSION: These findings indicate that age and EGFR mutation status do not significantly affect the effectiveness or toxicity of SABR for patients with inoperable early-stage NSCLC.

Change in treatment strategy for intracranial germinoma: long-term follow-up experience at a single institute.

BACKGROUND: Previous intracranial germinoma (IG) studies have investigated the effect of different radiotherapy (RT) volumes and the necessity for adjunctive chemotherapy, but there is currently no consensus on the best treatment for this tumor. METHODS: From January 1989 to December 2009, 80 IG patients (≤20 years old) were treated with various RT regimens. Of them, 14 patients had craniospinal irradiation (CSI) + primary boost (PB); 8 patients had whole-brain irradiation (WBI) + PB; 31 patients had whole ventricular irradiation (WVI) + PB; and 27 patients had focal RT only. Twenty-nine patients (36.2%) also received systemic chemotherapy (CHT). Survival was estimated by the Kaplan-Meier method and variables affecting survival were analyzed by the Cox proportional hazard model. RESULTS: Eleven patients (13.8%) developed local recurrence or dissemination after treatment, and 10 of these patients were in the focal RT group. The 5-year relapse-free survival (RFS) for the CSI, WBI, WVI, and focal RT patients were 100%, 85.7%, 100%, and 84.6%, respectively (P = .001). The 5-year overall survival (OS) for CSI, WBI, WVI, and focal RT patients was 100%, 83.3%, 100%, and 87.9%, respectively (P = .125). Focal irradiation (P = .02) and initial use of CHT (P = .021) were negatively associated with RFS. CONCLUSIONS: Focal RT plus CHT were associated with inferior control of IG and a higher incidence of CHT-related toxicities. Adjustment of the radiation volume to the whole ventricular system without CHT is sufficient for treatment of nondisseminated IGs, even with lower primary RT doses (<36 Gy).

5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells.

Human epithelial cancers account for approximately 50% of all cancer deaths. This type of cancer is characterized by excessive activation and expression of the epidermal growth factor receptor (EGFR). The EGFR pathway is critical for cancer cell proliferation, survival, metastasis and angiogenesis. The EGF-EGFR signaling pathway has been validated as an important anticancer drug target. Increasing numbers of targeted therapies against this pathway have been either approved or are currently under development. Here, we adopted a prodrug system that uses 5-fluorocytosine (5-FC) and human EGF (hEGF) fused with yeast cytosine deaminase (Fcy) to target EGFR-overexpressing cancer cells and to convert 5-FC to a significantly more toxic chemotherapeutic, 5-fluorouracil (5-FU). We cloned and purified the Fcy-hEGF fusion protein from Pichia pastoris yeast. This fusion protein specifically binds to EGFR with a similar affinity as hEGF, approximately 10 nM. Fcy-hEGF binds tightly to A431 and MDA-MB-468 cells, which overexpress EGFR, but it binds with a lower affinity to MDA-MB-231 and MCF-7, which express lower levels of EGFR. Similarly, the viability of EGFR-expressing cells was suppressed by Fcy-hEGF in the presence of increasing concentrations of 5-FC, and the IC(50) values for A431 and MDA-MB-468 were approximately 10-fold lower than those of MDA-MB-231 and MCF-7. This novel prodrug system, Fcy-hEGF/5-FC, might represent a promising addition to the available class of inhibitors that specifically target EGFR-expressing cancers.

Multiple effects of Honokiol on the life cycle of hepatitis C virus.

BACKGROUND: Honokiol, a small active molecular compound extracted from magnolia, has recently been shown to inhibit hepatitis C virus (HCV) infection in vitro. AIMS: This study further characterized aspects of the HCV lifecycle affected by the antiviral functions of honokiol. METHODS: The influence of honokiol on HCV infection, entry, translation and replication was assessed in Huh-7.5.1 cells using cell culture-derived HCV (HCVcc), HCV pseudo-type (HCVpp) and sub-genomic replicons. RESULTS: Honokiol had strong antiviral effect against HCVcc infection at non-toxic concentrations. Combined with interferon-α, its inhibitory effect on HCVcc was more profound than that of ribavirin. Honokiol inhibited the cell entry of lentiviral particles pseudo-typed with glycoproteins from HCV genotypes 1a, 1b, and 2a, but not of the vesicular stomatitis virus. It had inefficient activity on HCV internal ribosome entry site (IRES)-translation at concentrations with significant anti-HCVcc effects. The expression levels of components of replication complex, NS3, NS5A and NS5B, were down-regulated by honokiol in a dose-dependent manner. It also inhibited HCV replication dose dependently in both genotypes 1b and 2a sub-genomic replicons. CONCLUSIONS: Honokiol inhibits HCV infection by targeting cell entry and replication and, only at a concentration >30 µM, IRES-mediated translation of HCV life cycle. Based on its high therapeutic index (LD(50) /EC(90)  = 5.4), honokiol may be a promising drug for the treatment of HCV infection.

Boron neutron capture therapy for glioblastoma multiforme: enhanced drug delivery and antitumor effect following blood-brain barrier disruption induced by focused ultrasound.

AIM: This study investigated whether the efficacy of boron neutron capture therapy was enhanced by means of intravenous administration of boronophenylalanine (BPA) with blood-brain barrier disruption induced by focused ultrasound (FUS). MATERIALS & METHODS: BPA was administered, followed by pulsed FUS, and the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. Growth of the firefly luciferase-labeled glioma cells was monitored through noninvasive biophotonic imaging. Finally, the brain tissue was histologically examined after sacrifice. RESULTS: Compared with the nonsonicated tumor group, animals treated with an injection of 500 mg/kg of BPA followed by FUS exhibited not only significantly increased accumulation of the drug at the sonicated tumor site, but also a significantly elevated tumor-to-normal brain drug ratio (p < 0.05). DISCUSSION: The data demonstrated that FUS significantly enhances the tumor-to-normal brain drug ratio in the sonicated tumor and subsequently the efficacy of boron neutron capture therapy.

Treatment strategies for initially disseminated intracranial germinomas: experiences at a single institute.

PURPOSE: Initially disseminated intracranial germinomas (IDIGs) can be observed in pre-adult and adolescent brain tumor patients. However, the disease prognosis is undetermined, and the method of optimal treatment remains controversial. METHODS: From January 1990 to January 2011, data on 91 intracranial germinoma patients (≤20 years old) were gathered from the Pediatric Brain Tumor database at Taipei Veterans General Hospital. A total of seven patients with a median age of 17.0 years had IDIGs (lesion sites >2), including IDIGs in the ventricular system or the spinal column. Craniospinal irradiation (CSI) plus a primary or metastatic boost was the mainstay strategy for radiotherapy. Six out of a total of seven patients (85.7%) also received systemic chemotherapy (CHT) after radiotherapy. Survivals rates between IDIGs and patients without dissemination were estimated using the Kaplan-Meier method. RESULTS: The median follow-up time for all seven patients was 67.5 months (range, 10.3-142.3 months). None of the IDIG patients experienced a recurrence or mortality after the completion of treatment. The 5- and 10-year disease-free survival (DFS) between IDIG and non-dissemination patients were 100%, 100%, 93.0% and 78.6%, respectively (p = 0.339). The 5- and 10-year overall survival (OS) between IDIGs and non-dissemination cases were 100%, 100%, 93.7% and 89.4%, respectively (p = 0.473). CONCLUSIONS: IDIG patients did not show reduced survival compared to non-dissemination patients if optimal radiotherapy and chemotherapy were used together.