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.

Development of a tumor control probability model for boron neutron capture therapy of head and neck cancer.

The tumor control probability (TCP) model has been used for estimating the response of the radiation (photon) therapy for a given treatment dose (distribution). In Taiwan, boron neutron capture therapy (BNCT) is still at the stage of the clinical trials without standard dose prescription. In this study, universal survival curve (USC) model was selected as the TCP model for BNCT. The tumor response and dose distribution from protocol I of the clinical trial of the recurrent head and neck (H&N) cancer conducted by Taipei Veterans General Hospital and National Tsing Hua University were used to verify the TCP model established in this study. The results showed that, using the USC model as a biological model of dose conversion, the TCP calculated by the generalized Equivalent Uniform Dose (gEUD)-based TCP model can be used to well correlate the relationship between the tumor response and dose distribution of the patients of recurrent H&N cancer. The result shows that 25% and 60% of TCP correspond to partial response and complete response of H&N cancer, respectively. This study also indicated that, when BNCT was used to treat recurrent H&N cancer, the minimum dose was an important factor on the efficacy of the treatment. Minimum dose of 18 Gy-w corresponds to at least 60% of TCP.

A comparison of dose distributions in gross tumor volume between boron neutron capture therapy alone and combined boron neutron capture therapy plus intensity modulation radiation therapy for head and neck cancer.

Nine patients with recurrent head and neck (H&N) cancer received boron neutron capture therapy (BNCT) in one fraction at the Tsing-Hua Open pool reactor (THOR) utilizing the THORplan treatment planning system (TPS). The aims of the present study were to evaluate the use of intensity modulated radiation therapy (IMRT) of 45 Gy in 20 fractions to compensate for the dose heterogeneity in gross tumor volume observed with single-fraction BNCT with mean prescription dose 19 Gy (w), and to evaluate planning quality indices of simulated BNCT+IMRT versus single-fraction BNCT alone. All IMRT plans were generated using the Eclipse TPS which employs the analytical anisotropic algorithm. The conformity index for the gross tumor volume (GTV) was better for the BNCT+IMRT plan than for the BNCT-alone plan (p = 0.003). In addition, the BNCT+IMRT plan provided significantly better homogeneity in the GTV (p = 0.03). The cold spots in inhomogeneous dose distribution in the BNCT plan may be a key factor for H&N cancer recurrence. Our results suggest that single-fraction BNCT combined with compensated multi-fraction IMRT improves treatment homogeneity and conformity than single-fraction BNCT alone, especially for tumor volumes >100 cm3, and possibly increases local tumor control.

A volume-equivalent spherical necrosis-tumor-normal liver model for estimating absorbed dose in yttrium-90 microsphere therapy.

PURPOSE: Primary hepatocellular carcinoma and metastatic liver tumors are highly malignant tumors in Asia. The incidence of fatal liver cancer is also increasing in the United States. The aim of this study was to establish a spherical tumor model and determine its accuracy in predicting the absorbed dose in yttrium-90 (Y-90) microsphere therapy for liver cancer. METHODS: Liver morphology can be approximated by a spherical model comprising three concentric regions representing necrotic, tumor, and normal liver tissues. The volumes of these three regions represent those in the actual liver. A spherical tumor model was proposed to calculate the absorbed fractions in the spherical tumor, necrotic, and normal tissue regions. The THORplan treatment planning system and Monte Carlo N-particle extended codes were used for this spherical tumor model. Using the volume-equivalent method, a spherical tumor model was created to calculate the total absorbed fraction [under different tumor-to-healthy-liver ratios (TLRs)]. The patient-specific model (THORplan) results were used to verify the spherical tumor model results. RESULTS: The results for both the Y-90 spectrum and the Y-90 mean energy indicated that the absorbed fraction was a function of the tumor radius and mass. The absorbed fraction increased with tumor radius. The total absorbed fractions calculated using the spherical tumor model for necrotic, liver tumor, and normal liver tissues were in good agreement with the THORplan results, with differences of less than 3% for TLRs of 2-5. The results for the effect of TLR indicate that for the same tumor configuration, the total absorbed fraction decreased with increasing TLR; for the same shell tumor thickness and TLR, the total absorbed fraction was approximately constant; and for tumors with the same radius, the total fraction absorbed by the tumor increased with the shell thickness. CONCLUSIONS: The results from spherical tumor models with different tumor-to-healthy-liver ratios were highly consistent with the reference results (THORplan). These findings indicate that a spherical tumor model can provide good estimates of Y-90 doses in microsphere therapy and can be considered a first approximation for dose estimation in Y-90 microsphere therapy.

Distinct mutation profile and prognostic relevance in patients with hypoplastic myelodysplastic syndromes (h-MDS).

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased BM cellularity (NH-MDS), some have hypocellular BM (h-MDS). The reports concerning the differences in genetic alterations between h-MDS and NH-MDS patients are limited. In this study, 369 MDS patients diagnosed according to the WHO 2008 criteria were recruited. h-MDS patients had lower PB white blood cell and blast counts, and lower BM blast percentages, than those with NH-MDS. h-MDS was closely associated with lower-risk MDS, defined by the International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R). IPSS-R could properly predict the prognosis in h-MDS (P<0.001) as in NH-MDS patients. The h-MDS patients had lower incidences of RUNX1, ASXL1, DNMT3A, EZH2 and TP53 mutations than NH-MDS patients. The cumulated incidence of acute leukemic transformation at 5 years was 19.3% for h-MDS and 40.4% for NH-MDS patients (P= 0.001). Further, the patients with h-MDS had longer overall survival (OS) than those with NH-MDS (P= 0.001), and BM hypocellularity remains an independent favorable prognostic factor for OS irrespective of age, IPSS-R, and gene mutations. Our findings provide evidence that h-MDS indeed represent a distinct clinico-biological subgroup of MDS and can predict better leukemia-free survival and OS.

BNCT treatment planning for superficial and deep-seated tumors: Experience from clinical trial of recurrent head and neck cancer at THOR.

Under the collaboration between National Tsing Hua University and Taipei Veterans General Hospital, clinical trial of recurrent head-and-neck cancer by Boron neutron capture therapy at Tsing Hua open-pool reactor started on August 11, 2010. Up to January 2014, 17 patients were treated. Based on the treatment planning experiences of clinical trials using in-house designed THORplan, different setups should be used for superficial and deep-seated tumors. Superficial tumor treatment gains benefits from the use of patient collimator, while direct irradiation is a better choice for deep-seated tumor.

Hypoxia-inducible factor 2 alpha is essential for hepatic outgrowth and functions via the regulation of leg1 transcription in the zebrafish embryo.

The liver plays a vital role in metabolism, detoxification, digestion, and the maintenance of homeostasis. During development, the vertebrate embryonic liver undergoes a series of morphogenic processes known as hepatogenesis. Hepatogenesis can be separated into three interrelated processes: endoderm specification, hepatoblast differentiation, and hepatic outgrowth. Throughout this process, signaling molecules and transcription factors initiate and regulate the coordination of cell proliferation, apoptosis, differentiation, intercellular adhesion, and cell migration. Hifs are already recognized to be essential in embryonic development, but their role in hepatogenesis remains unknown. Using the zebrafish embryo as a model organism, we report that the lack of Hif2-alpha but not Hif1-alpha blocks hepatic outgrowth. While Hif2-alpha is not involved in hepatoblast specification, this transcription factor regulates hepatocyte cell proliferation during hepatic outgrowth. Furthermore, we demonstrated that the lack of Hif2-alpha can reduce the expression of liver-enriched gene 1 (leg1), which encodes a secretory protein essential for hepatic outgrowth. Additionally, exogenous mRNA expression of leg1 can rescue the small liver phenotype of hif2-alpha morphants. We also showed that Hif2-alpha directly binds to the promoter region of leg1 to control leg1 expression. Interestingly, we discovered overrepresented, high-density Hif-binding sites in the potential upstream regulatory sequences of leg1 in teleosts but not in terrestrial mammals. We concluded that hif2-alpha is a key factor required for hepatic outgrowth and regulates leg1 expression in zebrafish embryos. We also proposed that the hif2-alpha-leg1 axis in liver development may have resulted from the adaptation of teleosts to their environment.

Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom.

Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5' untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway.

Mode conversion using optical analogy of shortcut to adiabatic passage in engineered multimode waveguides.

A shortcut to adiabatic mode conversion in multimode waveguides using optical analogy of stimulated Raman adiabatic passage is investigated. The design of mode converters using the shortcut scheme is discussed. Computer-generated planar holograms are used to mimic the shaped pulses used to speed up adiabatic passage in quantum systems based on the transitionless quantum driving algorithm. The mode coupling properties are analyzed using the coupled mode theory and beam propagation simulations. We show reduced device length using the shortcut scheme as compared to the common adiabatic scheme. Modal evolution in the shortened device indeed follows the adiabatic eigenmode exactly amid the violation of adiabatic criterion.

Characterization of radioactive contaminants and water treatment trials for the Taiwan Research Reactor's spent fuel pool.

There were approximately 926 m(3) of water contaminated by fission products and actinides in the Taiwan Research Reactor's spent fuel pool (TRR SFP). The solid and ionic contaminants were thoroughly characterized using radiochemical analyses, scanning electron microscopy equipped with an energy dispersive spectrometer (SEM-EDS), and inductively coupled plasma optical emission spectrometry (ICP-OES) in this study. The sludge was made up of agglomerates contaminated by spent fuel particles. Suspended solids from spent ion-exchange resins interfered with the clarity of the water. In addition, the ionic radionuclides such as (137)Cs, (90)Sr, U, and α-emitters, present in the water were measured. Various filters and cation-exchange resins were employed for water treatment trials, and the results indicated that the solid and ionic contaminants could be effectively removed through the use of <0.9 µm filters and cation exchange resins, respectively. Interestingly, the removal of U was obviously efficient by cation exchange resin, and the ceramic depth filter composed of diatomite exhibited the properties of both filtration and adsorption. It was found that the ceramic depth filter could adsorb ß-emitters, α-emitters, and uranium ions. The diatomite-based ceramic depth filter was able to simultaneously eliminate particles and adsorb ionic radionuclides from water.

BNCT treatment planning of recurrent head-and-neck cancer using THORplan.

A cooperation program on Boron Neutron Capture Therapy (BNCT) between National Tsing Hua University (NTHU) and Taipei Veterans General Hospital (TPEVGH) was established in 2008. Clinical trial of recurrent head-and-neck cancer is the goal of the program. In this study, treatment plannings of two head-and-neck cancer cases are performed using treatment planning system THORplan developed at NTHU of Taiwan. The patients are assumed to be irradiated under current THOR epithermal neutron beam. The prescription dose is 20 Gy-Eq for at least 80% of tumor volume. The irradiation time to reach the target tumor dose can be kept within 1h. The skin dose is within the limiting dose of 11 Gy-Eq. The spinal cord dose is well within the limiting dose of 10 Gy-Eq. The use of an extension collimator for easier patient positioning is helpful in reducing the dose of eye lens to within the dose limit of 5 Gy-Eq. The irradiation time, however, will increase slightly due to the increase of source-to-tumor distance. The CPU time for treatment planning calculation is ~10 h. With the use of user friendly treatment planning system THORplan, dose planning for BNCT at THOR can be easily performed.

Development and verification of THORplan--a BNCT treatment planning system for THOR.

THORplan is a treatment planning system under continuous development and refinement at Tsing Hua University, Taiwan, for BNCT purpose. New features developed for homogeneous model calculation include material grouping model, and voxel data reconstruction model. Material grouping model is a two-step grouping method, tissue-volume-percent grouping method followed by atom-gram-density grouping method. The root mean square difference of neutron flux due to material grouping is <0.8%. In the voxel data reconstruction model, voxel neutron dose is calculated based on the material composition and dose of individual atom of each voxel, which is calculated by linear interpolation from the dose of individual atom of neighboring cells tallied in MCNP calculation. The detailed voxel model is used to benchmark the accuracy of the new features developed for the homogeneous model calculation. The maximum error of the neutron flux and dose of voxels using the homogeneous cell model is 5% and 7%, respectively. Big improvement of accuracy of voxel dose over the original dose calculation model based on F6 tally is observed at locations containing very heterogeneous compositions.

Purge-and-trap ion chromatography for the determination of trace ammonium ion in high-salinity water samples.

It has always been assumed that purge-and-trap (P&T) method is only used for the analysis of volatile organic compounds (VOCs) in aqueous samples. In this paper, a novel P&T preconcentrator has been developed for the determination of trace amounts of ammonium ion in high-salinity water samples by ion chromatography (IC). Method performance is evaluated as a function of concentration of assistant purging material, purging time, and flow rate. Under the optimum P&T conditions with the purified nitrogen gas at flow rate 40 mL/min for 15.0 min at 40 degrees C, the overall collection efficiency is independent of the concentration of ammonium over the range 1.2-5.9 microM. The enrichment factor (EF) of ammonium correlates the ratio of the sample volume to the acceptor solution volume in the trap vessel, providing potentially unlimited increase of the ammonium signal. Our results indicate that environmental samples with low levels of ammonium in matrices with high concentrations of sodium can be easily analyzed and the detection limit down to 75 nM (1.35 ppb) level, corresponding to picomole of ammonia in the injected sample. Calibration graph was constructed with ammonium standards ranging from 0.05 to 6.0 microM and the linearity of the present method was good as suggested by the square of correlation coefficients being better than 0.997. Thus, we have demonstrated that the P&T-IC method allows the routine determination of ammonium ion in seawater samples without cation interferences.

Carbonic anhydrase 2-like a and 15a are involved in acid-base regulation and Na+ uptake in zebrafish H+-ATPase-rich cells.

H(+)-ATPase-rich (HR) cells in zebrafish gills/skin were found to carry out Na+ uptake and acid-base regulation through a mechanism similar to that which occurs in mammalian proximal tubular cells. However, the roles of carbonic anhydrases (CAs) in this mechanism in zebrafish HR cells are still unclear. The present study used a functional genomic approach to identify 20 CA isoforms in zebrafish. By screening with whole mount in situ hybridization, only zca2-like a and zca15a were found to be expressed in specific groups of cells in zebrafish gills/skin, and further analyses by triple in situ hybridization and immunocytochemistry demonstrated specific colocalizations of the two zca isoforms in HR cells. Knockdown of zca2-like a caused no change in and knockdown of zca15a caused an increase in H+ activity at the apical surface of HR cells at 24 h postfertilization (hpf). Later, at 96 hpf, both the zca2-like a and zca15a morphants showed decreased H+ activity and increased Na+ uptake, with concomitant upregulation of znhe3b and downregulation of zatp6v1a (H+-ATPase A-subunit) expressions. Acclimation to both acidic and low-Na+ fresh water caused upregulation of zca15a expression but did not change the zca2-like a mRNA level in zebrafish gills. These results provide molecular physiological evidence to support the roles of these two zCA isoforms in Na+ uptake and acid-base regulation mechanisms in zebrafish HR cells.