Particle beam radiotherapy for head and neck tumors: radiobiological basis and clinical experience

BACKGROUND: Head and neck tumors are often located near critical organs, making it impossible to deliver a dose of conventional radiotherapy high enough to eradicate the disease. Our aim was to review the potential benefits and available clinical experience of particle beam therapy (hadrontherapy) in the treatment of these tumors. METHODS: A review of the literature was carried out through a MEDLINE search (publications between 1980 and 2005). RESULTS: A review of the available clinical data shows that particle beam therapy can offer several radiobiological and physical advantages over conventional photon radiotherapy: improved dose distribution permits dose escalation within the target and optimal sparing of normal tissue. Preclinical and clinical studies suggest that there may be benefits to using hadrontherapy for tumors characterized by poor radiosensitivity and critical location. At present, the most used hadrons are protons and, as yet on an experimental basis, carbon ions. It is now well accepted that there are certain indications for using proton therapy for skull base tumors (chordoma and chondrosarcoma), paranasal sinus carcinomas, selected nasopharyngeal tumors, and neutron/ion therapy for salivary gland carcinomas (in particular, adenoid cystic tumors). Its viability in other cases, such as locally advanced squamous cell carcinoma, melanoma, soft tissue sarcoma, and bone sarcoma, is still under investigation. CONCLUSIONS: Hadrontherapy can be beneficial in the treatment of tumors characterized by poor radiosensitivity and critical location. Further clinical and radiobiological studies are warranted for improved selection of patient population.     

Magnetization exchange with water and T1 relaxation of the downfield resonances in human brain spectra at 3.0 T

The use of water suppression for in vivo proton MR spectroscopy diminishes the signal intensities from resonances that undergo magnetization exchange with water, particularly those downfield of water. To investigate these exchangeable resonances, an inversion transfer experiment was performed using the metabolite cycling technique for non‐water‐suppressed MR spectroscopy from a large brain voxel in 11 healthy volunteers at 3.0 T. The exchange rates of the most prominent peaks downfield of water were found to range from 0.5 to 8.9 s^?1, while the T₁ relaxation times in absence of exchange were found to range from 175 to 525 ms. These findings may help toward the assignments of the downfield resonances and a better understanding of the sources of contrast in chemical exchange saturation transfer imaging. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Myocardial ischemia—Metabolic pathways and implications of increased glycolysis

Evidence is reviewed that favors the hypothesis that maintenance of glycolysis plays a special role in protecting membrane function in ischemia. Therefore all procedures stimulating glycolytic flux should be beneficial in ischemia, and procedures inhibiting flux should be harmful. However, a crucial consideration is the coronary flow rate. In severe ischemia, accumulation of protons, derived not directly from glycolytic flux but from the breakdown of ATP and from protonproducing cycles, will tend to inhibit glycolysis and to minimize any benefit from increased glycolytic flux. Therefore maintenance of intracellular pH is crucial to the concept of the benefits of glycolysis. It also follows that the severity of ischemia can determine whether or not enhanced glycolysis has a beneficial effect. It is argued that a multiple approach, including enhanced glycolytic flux, control of intracellular pH, and improved coronary flow, constitutes the combination most likely to benefit ischemia.     

Methylated tetra-amide derivatives of paramagnetic complexes for magnetic resonance biosensing with both BIRDS and CEST

Paramagnetic agents that utilize two mechanisms to provide physiological information by magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) are described. MRI with chemical exchange saturation transfer (CEST) takes advantage of the agent's exchangeable protons (e.g., -OH or -NH_x, where 2 ≥ x ≥ 1) to create pH contrast. The agent's incorporation of non-exchangeable protons (e.g., -CH_y, where 3 ≥ y ≥ 1) makes it possible to map tissue temperature and/or pH using an MRSI method called biosensor imaging of redundant deviation in shifts (BIRDS). Hybrid probes based upon 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate chelate (DOTA⁴⁻) and its methylated analog (1,4,7,10-tetraazacyclododecane-α, α′, α″, α‴-tetramethyl-1,4,7,10-tetraacetate, DOTMA⁴⁻) were synthesized, and modified to create new tetra-amide chelates. Addition of several methyl groups per pendent arm of the symmetrical chelates, positioned proximally and distally to thulium ions (Tm³⁺), gave rise to favorable BIRDS properties (i.e., high signal-to-noise ratio (SNR) from non-exchangeable methyl proton peaks) and CEST responsiveness (i.e., from amide exchangeable protons). Structures of the Tm³⁺ probes elucidate the influence of methyl group placement on sensor performance. An eight-coordinate geometry with high symmetry was observed for the complexes: Tm-L1 was based on DOTA⁴⁻, whereas Tm-L2 and Tm-L3 were based on DOTMA⁴⁻, where the latter contained an additional carboxylate at the distal end of each arm. The distance of Tm³⁺ from terminal methyl carbons is a key determinant for sustaining BIRDS temperature sensitivity without compromising CEST pH contrast; however, water solubility was influenced by introduction of hydrophobic methyl groups and hydrophilic carboxylate. Combined BIRDS and CEST detection of Tm-L2 , which features two high-SNR methyl peaks and a strong amide CEST peak, should enable simultaneous temperature and pH measurements for high-resolution molecular imaging in vivo.     

Effect of J coupling on 1.3‐ppm lipid methylene signal acquired with localised proton MRS at 3 T

The purpose of this work was to investigate the effect of J‐coupling interactions on the quantification and T₂ determination of 1.3‐ppm lipid methylene protons at 3 T. The response of the 1.3‐ppm protons of hexanoic, heptanoic, octanoic, linoleic and oleic acid was measured as a function of point‐resolved spectroscopy (PRESS) and stimulated echo acquisition mode (STEAM) TE. In addition, a narrow‐bandwidth refocusing PRESS sequence designed to rewind J‐coupling evolution of the 1.3‐ppm protons was applied to the five fatty acids, to corn oil and to tibial bone marrow of six healthy volunteers. Peak areas were plotted as a function of TE, and data were fitted to monoexponentially decaying functions to determine M_o (the extrapolated area for TE = 0 ms) and T₂ values. In phantoms, rewinding J‐coupling evolution resulted in 198%, 64%, 44%, 20% and 15% higher T₂ values for heptanoic, octanoic, linoleic and oleic acid, and corn oil, respectively, compared with those obtained with standard PRESS. The narrow‐bandwidth PRESS sequence also resulted in significant changes in M_o, namely ?77%, ?22%, 28%, 23% and 28% for heptanoic, octanoic, linoleic and oleic acid, and corn oil, respectively. T₂ values obtained with STEAM were closer to the values measured with narrow‐bandwidth PRESS. On average, in tibial bone marrow (six volunteers) rewinding J‐coupling evolution resulted in 21% ± 3% and 9 % ± 1% higher M_o and T₂ values, respectively. This work demonstrates that the consequence of neglecting to consider scalar coupling effects on the quantification of 1.3‐ppm lipid methylene protons and their T₂ values is not negligible. The linoleic and oleic acid T₂ results indicate that T₂ measures of lipids with standard MRS techniques are dependent on lipid composition. Copyright © 2015 John Wiley & Sons, Ltd.     

From the Cover: Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria

The catalytic domain of the F-ATPase in mitochondria protrudes into the matrix of the organelle, and is attached to the membrane domain by central and peripheral stalks. Energy for the synthesis of ATP from ADP and phosphate is provided by the transmembrane proton-motive-force across the inner membrane, generated by respiration. The proton-motive force is coupled mechanically to ATP synthesis by the rotation at about 100 times per second of the central stalk and an attached ring of c-subunits in the membrane domain. Each c-subunit carries a glutamate exposed around the midpoint of the membrane on the external surface of the ring. The rotation is generated by protonation and deprotonation successively of each glutamate. Each 360° rotation produces three ATP molecules, and requires the translocation of one proton per glutamate by each c-subunit in the ring. In fungi, eubacteria, and plant chloroplasts, ring sizes of c₁₀–c₁₅ subunits have been observed, implying that these enzymes need 3.3–5 protons to make each ATP, but until now no higher eukaryote has been examined. As shown here in the structure of the bovine F₁-c-ring complex, the c-ring has eight c-subunits. As the sequences of c-subunits are identical throughout almost all vertebrates and are highly conserved in invertebrates, their F-ATPases probably contain c₈-rings also. Therefore, in about 50,000 vertebrate species, and probably in many or all of the two million invertebrate species, 2.7 protons are required by the F-ATPase to make each ATP molecule.