Dose averaged linear energy transfer optimization for large sacral chordomas in carbon ion therapy.

BACKGROUND: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose-averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. PURPOSE: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)-weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). METHODS: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV-HD) larger than 250 cm 3 $250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE-weighted median dose prescription with the local effect model (LEM) was D RBE , 50 % = 73.6 Gy $\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ , L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and L min = 100 keV / µ m $\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$ . To compare the LETd optimized against reference plans, LETd and RBE-weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios ( ± 3.5 % $\pm 3.5\%$ range uncertainty and ± 3 mm $\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). RESULTS: The optimization method with L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) in the CTV-HD by 8.9 ± 1.5 keV / µ m $8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ ( 27 % $27\%$ ) (and 6.9 ± 1.3 keV / µ m $6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ ( 17 % $17\%$ )), without significant difference in the RBE-weighted dose. By allowing ± 5 % $\pm 5\%$ over- and under-dosage in the target, the LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) can be increased by 11.3 ± 1.2 keV / µ m $11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ ( 34 % $34\%$ ) (and 11.7 ± 3.4 keV / µ m $11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ ( 29 % $29\%$ )), using the optimization parameters L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ . The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. CONCLUSIONS: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE-weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE-weighted dose robustness and acquiring more in-room images remain crucial and inevitable aspects during treatment.

Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy.

To minimize radiation-induced lumbosacral neuropathy (RILSN), we employed sacral-nerve-sparing optimized carbon-ion therapy strategy (SNSo-CIRT) in treating 35 patients with pelvic sarcomas/chordomas. Plans were optimized using Local Effect Model-I (LEM-I), prescribed DRBE|LEM-I|D50% (median dose to HD-PTV) = 73.6 (70.4-76.8) Gy (RBE)/16 fractions. Sacral nerves were contoured between L5-S3 levels. DRBE|LEM-I to 5% of sacral nerves-to-spare (outside HD-CTV) (DRBE|LEM-I|D5%) were restricted to <69 Gy (RBE). The median follow-up was 25 months (range of 2-53). Three patients (9%) developed late RILSN (≥G3) after an average period of 8 months post-CIRT. The RILSN-free survival at 2 years was 91% (CI, 81-100). With SNSo-CIRT, DRBE|LEM-I|D5% for sacral nerves-to-spare = 66.9 ± 1.9 Gy (RBE), maintaining DRBE|LEM-I to 98% of HD-CTV (DRBE|LEM-I|D98%) = 70 ± 3.6 Gy (RBE). Two-year OS and LC were 100% and 93% (CI, 84-100), respectively. LETd and DRBE with modified-microdosimetric kinetic model (mMKM) were recomputed retrospectively. DRBE|LEM-I and DRBE|mMKM were similar, but DRBE-filtered-LETd was higher in sacral nerves-to-spare in patients with RILSN than those without. At DRBE|LEM-I cutoff = 64 Gy (RBE), 2-year RILSN-free survival was 100% in patients with <12% of sacral nerves-to-spare voxels receiving LETd > 55 keV/µm than 75% (CI, 54-100) in those with ≥12% of voxels (p < 0.05). DRBE-filtered-LETd holds promise for the SNSo-CIRT strategy but requires longer follow-up for validation.

Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety.

BACKGROUND: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. METHODS: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30-45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. RESULTS: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. CONCLUSIONS: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment-otherwise previously impossible.

Carbon Ion Dose Constraints in the Head and Neck and Skull Base: Review of MedAustron Institutional Protocols.

BACKGROUND: Dose constraints are of paramount importance for the outcome of any radiotherapy treatment. In this article, we report dose-volume constraints as well as currently used fractionation schedules for carbon ion radiotherapy as applied in MedAustron (Wiener Neustadt, Austria). MATERIALS AND METHODS: For fractionation schedules, both German and Japanese regimes were used. From the clinical experience of National Institute of Radiological Sciences (Chiba, Japan) and Heidelberg Ion Therapy (Heidelberg, Germany; formerly GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany) and the work by colleagues in Centro Nazionale Adroterapia Oncologica (Pavia, Italy) recalculating the dose from the microdosimetric kinetic model to the local effect model, we have set the dose constraints for critical organs of the head and neck area. Where no clinical data was available, an educated guess was made, based on data available from photon and proton series. RESULTS: We report the constraints for the optic nerve and chiasm, brainstem, spinal cord, cochlea, brain parenchyma, salivary gland, eye and adnexa, and mandibular/maxillary bone; constraints are grouped based on a fractionation scheme (German versus Japanese) and the risk of toxicity (safe, low to middle, and middle to high). CONCLUSION: We think validation of dose constraints should present a relevant part of the activity of any carbon ion radiotherapy facility, and we anticipate future multicentric, joint evaluations.

Interactions of gold-based drugs with proteins: crystal structure of the adduct formed between ribonuclease A and a cytotoxic gold(III) compound.

The reaction of Auoxo6, a dinuclear gold(III) complex, with the model protein bovine pancreatic ribonuclease is explored here by X-ray diffraction and ESI mass spectrometry. Data provide clues on the processes of adduct formation and of enzyme inhibition and, inductively, on the likely mode of action of this metallodrug.

Composición fitoquímica y nutricional de algunos frutos de árboles de interés forrajero de los llanos centrales de Venezuela / Phytochemical and nutritional composition of some forage fruit trees of the central llanos Venezuela

Para evaluar la composición fitoquímica y nutricional de algunos frutos de árboles de interés forrajero de los llanos centrales de Venezuela: Samán (Pithecellobium saman), Carocaro (Enterolobium cyclocarpum), Cují hediondo (Acacia macracantha), Cañafistolillo (Senna otomaria), Caruto (Genipa americana), Dividive (Caesalpinia coriaria), Granadillo (Caesalpinia granadillo), Guamacho (Pereskia guamacho), Tiamo (Acacia glomerosa), Guásimo (Guazuma ulmifolia), Merecure (Licania pyrifolia), Cují blanco (Prosopis juliflora); se procedió a determinar mediante el tamizaje fitoquímico la presencia de doce (12) metabolitos secundarios: fenoles totales (FT), flavonoides (Flav), taninos que precipitan las proteínas (TPP), taninos condensados (TC), esteroides (Est), quinonas (Quin), cumarinas (Cum), aminoácidos no proteicos (AANP), alcaloides (Alc), saponinas (Sap), triterpenos (Trip) y proantocianidinas (Proantc). El estudio fitoquímico arrojó altos niveles de Sap en Pithecellobium saman y Enterolobium cyclocarpum, lo cual pudiera causar problemas digestivos a los rumiantes. El 75 por ciento de los frutos mostró presencia de aminoácidos libres. Un 92 por ciento reaccionó positivamente a los TPP. Los contenidos de FT mostraron un amplio rango de variación (P<0,05), que oscilaron entre 0,46 y 16,28 por ciento. Los valores mas elevados en TC lo registraron Acacia macracantha (2,40 por ciento), Enterolobium cyclocarpum (1,18 por ciento) y Pithecellobium saman (1,01 por ciento). Con relación a la presencia de Sap, los ensayos cualitativos presentaron resultados con gran variabilidad entre las especies. El 75% de los frutos estudiados presentan alcaloides. El contenido de esteroides osciló entre 6,20 – 13 por ciento y se observó diferencias (P<0,05) entre los frutos evaluados. El 91 por ciento de los frutos reaccionó positivamente a las Cum. Los diferentes componentes del análisis químico arrojaron valores de proteína cruda (PC) entre 3,90 y 16 por ciento.

Evaluación nutricional del mantillo de un bosque seco tropical deciduo típico del nororiente del estado Guárico Venezuela / Nutritional evaluation of litter from a typical deciduos tropical dry forest in the northeastern part of Guárico state Venezuela

Para evaluar la composición nutricional de las diferentes fracciones del mantillo: hojarasca, pedúnculos, tallos, frutos secos, frutos carnosos y pequeñas partículas difíciles de identificar (detritus) de un bosque tropical deciduo típico del nororiente del estado Guárico, localizado a 9° 00'55'' latitud Norte y 64° 00'24'' longitud Oeste, Venezuela. Se procedió a cuantificar cada fracción del mantillo a través del análisis químico, así como también su degradabilidad in vitro e in situ. Los diferentes componentes del análisis químico arrojaron valores de proteína cruda (PC) entre 7,83 y 19,32 por ciento. Los contenidos de calcio en general no expresaron diferencias (P>0,05) para una misma fracción en distintas épocas del año. Los valores de fósforo para todas las fracciones oscilaron entre 0,05 a 0,42 por ciento, el mayor valor lo registró la fracción fruto de la época lluviosa. El contenido de Taninos Condensados (TC) fue superior en todas las fracciones del mantillo en la época seca en comparación a los valores obtenidos en la época lluviosa. Los valores más altos de TC fueron para la fracción fruto (30,31 por ciento) en la época seca. Los contenidos de fibra expresados como FND y FAD variron significativamente (P<0,05) entre las diferentes fracciones del mantillo y épocas del año. La degradabilidad in situ de la materia seca (DMS) no mostró diferencias (P>0,05) entre las fracciones hoja (47,67 por ciento); fruto (45,77 por ciento); detritus (39,14 por ciento) y tallo (33,01 por ciento). La fracción fruto (época seca) fue la que experimentó el valor más alto de EM (1.875 kcal/kg MS). La producción de materia seca total fue de 1.061,9 g/m²/año. En conclusión, los resultados indican que el mantillo representa un recurso valioso con potencialidades nutricionales capaces de complementar la alimentación de los animales rumiantes en la época de sequía