A method to predict space radiation biological effectiveness for non-cancer effects following intense Solar Particle Events.

In addition to the continuous exposure to cosmic rays, astronauts in space are occasionally exposed to Solar Particle Events (SPE), which involve less energetic particles but can deliver much higher doses. The latter can exceed several Gy in a few hours for the most intense SPEs, for which non-stochastic effects are thus a major concern. To identify adequate shielding conditions that would allow respecting the dose limits established by the various space agencies, the absorbed dose in the considered organ/tissue must be multiplied by the corresponding Relative Biological Effectiveness (RBE), which is a complex quantity depending on several factors including particle type and energy, considered biological effect, level of effect (and thus absorbed dose), etc. While in several studies only the particle-type dependence of RBE is taken into account, in this work we developed and applied a new approach where, thanks to an interface between the FLUKA Monte Carlo transport code and the BIANCA biophysical model, the RBE dependence on particle energy and absorbed dose was also considered. Furthermore, we included in the considered SPE spectra primary particles heavier than protons, which in many studies are neglected. This approach was then applied to the October 2003 SPE (the most intense SPE of solar cycle 23, also known as "Halloween event") and the January 2005 event, which was characterized by a lower fluence but a harder spectrum, i.e., with higher-energy particles. The calculation outcomes were then discussed and compared with the current dose limits established for skin and blood forming organs in case of 30-days missions. This work showed that the BIANCA model, if interfaced to a radiation transport code, can be used to calculate the RBE values associated to Solar Particle Events. More generally, this work emphasizes the importance of taking into account the RBE dependence on particle energy and dose when calculating equivalent doses.

Application to nonlinear optical properties of the RSX-QIDH double-hybrid range-separated functional.

The effective calculation of static nonlinear optical properties requires a considerably high accuracy at a reasonable computational cost, to tackle challenging organic and inorganic systems acting as precursors and/or active layers of materials in (nano-)devices. That trade-off implies to obtain very accurate electronic energies in the presence of externally applied electric fields to consequently obtain static polarizabilities ( α i j ) and hyper-polarizabilities ( ß i j k and γ i j k l ). Density functional theory is known to provide an excellent compromise between accuracy and computational cost, which is however largely impeded for these properties without introducing range-separation techniques. We thus explore here the ability of a modern (double-hybrid and range-separated) Range-Separated eXchange Quadratic Integrand Double-Hybrid exchange-correlation functional to compete in accuracy with more costly and/or tuned methods, thanks to its robust and parameter-free nature.

[Delayed cognitive impairment in patients with aortic stenosis treated with surgical valve replacement and transcatheter aortic valve implantation: a comparative study]. / Deterioro cognitivo tardío en pacientes con estenosis aórtica tratados con sustitución valvular quirúrgica y con implantación transcatéter de válvula aórtica: estudio comparativo.

INTRODUCTION: Cognitive impairment secondary to cerebrovascular events is a common complication of aortic valve replacement interventions. Our aim is to study the deterioration profile of patients who have undergone surgical valve replacement or transcatheter valve implantation (TAVI) and whether it differs according to the intervention they underwent and their baseline risk factors. PATIENTS AND METHODS: We conducted a prospective observational study with two non-equivalent groups of patients (TAVI group and surgical group) Intergroup comparisons were carried out in several cognitive domains, with a baseline assessment and follow-up measurements six and 12 months after the intervention. RESULTS: The TAVI group performed less well than the surgical group in executive and visuospatial functions, with scores partially determined by age (p < 0.01) and prior intellectual level (Pearson prior intelligence quotient-scalar test means: 0.665; p < 0.001). Mean scores at the three measurement points indicate a decline in executive function performance at six months, which is restored at 12 months. Sustained increases in memory were recorded at both time points, while visuospatial function and naming showed no subsequent recovery of the baseline levels. These trends are similar in both groups. CONCLUSION: The results obtained do not confirm the appearance of a specific process of post-intervention neurocognitive impairment in complicated aortic stenosis. The deterioration profile does not show any significant differences between groups, but is more evident in TAVI patients, due to the influence of variables related to sample selection.

TITLE: Deterioro cognitivo tardío en pacientes con estenosis aórtica tratados con sustitución valvular quirúrgica y con implantación transcatéter de válvula aórtica: estudio comparativo.Introducción. El deterioro cognitivo secundario a eventos cerebrovasculares es una complicación frecuente en las intervenciones de reemplazo de válvula aórtica. Nuestro objetivo es el estudio del perfil de deterioro de los pacientes sometidos a reemplazo valvular quirúrgico o implantación de prótesis transcatéter (TAVI) y si éste resulta diferente según la intervención a la que son sometidos y los factores de riesgo basales. Pacientes y métodos. Estudio observacional prospectivo, con dos grupos no equivalentes de pacientes (grupo TAVI y grupo quirúrgico). Se realizaron comparaciones intergrupo en varios dominios cognitivos, con una evaluación basal y mediciones de seguimiento seis y 12 meses después la intervención. Resultados. El grupo TAVI presentó resultados inferiores al grupo quirúrgico en funciones ejecutivas y visuoespaciales, puntuaciones parcialmente determinadas por la edad (p < 0,01) y el nivel intelectual previo (Pearson cociente intelectual previo-medias escalares en los test: 0,665; p < 0,001). La media de puntuaciones en los tres momentos de medición indica una disminución del rendimiento en funciones ejecutivas a los seis meses, que se recupera a los 12 meses. En memoria se registraron incrementos sostenidos en ambos momentos, en tanto que la función visuoespacial y la denominación no mostraron recuperación posterior de los niveles basales. Estas tendencias son similares en los dos grupos. Conclusión. Los resultados obtenidos no confirman la instauración de un proceso específico de deterioro neurocognitivo postintervención en la estenosis aórtica complicada. El perfil de deterioro no presenta diferencias significativas entre los grupos, pero es más evidente en los pacientes con TAVI, debido a la influencia de las variables de selección de la muestra.

Gastric adenocarcinoma: A review of the TNM classification system and ways of spreading.

Gastric cancer is the fifth most common cancer in the world. The most common histologic subtype is adenocarcinoma. Gastric adenocarcinomas are staged using the American Joint Committee on Cancer's 8th TNM classification. The perigastric ligaments, mesentery, omentum, and potential spaces between the parietal and visceral peritoneal linings play are important structures for staging. The spread of disease is influenced by the location of the tumor within the stomach, as well as by the anatomy related to the ligaments and lymph vessels. CT is the imaging modality of choice for the preoperative clinical staging of gastric cancer, and it is essential for planning treatment. To be able to do an adequate imaging workup, radiologists need to know the different pathways through which gastric cancer can spread: lymphatic, subperitoneal, direct invasion, transperitoneal, hematogenous, and extramural venous invasion.

Hepatocyte-like cells differentiated from methylmalonic aciduria cblB type induced pluripotent stem cells: A platform for the evaluation of pharmacochaperoning.

Methylmalonic aciduria cblB type (MMA cblB type, MMAB OMIM #251110), caused by a deficiency in the enzyme ATP:cob(I)alamin adenosyltransferase (ATR, E.C_2. 5.1.17), is a severe metabolic disorder with a poor prognosis despite treatment. We recently described the potential therapeutic use of pharmacological chaperones (PCs) after increasing the residual activity of ATR in patient-derived fibroblasts. The present work reports the successful generation of hepatocyte-like cells (HLCs) differentiated from two healthy and two MMAB induced pluripotent stem cell (iPSC) lines, and the use of this platform for testing the effects of PCs. The MMAB cells produced little ATR, showed reduced residual ATR activity, and had higher concentrations of methylmalonic acid compared to healthy HLCs. Differential proteome analysis revealed the two MMAB HCLs to show reproducible differentiation, but this was not so for the healthy HLCs. Interestingly, PC treatment in combination with vitamin B12 increased the amount of ATR available, and subsequently ATR activity, in both MMAB HLCs. More importantly, the treatment significantly reduced the methylmalonic acid content of both. In summary, the HLC model would appear to be an excellent candidate for the pharmacological testing of the described PCs, for analyzing the effects of new drugs, and investigating the repurposing of older drugs, before testing in animal models.

An updated review of the TNM classification system for cancer of the oesophagus and its complications.

Cancer of the esophagus is an aggressive cancer with high mortality. Because of the esophagus's lack of serosa and its peculiar lymphatic drainage, esophageal cancer is diagnosed in advanced stages. The eighth edition of the TNM (2017) aims to standardize care for esophageal cancer throughout the world; it includes not only patients treated with esophagectomy alone, but also those receiving neoadjuvant chemotherapy and/or radiotherapy. One new development in the eighth edition is that it establishes separate classifications for different time periods, with pathologic stage groups for prior to treatment (cTNM), after esophagectomy (pTNM), and after neoadjuvant therapy (ypTNM). The combined use of endoscopic ultrasound, CT, PET-CT, and MRI provides the greatest accuracy in determining the clinical stage, and these techniques are essential for planning treatment and for evaluating the response to neoadjuvant treatment. Esophagectomy continues to be the main treatment; it is also the elective gastrointestinal surgery that has the highest mortality, and it carries the risk of multiple complications, including anastomotic leaks, pulmonary complications, technical complications, and functional complications.

Biological effectiveness of He-3 and He-4 ion beams for cancer hadrontherapy: a study based on the BIANCA biophysical model.

While cancer therapy with protons and C-ions is continuously spreading, in the near future patients will be also treated with He-ions which, in comparison to photons, combine the higher precision of protons with the higher relative biological effectiveness (RBE) of C-ions. Similarly to C-ions, also for He-ions the RBE variation along the beam must be known as precisely as possible, especially for active beam delivery systems. In this framework the BIANCA biophysical model, which has already been applied to calculate the RBE along proton and C-ion beams, was extended to4He-ions and, following interface with the FLUKA code, was benchmarked against cell survival data on CHO normal cells and Renca tumour cells irradiated at different positions along therapeutic-like4He-ion beams at the Heidelberg Ion-beam Therapy centre, where the first He-ion patient will be treated soon. Very good agreement between simulations and data was obtained, showing that BIANCA can now be used to predict RBE following irradiation with all ion types that are currently used, or will be used soon, for hadrontherapy. Thanks to the development of a reference simulation database describing V79 cell survival for ion and photon irradiation, these predictions can be cell-type specific because analogous databases can be produced, in principle, for any cell line. Furthermore, survival data on CHO cells irradiated by a He-3 beam were reproduced to compare the biophysical properties of He-4 and He-3 beams, which is currently an open question. This comparison showed that, at the same depth, He-4 beams tend to have a higher RBE with respect to He-3 beams, and that this difference is also modulated by the considered physical dose, as well as the cell radiosensitivity. However, at least for the considered cases, no significant difference was found for the ratio between the RBE-weighted dose in the SOBP and that in the entrance plateau.

Does a single application of contraceptive cause pathological changes in bitches? / [Uma única aplicação de anticoncepcional causa alterações patológicas em cadelas?]

O presente trabalho objetivou avaliar os efeitos da administração em dose única de progestágenos em fêmeas caninas hígidas, as quais nunca haviam recebido tais fármacos. Foram selecionadas 20 cadelas, que foram examinadas clinicamente e por meio de exames complementares. Nessas cadelas, foi aplicado medroxiprogesterona por via subcutânea. Noventa dias após, as fêmeas foram esterilizadas cirurgicamente, sendo os tecidos reprodutivos encaminhados para histopatologia. Foi possível verificar que, aos 30 dias, 12 animais (60%) apresentaram hiperplasia mamária. Aos 90 dias, 18 animais (90%) apresentavam sinais de hiperplasia endometrial cística, tendo cinco (27,77%) destes animais apresentado conteúdo purulento no lúmen uterino. No exame microscópico, apenas uma fêmea não demonstrou alterações patológicas, sendo a única que recebeu o contraceptivo na fase correta (anestro). As demais fêmeas apresentaram alterações que variaram entre alterações circulatórias a hiperplasia endometrial cística grave. Assim, foi possível concluir que uma única aplicação de anticoncepcional em fêmeas hígidas pode causar complicações leves a graves.(AU)

[Neuropsychological profile in patients with myotonic dystrophy type 1: a four-year follow-up study]. / Perfil neuropsicológico en pacientes con distrofia miotónica tipo 1: estudio de seguimiento a cuatro años.

INTRODUCTION: Myotonic dystrophy type 1 (MD1), or Steinert's disease, is a multisystemic disorder of autosomal dominant inheritance, whose adult variant usually presents with multidomain cognitive impairment and affects patients' functionality and quality of life. AIM: To study the four-year history of cognitive functioning in a sample of patients with the adult variant of MD1. PATIENTS AND METHODS: The neurocognitive functions of a sample of 31 patients with MD1 are evaluated, of whom 24 repeat the test administered four years ago in the Neurology Service of the Complejo Hospitalario of Navarra. Data are collected from the cognitive domains that are most related to the deficits that usually present in MD1. RESULTS: The follow-up evaluation found that the visuospatial and visuoconstructive functions and alternating attention of the patients who underwent the study were affected, as was their daily functioning reported by the family. These results are in line with those obtained four years earlier, with no significant deterioration observed between the two measurements. A higher incidence of cognitive impairment was also displayed in 2018, with some cases of progression to dementia in Steinert's disease. CONCLUSION: Neurocognitive progression in MD1 seems to respond to a progressive pattern of degeneration, linked to the functions that are most affected from the beginning of the sequelae phase and which usually correspond to the domains of working memory, alternating attention, and visuospatial and visuoconstructive abilities.

TITLE: Perfil neuropsicológico en pacientes con distrofia miotónica tipo 1: estudio de seguimiento a cuatro años.Introducción. La distrofia miotónica tipo 1 (DM1), o enfermedad de Steinert, es un trastorno multisistémico de herencia autosómica dominante, cuya variante adulta suele cursar con deterioro cognitivo multidominio y afectación de la funcionalidad y la calidad de vida de los pacientes. Objetivo. Estudiar la evolución a cuatro años del funcionamiento cognitivo de una muestra de pacientes con la variante adulta de DM1. Pacientes y métodos. Se evalúan las funciones cognitivas de una muestra de 31 pacientes con DM1, de los cuales 24 repiten la evaluación administrada hace cuatro años en el Servicio de Neurología del Complejo Hospitalario de Navarra. Se recogen datos de los dominios neurocognitivos más relacionados con los déficits de presentación habitual en la DM1. Resultados. La evaluación de seguimiento constató la afectación de las funciones visuoespaciales y visuoconstructivas y de la atención alternante de los pacientes que se sometieron al estudio, así como de su funcionamiento cotidiano informado por la familia. Estos resultados están en línea con los obtenidos cuatro años atrás, sin que se haya objetivado un deterioro significativo entre ambas mediciones. Se demuestra, además, una mayor incidencia de deterioro cognitivo en 2018, con algunos casos de evolución a demencia en la enfermedad de Steinert. Conclusión. La evolución neuropsicológica en la DM1 parece responder a un patrón progresivo, ligado a las funciones que más se afectan desde los inicios de la fase de secuelas y que suelen corresponder a los dominios de memoria de trabajo, atención alternante y habilidades visuoespaciales y visuoconstructivas.

Adverse events of targeted anticancer therapies: what radiologists need to know. / Efectos adversos de las terapias dirigidas contra el cáncer: lo que el radiólogo debe saber.

The treatment of cancer has improved drastically in recent decades. Better understanding of tumor biology has enabled the development of new treatments, called targeted therapy. These drugs target specific signaling pathways that are necessary for the development of cancer. Immunotherapy is even more novel. These new agents can be classified into different groups, mainly according to their mechanism of action: VEGF inhibitors or anti-angiogenic agents, EGFR inhibitors, mTOR inhibitors, CTLA-4 inhibitors, or PD-1/PD-L1 inhibitors, etc. All these new treatments are accompanied by new adverse effects that radiologists need to know. Understanding the molecular mechanisms of targeted therapies and knowing their adverse effects are vital to imaging assessment and ensuring appropriate treatment.

Immediate breast reconstruction with latissimus dorsi flap for patients with local recurrence of breast cancer.

BACKGROUND: Ipsilateral breast cancer recurrence (IBTR) occurs in about 7% of patients with primary invasive breast tumor. Salvage mastectomy and breast reconstruction are often discussed and latissimus dorsi (LD) flap is frequently proposed. METHODS: We retrospectively investigated 111 consecutive locally relapsing patients who underwent salvage mastectomy and immediate LD reconstruction. All included patients with IBTR previously underwent conserving surgery for BC, and received a postoperative irradiation. Primary endpoints were disease free survival and overall survival. Secondary endpoints were surgical complications and re-interventions. RESULTS: Invasive ductal cancer was the most frequent histotype (60.4%) of breast cancer reappearance. rpT1, rpT2 and rpT3 were observed respectively in 50.5%, 20,7% and 3,6% of the patients. rpTis occurred in 11,7% of cases. Positive axillary nodes were observed in 9,9% of patients at reappearance. Post-operative complication other than seroma occurred in 17,1% of patients, while seroma at the donor site was observed in 61.3% of cases. At 5-year after surgery overall survival was 92% (95% CI: 85%-96%) and disease free survival was 78% (95% CI: 69%-85%). CONCLUSIONS: Immediate latissimus dorsi flap reconstruction in selected patients with isolated breast tumor recurrence, which occurred after breast irradiation, provides an effective treatment with a satisfactory outcome.

Cortical hypointensity in T2-weighted gradient-echo sequences in patients with progressive multifocal leukoencephalopathy. / Hipointensidad cortical en secuencias eco de gradiente T2 en la leucoencefalopatía multifocal progresiva.

INTRODUCTION: Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by the reactivation of the JC virus. This opportunistic encephalopathy mainly affects immunodepressed patients with stage III HIV infection, although in recent years it has also been found in association with treatment with immunosuppressors such as natalizumab. MRI plays an important role in both the early diagnosis and follow-up of this disease. Recently, it has been reported that hypointensities in U-fibers and cortex adjacent to white-matter lesions characteristic of the disease can be identified on T2-weighted gradient-echo and susceptibility-weighted sequences in patients with progressive multifocal leukoencephalopathy. OBJECTIVE: We aimed to analyze the presence and usefulness of cortical hypointensity on T2-weighted gradient-echo sequences in relation to the diagnosis of progressive multifocal leukoencephalopathy and to review the literature on the topic. MATERIAL AND METHODS: We analyze three cases of progressive multifocal leukoencephalopathy seen at our center in three patients with immunosuppression of different origins: one with stage III HIV infection, one with multiple sclerosis being treated with natalizumab, and one with rheumatoid arthritis being treated with rituximab. RESULTS: In all three cases MRI showed the cortical hypointensity adjacent to the white-matter lesion in the T2-weighted gradient-echo sequence. In the patient with multiple sclerosis, this sign appeared earlier than the abnormal signal in the white matter. The patient being treated with rituximab was diagnosed postmortem and the pathology findings correlated with the MRI findings. CONCLUSION: The finding of cortical hypointensity on T2-weighted gradient-echo MRI sequences seems to support the diagnosis of progressive multifocal leukoencephalopathy, regardless of the type of immunosuppression, so this finding should routinely assessed in patients suspected of having this disease.

Prognostic value of energy expenditure and respiratory quotient measuring in patients with liver cirrhosis.

BACKGROUND & AIMS: Resting energy expenditure (REE) and respiratory quotient (RQ) as measured by indirect calorimetry (IC) may correlate with muscle mass and represent prognostic indicators in treating patients with liver cirrhosis. We aimed to assess the correlation of IC-measured REE and RQ with skeletal muscle mass (SM), mortality, and REE values as estimated by Harris-Benedict, European guidelines (EG), and Brazilian guidelines-DITEN (BG) equations in patients with liver cirrhosis. METHODS: In this prospectively designed study, REE was measured in 126 male patients with liver cirrhosis by IC and predicted by Harris-Benedict, EG (35 kcal/kg current weight), and BG (30 kcal/kg current weight) guidelines. Measurements were obtained at the time of admission to the study. Body composition was determined by whole-body dual-energy X-ray absorptiometry. The association between REE and 3-year survival was investigated. RESULTS: Cirrhosis etiology was classified as alcohol related (59.0%), viral (20.1%), cryptogenic (11.8%), or other (9.0%). Mean Child-Pugh and MELD indexes were 8.30 ± 2.0 and 14.38 ± 6.12, respectively. RQ showed a moderate correlation with SM (r = 0.64), while IC-measured REE was inversely associated with mortality (multivariate Cox Regression, HR = 0.88, 95% CI: 0.78; 1, p = 0.04). Among the predictive equations for REE, only Harris-Benedict yielded values close to the IC, with a positive Pearson correlation (r = 0.77), excellent accuracy (Cb = 0.98), and positive Lin's concordance correlation (CCC = 0.75). However, a large standard deviation was observed; HB-measured REE did not correlate with mortality. CONCLUSIONS: RQ and REE, as measured by IC, may be valuable tools for evaluating the severity of cirrhosis, by reflecting SM and predicting mortality, respectively. The predictive equations for REE included in this study cannot replace IC for this purpose. REGISTERED AT: www.clinicalTrials.gov (NCT02421848).

Monte Carlo simulation tool for online treatment monitoring in hadrontherapy with in-beam PET: A patient study.

Hadrontherapy is a method for treating cancer with very targeted dose distributions and enhanced radiobiological effects. To fully exploit these advantages, in vivo range monitoring systems are required. These devices measure, preferably during the treatment, the secondary radiation generated by the beam-tissue interactions. However, since correlation of the secondary radiation distribution with the dose is not straightforward, Monte Carlo (MC) simulations are very important for treatment quality assessment. The INSIDE project constructed an in-beam PET scanner to detect signals generated by the positron-emitting isotopes resulting from projectile-target fragmentation. In addition, a FLUKA-based simulation tool was developed to predict the corresponding reference PET images using a detailed scanner model. The INSIDE in-beam PET was used to monitor two consecutive proton treatment sessions on a patient at the Italian Center for Oncological Hadrontherapy (CNAO). The reconstructed PET images were updated every 10 s providing a near real-time quality assessment. By half-way through the treatment, the statistics of the measured PET images were already significant enough to be compared with the simulations with average differences in the activity range less than 2.5 mm along the beam direction. Without taking into account any preferential direction, differences within 1 mm were found. In this paper, the INSIDE MC simulation tool is described and the results of the first in vivo agreement evaluation are reported. These results have justified a clinical trial, in which the MC simulation tool will be used on a daily basis to study the compliance tolerances between the measured and simulated PET images.

Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers.

Identification of very long-chain acyl-CoA dehydrogenase deficiency is possible in the expanded newborn screening (NBS) due to the increase in tetradecenoylcarnitine (C14:1) and in the C14:1/C2, C14:1/C16, C14:1/C12:1 ratios detected in dried blood spots. Nevertheless, different confirmatory tests must be performed to confirm the final diagnosis. We have revised the NBS results and the results of the confirmatory tests (plasma acylcarnitine profiles, molecular findings, and lymphocytes VLCAD activity) for 36 cases detected in three Spanish NBS centers during 4 years, correlating these with the clinical outcome and treatment. Our aim was to distinguish unambiguously true cases from disease carriers in order to obtain useful diagnostic information for clinicians that can be applied in the follow-up of neonates identified by NBS.Increases in C14:1 and of the different ratios, the presence of two pathogenic mutations, and deficient enzyme activity in lymphocytes (<12% of the intra-assay control) identified 12 true-positive cases. These cases were given nutritional therapy and all of them are asymptomatic, except one. Seventeen individuals were considered disease carriers based on the mild increase in plasma C14:1, in conjunction with the presence of only one mutation and/or intermediate residual activity (18-57%). In addition, seven cases were classified as false positives, with normal biochemical parameters and no mutations in the exonic region of ACADVL. All these carriers and the false positive cases remained asymptomatic. The combined evaluation of the acylcarnitine profiles, genetic results, and residual enzyme activities have proven useful to definitively classify individuals with suspected VLCAD deficiency into true-positive cases and carriers, and to decide which cases need treatment.

Anthracycline-based triplets do not improve the efficacy of platinum-fluoropyrimidine doublets in first-line treatment of advanced gastric cancer: real-world data from the AGAMEMON National Cancer Registry.

BACKGROUND: Although anthracycline-based triplets are one of the most widely used schedules to treat advanced gastric cancer (AGC), the benefit of including epirubicin in these therapeutic combinations remains unknown. This study aims to evaluate both the efficacy and tolerance of triplets with epirubicin vs. doublets with platinum-fluoropyrimidine in a national AGC registry. METHODS: Patients with AGC treated with polychemotherapy without trastuzumab at 28 hospitals in Spain between 2008 and 2016 were included. The effect of anthracycline-based triplets against doublets was evaluated by propensity score matching (PSM) and Cox proportional hazards (PH) regression. RESULT: A total of 1002 patients were included (doublets, n = 653; anthracycline-based triplets, n = 349). The multivariable Cox PH regression failed to detect significantly increased OS in favor of triplets with anthracyclines: HR 0.90 (95% CI, 0.78-1.05), p = 0.20035. After PSM, the sample contained 325 pairs with similar baseline characteristics. This method was also unable to reveal an increase in OS: 10.5 (95% CI, 9.7-12.3) vs. 9.9 (95% CI, 9.2-11.4) months, HR 0.91 (CI 95%, 0.76-1.083), and (log-rank test, p = 0.226). Response rates (42.1 vs. 33.1%, p = 0.12) and PFS (HR 0.95, CI 95%, 0.80-1.13, log-rank test, p = 0.873) were not significantly higher with epirubicin-based regimens. The triplets were associated with greater grade 3-4 hematological toxicity, and increased hospitalization due to toxicity by 68%. The addition of epirubicin is viable, but 23.7% discontinued treatment because of adverse effects or patient decision. CONCLUSION: Anthracyclines added to platinum-fluoropyrimidine doublets did not improve the response rate or survival outcomes in patients with AGC but entailed greater toxicity.

Helium ions at the heidelberg ion beam therapy center: comparisons between FLUKA Monte Carlo code predictions and dosimetric measurements.

In the field of particle therapy helium ion beams could offer an alternative for radiotherapy treatments, owing to their interesting physical and biological properties intermediate between protons and carbon ions. We present in this work the comparisons and validations of the Monte Carlo FLUKA code against in-depth dosimetric measurements acquired at the Heidelberg Ion Beam Therapy Center (HIT). Depth dose distributions in water with and without ripple filter, lateral profiles at different depths in water and a spread-out Bragg peak were investigated. After experimentally-driven tuning of the less known initial beam characteristics in vacuum (beam lateral size and momentum spread) and simulation parameters (water ionization potential), comparisons of depth dose distributions were performed between simulations and measurements, which showed overall good agreement with range differences below 0.1 mm and dose-weighted average dose-differences below 2.3% throughout the entire energy range. Comparisons of lateral dose profiles showed differences in full-width-half-maximum lower than 0.7 mm. Measurements of the spread-out Bragg peak indicated differences with simulations below 1% in the high dose regions and 3% in all other regions, with a range difference less than 0.5 mm. Despite the promising results, some discrepancies between simulations and measurements were observed, particularly at high energies. These differences were attributed to an underestimation of dose contributions from secondary particles at large angles, as seen in a triple Gaussian parametrization of the lateral profiles along the depth. However, the results allowed us to validate FLUKA simulations against measurements, confirming its suitability for 4He ion beam modeling in preparation of clinical establishment at HIT. Future activities building on this work will include treatment plan comparisons using validated biological models between proton and helium ions, either within a Monte Carlo treatment planning engine based on the same FLUKA code, or an independent analytical planning system fed with a validated database of inputs calculated with FLUKA.