Robustness of carbon-ion radiotherapy against DNA damage repair associated radiosensitivity variation based on a biophysical model.

BACKGROUND: Interpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome. PURPOSE: To apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient-to-patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches. METHODS AND MATERIALS: The "UNIfied and VERSatile bio response Engine" (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance. RESULTS: UNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R2 > 0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of D 50 ${{D}_{50}}$ in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de-escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a D 2 ${{D}_2}$ of 2.65 to 1.64 Gy, which lies below the level found for CIRT ( D 2 ${{D}_2}$  = 2.41 Gy) for the analyzed plan and parameters. However, even after de-escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT ( D m e a n ${{D}_{mean}}$ of 0.75, 0.46, and 0.24 Gy for the conventional plan, its de-escalation and CIRT, respectively). CONCLUSIONS: The framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de-escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT.

Reversible dementia and insomnia in ABGA related encephalitis.

BACKGROUND: ABGAs are historically associated with Encephalitis Lethargica (EL). Typically ABGAs are also found in children resulting in a variety of neuropsychiatric and extrapyramidal disorders, rare cases are reported in adults with atypical movement disorders. No description of basal ganglia reversible lesions related to ABGAs are reported and these antibodies are not included in the list of autoimmune encephalitis. METHODS AND RESULTS: A 55 years old female presented sub-acute onset of an anxious-depressive disorder and obsessive-compulsive behavior associated with intractable insomnia affecting sleep onset and sleep maintenance. Brain-MRI showed diffuse hyperintensities on FLAIR sequences in the basal ganglia. A therapy with IV-immunoglobulin was started and the clinical condition improved dramatically and insomnia and psychiatric symptoms resolved completely. CONCLUSION: Our case highlights the importance of making a fast diagnosis. When caught early ABGAs-related encephalitis is susceptible of a good outcome and response to treatment. Reversible insomnia and dementia in our case expand ABGA clinical presentation in adults and favors the hypothesis of an immune pathogenesis for Encephalitis Lethargica, especially in the hyperkinetic form as previously suggested, as in our case.

Status epilepticus: Is there a Stage 1 plus?

In status epilepticus (SE), "time is brain." Currently, first-line therapy consists of benzodiazepines (BDZs) and SE is classified by the response to treatment; stage 2 or established SE is defined as "BDZ-resistant SE." Nonetheless, this classification does not always work, especially in the case of prolonged convulsive SE, where many molecular changes occur and γ-aminobutyric acid signaling becomes excitatory. Under these circumstances, BDZ therapy might not be optimal, and might be possibly detrimental, if given alone; as the duration of SE increases, so too does BDZ resistance. Murine models of SE showed how these cases might benefit more from synergistic combined therapy from the start. The definition of Stage 1 plus is suggested, as a stage requiring combined therapy from the start, which includes prolonged SE with seizure activity going on for >10 min, the time that marks the disruption of receptor homeostasis, with increased internalization. This specific stage might require a synergistic approach from the start, with a combination of first- and second-line treatment.

The Dark side of the White Matter. Diffuse subcortical White Matter Hypointensity on T2/FLAIR: A systematic review of a frequently underrecognized sign.

BACKGROUND AND OBJECTIVES: Many reversible brain MRI abnormalities have been described, among these the most frequently reported are cortical hyperintensities on FLAIR/T2 occurring during seizures. Much less attention has been given to those situations where White Matter goes Dark: subcortical white matter hypointensity on T2/FLAIR. Our aim is to identify the medical condition "Dark White Matter" (DWM) is more frequently associated with. This is the first systematic review on DWM. METHODS: PubMed was searched in August 2023. Included studies were those reporting Diffuse Subcortical White Matter Hypointensity on T2/FLAIR. Mainly case reports were included. Individual patient-level data was included whenever available. Frequency measures of the different diseases were calculated. RESULTS: 56 studies were included, 228 patients were eligible for analysis. DWM happened in isolation, with no cortical abnormalities, in 71 cases and was associated with seizures in >61.4% of cases. The most frequently DWM-associated disease was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma. Frequency of NKH was 32%. NKH was associated with seizures in 100% of cases and the most frequently involved lobe was the occipital one. When considering only the subgroup of patients with seizures, DWM was indicative of NKH in 51.4% of cases and Encephalitis in 26.4% of cases. Key limitations are heterogeneity and missing data. DISCUSSION: DWM is frequently underdiagnosed. This sign can exist alone and it is not merely a consequence of cortical involvement. Moreover, it has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment. We also discuss the pathogenesis of DWM by finding a common link between the most frequently associated diseases.

Using the photon isoeffective dose formalism to compare and combine BNCT and CIRT in a head and neck tumour.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.

Footloose (footloose), footloose.

A 78-year-old woman without past relevant medical history presented to the emergency department for acute transient dysarthria. NIHSS was 0/42. Neurological examination revealed chorea-like movements over the left limbs, especially the foot. No other neurological signs were present. CT perfusion showed right cortical hypoperfusion due to right M2 occlusion, basal-ganglia perfusion was normal. Brain MRI revealed a small focus of restricted diffusion in the right insula, sparing basal ganglia. Based on the neuroimaging features and clinical correlation, despite the NIHSS score, we decided to treat the patient with alteplase, after iv-thrombolysis hyperkinetic movements ceased completely. Brain-MRI performed 72 h after symptom onset confirmed a confined insular ischemic lesion without the involvement of deep gray matter structures. Hyperkinetic movement disorders, such as hemichorea hemiballismus, are rare presentations of stroke, basal ganglia are mainly involved even if the insular cortex has been described too. Clinical decision on whether to treat ischemic stroke does not include movement disorders. Our case underscores NIHSS limitations in clinical practice.

Regional Targeted Subcutaneous Injection of Botulinum Neurotoxin Type A in Refractory Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study.

In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy of an individualized technique of subcutaneous injection of botulinum toxin type A (BoNT-A) targeted (SjBoT) to the occipital or trigeminal skin area in non-responder patients with chronic migraine (CM). Patients who had not previously responded to at least two treatments of intramuscular injections of BoNT-A were randomly assigned (2:1) to receive two subcutaneous administrations of BoNT-A (up to 200 units) with the SjBoT injection paradigm or placebo. Following the skin area where the maximum pain began, treatment was given in the trigeminal or occipital region bilaterally. The primary endpoint changed in monthly headache days from baseline to the last 4 weeks. Among 139 randomized patients, 90 received BoNT-A and 49 received placebo, and 128 completed the double-blind phase. BoNT-A significantly reduced monthly headache days versus placebo (-13.2 versus -1.2; p < 0.0001) in the majority of patients who had cutaneous allodynia. Other secondary endpoints, including measures for disability (Migraine Disability Assessment questionnaire from baseline 21.96 to 7.59 after treatment, p = 0.028), also differed. Thus, in non-responder patients with CM, BoNT-A significantly reduced migraine days when administered according to the "follow the origin of maximum pain" approach using SjBoT injection paradigm.

Particle Reirradiation of Malignant Epithelial and Neuroectodermal Sinonasal Tumors: A Case Series from CNAO.

Sinonasal cancers (SNCs) are rare and heterogeneous in histology and biological behavior. The prognosis is generally unfavorable, especially in inoperable cases. In recent years, for some histologies, such as undifferentiated sinonasal carcinoma (SNUC), multimodal treatment with a combination of induction chemotherapy, surgery, and chemo/radiotherapy (RT) has improved the prognosis. Nevertheless, still about half of the patients treated incur a recurrence, in most of the cases at the local site. Surgery with and without RT is usually the treatment choice in cases of recurrence after previous RT in combination with systemic therapy or RT in a histology-driven fashion. In the case of inoperable disease or contraindications to surgery, RT is still a valid treatment option. In this context, hadron therapy with protons (PT) or carbon ions (CIRT) is often preferred due to the physical and biological characteristics of charged particles, allowing the administration of high doses to the tumor target while sparing the surrounding healthy tissues and potentially limiting the side effects due to the high cumulative dose. In the absence of a standard of care for the recurrent setting, we aimed to investigate the role of re-RT with PT or CIRT. We retrospectively analysed 15 patients with recurrent, previously irradiated, SNCs treated at our institution between 2013 and 2020. Local control (LC) and overall survival (OS) were estimated by the Kaplan-Meier method. Acute and late toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events CTCAE version 5.0. A total of 13 patients received CIRT and 2 patients received PT. The median re-RT dose was 54 GyRBE (range 45-64 GyRBE) delivered in 3 or 4 GyRBE/fr (fraction) for the CIRT, and 2 Gy RBE/fr for the PT schedule. LC was 44% at the 1-year follow-up and 35.2% at the 3-year follow-up. OS at 1 and 3 years were 92.9% and 38.2%, respectively. Fourteen patients developed G1-G2 acute toxicity (dermatitis and mucositis), and no patients developed G3-G5. Regarding late toxicity, 10 patients encountered at maximum G1-2 events, and 4 did not experience any toxicity. Only for one patient G3 late toxicity was reported (dysphagia requiring a percutaneous endoscopic gastrostomy).

In Vitro Effects of Photon Beam and Carbon Ion Radiotherapy on the Perineural Invasion of Two Cell Lines of Neurotropic Tumours.

Primary mucosal melanoma (PMM) and pancreatic ductal adenocarcinoma (PDAC) are two aggressive malignancies, characterized by intrinsic radio-chemoresistance and neurotropism, a histological feature resulting in frequent perineural invasion (PNI), supported by neurotrophic factors secreted in the tumour microenvironment (TME), such as neurotrophin-3 (NT-3). Carbon-ion radiotherapy (CIRT) could represent an effective option in unresectable PMM and PDAC. Only a few data about the effects of CIRT on PNI in relation to NT-3 are available in the literature, despite the numerous pieces of evidence revealing the peculiar effects of this type of radiation on tumour cell migration. This in vitro study investigated for the first time the response of PMM and PDAC cells to NT-3 and evaluated the effects of conventional photon beam radiotherapy (XRT) and CIRT on cell viability, proliferation, and migration. Our results demonstrated the greater capacity of C-ions to generally decrease cell viability, proliferation, and migration, while the addition of NT-3 after both types of irradiation determined an increase in these features, maintaining a dose-dependent trend and acting more effectively as a chemoattractant than inductor in the case of migration.

Characterization of a flat-panel detector for 2D dosimetry in scanned proton and carbon ion beams.

PURPOSE: To fully characterize the flat panel detector of the new Sphinx Compact device with scanned proton and carbon ion beams. MATERIALS AND METHODS: The Sphinx Compact is designed for daily QA in particle therapy. We tested its repeatability and dose rate dependence as well as its proportionality with an increasing number of particles and potential quenching effect. Potential radiation damage was evaluated. Finally, we compared the spot characterization (position and profile FWHM) with our radiochromic EBT3 film baseline. RESULTS: The detector showed a repeatability of 1.7% and 0.9% for single spots of protons and carbon ions, respectively, while for small scanned fields it was inferior to 0.2% for both particles. The response was independent from the dose rate (difference from nominal value < 1.5%). We observed an under-response due to quenching effect for both particles, mostly for carbon ions. No radiation damage effects were observed after two months of weekly use and approximately 1350 Gy delivered to the detector. Good agreement was found between the Sphinx and EBT3 films for the spot position (central-axis deviation within 1 mm). The spot size measured with the Sphinx was larger compared to films. For protons, the average and maximum differences over different energies were 0.4 mm (3%) and 1 mm (7%); for carbon ions they were 0.2 mm (4%) and 0.4 mm (6%). CONCLUSIONS: Despite the quenching effect the Sphinx Compact fulfills the requirements needed for constancy checks and could represent a time-saving tool for daily QA in scanned particle beams.

Ecchordosis physaliphora presenting as hypnic headache.

Ecchordosis physaliphora (EP) is a rare benign congenital hamartomatous lesion originating from remnants of the notochord. EP has never been associated with hypnic headache before. We report for the first time two cases of EP associated with an hypnic headache. The latter is a form of sleep-related nocturnal headache whose pathogenesis has not been fully elucidated. A 61-year-old woman and a 41-year-old man had been complaining of a dull headache that woke them up every night for many months. In both cases, an enlarged cystic lesion in the prepontine cistern, compatible with ecchordosis physaliphora, was found on brain MRI. A diagnosis of hypnic headache secondary to EP was made. Ecchordosis physaliphora presenting as hypnic headache had never been described before. The low prevalence of both conditions (EP and HH) and their presence in two cases might suggest a possible causal association between the two conditions.

Natalizumab wearing-off symptoms: effect of extend interval dosing during Sars-CoV-2 pandemic.

BACKGROUND: Many patients treated with Natalizumab experience wearing-off symptoms (WoS) towards the end of the administration cycle. During the pandemic we advised and asked patients undergoing treatment with Natalizumab if they wanted to be shifted from a standard interval dosing (StID of 4 weeks) to an extended interval dosing (ExID of 5-6 weeks), regardless of their JCV index. Our main objective was to study prevalence and incidence of WoS when ExID was adopted. METHODS: We enrolled 86 patients, from May 2020 to January 2021, evaluated at baseline and during a 6 months follow-up with a survey focused on WoS, Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS) and MRI. RESULTS: Among the 86 patients, 32 (37.2%) reported WoS. Most common one was fatigue (93.7%). Mean EDSS was higher in the group reporting WoS (3.8 WoS vs 3.1 non-WoS, p < 0.05). Sphincterial function was the EDSS item that significantly differed between the WoS group and the non-WoS group (1.4 WoS vs 0.6 non-WoS, p < 0.001). WoS correlate with the FSS scale (p < 0.001). CONCLUSION: Adopting an extended interval dosing does not result in significantly different occurrence of WoS between the ExID and the StID populations, in our cohort of patients. Interestingly, there is a strong correlation between WoS and a higher EDSS and FSS. Safety and efficacy of Natalizumab with ExID are relatively preserved in our study.

Dosimetric validation of a GPU-based dose engine for a fast in silico patient-specific quality assurance program in light ion beam therapy.

BACKGROUND: With rapid evolutions of fast and sophisticated calculation techniques and delivery technologies, clinics are almost facing a daily patient-specific (PS) plan adaptation, which would make a conventional experimental quality assurance (QA) workflow unlikely to be routinely feasible. Therefore, in silico approaches are foreseen by means of second-check independent dose calculation systems possibly handling machine log-files. PURPOSE: To validate the in-house developed GPU-dose engine, FRoG, for light ion beam therapy (protons and carbon ions) as a second-check independent calculation system and to integrate machine log-file analysis into the patient-specific quality assurance (PSQA) program. METHODS: Spot sizes, depth-dose distributions, and absolute dose calibrations were configured into FRoG and a set of nine regular-shaped targets in combination with more than 170 clinical treatment fields were tested against pinpoint ionization chamber measurements. Both the treatment planning system DICOM RTplans and machine treatment log-files were used as input for the dose kernel in water, and a 3D local γ (1 mm/2%) index was used as the main evaluation metric. RESULTS: Calculated configuration data matched experimental measurements with submillimetric agreement. For regular-shaped targets, the unsigned average relative difference between calculated and measured dose values was less than 2% for both protons and carbon ions. The mean γ passing rate (PR) was around 98% for both particle species. For clinical treatment beams, DICOM-based recalculations showed a γ-PR more than 99% for both particle species. The same level of agreement was preserved for protons when moving to log-file-based recalculations. A score of around 95% was registered for carbon ion beams, once excluding low-quality machine log-files. Unsigned average relative difference against acquired data was less than 2% also for real clinical beams. CONCLUSIONS: FRoG was proven as an accurate and reliable tool for PSQA in scanning light ion beam therapy. The proposed method allows for an extremely efficient workflow, without compromising the quality of the plan verification procedure.

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO.

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan.

Olamkicept(sgp130Fc): The missing trial in Neuromyelitis Optica Spectrum Disorder.

Satralizumab, an antibody against IL-6R, has been recently approved in Neuromyelitis optica spectrum disorder(NMOSD). Targeting IL-6 or IL-6 Receptor(like Satralizumab does) results in inhibition of both pro and anti-inflammatory pathways of IL-6. Sgp130FC(Olamkicept) is a monoclonal antibody that prevents only the proinflammatory pathway of IL-6 to be activated, and could represent a better way to target IL-6 pathway in Neuromyelitis optica spectrum disorder.

Satralizumab might not be enough. Olamkicept (sgp130Fc) in Neuromyelitis Optica Spectrum Disorder.

Satralizumab, the monoclonal antibody against IL-6R, has been approved not long ago in Neuromyelitis Optica Spectrum Disorder (NMOSD). Nonetheless, inhibiting IL-6 Receptor might not be enough, since Satralizumab results in inhibition of both pro and antiinflammatory pathways of IL-6. The detrimental role of IL-6 in NMOSD could be mainly played by the trans-signaling. Olamkicept (sgp130Fc) is a monoclonal antibody that prevents only the trans-signaling pathway of IL-6 to be activated. Targeting only the trans-signaling pathway (the pro-inflammatory one) with Olamkicept/sgp130Fc could lead to avoidance of potential harmful effect of global IL-6 blockade such as profound immunosuppression and it could also mean leaving the "good side" of IL-6 on, while turning the "bad side" off.

First application of the BIANCA biophysical model to carbon-ion patient cases.

Objective.The main objective of this work consists of applying, for the first time, the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model to the RBE calculation for C-ion cancer patients, and comparing the outcomes with those obtained by the LEM I model, which is applied in clinics. Indeed, the continuous development of heavy-ion cancer therapy requires modelling of biological effects of ion beams on tumours and normal tissues. The relative biological effectiveness (RBE) of heavy ions is higher than that of protons, with a significant variation along the beam path. Therefore, it requires a precise modelling, especially for the pencil-beam scanning technique. Currently, two radiobiological models, LEM I and MKM, are in use for heavy ions in scanned pencil-beam facilities.Approach.Utilizing an interface with the FLUKA Particle Therapy Tool, BIANCA was applied to re-calculate the RBE-weighted dose distribution for carbon-ion treatment of three patients (chordoma, head-and-neck and prostate) previously irradiated at CNAO, where radiobiological optimization was based on LEM I. The predictions obtained by BIANCA were based either on chordoma cell survival (RBEsurv), or on dicentric aberrations in peripheral blood lymphocytes (RBEab), which are indicators of late normal tissue damage, including secondary tumours. The simulation outcomes were then compared with those provided by LEM I.Main results.While in the target and in the entrance channel BIANCA predictions were lower than those obtained by LEM I, the two models provided very similar results in the considered OAR. The observed differences betweenRBEsurvandRBEab(which were also dependent on fractional dose and LET) suggest that in normal tissues the information on cell survival should be integrated by information more closely related to the induction of late damage, such as chromosome aberrations.Significance.This work showed that BIANCA is suitable for treatment plan optimization in ion-beam therapy, especially considering that it can predict both cell survival and chromosome aberrations and has previously shown good agreement with carbon-ion experimental data.

Proton Radiation Therapy for Nasopharyngeal Cancer Patients: Dosimetric and NTCP Evaluation Supporting Clinical Decision.

(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔDmean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (-12.5%), brain necrosis (-2.3%), mucositis (-3.2%), tinnitus (-8.6%), hypothyroidism (-9.3%), and trismus (-5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3-T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain.