Search

Prophylactic cranial irradiation (PCI) was recommended for limited‐stage small‐cell lung cancer (SCLC) patients with complete or partial response to primary chemoradiotherapy. But it is still controversial regarding its role in SCLC patients who have had radical resection. This meta‐analysis aims to evaluate the efficacy of PCI in resected SCLC patients. We searched PubMed, EMBASE, Web of Science, CENTRAl, and ClinicalTrials for controlled trials and cohort studies regarding PCI in postoperative SCLC patients. The correlation between PCI and post‐operative outcomes in SCLC patients, including survival and brain metastasis rate (BMR), was examined using hazard ratios (HRs) and risk ratios with corresponding 95% confidence intervals. Quality of studies was assessed by the Newcastle–Ottawa Scale (NOS), and publication bias was assessed by Begg's test. Meta‐analysis of eight studies with 2688 patients in total showed PCI was associated with improved overall survival (OS) for resected SCLC (HR: 0.65, 95% CI: 0.57–0.75, p < 0.01). In addition, subgroup analysis on three studies including 923 patients confirmed the protective role of postoperative PCI in N0 SCLC patients (HR: 0.79, 95% CI: 0.61–0.97, p < 0.05). There was also a significant reduction in BMR in the PCI group pooled from six studies (HR: 0.58, 95% CI: 0.40–0.85, p < 0.01). The use of PCI delayed brain recurrence and improved OS in patients with resected, stage I‐III SCLC. Importantly, patients with N0 SCLC can also benefit from postoperative PCI. In future studies, PCI's role in patients with resected N0 SCLC at different T stage may need to be explored. [ABSTRACT FROM AUTHOR]

Background: Posterior fossa irradiation with or without whole brain irradiation results in high doses of radiation to the thalamus, hippocampus, and putamen, structures critical to cognitive functioning. As a result, children with brain tumors treated with cranial irradiation (CRT) may experience significant cognitive late effects. We sought to determine the effect of radiation to those structures on neuropsychological outcome. Methods: Forty‐seven children with a history of posterior fossa tumor (17 treated with surgery; 11 with surgery and chemotherapy; and 19 with surgery, chemotherapy, and CRT) underwent neuroimaging and neuropsychological assessment at a mean of 4.8 years after treatment, along with 17 healthy sibling controls. The putamen, thalamus, and hippocampus were segmented on each participant's magnetic resonance imaging for diffusion indices and volumes, and in the radiation treatment group, radiation dose to each structure was calculated. Results: Performance on visuoconstruction and spatial learning and memory was lower in patient groups than controls. Volume of the thalamus, when controlling for age, was smaller in the patient group treated with CRT than other groups. Higher radiation doses to the putamen correlated with higher fractional anisotropy in that structure. Higher radiation dose to the hippocampus correlated with lower spatial learning, and higher dose to thalami and putamina to lower verbal and nonverbal reasoning. Conclusions: All children with posterior fossa tumors, regardless of treatment modality, had cognitive deficits compared to their sibling controls. Posterior fossa irradiation may affect thalamic volume and aspects of verbal and nonverbal cognitive functioning. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Whole Brain Radiation Therapy (WBRT) has been effective in the management of brain metastases, giving good local control but has shown to have potential neurocognitive effects. Assessing its effect on neurocognitive function is decisive assessing quality of life and therapeutic decision-making. METHOD: This is an observational study at R. G. Kar Medical College and Hospital from May 2022 to April 2023 involving 60 biopsy proven carcinoma patients with brain metastases fulfilling inclusion and exclusion criteria. All received 30Gray (Gy)/10# WBRT over 2 weeks. Neurocognitive function assessment using Mini Mental State Examination (MMSE) were conducted before and at 2nd, 3rd, and 6th months post WBRT. RESULTS: The study, encompassing a median age of 58, revealed 43.3% had lung primary and 35% breast primary. Mean MMSE score was 27 pre radiation. Following WBRT, a more than equals to 3-point MMSE decrease occurred in 6.6%, 11.6%, and 18.3% at 2nd, 3rd, and 6th months post radiation respectively. Neurocognitive decline was 36% for those above 50 years and 64% for those below 50 years by the 6th month. At 2nd months 88.3% patients had controlled disease having a decrease in MMSE score by 1.6, while 11.6% with uncontrolled disease showed 3.1 MMSE change and the same trend continued at 3rd and 6th month observations. CONCLUSION: WBRT is crucial for local control of brain metastases, but neurocognitive decline, especially under 50, is of major concern. Study results offers awareness for pre-treatment counseling on WBRT benefits, risks and consideration for Hippocampal Avoidance WBRT or WBRT with memantine, and requires further extensive research.

Background Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown. Methods Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided. Results Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P  < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory. Conclusion Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions. [ABSTRACT FROM AUTHOR]

Cranial radiotherapy is a major treatment for leukemia and brain tumors. Our previous study found abscopal effects of cranial irradiation could cause spermatogenesis disorder in mice. However, the exact mechanisms are not yet fully understood. In the study, adult male C57BL/6 mice were administrated with 20 Gy X-ray cranial irradiation (5 Gy per day for 4 days consecutively) and sacrificed at 1, 2 and 4 weeks. Tandem Mass Tag (TMT) quantitative proteomics of testis was combined with bioinformatics analysis to identify key molecules and signal pathways related to spermatogenesis at 4 weeks after cranial irradiation. GO analysis showed that spermatogenesis was closely related to oxidative stress and inflammation. Severe oxidative stress occurred in testis, serum and brain, while serious inflammation also occurred in testis and serum. Additionally, the sex hormones related to hypothalamic-pituitary-gonadal (HPG) axis were disrupted. PI3K/Akt pathway was activated in testis, which upstream molecule SCF/C-Kit was significantly elevated. Furthermore, the proliferation and differentiation ability of spermatogonial stem cells (SSCs) were altered. These findings suggest that cranial irradiation can cause spermatogenesis disorder through brain-blood-testicular cascade oxidative stress, inflammation and the secretory dysfunction of HPG axis, and SCF/C-kit drive this process through activating PI3K/Akt pathway.

Paediatric patients receiving cranial irradiation therapy for brain tumours are at increased risk of cerebrovascular complications. Radiation-induced moyamoya syndrome (MMS) is a well-recognised complication of this. We present a case of an 8-year-old boy with a history of medulloblastoma, who underwent surgical excision followed by post-operative adjuvant oncological treatment. Six years later, he developed cerebellar/intraventricular haemorrhage. He underwent an emergency external ventricular drain (EVD) insertion followed by posterior fossa suboccipital craniotomy. On dural opening, an abnormal vessel was visualised on the surface of the right cerebellar hemisphere, which was not disturbed. No obvious abnormalities were identified intra-operatively. Cerebral catheter angiography confirmed the presence of a right-sided occipital artery (OA) to posterior inferior cerebellar artery (PICA) extracranial to intracranial (EC-IC) bypass with a zone of the distal PICA territory supplied by this EC-IC bypass. A presumed flow aneurysm originated from the bypass in the distal PICA, identified as cause for the haemorrhage. We highlight a rare cause for intracranial haemorrhage in this cohort of patients. Children who have undergone radiotherapy may have exquisitely sensitive cerebral vasculature and need careful vigilance and evaluation for vasculopathic complications following spontaneous haemorrhage. [ABSTRACT FROM AUTHOR]

Cranial irradiation is associated with several adverse events such as endocrinopathy, growth retardation, neurocognitive impairment, secondary malignancies, cerebral vasculopathy, and potential stroke. The better side effects profile of proton beam therapy compared with that of photon radiation therapy is due to its physical properties, mainly the sharp dose fall-off after energy deposition in the Bragg peak. Despite the better toxicity profile of proton beam therapy, the risk of moyamoya syndrome still exists. We conducted a systematic review of the existing literature on moyamoya syndrome after receiving cranial radiation therapy for pediatric brain tumors to investigate the incidence of moyamoya syndrome after receiving photon versus proton radiation therapy. In this review, we report that the incidence of moyamoya syndrome after receiving proton beam therapy is almost double that of photon-induced moyamoya syndrome. Patients who received proton beam therapy for the management of pediatric brain tumors are more likely to develop moyamoya syndrome at the age of less than 5 years. Meanwhile, most patients with proton-induced moyamoya are more likely to be diagnosed within the first 2 years after the completion of their proton beam therapy. [ABSTRACT FROM AUTHOR]

Cranial radiotherapy is an important treatment for intracranial and head and neck tumors. To investigate the effects of cranial irradiation (C-irradiation) on gut microbiota and metabolomic profile, the feces, plasma and cerebral cortex were isolated after exposing mice to cranial X-ray irradiation at a dose rate of 2.33 Gy/min (5 Gy/d for 4 d consecutively). The gut microorganisms and metabolites were detected by 16 S rRNA gene sequencing method and LC-MS method, respectively. We found that compared with sham group, the gut microbiota composition changed at 2 W and 4 W after C-irradiation at the genus level. The fecal metabolomics showed that compared with Sham group, 44 and 66 differential metabolites were found to be annotated into metabolism pathways at 2 W and 4 W after C-irradiation, which were significantly enriched in the arginine and proline metabolism. Metabolome analysis of serum and cerebral cortex showed that, at 4 W after C-irradiation, the expression pattern of metabolites in serum samples of mice was similar to that of sham group, and the cerebral cortex metabolites of the two groups were completely separated. KEGG functional analysis showed that serum and brain tissue differential metabolites were respectively enriched in tryptophan metabolism, and arginine proline metabolism. The correlation analysis showed that the changes of gut microbiota genera were significantly correlated with the changes of metabolism, especially Helicobacter, which was significantly correlated with many different metabolites at 4 W after C-irradiation. These data suggested that C-irradiation could affect the gut microbiota and metabolism profile, even at relatively long times after C-irradiation.

Abstract Background We investigated the role of prophylactic cranial irradiation (PCI) in limited‐stage small‐cell lung cancer (LS‐SCLC) according to tumor response in the magnetic resonance imaging (MRI) era. Methods We retrospectively evaluated patients with LS‐SCLC without brain metastases (BMs) on MRI who achieved either complete response (CR) or partial response (PR) after initial chemoradiotherapy at our center from 2006 to 2017. Results This study comprised 116 patients (median age, 58 years; men, 92; women, 24). After initial chemoradiotherapy, 53 patients achieved CR, while 63 patients achieved PR. Eighty‐three patients received PCI. Patients who received PCI had better overall survival (OS, 5‐year: 52.5% vs. 35.1%; p = 0.012) and progression‐free survival (PFS, 5‐year: 45.0% vs. 28.2%; p = 0.001) and a lower incidence of BMs (5‐year: 18.3% vs. 39.4%; p = 0.010). In the subgroup analysis, PCI improved OS (5‐year: 67.8% vs. 46.7%, p = 0.005) and PFS (5‐year: 65.2% vs. 35.0%, p = 0.021) and decreased BM risk (5‐year: 12.1% vs. 52.4%, p = 0.002) for patients with CR. However, PCI had no benefit (5‐year OS: 40.5% vs. 35.6%, p = 0.763; 5‐year BMs: 24.6% vs. 31.9%, p = 0.561) for patients with PR. Conclusions Tumor response remained an important factor for selecting patients for PCI in the MRI era. PCI should be recommended for patients with LS‐SCLC who achieve CR after initial thoracic chemoradiotherapy.

Background: Whole Brain Radiation Therapy (WBRT) has been effective in the management of brain metastases, giving good local control but has shown to have potential neurocognitive effects. Assessing its effect on neurocognitive function is decisive assessing quality of life and therapeutic decision-making. Methods: This is an observational study at R. G. Kar Medical College and Hospital from May 2022 to April 2023 involving 60 biopsy-proven carcinoma patients with brain metastases fulfilling inclusion and exclusion criteria. All received 30Gray (Gy)/10# WBRT over 2 weeks. Neurocognitive function assessments using Mini-Mental State Examination (MMSE) were conducted before and at the 2nd, 3rd, and 6th months post-WBRT. Results: The study, encompassing a median age of 58, revealed that 43.3% had lung primary and 35% breast primary. The mean MMSE score was 27 pre-radiation. Following WBRT, a more than equal to 3-point MMSE decrease occurred in 6.6%, 11.6%, and 18.3% at the 2nd, 3rd, and 6th months post-radiation respectively. Neurocognitive decline was 36% for those above 50 years and 64% for those below 50 years by the 6th month. In 2nd month 88.3% of patients had controlled disease having a decrease in MMSE score by 1.6, while 11.6% with uncontrolled disease showed 3.1 MMSE change and the same trend continued in 3rd and 6th month observations. Conclusion: WBRT is crucial for local control of brain metastases, but neurocognitive decline, especially under 50, is of major concern. Study results offer awareness for pre-treatment counseling on WBRT benefits, risks, and consideration for Hippocampal Avoidance of WBRT or WBRT with memantine, and requires further extensive research. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the image quality of deep learning–based reconstruction (DLR), model-based (MBIR), and hybrid iterative reconstruction (HIR) algorithms for lower-dose (LD) unenhanced head CT and compare it with those of standard-dose (STD) HIR images. Methods: This retrospective study included 114 patients who underwent unenhanced head CT using the STD (n = 57) or LD (n = 57) protocol on a 320-row CT. STD images were reconstructed with HIR; LD images were reconstructed with HIR (LD-HIR), MBIR (LD-MBIR), and DLR (LD-DLR). The image noise, gray and white matter (GM-WM) contrast, and contrast-to-noise ratio (CNR) at the basal ganglia and posterior fossa levels were quantified. The noise magnitude, noise texture, GM-WM contrast, image sharpness, streak artifact, and subjective acceptability were independently scored by three radiologists (1 = worst, 5 = best). The lesion conspicuity of LD-HIR, LD-MBIR, and LD-DLR was ranked through side-by-side assessments (1 = worst, 3 = best). Reconstruction times of three algorithms were measured. Results: The effective dose of LD was 25% lower than that of STD. Lower image noise, higher GM-WM contrast, and higher CNR were observed in LD-DLR and LD-MBIR than those in STD (all, p ≤ 0.035). Compared with STD, the noise texture, image sharpness, and subjective acceptability were inferior for LD-MBIR and superior for LD-DLR (all, p < 0.001). The lesion conspicuity of LD-DLR (2.9 ± 0.2) was higher than that of HIR (1.2 ± 0.3) and MBIR (1.8 ± 0.4) (all, p < 0.001). Reconstruction times of HIR, MBIR, and DLR were 11 ± 1, 319 ± 17, and 24 ± 1 s, respectively. Conclusion: DLR can enhance the image quality of head CT while preserving low radiation dose level and short reconstruction time. Key Points: • For unenhanced head CT, DLR reduced the image noise and improved the GM-WM contrast and lesion delineation without sacrificing the natural noise texture and image sharpness relative to HIR. • The subjective and objective image quality of DLR was better than that of HIR even at 25% reduced dose without considerably increasing the image reconstruction times (24 s vs. 11 s). • Despite the strong noise reduction and improved GM-WM contrast performance, MBIR degraded the noise texture, sharpness, and subjective acceptance with prolonged reconstruction times relative to HIR, potentially hampering its feasibility. [ABSTRACT FROM AUTHOR]

Background: We investigated the role of prophylactic cranial irradiation (PCI) in limited‐stage small‐cell lung cancer (LS‐SCLC) according to tumor response in the magnetic resonance imaging (MRI) era. Methods: We retrospectively evaluated patients with LS‐SCLC without brain metastases (BMs) on MRI who achieved either complete response (CR) or partial response (PR) after initial chemoradiotherapy at our center from 2006 to 2017. Results: This study comprised 116 patients (median age, 58 years; men, 92; women, 24). After initial chemoradiotherapy, 53 patients achieved CR, while 63 patients achieved PR. Eighty‐three patients received PCI. Patients who received PCI had better overall survival (OS, 5‐year: 52.5% vs. 35.1%; p = 0.012) and progression‐free survival (PFS, 5‐year: 45.0% vs. 28.2%; p = 0.001) and a lower incidence of BMs (5‐year: 18.3% vs. 39.4%; p = 0.010). In the subgroup analysis, PCI improved OS (5‐year: 67.8% vs. 46.7%, p = 0.005) and PFS (5‐year: 65.2% vs. 35.0%, p = 0.021) and decreased BM risk (5‐year: 12.1% vs. 52.4%, p = 0.002) for patients with CR. However, PCI had no benefit (5‐year OS: 40.5% vs. 35.6%, p = 0.763; 5‐year BMs: 24.6% vs. 31.9%, p = 0.561) for patients with PR. Conclusions: Tumor response remained an important factor for selecting patients for PCI in the MRI era. PCI should be recommended for patients with LS‐SCLC who achieve CR after initial thoracic chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Purpose of the study. To analyze the physical and neuropsychiatric development of pediatric patients who underwent cranial irradiation in the period from 2015 to 2020 in the radiotherapy department of the National Research Center of Oncology and to assess the risk of post-radiation complications.Materials and methods. 17 children aged from 3 to 17 years were hospitalized under medical supervision in the department of pediatric oncology of the National Medical Research Centre for Oncology. All the children underwent a course of conformal radiation therapy totally on the brain area and the first two cervical vertebrae in the radiotherapy department of the National Medical Research Centre for Oncology. 13 patients (76.7 %) underwent radiation therapy due to the prevention of neuroleukemia with a total dose of 12 Gy (a dose per fraction was 2 Gy), 2 patients with a confirmed relapse of acute lymphoblastic leukaemia (ALL) (11.65 %), 1 patient with a confirmed diagnosis of neuroleukemia (5.8 %) and 1 patient from the high-risk group (5.8 %) – with a total dose of 18 Gy (a dose per fraction was 2 Gy). Further 75 month regular medical checkup was carried out on the basis of the Regional Children's Clinical Hospital for.Results. None of the surviving patients showed growth retardation. Two patients (11.65 %) complained of increased fatigue, decreased concentration; one patient (5.8 %) showed unmotivated irritability and aggression during the examination. Intellectual development corresponded to age in all patients (100 %). One patient (5.8 %) experienced episodes of nausea and vomiting (grade 1 on the CTCAE scale), three patients (17.7 %) suffered from headache (grade 2 on the CTCAE scale), three patients (17.7 %) complained of fever up to 38 °C (1 degree on the CTCAE scale). Two out of 17 ALL patients died due to disease progression.Conclusion. Taking into account the different time intervals between treatment and the moment of the study (from 9 to 75 months), cranial irradiation demonstrates relative safety for patients undergoing treatment during critical periods of development of both physical and neuropsychic spheres. However, an objective assessment of the development prospects is difficult due to the relatively short time after undergoing therapy (from 9 to 75 months) and a small sample of patients.

Introduction: The use of cranial re-irradiation is growing with improving overall survival and the advent of high-precision radiotherapy techniques. Still the value of re-irradiation needs careful evaluation regarding safety and efficacy. We analyzed dosimetric and clinical data of patients receiving cranial re-irradiation using EQD2 sum plans. Methods and material: We retrospectively analyzed the data of 76 patients who received repeated cranial radiotherapy from 02/2013 to 09/2016. 34 patients suffered from recurrent primary brain tumors, 42 from brain metastases. Dosimetric analysis was performed accumulating EQD2 dose distributions based on rigid image registration. Clinical and radiological data was collected at follow-ups including toxicity, local control and overall survival. Results: In total 76 patients had at least 2 courses of intracranial radiotherapy. The median accumulated prescription EQD2 dose was 96.5 Gy2 for all radiation courses combined. The median D(0.1 cc) of the brain for patients receiving more than 100 Gy2 was 114 Gy2 with a highest dose of 161.5 Gy2. 74% of patients suffered from low grade (G1–G2) acute toxicity, only two high grade (>G3) toxicities were recorded.Median overall survival from the time of first re-irradiation was 57 weeks (range 4–186 weeks). The median time to local failure for patients with a primary brain tumor was not reached and 24 weeks (range 1–77 weeks) for patients with brain metastases. Conclusion: Repeated radiotherapy appears both safe and efficient in patients with recurrent primary or secondary brain tumors with doses to the brain up to 120 Gy2 EQD2, doses below 100 Gy2 for brainstem and doses below 75 Gy2 EQD2 to chiasm and optic nerves.

Abstract Background The management of melanoma with brain metastases (MBM) is increasingly complex, especially given recent improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a longstanding radiotherapy technique for which reported patient outcomes and experiences are limited. We sought to report our institutional outcomes for MBM patients receiving WBRT and assess whether other clinical factors impact prognosis. Methods A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000 to 2018 treated with WBRT, with or without other systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), distant failure-free survival (DFFS), local failure-free survival (LFFS), and progression-free survival (PFS) were assessed. Data on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits, was also captured. Results 63 patients with MBM were ultimately included in our study. 69% of patients had 5 or more brain metastases at the time of WBRT, and 68% had extracranial disease. The median dose of WBRT was 30 Gy over 10 fractions. Median follow-up was 4.0 months. Patients receiving WBRT had a median OS of 7.0 months, median PFS of 2.2 months, median DFFS of 6.1 months, and median LFFS of 4.9 months. Performance status correlated with OS on both univariate and multivariable analysis. BRAF inhibitor was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07–0.79, p = 0.019), and this effect extended to multivariable analysis as well. Post-WBRT intralesional hemorrhage decreased DFFS on both univariate and multivariable analysis. Of patients with post-treatment brain scans available, there was a 16% rate of radionecrosis, 32% rate of hemorrhage, and 19% rate of memory deficits. Conclusions Outcomes for MBM patients receiving WBRT indicate that WBRT remains an effective treatment strategy to control intracranial disease. Treatment-related toxicities such as intralesional hemorrhage, necrosis, or neurocognitive side effects are limited. With continued innovations in WBRT technique and systemic therapy development, MBM outcomes may continue to improve. Further trials should evaluate the role of WBRT in the modern context.

Purpose: Although an increasing body of literature suggests a relationship between brain irradiation and deterioration of neurocognitive function, it remains as the standard therapeutic and prophylactic modality in patients with brain tumors. This review was aimed to abstract and evaluate the prediction models for radiation-induced neurocognitive decline in patients with primary or secondary brain tumors. Methods: MEDLINE was searched on October 31, 2021 for publications containing relevant truncation and MeSH terms related to "radiotherapy," "brain," "prediction model," and "neurocognitive impairments." Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool. Results: Of 3,580 studies reviewed, 23 prediction models were identified. Age, tumor location, education level, baseline neurocognitive score, and radiation dose to the hippocampus were the most common predictors in the models. The Hopkins verbal learning (n = 7) and the trail making tests (n = 4) were the most frequent outcome assessment tools. All studies used regression (n = 14 linear, n = 8 logistic, and n = 4 Cox) as machine learning method. All models were judged to have a high risk of bias mainly due to issues in the analysis. Conclusion: Existing models have limited quality and are at high risk of bias. Following recommendations are outlined in this review to improve future models: developing cognitive assessment instruments taking into account the peculiar traits of the different brain tumors and radiation modalities; adherence to model development and validation guidelines; careful choice of candidate predictors according to the literature and domain expert consensus; and considering radiation dose to brain substructures as they can provide important information on specific neurocognitive impairments. [ABSTRACT FROM AUTHOR]

PurposeAlthough an increasing body of literature suggests a relationship between brain irradiation and deterioration of neurocognitive function, it remains as the standard therapeutic and prophylactic modality in patients with brain tumors. This review was aimed to abstract and evaluate the prediction models for radiation-induced neurocognitive decline in patients with primary or secondary brain tumors.MethodsMEDLINE was searched on October 31, 2021 for publications containing relevant truncation and MeSH terms related to “radiotherapy,” “brain,” “prediction model,” and “neurocognitive impairments.” Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool.ResultsOf 3,580 studies reviewed, 23 prediction models were identified. Age, tumor location, education level, baseline neurocognitive score, and radiation dose to the hippocampus were the most common predictors in the models. The Hopkins verbal learning (n = 7) and the trail making tests (n = 4) were the most frequent outcome assessment tools. All studies used regression (n = 14 linear, n = 8 logistic, and n = 4 Cox) as machine learning method. All models were judged to have a high risk of bias mainly due to issues in the analysis.ConclusionExisting models have limited quality and are at high risk of bias. Following recommendations are outlined in this review to improve future models: developing cognitive assessment instruments taking into account the peculiar traits of the different brain tumors and radiation modalities; adherence to model development and validation guidelines; careful choice of candidate predictors according to the literature and domain expert consensus; and considering radiation dose to brain substructures as they can provide important information on specific neurocognitive impairments.

TRACT A case of recurrent nasopharyngeal cancer with osteonecrosis of clivus along with cranial nerve palsy after re-irradiation with a fatal outcome is presented. A 33-year-old female is presented with palpable bilateral enlarged lymph nodes. A mass in the endoscopy of the nasopharynx was biopsied. Histological investigation of the biopsy specimens showed non-keratinized differentiated squamous cell carcinoma. According to the American Joint Committee on Cancer 8th edition, her cancer was T1N2M0 Stage 3. Radiotherapy was delivered after the induction chemotherapy. After 4 years, she had a recurrence and 60 Gy re-irradiation in 30 fractions was delivered after 8 months from recurrence. Six months from re-irradiation; first, bulbar palsy was observed in our patient, magnetic resonance imaging revealed radiotherapy-related osteonecrosis and platybasia due to anterior compression of the cervicomedullary junction. Re-irradiation local control rates are increasing with the advancements of new radiation techniques. As the survival of re-irradiated patients increases, late complications can be fatal. [ABSTRACT FROM AUTHOR]

Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a high-grade lung neuroendocrine tumor with a poor prognosis, similar to small cell lung cancer (SCLC). However, it remains unclear whether to treat LCNEC as non-small-cell lung cancer (NSCLC) or as SCLC. We reviewed our experiences to suggest appropriate treatment strategy for resected pulmonary LCNEC. Materials and Methods: Forty-four patients were treated for pathologically diagnosed pulmonary LCNEC during 2005–2018. We considered curative surgery first in early-stage or some locally advanced tumors, unless medically inoperable. Adjuvant treatments were decided considering patient’s clinical and pathological features. After excluding two stage I tumors with radiotherapy alone and three stage III tumors with upfront chemotherapy, we analyzed 39 patients with stage I–III pulmonary LCNEC, who underwent curative resection first. Results: Adjuvant chemotherapy (NSCLC-based 91%, SCLC-based 9%) was performed in 62%, and adjuvant radiotherapy was done in three patients for pN2 or positive margin. None received prophylactic cranial irradiation (PCI). With a median follow-up of 30 months, the 2- and 5-year overall survival (OS) rates were 68% and 51%, and the 2- and 5-year recurrence-free survival (RFS) rates were 49% and 43%, respectively. Aged ≥67 years and SCLC-mixed pathology were significant poor prognostic factors for OS or RFS (p < 0.05). Among 17 recurrences, regional failures were most common (n = 6), and there were five brain metastases. Conclusions: Surgery and adjuvant treatment (without PCI) could achieve favorable outcomes in pulmonary LCNEC, which was more similar to NSCLC, although some factors worsened the prognosis. The importance of intensified adjuvant therapies with multidisciplinary approach remains high. [ABSTRACT FROM AUTHOR]

To investigate whether the abscopal effects of cranial irradiation (C-irradiation) cause testicular damage in mice, male C57BL/6 mice (9weeks of age) were randomly divided into a sham irradiation group, a shielded group and a C-irradiation group and administered sham/shielded irradiation or C-irradiation at a dose rate of 2.33Gy/min (5Gy/d for 4 d consecutively). All mice were sacrificed at 4weeks after C-irradiation. We calculated the testis index, observed testicular histology by haematoxylin-eosin (HE) staining and observed testicular ultrastructure by transmission electron microscopy. Western blotting was used to determine the protein levels of Bax, Bcl-2, Cleaved caspase 3, glial cell line-derived neurotrophic factor (GDNF) and stem cell factor (SCF) in the testes of mice. Immunofluorescence staining was performed to detect the expression of Cleaved caspase 3 and 3β hydroxysteroid dehydrogenase (3βHSD), and a TUNEL assay was used to confirm the location of apoptotic cells. The levels of testosterone (T), GDNF and SCF were measured by ELISA. We also evaluated the sperm quality in the cauda epididymides by measuring the sperm count, abnormality, survival rate and apoptosis rate. The results showed that there was no significant difference in testicular histology, ultrastructure or sperm quality between the shielded group and sham group. Compared with the sham/shielded group, the C-irradiation group exhibited a lower testis index and severely damaged testicular histology and ultrastructure at 4weeks after C-irradiation. The levels of apoptosis in the testes increased markedly in the C-irradiation group, especially in spermatogonial stem cells. The levels of serum T and testicular 3βHSD did not obviously differ between the sham group and the C-irradiation group, but the levels of GDNF and SCF in the testes increased in the C-irradiation group, compared with the sham group. In addition, the sperm count and survival rate decreased in the C-irradiation group, while the abnormality and apoptosis rate increased. Under these experimental conditions, the abscopal effects of C-irradiation induced testicular damage with regard to both structure and function and ultimately decreased sperm quality in mice. These findings provide novel insights into prevention and treatment targets for male reproductive damage induced by C-irradiation.

To investigate whether the abscopal effects of cranial irradiation (C-irradiation) cause testicular damage in mice, male C57BL/6 mice (9weeks of age) were randomly divided into a sham irradiation group, a shielded group and a C-irradiation group and administered sham/shielded irradiation or C-irradiation at a dose rate of 2.33Gy/min (5Gy/d for 4 d consecutively). All mice were sacrificed at 4weeks after C-irradiation. We calculated the testis index, observed testicular histology by haematoxylin-eosin (HE) staining and observed testicular ultrastructure by transmission electron microscopy. Western blotting was used to determine the protein levels of Bax, Bcl-2, Cleaved caspase 3, glial cell line-derived neurotrophic factor (GDNF) and stem cell factor (SCF) in the testes of mice. Immunofluorescence staining was performed to detect the expression of Cleaved caspase 3 and 3β hydroxysteroid dehydrogenase (3βHSD), and a TUNEL assay was used to confirm the location of apoptotic cells. The levels of testosterone (T), GDNF and SCF were measured by ELISA. We also evaluated the sperm quality in the cauda epididymides by measuring the sperm count, abnormality, survival rate and apoptosis rate. The results showed that there was no significant difference in testicular histology, ultrastructure or sperm quality between the shielded group and sham group. Compared with the sham/shielded group, the C-irradiation group exhibited a lower testis index and severely damaged testicular histology and ultrastructure at 4weeks after C-irradiation. The levels of apoptosis in the testes increased markedly in the C-irradiation group, especially in spermatogonial stem cells. The levels of serum T and testicular 3βHSD did not obviously differ between the sham group and the C-irradiation group, but the levels of GDNF and SCF in the testes increased in the C-irradiation group, compared with the sham group. In addition, the sperm count and survival rate decreased in the C-irradiation group, while the abnormality and apoptosis rate increased. Under these experimental conditions, the abscopal effects of C-irradiation induced testicular damage with regard to both structure and function and ultimately decreased sperm quality in mice. These findings provide novel insights into prevention and treatment targets for male reproductive damage induced by C-irradiation. [ABSTRACT FROM AUTHOR]

Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions in mice. Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus. Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice. Conclusion: LW-AFC ameliorates cranial irradiation–induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy. [ABSTRACT FROM AUTHOR]

Cranial radiotherapy is a major treatment for leukemia and brain tumors. Our previous study found abscopal effects of cranial irradiation could cause spermatogenesis disorder in mice. However, the exact mechanisms are not yet fully understood. In the study, adult male C57BL/6 mice were administrated with 20 Gy X-ray cranial irradiation (5 Gy per day for 4 days consecutively) and sacrificed at 1, 2 and 4 weeks. Tandem Mass Tag (TMT) quantitative proteomics of testis was combined with bioinformatics analysis to identify key molecules and signal pathways related to spermatogenesis at 4 weeks after cranial irradiation. GO analysis showed that spermatogenesis was closely related to oxidative stress and inflammation. Severe oxidative stress occurred in testis, serum and brain, while serious inflammation also occurred in testis and serum. Additionally, the sex hormones related to hypothalamic-pituitary-gonadal (HPG) axis were disrupted. PI3K/Akt pathway was activated in testis, which upstream molecule SCF/C-Kit was significantly elevated. Furthermore, the proliferation and differentiation ability of spermatogonial stem cells (SSCs) were altered. These findings suggest that cranial irradiation can cause spermatogenesis disorder through brain-blood-testicular cascade oxidative stress, inflammation and the secretory dysfunction of HPG axis, and SCF/C-kit drive this process through activating PI3K/Akt pathway. • Cranial irradiation altered protein profile of testis related to spermatogenesis. • Cranial irradiation triggered brain-blood-testis cascade response. • Hypothalamic-pituitary-gonadal axis mediated spermatogenesis disorder. [ABSTRACT FROM AUTHOR]

Abstract Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long‐term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell‐based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell‐derived growth factor and significant attenuation of radiation‐induced increases in postsynaptic density protein 95 and activated microglia were found ipsi‐ and contra‐lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC‐derived EVs. These findings document potent far‐reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation.

Despite advancements in the radiotherapeutic management of brain malignancies, resultant sequelae include persistent cognitive dysfunction in the majority of survivors. Defining the precise causes of normal tissue toxicity has proven challenging, but the use of preclinical rodent models has suggested that reductions in neurogenesis and microvascular integrity, impaired synaptic plasticity, increased inflammation, and alterations in neuronal structure are contributory if not causal. As such, strategies to reverse these persistent radiotherapy-induced neurological disorders represent an unmet medical need. AM251, a cannabinoid receptor 1 reverse agonist known to facilitate adult neurogenesis and synaptic plasticity, may help to ameliorate radiation-induced CNS impairments. To test this hypothesis, three treatment paradigms were used to evaluate the efficacy of AM251 to ameliorate radiation-induced learning and memory deficits along with disruptions in mood at 4 and 12 weeks postirradiation. Results demonstrated that acute (four weekly injections) and chronic (16 weekly injections) AM251 treatments (1 mg/kg) effectively alleviated cognitive and mood dysfunction in cranially irradiated mice. The beneficial effects of AM251 were exemplified by improved hippocampal- and cortical-dependent memory function on the novel object recognition and object in place tasks, while similar benefits on mood were shown by reductions in depressive- and anxiety-like behaviors on the forced swim test and elevated plus maze. The foregoing neurocognitive benefits were associated with significant increases in newly born (doublecortin+) neurons (1.7-fold), hippocampal neurogenesis (BrdU+/NeuN+mature neurons, 2.5-fold), and reduced expression of the inflammatory mediator HMGB (1.2-fold) in the hippocampus of irradiated mice. Collectively, these findings indicate that AM251 ameliorates the effects of clinically relevant cranial irradiation where overall neurological benefits in memory and mood coincided with increased hippocampal cell proliferation, neurogenesis, and reduced expression of proinflammatory markers.

The kynurenine pathway (KP, IDO/Kyn pathway) is an important metabolic pathway related to many diseases. Although cranial radiotherapy is the mainstay in metastatic tumors management, its efficacy is limited owing to the associated neuropsychiatric disorders. Sildenafil (SD) and simvastatin (SV) were reported to have antioxidant/anti-inflammatory effects and to serve as NO donor/BH4 regulator, respectively. Fluoxetine (Fx) is an FDA-approved anti-depressant agent and one of the selective serotonin reuptake inhibitor drugs (SSRI), used in neurological disorder treatment. The study objective was to investigate the role of cranial irradiation (C-IR) on KP signaling impairment and the possible intervention by SD and/or SV (as nitric oxide (NO) donor/Tetrahydrobiopterin (BH4) regulatory) on KP following C-IR-induced disruption compared with Fx (as standard drug).Herein, rats were exposed to C-IR at a single dose level of 25 Gy, then treated with sildenafil (SD) and/or simvastatin (SV), and fluoxetine (Fx) at doses of 75, 20, 10 mg/kg/day, respectively. The body weight gain and forced swimming test (FST) were used for evaluation along with the biochemical quantifications of KP intermediates and histopathological examination of cortex and hippocampus. The results indicated a significant activation of KP following C-IR as manifested by decreased Trp content and increased activities of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) with a rise in kynurenine (KYN) and quinolinic acid (QA) hippocampal contents. In addition, a state of C-IR-induced oxidative stress, inflammation, NO-pathway dysregulation and neuronal apoptosis were observed as compared to the control group. However, significant modulations were recorded after the combined administration of SD and SV than those offered by each of them alone and by Fx. The biochemical assessment results were supported by the histopathological tissue examination. It could be concluded that the co-administration of SV and SD offers a neuroprotective effect against irradiation-induced brain injury due to its NO donor/BH4 regulatory activities, anti-inflammatory and antioxidant properties that modulate IDO/KYN pathway. [ABSTRACT FROM AUTHOR]

Despite advancements in the radiotherapeutic management of brain malignancies, resultant sequelae include persistent cognitive dysfunction in the majority of survivors. Defining the precise causes of normal tissue toxicity has proven challenging, but the use of preclinical rodent models has suggested that reductions in neurogenesis and microvascular integrity, impaired synaptic plasticity, increased inflammation, and alterations in neuronal structure are contributory if not causal. As such, strategies to reverse these persistent radiotherapy-induced neurological disorders represent an unmet medical need. AM251, a cannabinoid receptor 1 reverse agonist known to facilitate adult neurogenesis and synaptic plasticity, may help to ameliorate radiation-induced CNS impairments. To test this hypothesis, three treatment paradigms were used to evaluate the efficacy of AM251 to ameliorate radiation-induced learning and memory deficits along with disruptions in mood at 4 and 12 weeks postirradiation. Results demonstrated that acute (four weekly injections) and chronic (16 weekly injections) AM251 treatments (1 mg/kg) effectively alleviated cognitive and mood dysfunction in cranially irradiated mice. The beneficial effects of AM251 were exemplified by improved hippocampal- and cortical-dependent memory function on the novel object recognition and object in place tasks, while similar benefits on mood were shown by reductions in depressive- and anxiety-like behaviors on the forced swim test and elevated plus maze. The foregoing neurocognitive benefits were associated with significant increases in newly born (doublecortin+) neurons (1.7-fold), hippocampal neurogenesis (BrdU+/NeuN+mature neurons, 2.5-fold), and reduced expression of the inflammatory mediator HMGB (1.2-fold) in the hippocampus of irradiated mice. Collectively, these findings indicate that AM251 ameliorates the effects of clinically relevant cranial irradiation where overall neurological benefits in memory and mood coincided with increased hippocampal cell proliferation, neurogenesis, and reduced expression of proinflammatory markers. [ABSTRACT FROM AUTHOR]

Summary: Cranial irradiation (IR) is an effective adjuvant therapy in the treatment of childhood brain tumors but results in long-lasting cognitive deficits associated with impaired neurogenesis, as evidenced in rodent models. Metformin has been shown to expand the endogenous neural stem cell (NSC) pool and promote neurogenesis under physiological conditions and in response to neonatal brain injury, suggesting a potential role in neurorepair. Here, we assess whether metformin pretreatment, a clinically feasible treatment for children receiving cranial IR, promotes neurorepair in a mouse cranial IR model. Using immunofluorescence and the in vitro neurosphere assay, we show that NSCs are depleted by cranial IR but spontaneously recover, although deficits to proliferative neuroblasts persist. Metformin pretreatment enhances the recovery of neurogenesis, attenuates the microglial response, and promotes recovery of long-term olfactory memory. These findings indicate that metformin is a promising candidate for further preclinical and clinical investigations of neurorepair in childhood brain injuries.

Background and Purpose: Brain metastasis is among the leading causes of death in patients with non-small-cell lung cancer (NSCLC). Through yet unknown mechanisms, prophylactic cranial irradiation (PCI) can significantly decrease the incidence of brain metastases. Given that PCI probably exerts indirect anti-tumoral effects by turning cerebral "soil" unfavorable for the colonization of metastatic tumor "seeds". This study aims to reveal how PCI regulates the brain microenvironment conducing to a reduction in brain metastases. Materials and Methods: Key markers of M1/M2 microglia types and mesenchymal-to-epithelial transition (MET) were analyzed by qRT-PCR and Western Blot in vitro. The target miR-9 was obtained by miRNA array analysis and confirmed by qRT-PCR in microglia. We used miRTarBase and TargetScan to analyze the target genes of miR-9 and confirmed by luciferase activity assay. Anti-metastatic effects of irradiation on the brain were evaluated by intravital imaging using a brain metastatic A549-F3 cell line in a nude mouse model. Results: Irradiation induced M1 microglia activation, which inhibited the MET process of A549 cell lines. Furthermore, levels of miR-9 secreted by irradiated M1 microglia significantly increased and played a vital role in the inhibition of the A549 MET process by directly targeting CDH1, concurrently decreasing cell capacity for localization in the brain, thus reducing brain metastases. Conclusion: We demonstrated that miR-9 secreted by irradiated M1-type microglia played an important role in modulating A549 cell lines into mesenchymal phenotype and further decreased their localization capabilities in the brain. Our findings signify the modulating effect of irradiation on metastatic soil and the cross-talk between tumour cells and the metastatic microenvironment; importantly, they provide new opportunities for effective anti-metastasis therapies, especially for brain metastasis patients. [ABSTRACT FROM AUTHOR]

Background: The management of melanoma with brain metastases (MBM) is increasingly complex, especially given recent improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a longstanding radiotherapy technique for which reported patient outcomes and experiences are limited. We sought to report our institutional outcomes for MBM patients receiving WBRT and assess whether other clinical factors impact prognosis.Methods: A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000 to 2018 treated with WBRT, with or without other systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), distant failure-free survival (DFFS), local failure-free survival (LFFS), and progression-free survival (PFS) were assessed. Data on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits, was also captured.Results: 63 patients with MBM were ultimately included in our study. 69% of patients had 5 or more brain metastases at the time of WBRT, and 68% had extracranial disease. The median dose of WBRT was 30 Gy over 10 fractions. Median follow-up was 4.0 months. Patients receiving WBRT had a median OS of 7.0 months, median PFS of 2.2 months, median DFFS of 6.1 months, and median LFFS of 4.9 months. Performance status correlated with OS on both univariate and multivariable analysis. BRAF inhibitor was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07-0.79, p = 0.019), and this effect extended to multivariable analysis as well. Post-WBRT intralesional hemorrhage decreased DFFS on both univariate and multivariable analysis. Of patients with post-treatment brain scans available, there was a 16% rate of radionecrosis, 32% rate of hemorrhage, and 19% rate of memory deficits.Conclusions: Outcomes for MBM patients receiving WBRT indicate that WBRT remains an effective treatment strategy to control intracranial disease. Treatment-related toxicities such as intralesional hemorrhage, necrosis, or neurocognitive side effects are limited. With continued innovations in WBRT technique and systemic therapy development, MBM outcomes may continue to improve. Further trials should evaluate the role of WBRT in the modern context. [ABSTRACT FROM AUTHOR]

Cranial radiotherapy has several side effects. One of the most important complications is radiation caries that endangers the treatment prognosis. In the literature, the use of crowns and bridges for irradiated patients has been suggested as a contraindication. In addition, due to the risk of osteoradionecrosis (ORN), there are doubts about tooth extraction and implant placement. Here, we present a treatment sequence and recalls for an irradiated young patient. For irradiated patients, it is recommended to replace teeth with implants when there is no possibility for supragingival prosthetic margin.

Abstract With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3–3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4–17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.

Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long‐term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6 Gy whole‐head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20 weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation‐related pathways were up‐regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid‐stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction‐related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation. [ABSTRACT FROM AUTHOR]

Summary: We investigated the long‐term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high‐risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non‐inferiority EORTC 58832 study (1983–1989). Median follow‐up was 20 years (range 4–32 years). The 25‐year disease‐free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25‐year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28–1·79]; test of non‐inferiority: P = 0·01} was not increased without CRT. The 25‐year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25‐year event‐free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57–1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53–1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective study compares higher-dose whole-brain radiotherapy (hdWBRT) with reduced-dose WBRT (rdWBRT) in terms of clinical efficacy and toxicity profile in patients treated for primary central nervous system lymphoma (PCNSL). Materials and Methods: Radiotherapy followed by high-dose methotrexate (HD-MTX)-based chemotherapy was administered to immunocompetent patients with histologically confirmed PCNSL between 2000 and 2016. Response to chemotherapy was taken into account when prescribing the radiation dose to the whole brain and primary tumor bed. The whole brain dose was =23.4 Gy for rdWBRT (n = 20) and >23.4 Gy for hdWBRT (n = 68). Patients manifesting cognitive disturbance, memory impairment and dysarthria were considered to have neurotoxicity. A median follow-up was 3.62 years. Results: The 3-year overall survival (OS) and progression-free survival (PFS) were 70.0% and 48.9% with rdWBRT, and 63.2% and 43.2% with hdWBRT. The 3-year OS and PFS among patients with partial response (n = 45) after chemotherapy were 77.8% and 53.3% with rdWBRT, and 58.3% and 45.8% with hdWBRT (p > 0.05). Among patients with complete response achieved during follow-up, the 3-year freedom from neurotoxicity (FFNT) rate was 94.1% with rdWBRT and 62.4% with hdWBRT. Among patients aged =60 years, the 3-year FFNT rate was 87.5% with rdWBRT and 39.1% with hdWBRT (p = 0.49). Neurotoxicity was not observed after rdWBRT in patients aged below 60 years. Conclusion: rdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in partial response after chemotherapy. [ABSTRACT FROM AUTHOR]

Copyright of Oncologist is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

• The DS-GPA is widely used to predict survival of brain metastases patients. • Validation of this model is necessary in a subgroup treated with SRS. • The DS-GPA performs well in classifying patients into prognostic subgroups. • The predicted median survival should not be communicated as a point-prediction. Multiple prognostic models for predicting survival after treatment for brain metastases have been developed. One of them, the diagnosis-specific Graded Prognostic Assessment (DS-GPA), has been developed to predict the median survival for brain metastases from the most frequent primary sites: lung carcinoma, breast cancer, melanoma, renal cell cancer and gastrointestinal tumours. In this study we aim to compare the survival predicted by the DS-GPA to actual survival, and to assess this models performance on both population and individual levels. We identified a consecutive cohort of patients treated with SRS for brain metastases in our institute. DS-GPA scores were calculated for each patient, and the median survival for each DS-GPA group was calculated. Differences in survival between DS-GPA groups were tested with Wilcoxon Signed Rank tests and log-rank tests. In total 367 patients were included in the analysis. Median survival in our cohort is largely comparable to corresponding DS-GPA cohorts, but some notable differences are present. There was a significantly shorter median survival (15.4 months, compared to 26.5 months) in the adenocarcinoma NSCLC subgroup with a GPA score of 2.3–3. We confirmed the significant differences in survival time for most cancer-specific subgroups. DS-GPA seems to be a reliable tool to classify patients with brain metastases treated with SRS into prognostic subgroups. However, we found some aberrations from predicted median survival times, which may be due to specific characteristics of the populations of patients treated with SRS versus other patients. [ABSTRACT FROM AUTHOR]

• New RT innovations enable sparing of brain areas susceptible to radiation damage. • Interest in the effect of radiation therapy on the cerebral cortex has increased. • We found papers with great heterogeneity and lacking in methodological strength. • More robust research is needed to make recommendations for clinical practice. Cognitive decline has a clear impact on quality of life in patients who have received cranial radiation treatment. The pathophysiological process is most likely multifactorial, with a possible role for decreased cortical thickness and volume. As radiotherapy treatment systems are becoming more sophisticated, precise sparing of vulnerable regions and tissue is possible. This allows radiation oncologists to make treatment more patient-tailored. A systematic search was performed to collect and review all available evidence regarding the effect of cranial radiation treatment on cortical thickness and volume. We searched the Pubmed, Embase and Cochrane databases, with an additional reference check in the Scopus database. Studies that examined cortical changes on MRI within patients as well as between treated and non-treated patients were included. The quality of the studies was assessed with a checklist specially designed for this review. No meta-analysis was performed due to the lack of randomised trials. Out of 1915 publications twenty-one papers were selected, of which fifteen observed cortical changes after radiation therapy. Two papers reported radiation-dependent decrease in cortical thickness within patients one year after radiation treatment, suggesting a clear relation between the two. However, study quality was considered mostly suboptimal, and there was great inhomogeneity between the included studies. This means that, although there has been increasing interest in the effects of radiation treatment on cortex morphology, no reliable conclusion can be drawn based on the currently available evidence. This calls for more research, preferably with a sufficiently large patient population, and adequate methodology. [ABSTRACT FROM AUTHOR]

Moyamoya syndrome (MMS) is an uncommon late complication after cranial irradiation. Its hemorrhagic presentation from the associated pseudo-aneurysm is extremely rare, and the optimal management strategy is undetermined. We herein report a 36-year-old man who developed intraventricular hemorrhage from a pseudo-aneurysm at the extended left anterior choroidal artery as an abnormal collateral of MMS 30 years after surgical removal and cranial irradiation for childhood craniopharyngioma. Catheter angiography confirmed the diagnosis of MMS, and multiple pseudo-aneurysms were evident at the ipsilateral abnormal choroidal collateral, one of which was considered to be a source of bleeding. The patient underwent left superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis with indirect pial synangiosis based on the observation that the development of choroidal collateral may be associated with a high rebleeding risk in hemorrhagic moyamoya disease. The patient was discharged without neurological deficit, and postoperative magnetic resonance angiography confirmed the STA-MCA bypass to be patent. Catheter angiography 1 year after revascularization surgery revealed the complete disappearance of the pseudoaneurysms with the apparently patent STA-MCA bypass. The patient did not exhibit any cerebrovascular events during the follow-up period of 16 months. In conclusion, hemorrhagic MMS with choroidal collateral as a dangerous anastomosis was effectively managed by STA-MCA anastomosis. Although long-term follow-up is necessary to evaluate our strategy, the favorable disappearance of pseudoaneurysms after revascularization surgery in the present case strongly suggests that STA-MCA anastomosis has a potential role for preventing rebleeding in MMS after cranial irradiation. [ABSTRACT FROM AUTHOR]

Background: The use of cranial radiotherapy for central nervous system (CNS) prophylaxis in children with acute lymphoblastic leukemia (ALL) is debated owing to its effect on neurocognitive functioning, as only <30% of the patients present with low risk in India and majority of the patients with high risk have to be treated with cranial radiation therapy (CRT) to prevent relapse. Given the increasing number of ALL survivors in India, the effect of CRT on neurocognitive functioning in children with ALL needs to be studied. Methods: Children (n = 44) with ALL who received CRT, intrathecal methotrexate (IT-MTX), and high-dose methotrexate (HD-MTX) for CNS prophylaxis as part of the modified Berlin-Frankfurt-Munster 95 protocol were included. Neurocognitive assessments and magnetic resonance image were performed to assess neurocognitive functioning and neuroanatomical structures, respectively. Five assessments were performed during the induction, end of re-induction I and II, commencement of maintenance, and end of maintenance phases of the modified BFM-95 protocol. Neurocognitive data of children with ALL were compared with those of healthy children (n = 60) at the baseline and after the final assessment. Results: A significant deterioration was observed in the performance intelligence, visuospatial ability, processing speed, and verbal retention domains after the completion of CNS prophylaxis. Three children had white matter changes on magnetic resonance imaging and showed reduced functioning in performance intelligence quotient, working memory, visual immediate and delayed memory, processing speed, verbal retention, visuospatial ability, processing speed, attention, planning and fine motor skills, and verbal comprehension. Children with ALL had poorer neuropsychological functioning when compared with healthy children. Conclusion: CNS prophylactic therapy as part of the BFM-95 protocol had an adverse effect on the neuropsychological functioning of children with ALL, and the effect was more pronounced when CRT was added to the treatment. [ABSTRACT FROM AUTHOR]

Cranial radiotherapy is an important treatment for intracranial and head and neck tumors. To investigate the effects of cranial irradiation (C-irradiation) on gut microbiota and metabolomic profile, the feces, plasma and cerebral cortex were isolated after exposing mice to cranial X-ray irradiation at a dose rate of 2.33 Gy/min (5 Gy/d for 4 d consecutively). The gut microorganisms and metabolites were detected by 16 S rRNA gene sequencing method and LC-MS method, respectively. We found that compared with sham group, the gut microbiota composition changed at 2 W and 4 W after C-irradiation at the genus level. The fecal metabolomics showed that compared with Sham group, 44 and 66 differential metabolites were found to be annotated into metabolism pathways at 2 W and 4 W after C-irradiation, which were significantly enriched in the arginine and proline metabolism. Metabolome analysis of serum and cerebral cortex showed that, at 4 W after C-irradiation, the expression pattern of metabolites in serum samples of mice was similar to that of sham group, and the cerebral cortex metabolites of the two groups were completely separated. KEGG functional analysis showed that serum and brain tissue differential metabolites were respectively enriched in tryptophan metabolism, and arginine proline metabolism. The correlation analysis showed that the changes of gut microbiota genera were significantly correlated with the changes of metabolism, especially Helicobacter , which was significantly correlated with many different metabolites at 4 W after C-irradiation. These data suggested that C-irradiation could affect the gut microbiota and metabolism profile, even at relatively long times after C-irradiation. • Hypofractionated radiation is a promising new strategy for radiotherapy. • Cranial X-ray irradiation altered gut microbial composition. • Cranial X-ray irradiation altered metabolism profile of feces, serum and cerebral cortex. [ABSTRACT FROM AUTHOR]