Radiation enhancement using focussed ultrasound-stimulated microbubbles for head and neck cancer: A phase 1 clinical trial.

BACKGROUND AND PURPOSE: Preclinical research demonstrated that the exposure of microbubbles (intravascular gas microspheres) to focussed ultrasound within the targeted tumour upregulates pro-apoptotic pathways and enhances radiation-induced tumour cell death. This study aimed to assess the safety and efficacy of magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubbles (MRgFUS-MB) for head and neck cancers (HN). MATERIALS AND METHODS: This prospective phase 1 clinical trial included patients with newly diagnosed or recurrent HN cancer (except nasopharynx malignancies) for whom locoregional radiotherapy with radical- or palliative-intent as deemed appropriate. Patients with contraindications for microbubble administration or contrast-enhanced MR were excluded. MR-coupled focussed ultrasound sonicated intravenously administered microbubbles within the MR-guided target volume. Patients receiving 5-10 and 33-35 radiation fractions were planned for 2 and 3 MRgFUS-MB treatments, respectively. Primary endpoint was toxicity per CTCAEv5.0. Secondary endpoint was tumour response at 3 months per RECIST 1.1 criteria. RESULTS: Twelve patients were enrolled between Jun/2020 and Nov/2023, but 1 withdrew consent. Eleven patients were included in safety analysis. Median follow-up was 7 months (range, 0.3-38). Most patients had oropharyngeal cancer (55 %) and received 20-30 Gy/5-10 fractions (63 %). No systemic toxicity or MRgFUS-MB-related adverse events occurred. The most severe acute adverse events were radiation-related grade 3 toxicities in 6 patients (55 %; dermatitis in 3, mucositis in 1, dysphagia in 6). No radiation necrosis or grade 4/5 toxicities were reported. 8 patients were included in the 3-month tumour response assessment: 4 had partial response (50 %), 3 had complete response (37.5 %), and 1 had progressive disease (12.5 %). CONCLUSIONS: MRgFUS-MB treatment was safe and associated with high rates of tumour response at 3 months.

Risk-stratification for treatment de-intensification in WNT-pathway medulloblastoma: finding the optimal balance between survival and quality of survivorship.

INTRODUCTION: Advances in molecular biology have led to consensus classification of medulloblastoma into four broad molecular subgroups - wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively. Traditionally, children >3 years of age, with no/minimal residual tumor (<1.5 cm2) and lack of metastasis were classified as average-risk disease with >80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm2), and leptomeningeal metastases either alone or in combination were considered high-risk features yielding much worse 5-year survival (30-60%). This clinico-radiological risk-stratification has been refined by incorporating molecular/genetic information. Contemporary multi-modality management for non-infantile medulloblastoma entails maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. Aggressive multi-modality management achieves good survival but is associated with substantial dose-dependent treatment-related toxicity prompting conduct of subgroup-specific prospective clinical trials. AREAS COVERED: We conducted literature search on PubMed from 1969 till 2023 to identify putative prognostic factors and risk-stratification for medulloblastoma, including molecular subgrouping. Based on previously published data, including our own institutional experience, we discuss molecular risk-stratification focusing on WNT-pathway medulloblastoma to identify candidates suitable for treatment de-intensification to strike the optimal balance between survival and quality of survivorship. EXPERT OPINION: Prospective clinical trials and emerging biological information should further refine risk-stratification in WNT-pathway medulloblastoma.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

BACKGROUND: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. METHODS AND FINDINGS: This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. CONCLUSIONS: MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT04431674.

Apriori prediction of chemotherapy response in locally advanced breast cancer patients using CT imaging and deep learning: transformer versus transfer learning.

Objective: Neoadjuvant chemotherapy (NAC) is a key element of treatment for locally advanced breast cancer (LABC). Predicting the response to NAC for patients with Locally Advanced Breast Cancer (LABC) before treatment initiation could be beneficial to optimize therapy, ensuring the administration of effective treatments. The objective of the work here was to develop a predictive model to predict tumor response to NAC for LABC using deep learning networks and computed tomography (CT). Materials and methods: Several deep learning approaches were investigated including ViT transformer and VGG16, VGG19, ResNet-50, Res-Net-101, Res-Net-152, InceptionV3 and Xception transfer learning networks. These deep learning networks were applied on CT images to assess the response to NAC. Performance was evaluated based on balanced_accuracy, accuracy, sensitivity and specificity classification metrics. A ViT transformer was applied to utilize the attention mechanism in order to increase the weight of important part image which leads to better discrimination between classes. Results: Amongst the 117 LABC patients studied, 82 (70%) had clinical-pathological response and 35 (30%) had no response to NAC. The ViT transformer obtained the best performance range (accuracy = 71 ± 3% to accuracy = 77 ± 4%, specificity = 86 ± 6% to specificity = 76 ± 3%, sensitivity = 56 ± 4% to sensitivity = 52 ± 4%, and balanced_accuracy=69 ± 3% to balanced_accuracy=69 ± 3%) depending on the split ratio of train-data and test-data. Xception network obtained the second best results (accuracy = 72 ± 4% to accuracy = 65 ± 4, specificity = 81 ± 6% to specificity = 73 ± 3%, sensitivity = 55 ± 4% to sensitivity = 52 ± 5%, and balanced_accuracy = 66 ± 5% to balanced_accuracy = 60 ± 4%). The worst results were obtained using VGG-16 transfer learning network. Conclusion: Deep learning networks in conjunction with CT imaging are able to predict the tumor response to NAC for patients with LABC prior to start. A ViT transformer could obtain the best performance, which demonstrated the importance of attention mechanism.

PRRT with Lu-177 DOTATATE in Treatment-Refractory Progressive Meningioma: Initial Experience from a Tertiary-Care Neuro-Oncology Center.

PURPOSE: Refractory and/or recurrent meningiomas have poor outcomes, and the treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been used in this setting with promising results. We have documented our experience of using intravenous (IV) and intra-arterial (IA) approaches of Lu-177 DOTATATE PRRT. METHODS: Eight patients with relapsed/refractory high-grade meningioma received PRRT with Lu-177 DOTATATE by IV and an IA route. At least 2 cycles were administered. Time to progression was calculated from the first PRRT session to progression. The response was assessed on MRI using RANO criteria, and visual analysis of uptake was done on Ga-68 DOTANOC PET/CT. Post-therapy dosimetry calculations for estimating the absorbed dose were performed. RESULTS: Median time to progression was 8.9 months. One patient showed disease progression, whereas seven patients showed stable disease at 4 weeks following 2 cycles of PRRT. Dosimetric analysis showed higher dose and retention time by IA approach. No significant peri-procedural or PRRT associated toxicity was seen. CONCLUSION: PRRT is a safe and effective therapeutic option for relapsed/refractory meningioma. The IA approach yields better dose delivery and should be routinely practised.

Quantitative ultrasound radiomics guided adaptive neoadjuvant chemotherapy in breast cancer: early results from a randomized feasibility study.

Background: In patients with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy (NAC), quantitative ultrasound (QUS) radiomics can predict final responses early within 4 of 16-18 weeks of treatment. The current study was planned to study the feasibility of a QUS-radiomics model-guided adaptive chemotherapy. Methods: The phase 2 open-label randomized controlled trial included patients with LABC planned for NAC. Patients were randomly allocated in 1:1 ratio to a standard arm or experimental arm stratified by hormonal receptor status. All patients were planned for standard anthracycline and taxane-based NAC as decided by their medical oncologist. Patients underwent QUS imaging using a clinical ultrasound device before the initiation of NAC and after the 1st and 4th weeks of treatment. A support vector machine-based radiomics model developed from an earlier cohort of patients was used to predict treatment response at the 4th week of NAC. In the standard arm, patients continued to receive planned chemotherapy with the treating oncologists blinded to results. In the experimental arm, the QUS-based prediction was conveyed to the responsible oncologist, and any changes to the planned chemotherapy for predicted non-responders were made by the responsible oncologist. All patients underwent surgery following NAC, and the final response was evaluated based on histopathological examination. Results: Between June 2018 and July 2021, 60 patients were accrued in the study arm, with 28 patients in each arm available for final analysis. In patients without a change in chemotherapy regimen (53 of 56 patients total), the QUS-radiomics model at week 4 of NAC that was used demonstrated an accuracy of 97%, respectively, in predicting the final treatment response. Seven patients were predicted to be non-responders (observational arm (n=2), experimental arm (n=5)). Three of 5 non-responders in the experimental arm had chemotherapy regimens adapted with an early initiation of taxane therapy or chemotherapy intensification, or early surgery and ended up as responders on final evaluation. Conclusion: The study demonstrates the feasibility of QUS-radiomics adapted guided NAC for patients with breast cancer. The ability of a QUS-based model in the early prediction of treatment response was prospectively validated in the current study. Clinical trial registration: clinicaltrials.gov, ID NCT04050228.

Clinico-Radiological Outcomes in WNT-Subgroup Medulloblastoma.

Medulloblastoma (MB) comprises four broad molecular subgroups, namely wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively, with subgroup-specific developmental origins, unique genetic profiles, distinct clinico-demographic characteristics, and diverse clinical outcomes. This is a retrospective audit of clinical outcomes in molecularly confirmed WNT-MB patients treated with maximal safe resection followed by postoperative standard-of-care risk-stratified adjuvant radio(chemo)therapy at a tertiary-care comprehensive cancer centre. Of the 74 WNT-MB patients registered in a neuro-oncology unit between 2004 to 2020, 7 patients accrued on a prospective clinical trial of treatment deintensification were excluded, leaving 67 patients that constitute the present study cohort. The median age at presentation was 12 years, with a male preponderance (2:1). The survival analysis was restricted to 61 patients and excluded 6 patients (1 postoperative mortality plus 5 without adequate details of treatment or outcomes). At a median follow-up of 72 months, Kaplan-Meier estimates of 5-year progression-free survival and overall survival were 87.7% and 91.2%, respectively. Traditional high-risk features, large residual tumour (≥1.5 cm2), and leptomeningeal metastases (M+) did not significantly impact upon survival in this molecularly characterized WNT-MB cohort treated with risk-stratified contemporary multimodality therapy. The lack of a prognostic impact of conventional high-risk features suggests the need for refined risk stratification and potential deintensification of therapy.

Quantitative US Delta Radiomics to Predict Radiation Response in Individuals with Head and Neck Squamous Cell Carcinoma.

Purpose To investigate the role of quantitative US (QUS) radiomics data obtained after the 1st week of radiation therapy (RT) in predicting treatment response in individuals with head and neck squamous cell carcinoma (HNSCC). Materials and Methods This prospective study included 55 participants (21 with complete response [median age, 65 years {IQR: 47-80 years}, 20 male, one female; and 34 with incomplete response [median age, 59 years {IQR: 39-79 years}, 33 male, one female) with bulky node-positive HNSCC treated with curative-intent RT from January 2015 to October 2019. All participants received 70 Gy of radiation in 33-35 fractions over 6-7 weeks. US radiofrequency data from metastatic lymph nodes were acquired prior to and after 1 week of RT. QUS analysis resulted in five spectral maps from which mean values were extracted. We applied a gray-level co-occurrence matrix technique for textural analysis, leading to 20 QUS texture and 80 texture-derivative parameters. The response 3 months after RT was used as the end point. Model building and evaluation utilized nested leave-one-out cross-validation. Results Five delta (Δ) parameters had statistically significant differences (P < .05). The support vector machines classifier achieved a sensitivity of 71% (15 of 21), a specificity of 76% (26 of 34), a balanced accuracy of 74%, and an area under the receiver operating characteristic curve of 0.77 on the test set. For all the classifiers, the performance improved after the 1st week of treatment. Conclusion A QUS Δ-radiomics model using data obtained after the 1st week of RT from individuals with HNSCC predicted response 3 months after treatment completion with reasonable accuracy. Keywords: Computer-Aided Diagnosis (CAD), Ultrasound, Radiation Therapy/Oncology, Head/Neck, Radiomics, Quantitative US, Radiotherapy, Head and Neck Squamous Cell Carcinoma, Machine Learning Clinicaltrials.gov registration no. NCT03908684 Supplemental material is available for this article. © RSNA, 2024.

CDKN2A/B deletion in IDH-mutant astrocytomas: An evaluation by Fluorescence in-situ hybridization.

INTRODUCTION: CDKN2A/B homozygous deletion is one of the defining features of grade 4 in IDH-mutant astrocytic tumours. AIM: To evaluate CDKN2A/B-deletion in IDH-mutant astrocytic tumours and its clinicopathological impact. MATERIALS AND METHODS: CDKN2A/B-deletion was evaluated by Fluorescence in-situ hybridisation (FISH) and interpreted by two recently accepted methods. RESULTS: Eighty-three out of 94 cases (histologically-grade 2: 3, grade 3: 46, grade 4: 34) were interpretable on FISH. Concordant CDKN2A/B-deletion was observed in 71% (27/38) of lower-grade tumours (n = 49) and 90% (27/30) of histological grade 4 tumours (n = 34). Both the interpretation methods showed good agreement (Kappa = 0.75). CDKN2A/B-deletion showed an inverse correlation for < 10% MIB-1 labeling index (p = 0.01) while that by method-2 showed a significant correlation for grade 4 (p = 0.02). No significant correlation was observed for any other clinicopathological parameters. Twenty-four patients showed progression/recurrence (including deaths), and no significant difference in frequency of CDKN2A/B deletion was observed among cases with disease progression across different histological grades. CONCLUSIONS: CDKN2A/B-deletion was observed across all the histological grades of IDH-mutant astrocytic tumours, expectedly more in the higher grade. FISH, as a method, can be used for the detection of CDKN2A/B homozygous deletion, when there is concordant interpretation.

Post-ictal changes presenting as late pseudoprogression on MRI and PET in a patient with diffuse glioma: Case report and brief literature review.

Following completion of adjuvant radiation and chemotherapy imaging surveillance forms a major role in the management of diffuse gliomas. The primary role of imaging is to detect recurrences earlier than clinical symptomatology. Magnetic resonance imaging (MRI) is considered the gold standard in follow-up protocols owing to better soft tissue delineation and multiparametric nature. True recurrence can often mimic treatment-related changes, it is of paramount importance to differentiate between the two entities as the clinical course is divergent. Addition of functional sequences like perfusion, spectroscopy and metabolic imaging can provide further details into the microenvironment. In equivocal cases, a follow-up short interval imaging might be obtained to settle the diagnostic dilemma. Here, we present a patient with diagnosis of recurrent oligodendroglioma treated with adjuvant chemoradiation, presenting with seizures five years post-completion of chemotherapy for recurrence. On MRI, subtle new onset gyral thickening of the left frontal region with mild increase in perfusion and patchy areas of raised choline. FET-PET (fluoro-ethyltyrosine) showed an increased tumour-to-white matter (T/Wm) ratio favouring tumour recurrence. Based on discussion in a multi-disciplinary joint clinic, short interval follow-up MRI was undertaken at two months showing decrease in gyral thickening and resolution of enhancing areas in left frontal lobe. Repeat imaging one year later demonstrated stable disease status without further new imaging findings. Given the changes resolving completely without any anti-tumoral intervention, we conclude this to be peri-ictal pseudoprogression, being the second such case described in India.

Patterns of Care in Craniopharyngioma: Clinical Outcomes After Surgery and Radiation Therapy in a Real-World Setting.

OBJECTIVE: Craniopharyngioma (CP) is a benign neuroepithelial tumor generally treated with maximal safe resection and radiation therapy (RT) in incompletely resected CP or in recurrent tumors to achieve long-term control. We analyzed the clinical outcomes of patients with CPs treated with a multimodality approach. PATIENTS AND METHODS: A retrospective clinical audit of histologically proven CPs registered between 2008 and 2019 at a specialized neuro-oncology center in India was performed. Time-to-event outcomes (overall survival [OS] and progression-free survival [PFS]) were analyzed. RESULTS: One hundred and twenty-two patients with CP were analyzed. The median age of the population was 14 years (interquartile range [IQR], 8-26) with a significant male preponderance. Gross total resection was achieved in only 25% of patients. At a median follow-up of 57.1 months (IQR, 27.8-87.8), 5-year estimates of PFS and OS were 52% (95% confidence interval, 46%-63.4%) and 85.8% (95% confidence interval, 78.6%-93%), respectively. Recurrence or progression was observed in 48 of 122 patients (39.3%) at a median time of 84.4 months (IQR, 24.7-174.8). On multivariate analysis, the absence of residual disease (P = 0.004), near-total resection (P = 0.035), and use of up-front adjuvant RT (P < 0.001) significantly improved the 5-year PFS, whereas the absence of extracavernous extension (P = 0.058) and any use of postoperative RT (P = 0.026) significantly improved the 5-year OS. CONCLUSIONS: This study represents one of the largest single-institutional series of CPs, showing improved PFS with up-front adjuvant RT in most cases of CP. Deferring adjuvant RT should be considered only in patients with no evidence of residual disease (as shown on dedicated sellar imaging) after primary surgery.

Recommended first-line management of asymptomatic brain metastases from EGFR mutant and ALK positive non-small cell lung cancer varies significantly according to specialty: an international survey of clinical practice.

Background: The role for radiotherapy or surgery in the upfront management of brain metastases (BrM) in epidermal growth factor receptor mutant (EGFRm) or anaplastic lymphoma kinase translocation positive (ALK+) non-small cell lung cancer (NSCLC) is uncertain because of a lack of prospective evidence supporting tyrosine kinase inhibitor (TKI) monotherapy. Further understanding of practice heterogeneity is necessary to guide collaborative efforts in establishing guideline recommendations. Methods: We conducted an international survey among medical (MO), clinical (CO), and radiation oncologists (RO), as well as neurosurgeons (NS), of treatment recommendations for asymptomatic BrM (in non-eloquent regions) EGFRm or ALK+ NSCLC patients according to specific clinical scenarios. We grouped and compared treatment recommendations according to specialty. Responses were summarized using counts and percentages and analyzed using the Fisher exact test. Results: A total of 449 surveys were included in the final analysis: 48 CO, 85 MO, 60 NS, and 256 RO. MO and CO were significantly more likely than RO and NS to recommend first-line TKI monotherapy, regardless of the number and/or size of asymptomatic BrM (in non-eloquent regions). Radiotherapy in addition to TKI as first-line management was preferred by all specialties for patients with ≥4 BrM. NS recommended surgical resection more often than other specialties for BrM measuring >2 cm. Conclusions: Recommendations for the management of BrM from EGFRm or ALK+ NSCLC vary significantly according to oncology sub-specialties. Development of multidisciplinary guidelines and further research on establishing optimal treatment strategies is warranted.

Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma.

Background: Contemporary standard-of-care for newly diagnosed glioblastoma (GBM) is maximal safe resection followed by postoperative focal conformal radiotherapy (RT) plus concurrent temozolomide (TMZ) and 6-cycles of adjuvant TMZ (Stupp regimen). However, many patients continue to receive extended adjuvant TMZ (beyond 6-cycles) without solid scientific evidence. This review pools data from nonrandomized studies and randomized controlled trials (RCTs) comparing extended adjuvant TMZ (>6-cycles) to standard adjuvant TMZ (6-cycles) in patients with newly diagnosed GBM for updated evidence-synthesis. Methods: This systematic review and meta-analysis was carried out in accordance with the Cochrane methodology including quality assessment of primary studies. Primary outcome of interest was comparative efficacy defined as progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) for PFS and OS with corresponding 95% confidence interval (CIs) were extracted/computed from individual primary studies and pooled using random-effects model. Any p-value <0.05 was considered statistically significant. Results: Evidence-synthesis was based on pooling of data from 2578 patients enrolled in 16 nonrandomized comparative studies and 5 RCTs. Overall, extended adjuvant TMZ was associated with statistically significant reduction in the risk of progression (HR = 0.72, 95%CI: 0.60-0.87; p = 0.007) and death (HR = 0.71, 95%CI: 0.57-0.90; p = 0.004) compared to standard adjuvant TMZ. However, on subgroup analysis, survival benefit of extended adjuvant TMZ was limited to data synthesized from retrospective nonrandomized comparative studies with no statistically significant difference in outcomes seen after pooling of data from RCTs only. Conclusion: Apparent survival benefit of extended adjuvant TMZ in newly diagnosed GBM is largely driven by nonrandomized comparative studies with high inherent potential for multiple biases.

Novel MRI-guided focussed ultrasound stimulated microbubble radiation enhancement treatment for breast cancer.

Preclinical studies have demonstrated focused ultrasound (FUS) stimulated microbubble (MB) rupture leads to the activation of acid sphingomyelinase-ceramide pathway in the endothelial cells. When radiotherapy (RT) is delivered concurrently with FUS-MB, apoptotic pathway leads to increased cell death resulting in potent radiosensitization. Here we report the first human trial of using magnetic resonance imaging (MRI) guided FUS-MB treatment in the treatment of breast malignancies. In the phase 1 prospective interventional study, patients with breast cancer were treated with fractionated RT (5 or 10 fractions) to the disease involving breast or chest wall. FUS-MB treatment was delivered before 1st and 5th fractions of RT (within 1 h). Eight patients with 9 tumours were treated. All 7 evaluable patients with at least 3 months follow-up treated for 8 tumours had a complete response in the treated site. The maximum acute toxicity observed was grade 2 dermatitis in 1 site, and grade 1 in 8 treated sites, at one month post RT, which recovered at 3 months. No RT-related late effect or FUS-MB related toxicity was noted. This study demonstrated safety of combined FUS-MB and RT treatment. Promising response rates suggest potential strong radiosensitization effects of the investigational modality.Trial registration: clinicaltrials.gov, identifier NCT04431674.

Imaging-Based Patterns of Failure following Re-Irradiation for Recurrent/Progressive High-Grade Glioma.

BACKGROUND: Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. METHODS: Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20-80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. RESULTS: Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemotherapy. The median time to recurrence was 9 months. Central, marginal, and distant failures were seen in 27 (73%), 4 (11%), and 6 (16%) patients, respectively. None of the patient-, disease-, or treatment-related factors were significantly different across different recurrence patterns. CONCLUSION: Failures are seen predominantly within the high-dose region following ReRT in recurrent/ progressive HGG.

Pearls & Oy-sters: Primary Diffuse Leptomeningeal Melanocytosis: A Diagnostic Conundrum.

Primary diffuse leptomeningeal melanocytosis (PDLM) is an extremely rare CNS tumor with nonspecific clinicoradiologic features that overlap considerably with aseptic meningitis posing significant diagnostic and therapeutic challenges. We present one such case report of a patient treated empirically at first presentation as aseptic viral meningitis based on MRI and CSF analysis. Diagnosis of PDLM was established subsequently through meningeal biopsy that demonstrated a melanocytic tumor with fine granular melanin pigment without significant mitoses. Her systemic and ocular examination was unremarkable. Whole-body 18F-fluorodeoxyglucose PET/CT (FDG-PET/CT) did not identify any other primary site. Following ventriculoperitoneal shunt to relieve hydrocephalus, she was treated with definitive craniospinal irradiation plus whole-brain boost and remains stable on periodic clinicoradiologic surveillance. Optimal management of PDLM lacks consensus with role of radiotherapy, chemotherapy, targeted therapy and immunotherapy being controversial.

WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go?

Novel biological insights have established that medulloblastoma is a heterogenous disease comprising four broad molecular subgroups - WNT, SHH, Group 3, and Group 4 respectively, resulting in the incorporation of molecular/genetic information in 5th edition of WHO classification and contemporary risk-stratification. Concerns regarding therapy-related late toxicity in long-term survivors have led to systematic attempts at treatment de-intensification in good-risk medulloblastoma. Given the excellent survival (>90%) of WNT-pathway medulloblastoma, prospective clinical trials have focused on optimization of therapy to balance survival versus quality of survival. The currently accepted definition of low-risk WNT-pathway medulloblastoma includes children <16 years of age with residual tumour <1.5 cm2 and no evidence of metastases. This systematically excludes adolescents and young adults who have been perceived to have worse outcomes. We have previously reported long-term survival of our adolescent and young adult cohort that were largely comparable to childhood medulloblastoma. We now report on molecularly characterized WNT-subgroup patients treated between 2004-2020 with risk-stratified multi-modality therapy to identify differences between childhood (<15 years) versus adolescent and young adults (>15 years). Despite modest differences in disease status at presentation and treatment modality, there were no significant differences in patterns of failure or survival between childhood versus adolescent and young adult WNT-pathway medulloblastoma. Two de-intensification trials in low-risk WNT-pathway medulloblastoma - first testing omission of upfront craniospinal irradiation and second a primary chemotherapy approach after surgery - had to be terminated prematurely due to unacceptably high relapse rates suggesting that craniospinal irradiation remains an integral component of treatment. The presence of TP53 mutations and OTX2 gains have recently been reported as independent negative prognostic factors in a multi-institutional cohort of WNT-pathway medulloblastoma raising questions on eligibility of such patients for de-escalation trials. The definition of low-risk WNT-pathway medulloblastoma may need to be refined in light of recent clinical data and newer biological information.

Predicting IDH subtype of grade 4 astrocytoma and glioblastoma from tumor radiomic patterns extracted from multiparametric magnetic resonance images using a machine learning approach.

Background and purpose: Semantic imaging features have been used for molecular subclassification of high-grade gliomas. Radiomics-based prediction of molecular subgroups has the potential to strategize and individualize therapy. Using MRI texture features, we propose to distinguish between IDH wild type and IDH mutant type high grade gliomas. Methods: Between 2013 and 2020, 100 patients were retrospectively analyzed for the radiomics study. Immunohistochemistry of the pathological specimen was used to initially identify patients for the IDH mutant/wild phenotype and was then confirmed by Sanger's sequencing. Image texture analysis was performed on contrast-enhanced T1 (T1C) and T2 weighted (T2W) MR images. Manual segmentation was performed on MR image slices followed by single-slice multiple sampling image augmentation. Both whole tumor multislice segmentation and single-slice multiple sampling approaches were used to arrive at the best model. Radiomic features were extracted, which included first-order features, second-order (GLCM-Grey level co-occurrence matrix), and shape features. Feature enrichment was done using LASSO (Least Absolute Shrinkage and Selection Operator) regression, followed by radiomic classification using Support Vector Machine (SVM) and a 10-fold cross-validation strategy for model development. The area under the Receiver Operator Characteristic (ROC) curve and predictive accuracy were used as diagnostic metrics to evaluate the model to classify IDH mutant and wild-type subgroups. Results: Multislice analysis resulted in a better model compared to the single-slice multiple-sampling approach. A total of 164 MR-based texture features were extracted, out of which LASSO regression identified 14 distinctive GLCM features for the endpoint, which were used for further model development. The best model was achieved by using combined T1C and T2W MR images using a Quadratic Support Vector Machine Classifier and a 10-fold internal cross-validation approach, which demonstrated a predictive accuracy of 89% with an AUC of 0.89 for each IDH mutant and IDH wild subgroup. Conclusion: A machine learning classifier of radiomic features extracted from multiparametric MRI images (T1C and T2w) provides important diagnostic information for the non-invasive prediction of the IDH mutant or wild-type phenotype of high-grade gliomas and may have potential use in either escalating or de-escalating adjuvant therapy for gliomas or for using targeted agents in the future.