Establishment of Different Intraoperative Monitoring and Mapping Techniques and Their Impact on Survival, Extent of Resection, and Clinical Outcome in Patients with High-Grade Gliomas-A Series of 631 Patients in 14 Years.

BACKGROUND: The resection of brain tumors can be critical concerning localization, but is a key point in treating gliomas. Intraoperative neuromonitoring (IONM), awake craniotomy, and mapping procedures have been incorporated over the years. Using these intraoperative techniques, the resection of eloquent-area tumors without increasing postoperative morbidity became possible. This study aims to analyze short-term and particularly long-term outcomes in patients diagnosed with high-grade glioma, who underwent surgical resection under various technical intraoperative settings over 14 years. METHODS: A total of 1010 patients with high-grade glioma that underwent resection between 2004 and 2018 under different monitoring or mapping procedures were screened; 631 were considered eligible for further analyses. We analyzed the type of surgery (resection vs. biopsy) and type of IONM or mapping procedures that were performed. Furthermore, the impact on short-term (The National Institute of Health Stroke Scale, NIHSS; Karnofsky Performance Scale, KPS) and long-term (progression-free survival, PFS; overall survival, OS) outcomes was analyzed. Additionally, the localization, extent of resection (EOR), residual tumor volume (RTV), IDH status, and adjuvant therapy were approached. RESULTS: In 481 patients, surgery, and in 150, biopsies were performed. The number of biopsies decreased significantly with the incorporation of awake surgeries with bipolar stimulation, IONM, and/or monopolar mapping (p < 0.001). PFS and OS were not significantly influenced by any intraoperative technical setting. EOR and RTV achieved under different operative techniques showed no statistical significance (p = 0.404 EOR, p = 0.186 RTV). CONCLUSION: Based on the present analysis using data from 14 years and more than 600 patients, we observed that through the implementation of various monitoring and mapping techniques, a significant decrease in biopsies and an increase in the resection of eloquent tumors was achieved. With that, the operability of eloquent tumors without a negative influence on neurological outcomes is suggested by our data. However, a statistical effect of monitoring and mapping procedures on long-term outcomes such as PFS and OS could not be shown.

Combined use of 3D printing and mixed reality technology for neurosurgical training: getting ready for brain surgery.

OBJECTIVE: Learning surgical skills is an essential part of neurosurgical training. Ideally, these skills are acquired to a sufficient extent in an ex vivo setting. The authors previously described an in vitro brain tumor model, consisting of a cadaveric animal brain injected with fluorescent agar-agar, for acquiring a wide range of basic neuro-oncological skills. This model focused on haptic skills such as safe tissue ablation technique and the training of fluorescence-based resection. As important didactical technologies such as mixed reality and 3D printing become more readily available, the authors developed a readily available training model that integrates the haptic aspects into a mixed reality setup. METHODS: The anatomical structures of a brain tumor patient were segmented from medical imaging data to create a digital twin of the case. Bony structures were 3D printed and combined with the in vitro brain tumor model. The segmented structures were visualized in mixed reality headsets, and the congruence of the printed and the virtual objects allowed them to be spatially superimposed. In this way, users of the system were able to train on the entire treatment process from surgery planning to instrument preparation and execution of the surgery. RESULTS: Mixed reality visualization in the joint model facilitated model (patient) positioning as well as craniotomy and the extent of resection planning respecting case-dependent specifications. The advanced physical model allowed brain tumor surgery training including skin incision; craniotomy; dural opening; fluorescence-guided tumor resection; and dura, bone, and skin closure. CONCLUSIONS: Combining mixed reality visualization with the corresponding 3D printed physical hands-on model allowed advanced training of sequential brain tumor resection skills. Three-dimensional printing technology facilitates the production of a precise, reproducible, and worldwide accessible brain tumor surgery model. The described model for brain tumor resection advanced regarding important aspects of skills training for neurosurgical residents (e.g., locating the lesion, head position planning, skull trepanation, dura opening, tissue ablation techniques, fluorescence-guided resection, and closure). Mixed reality enriches the model with important structures that are difficult to model (e.g., vessels and fiber tracts) and advanced interaction concepts (e.g., craniotomy simulations). Finally, this concept demonstrates a bridging technology toward intraoperative application of mixed reality.

Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells.

Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) responseHIGH state of dendritic cell (DC) vaccines, with efficacious clinical impact. However, preclinical DC vaccines recapitulating this state by combining immunogenic cancer cell death with induction of type I IFN responses fail to regress mouse tumors lacking T cell infiltrates. Here, in lymph nodes (LNs), instead of activating CD4+/CD8+ T cells, DCs stimulate immunosuppressive programmed death-ligand 1-positive (PD-L1+) LN-associated macrophages (LAMs). Moreover, DC vaccines also stimulate PD-L1+ tumor-associated macrophages (TAMs). This creates two anatomically distinct niches of PD-L1+ macrophages that suppress CD8+ T cells. Accordingly, a combination of PD-L1 blockade with DC vaccines achieves significant tumor regression by depleting PD-L1+ macrophages, suppressing myeloid inflammation, and de-inhibiting effector/stem-like memory T cells. Importantly, clinical DC vaccines also potentiate T cell-suppressive PD-L1+ TAMs in glioblastoma patients. We propose that a multimodal immunotherapy and vaccination regimen is mandatory to overcome T cell-depleted tumors.

Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.

PURPOSE: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.

Assessment of Brain Tumour Perfusion Using Early-Phase 18F-FET PET: Comparison with Perfusion-Weighted MRI.

PURPOSE: Morphological imaging using MRI is essential for brain tumour diagnostics. Dynamic susceptibility contrast (DSC) perfusion-weighted MRI (PWI), as well as amino acid PET, may provide additional information in ambiguous cases. Since PWI is often unavailable in patients referred for amino acid PET, we explored whether maps of relative cerebral blood volume (rCBV) in brain tumours can be extracted from the early phase of PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). PROCEDURE: Using a hybrid brain PET/MRI scanner, PWI and dynamic 18F-FET PET were performed in 33 patients with cerebral glioma and four patients with highly vascularized meningioma. The time interval from 0 to 2 min p.i. was selected to best reflect the blood pool phase in 18F-FET PET. For each patient, maps of MR-rCBV, early 18F-FET PET (0-2 min p.i.) and late 18F-FET PET (20-40 min p.i.) were generated and coregistered. Volumes of interest were placed on the tumour (VOI-TU) and normal-appearing brain (VOI-REF). The correlation between tumour-to-brain ratios (TBR) of the different parameters was analysed. In addition, three independent observers evaluated MR-rCBV and early 18F-FET maps (18F-FET-rCBV) for concordance in signal intensity, tumour extent and intratumoural distribution. RESULTS: TBRs calculated from MR-rCBV and 18F-FET-rCBV showed a significant correlation (r = 0.89, p < 0.001), while there was no correlation between late 18F-FET PET and MR-rCBV (r = 0.24, p = 0.16) and 18F-FET-rCBV (r = 0.27, p = 0.11). Visual rating yielded widely agreeing findings or only minor differences between MR-rCBV maps and 18F-FET-rCBV maps in 93 % of the tumours (range of three independent raters 91-94%, kappa among raters 0.78-1.0). CONCLUSION: Early 18F-FET maps (0-2 min p.i.) in gliomas provide similar information to MR-rCBV maps and may be helpful when PWI is not possible or available. Further studies in gliomas are needed to evaluate whether 18F-FET-rCBV provides the same clinical information as MR-rCBV.

Feasibility of intraoperative neuromonitoring and cortical/subcortical mapping in patients with cerebral lesions of highly functional localizations-pathway to case adapted monitoring and mapping procedures.

Background: Intraoperative neuromonitoring (IONM) and mapping procedures via direct cortical stimulation (DCS) are required for resection of eloquently located cerebral lesions. In our neurooncological department, mapping and monitoring are used either combined or separately for surgery of functional lesions. The study aims to provide a practical insight into strengths and pitfalls of intraoperative neuromonitoring and mapping in supratentorial functionally located infiltrating lesions. Methods: IONM and mapping techniques performed in eloquent located brain tumors were analyzed with a focus on neurological outcome and resection results obtained via MRI. Additionally, the surgeons' view on obligatory techniques was explored retrospectively immediately after surgery. To evaluate the impact of the described items, we correlated intraoperative techniques in various issues. Results: Majority of the 437 procedures were performed as awake surgery (53%). Monopolar stimulation was used in 348 procedures and correlated with a postoperative temporary neurological deficit. Bipolar stimulation was performed in 127 procedures, particularly on tumors in the left hemisphere for language mapping. Overall permanent deficit was seen in 2% of the patients; neither different mapping or monitoring modes nor stimulation intensity, localization, or histopathological findings correlated significantly with permanent deficits. Evaluation of post-OP MRI revealed total resection (TR) in 209 out of 417 cases. Marginal residual volume in cases where total resection was assumed but MRI failed to proof TR was found (0.4 ml). Surgeons' post-OP evaluation of obligatory techniques matched in 73% with the techniques actually used. Conclusion: We report 437 surgical procedures on highly functional located brain lesions. Resection without permanent deficit was adequately achievable in 98% of the procedures. Chosen mapping or monitoring techniques mostly depended on localization and vascular conflicts but also in some procedures on availability of resources, which was emphasized by the post-OP surgeons' evaluation. With the present study, we aimed to pave the way to á la carte choice of monitoring and or mapping techniques, reflecting the possibilities of even supratotal resection in eloquent brain tumor lesions and the herewith increased need for monitoring and limiting resources.

The Effect of Wire Versus Magnetic Seed Localization on Lumpectomy Cavity Size.

PURPOSE: Our purpose was to assess whether an association exists between surgical localization technique and lumpectomy cavity size on radiation therapy planning computed tomography (CT) scan. METHODS AND MATERIALS: A single-institution retrospective review was conducted of women undergoing breast conserving surgery with wire or magnetic seed guided lumpectomy followed by adjuvant radiation therapy from 2018 to 2021. Patients of a surgeon only performing 1 localization technique or undergoing bracketed localization were excluded. The primary outcome was lumpectomy cavity size on simulation CT. Confounding due to imbalance in patient and tumor factors was addressed with overlap weights derived from a propensity score analysis and used in a weighted multivariable analysis. Secondary outcomes included positive margins, total pathologic volume, boost delivery, and boost modality. RESULTS: Of 617 women who received lumpectomy during the study period, 387 were included in final analysis. Tumors of patients undergoing seed localization were more likely unifocal, assessable by ultrasound, and smaller. Seed use rates ranged from 27.7% to 70.7% per surgeon. There was no difference in positive margins (6.4 vs 5.4%, P = .79) or second surgeries (9.4 vs 8.1%, P = .79) between groups. Close margin rates were similar for ductal carcinoma in situ (P = .35) and invasive carcinoma (P = .97). In unadjusted bivariable analyses, wire localization was associated with larger total pathology volume (P = .004), but localization technique showed no association with CT cavity volume (P = .15). After adjusting for potentially confounding variables, multivariable analysis failed to show an association between localization technique and either CT cavity (P = .35) or total path volume (P = .08). There was no difference in indicated-boost delivery (P = .15) or electron boost (P = .14) by localization technique. CONCLUSIONS: There was no significant difference in CT cavity size by localization technique, suggesting choice between surgical techniques does not impede radiation therapy boost delivery.

Functional Outcome and Overall Survival in Patients with Primary or Secondary CNS Lymphoma after Surgical Resection vs. Biopsy.

BACKGROUND: Central nervous system lymphoma (CNSL) is rare form of brain tumour. It manifests either as primary CNS lymphoma (pCNSL) originating within the central nervous system or as secondary CNS lymphoma (sCNSL), arising as cerebral metastases of systemic lymphoma. For a significant period, surgical resection was considered obsolete due to the favourable response to chemotherapy and the associated risk of postoperative deficits. The objective of the present study was to demonstrate the benefits of resection in CNSL patients, including extended survival and improved postoperative function. METHODS: A retrospective study involving patients diagnosed with either PCNSL or SCNSL that were surgically approached at our neurosurgical department between 2010 and 2022 was conducted. Patients were categorised into three subgroups based on their neurosurgical approach: (1) stereotactical biopsy, (2) open biopsy, (3) resection. We then performed statistical analyses to assess overall survival (OS) and progression-free survival (PFS). Additionally, we examined various secondary factors such as functional outcome via Karnofsky Performance Index (KPS) and prognosis scoring. RESULTS: 157 patients diagnosed with PCNSL or SCNSL were enclosed in the study. Of these, 101 underwent stereotactic biopsy, 21 had open biopsy, and 35 underwent resection. Mean age of the cohort was 64.94 years, with majority of patients being female (54.1%). The resection group showed longest OS at 44 months (open biopsy = 13 months, stereotactic biopsy = 9 months). Calculated median follow-up was 34.5 months. In the Cox regression model, postoperative KPS 70% (p < 0.001) and resection vs. stereotactic biopsy (p = 0.040) were identified as protective factors, whereas older age at diagnosis was identified as a risk factor (p < 0.001). In the one-way analysis of variance, differences in postoperative KPS were found among all groups (p = 0.021), while there was no difference in preoperative KPS among the groups. CONCLUSIONS: Our data show a favourable outcome when resection is compared to either stereotactic or open biopsy. Additionally, the marginally improved postoperative functional status observed in patients who underwent resection, as opposed to in those who underwent biopsy, provides further evidence in favour of the advantages of surgical resection for enhancing neurological deficits.

Resection of Eloquent Located Brain Tumors by Mapping Only-A Feasibility Study.

BACKGROUND: Patients with eloquently located cerebral lesions require surgery that usually employs mapping and monitoring techniques for the preservation of motor and language function. However, in many cases, mapping only might be sufficient, reducing the need for technical and personnel logistics. Here, we report our experiences using a device that can be operated by the surgeon independently, providing mapping techniques but omitting monitoring techniques. METHODS: For monopolar and bipolar cortical/subcortical stimulation, pre-set programs were available and intraoperatively used-two enabling EMG real-time tracking of eight muscles for monopolar (cortical/subcortical) mapping, and two programs for 60 Hz stimulation, one with EMG and one without. Motor mapping was performed under continuous observation of the screened EMG signal and acoustic feedback by the surgeon. For the 60 Hz stimulation, a standard bipolar stimulation probe was connected through a second port. The preoperative application of the subdermal EMG needles, as well as the intraoperative handling of the device, were performed by the surgeons independently. Postoperatively, an evaluation of the autonomous handling and feasibility of the device for the chosen test parameters was conducted. RESULTS: From 04/19-09/21, 136 procedures in patients with eloquently located cerebral lesions were performed by using the "mapping-only" device. Mapping was performed in 82% of the monopolar cases and in 42% of the bipolar cases. Regarding the setup and sufficiency for the cortical/subcortical mapping, the device was evaluated as independently usable for motor and language mapping in 129 procedures (95%). Gross total resection was achieved, or functional limit throughout resection was reached, in 79% of the patients. 13 patients postoperatively suffered from a new neurological deficit. At the 3-6-month follow-up, three patients showed persistent deficit (2%). All of them had language disturbances. The setup time for the device was less than 7 min. CONCLUSIONS: The device was evaluated as sufficient in over 90% of cases concerning monopolar and bipolar mapping, and the setup and handling was sufficient in all patients. With the present data we show that in well-selected cases, a very simple system providing mapping only is sufficient to achieve gross total resection with the preservation of functionality.

Systematic Literature Review of Machine Learning Algorithms Using Pretherapy Radiologic Imaging for Glioma Molecular Subtype Prediction.

BACKGROUND: The molecular profile of gliomas is a prognostic indicator for survival, driving clinical decision-making for treatment. Pathology-based molecular diagnosis is challenging because of the invasiveness of the procedure, exclusion from neoadjuvant therapy options, and the heterogeneous nature of the tumor. PURPOSE: We performed a systematic review of algorithms that predict molecular subtypes of gliomas from MR Imaging. DATA SOURCES: Data sources were Ovid Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science. STUDY SELECTION: Per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 12,318 abstracts were screened and 1323 underwent full-text review, with 85 articles meeting the inclusion criteria. DATA ANALYSIS: We compared prediction results from different machine learning approaches for predicting molecular subtypes of gliomas. Bias analysis was conducted for each study, following the Prediction model Risk Of Bias Assessment Tool (PROBAST) guidelines. DATA SYNTHESIS: Isocitrate dehydrogenase mutation status was reported with an area under the curve and accuracy of 0.88 and 85% in internal validation and 0.86 and 87% in limited external validation data sets, respectively. For the prediction of O6-methylguanine-DNA methyltransferase promoter methylation, the area under the curve and accuracy in internal validation data sets were 0.79 and 77%, and in limited external validation, 0.89 and 83%, respectively. PROBAST scoring demonstrated high bias in all articles. LIMITATIONS: The low number of external validation and studies with incomplete data resulted in unequal data analysis. Comparing the best prediction pipelines of each study may introduce bias. CONCLUSIONS: While the high area under the curve and accuracy for the prediction of molecular subtypes of gliomas are reported in internal and external validation data sets, limited use of external validation and the increased risk of bias in all articles may present obstacles for clinical translation of these techniques.

Long-term neurocognitive function and quality of life after multimodal therapy in adult glioma patients: a prospective long-term follow-up.

PURPOSE: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients' neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. METHODS: Seventy-one glioma patients (WHO grade 1-4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6-11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. RESULTS: Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. CONCLUSIONS: Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.

Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.

PURPOSE: Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. METHODS: This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters. RESULTS: We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (P = .79). Incision-suture times (P < .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS (P < .001) and OS (P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors (P = .006). CONCLUSION: We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.

Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8+ T cells remain disputed. Using multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8+ T cell states. CD8+ T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8+ TEX). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4+:CD8+ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8+ T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8+ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8+ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.

The impact of preoperative MRI-based apparent diffusion coefficients on local recurrence and outcome in patients with cerebral metastases.

BACKGROUND: Surgery of single cerebral metastases is standard but frequently fails to achieve local tumour control. Reliable predictors for local tumour progression and overall survival are unknown. MRI-based apparent diffusion coefficients (ADC) correlate with tumour cellularity and invasion. The present study analysed a potential relation between the MRI based apparent diffusion coefficients local recurrence and outcome in patients with brain metastases. METHODS: A retrospective analysis was performed for patients with cerebral metastases and complete surgical resection evaluated by an early postoperative MRI < 72h. Minimal ADC and mean ADC were assessed in preoperative 1,5T-MRI scans by placing regions of interests in the tumour and the peritumoural tissue. RESULTS: Analysis of the relation between ADC values, local progression and outcome was performed in 86 patients with a mean age of 59 years (range 33-83 years). Primary site was NSCLC in 37.2% of all cases. Despite complete resection 33.7% of all patients suffered from local in-brain-progression. There were no significant differences in ADC values in groups based on histology. In the present cohort, the mean ADCmin and the mean ADCmean within the metastasis did not differ significantly between patients with and without a later local in-brain progression (634 × 10-6 vs. 661 × 10-6 mm2/s and 1324 × 10-6 vs. 1361 × 10-6 mm2/s; 1100 × 10-6 vs. 1054 × 10-6 mm2/s; each p > 0.05). Mean ADC values did not correlate significantly with PFS and OAS. CONCLUSION: In the present study analysed ADC values had no significant impact on local in brain progression and survival parameters.

Prophylactic mastectomy and occult malignancy: Surgical and imaging considerations.

BACKGROUND: Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations. METHODS: All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM. RESULTS: The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM. CONCLUSIONS: Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

In-Vitro Use of Verteporfin for Photodynamic Therapy in Glioblastoma.

BACKGROUND: Stummer et al. established fluorescence-guided surgery (FGS) for glioblastoma (GBM) using 5-aminolevulinic acid (5-ALA). Its metabolite, protoporphyrin IX (PPIX), is also a photosensitizer and can be used for photodynamic therapy (PDT) using a laser beam of 635 nm. The porphyrin derivate verteporfin (VP) was discovered to have properties to penetrate the brain, pharmacologically target glioma cells, and is approved for PDT of choroidal neovascularization in wet age-related macular degeneration at 689 nm. OBJECTIVE: To elucidate whether GBM cell lines are susceptible to PDT with second-generation photosensitizer VP. METHODS: Human glioma cell lines LN229, HSR-GBM1, and a low-passage patient-derived GBM cell line P1 were treated with variable concentrations of VP for 24 h, followed by PDT at 689 nm using a diode laser light. Cell viability was measured using the MTT assay and VP uptake was measured using a desktop cytometer. RESULTS: Significantly higher cell death following PDT with VP compared to VP treatment alone or no treatment was detected in all cell models (LN229, HSR-GBM1, P1). Flowcytometric measurements revealed a concentration-dependent cellular uptake of VP after 24 h incubation up to 99% at 10 µM (HSR-GBM1). CONCLUSION: This study demonstrates that PDT with VP causes cell death in GBM cells at marginal concentrations. Additionally, red spectrum fluorescence was detected at therapeutic concentrations in all cell lines, validating the cellular uptake of VP in GBM cells. VP, therefore, is not only a potential drug for targeting GBM pharmacologically but can be used as an optical imaging dye in surgery and photosensitizer to make GBM susceptible to PDT.

Two Decades of Brain Tumour Imaging with O-(2-[18F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians' rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.