Stereotactic radiosurgery for brain metastases from pelvic gynecological malignancies: oncologic outcomes, validation of prognostic scores, and dosimetric evaluation

IntroductionStereotactic radiosurgery is a well-established treatment option in the management of brain metastases. Multiple prognostic scores for prediction of survival following radiotherapy exist, but are not disease-specific or validated for radiosurgery in women with primary pelvic gynecologic malignancies metastatic to the brain. The aim of the present study is to evaluate the feasibility, safety, outcomes, and impact of established prognostic scores.MethodsWe retrospectively identified 52 patients treated with radiotherapy for brain metastases between 2008 and 2021. Stereotactic radiosurgery was utilized in 31 patients for an overall number of 75 lesions; the remaining 21 patients received whole-brain radiotherapy. Kaplan-Meier survival analysis and the log-rank test were used to calculate and compare survival curves and univariate and multivariate Cox regression to assess the influence of cofactors on recurrence, local control, and prognosis.ResultsWith a median follow-up of 10.7 months, overall survival rates post radiosurgery were 65.3%, 51.3%, and 27.7% for 1, 2, and 5 years, respectively, which were significantly higher than post whole-brain radiotherapy (p=0.049). Five local failures (6.7%) were detected, resulting in 1 and 2 year local cerebral control rates of 97.4% and 94.0%, respectively. Univariate factors for prediction of superior overall survival were high performance status (p=0.030) and application of three prognostic scores, especially the Recursive Partitioning Analysis score (p=0.028). Uni- and multivariate analysis revealed that extracranial progression prior to radiosurgery was significant for inferior overall survival (p<0.0001). Radionecrosis was diagnosed in five women (16%); long-term neurotoxicity was significantly worse after whole-brain radiotherapy compared with radiosurgery (p=0.023).ConclusionStereotactic radiosurgery for brain metastases from pelvic gynecologic malignancies appears to be safe and well tolerated, achieving promising local cerebral control. Prognostic scores were shown to be transferable and radiosurgery should be recommended as primary intracranial treatment, especially in women with no prior extracranial progression and Recursive Partitioning Analysis class I.

MLTI-02. Impact of driver mutations on timing, pattern, treatment, and outcome in patients with brain metastases from non-small cell lung cancer

Objective To assess the impact of driver mutations in non-small cell lung cancer (NSCLC) on the formation and treatment outcome of brain metastases (BM). Patients and methods We retrospectively analyzed patients with BM from NSCLC with respect to driver mutations and assessed timing and pattern of BM development as well as local cerebral control and survival after BM treatment. Results We included 253 patients. Histology was adenocarcinoma in 223, squamous cell carcinoma in 25 and not otherwise specified (NOS) in five patients. All tumors were analyzed for known alterations in NSCLC by panel sequencing and fluorescence in situ hybridization (FISH). An activating KRAS mutation (n=85) was the most prevalent mutation, followed by activating EGFR mutation (n=31) and MET amplification (n=29). Other mutations were detected in 27 patients. No alterations were found in 102 patients. Time to BM development did not differ between the molecular groups (p=.22), nor did the number (p=.72) or location (supra- vs. infratentorial; p=.76) of the BM. Patients underwent multimodal cerebral treatment comprising surgery followed by radiotherapy and/or stereotactic radiosurgery (n=138), whole brain radiotherapy (n=13) or stereotactic radiosurgery alone (n=102). Systemic treatment was initiated or continued after BM therapy in 169 patients and its frequency did not differ significantly between genotypes (p=.08) while the modality of medical treatment depended on genotype (p&lt;0.0001). The latter showed longer local cerebral control rates compared to other mutations (0.23) and a longer overall survival compared to KRAS and wild type genotypes (p=.015). Systemic treatment (HR 2.1 95%CI 1.4–3.0; p&lt;.0001) and a good clinical status (HR 2.1 95%CI 1.2–3.7; p=0.014) were the only independent factors for further survival. Conclusion The actual known driver mutations do not influence BM formation. Specific genotypes show a better oncological course, presumably due to available molecular treatment.

MLTI-03. The relevance of the count of brain metastases for treatment and outcome in NSCLC

Background and Purpose While data reporting the number of brain metastasis as a prognostic factor for patients with NSCLC, we analyzed whether the prognostic importance of the mere count of brain metastasis in a modern, multimodal treatment setting. Patients and Methods We retrospectively analyzed patients treated for BM from non-small lung cancer between 2010 and 2020. Demographics, baseline characteristics, and tumor-associated parameters were retrieved from an electronic database. Prognostic factors for local cerebral control and survival were identified using the log-rank test and Cox regression analysis. Results We included 343 consecutive patients (male n=187, female n=156; median age 61 years). Histological subtypes were adenocarcinoma (n=283), squamous-cell carcinoma (n=42) and neuroendocrine carcinoma (n=18). The median number of BM was one (range 1–20). Single (n = 189), oligo (n=110) and multiple BM (n=44) showed in total a median follow up of 10 months (minimum 1, maximum 142). Treatment comprised surgical resection (n=218) with radiotherapy, stereotactic radiosurgery (n=125) and adjuvant systemic therapy (n=203). The median local cerebral control was 11 months (95%CI 8.5 – 13.5) and the median overall survival was 16 months (95%CI 12.8 – 19.2). The number of BM did not influence local control and overall survival rates (p = 0.234 and p = 0.210, respectively). Controlled systemic disease (HR 0.42; 95% CI 0.2284–0.633; p&lt;0.0001), clinical status (Karnofsky Performance Score &gt; 70; HR 0.41; 95% CI 0.265–0.661; p&lt;0.0001) and adjuvant systemic therapy (HR 0.38; 95% CI 0.279–0.530; p&lt;0.0001) were independent prognostic factors for survival. Conclusions The mere number of brain metastases is not a prognostic factor for survival and local cerebral control in a multimodal treatment setting.

Purkinje Cell Activity During Suppression of Voluntary Eye Movements in Rhesus Macaques

Conscious control of actions helps us to reach our goals by suppressing responses to distracting external stimuli. The cerebellum has been suggested to complement cerebral control of inhibition of targeted movements (conscious control), though by what means, remains unclear. By measuring Purkinje cell (PC) responses during antisaccades, we show that the cerebellum not only plays a role in the execution of eye movements, but also in during the volitional inhibition thereof. We found that simple spike (SS) modulation during instruction and execution of prosaccades and antisaccades was prominent in PCs of both medial and lateral cerebellum, showing distinct, time-ordered sequences, but each with different sensitivities for execution and trial-history. SS activity in both regions modulated bidirectionally, with both facilitation (increasing SS firing) and suppression (decreasing SS firing) PCs showing firing-rate changes associated with instruction and execution, respectively. These findings show that different cerebellar regions can contribute to behavioral control and inhibition, but with different propensities, enriching the cerebellar machinery in executive control.

Right-Handers Speak with the Left Hemisphere, Left-Handers with the Right

In 1865 Paul Broca stated, “we speak with the left hemisphere.” In many accounts of Broca’s work, he was referring to right-handers and meant that left-handers speak with the right hemisphere—what I call the “reversal hypothesis.” They go on to note his error in light of current evidence that the majority of left-handers speak with the left. Eling (1984) called such accounts misrepresentations, arguing that Broca’s analysis of the relation between cerebral control for speech and handedness was more compatible with current evidence. He suggested that our better understanding of the relation might have come sooner “had the original papers been properly read” (p. 159). Who, then, originated the “reversal hypothesis,” when and how did it rise to become a neuropsychological “rule,” when and how did it fall, and did Broca ever correct the record or change his mind? These questions and more are addressed in this chapter.

Hyperventilation, cerebral perfusion, and syncope

This review summarizes evidence in humans for an association between hyperventilation (HV)-induced hypocapnia and a reduction in cerebral perfusion leading to syncope defined as transient loss of consciousness (TLOC). The cerebral vasculature is sensitive to changes in both the arterial carbon dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2 the contribution of a low PaCO2 to the early postural reduction in middle cerebral artery blood velocity is transient. HV together with postural stress does not reduce cerebral perfusion to such an extent that TLOC develops. However when HV is combined with cardiovascular stressors like cold immersion or reduced cardiac output brain perfusion becomes jeopardized. Whether, in patients with cardiovascular disease and/or defect, cerebral blood flow cerebral control HV-induced hypocapnia elicits cerebral hypoperfusion, leading to TLOC, remains to be established.