Biology-guided radiotherapy in metastatic prostate cancer: time to push the envelope?

The therapeutic landscape of metastatic prostate cancer has undergone a profound revolution in recent years. In addition to the introduction of novel molecules in the clinics, the field has witnessed a tremendous development of functional imaging modalities adding new biological insights which can ultimately inform tailored treatment strategies, including local therapies. The evolution and rise of Stereotactic Body Radiotherapy (SBRT) have been particularly notable in patients with oligometastatic disease, where it has been demonstrated to be a safe and effective treatment strategy yielding favorable results in terms of disease control and improved oncological outcomes. The possibility of debulking all sites of disease, matched with the ambition of potentially extending this treatment paradigm to polymetastatic patients in the not-too-distant future, makes Biology-guided Radiotherapy (BgRT) an attractive paradigm which can be used in conjunction with systemic therapy in the management of patients with metastatic prostate cancer.

External validation of three prognostic scores for brain metastasis velocity in patients treated with intracranial stereotactic radiotherapy.

BACKGROUND AND INTRODUCTION: Brain metastasis velocity (BMV) has been proposed as a prognostic factor for overall survival (OS) in patients with brain metastases (BMs). In this study, we conducted an external validation and comparative assessment of the performance of all three BMV scores. MATERIALS AND METHODS: Patients treated with intracranial stereotactic radiotherapy (SRT) for BM at a single center between 2014 and 2018 were identified. Where possible, all three BMV scores were calculated. Log-rank tests and linear, logistic and Cox regression analysis were used for validation and predictor identification of OS. RESULTS: For 333 of 384 brain metastasis patients, at least one BMV score could be calculated. In a sub-group of 187 patients, "classic" BMV was validated as categorical (p < 0.0001) and continuous variable (HR 1.02; 95% CI 1.02-1.03; p < 0.0001). In a sub-group of 284 patients, "initial" BMV was validated as categorical variable (high-risk vs. low-risk; p < 0.01), but not as continuous variable (HR 1.02; 95% CI 0.99-1.04; p = 0.224). "Volume-based" BMV could not be validated in a sub-group of 104 patients. On multivariable Cox regression analysis, iBMV (HR 1.85; 95% CI 1.01-3.38; p < 0.05) and cBMV (HR 2.32; 95% CI 1.15 4.68; p < 0.05) were predictors for OS for intermediate-risk patients after first SRT and first DBFs, respectively. cBMV proved to be the dominant predictor for OS for high-risk patients (HR 2.99; 95% CI 1.30-6.91; p < 0.05). CONCLUSION: This study externally validated cBMV and iBMV as prognostic scores for OS in patients treated with SRT for BMs whereas validation of vBMV was not achieved.

Difference in safety and humoral response to mRNA SARS-CoV-2 vaccines in patients with autoimmune neurological disorders: the ANCOVAX study.

BACKGROUND: Assessing the safety of SARS-CoV-2 mRNA vaccines and the effect of immunotherapies on the seroconversion rate in patients with autoimmune neurological conditions (ANC) is relevant to clinical practice. Our aim was to assess the antibody response to and safety of SARS-CoV-2 mRNA vaccines in ANC. METHODS: This longitudinal study included ANC patients vaccinated with two doses of BNT162b2 or mRNA-1273 between March and August 2021. Side effects were assessed 2-10 days after each dose. Neurological status and anti-spike receptor binding domain antibody levels were evaluated before vaccination and 4 weeks after the second dose. Healthcare-workers served as controls for antibody levels. RESULTS: We included 300 ANC patients (median age 52, IQR 40-65), and 347 healthcare-workers (median age 45, IQR 34-54). mRNA-1273 vaccine was associated with an increased risk of both local (OR 2.52 95% CI 1.45-4.39, p = 0.001) and systemic reactions (OR 2.51% CI 1.49-4.23, p = 0.001). The incidence of relapse was not different before and after vaccine (Incidence rate ratio 0.72, 95% CI 0.29-1.83). Anti-SARS-CoV-2 IgG were detected in 268 (89.9%) patients and in all controls (p < 0.0001). BNT162b2 vaccine (OR 8.84 95% CI 2.32-33.65, p = 0.001), anti-CD20 mAb (OR 0.004 95% CI 0.0007-0.026, p < 0.0001) and fingolimod (OR 0.036 95% CI 0.002-0.628, p = 0·023) were associated with an increased risk of not developing anti-SARS-CoV-2 IgG. CONCLUSION: SARS-CoV-2 mRNA vaccines were safe in a large group of ANC patients. Anti-CD20 and fingolimod treatment, as well as vaccination with the BNT162b2 vaccine, led to a reduced humoral response. These findings could inform vaccine policies in ANC patients undergoing immunotherapy.

A Pilot Study of 24-h Motor Activity Patterns in Multiple Sclerosis: Pre-Planned Follow-Up at 2 Years.

Early multiple sclerosis (MS) predictive markers of disease activity/prognosis have been proposed but are not universally accepted. Aim of this pilot prospective study is to verify whether a peculiar hyperactivity, observed at baseline (T0) in early relapsing-remitting (RR) MS patients, could represent a further prognostic marker. Here we report results collected at T0 and at a 24-month follow-up (T1). Eighteen RRMS patients (11 females, median Expanded Disability Status Scale-EDSS score 1.25, range EDSS score 0-2) were monitored at T0 (mean age 32.33 ± 7.51) and T1 (median EDSS score 1.5, range EDSS score 0-2.5). Patients were grouped into two groups: responders (R, 14 patients) and non-responders (NR, 4 patients) to treatment at T1. Each patient wore an actigraph for one week to record the 24-h motor activity pattern. At T0, NR presented significantly lower motor activity than R between around 9:00 and 13:00. At T1, NR were characterized by significantly lower motor activity than R between around 12:00 and 17:00. Overall, these data suggest that through the 24-h motor activity pattern, we can fairly segregate at T0 patients who will show a therapeutic failure, possibly related to a more active disease, at T1. These patients are characterized by a reduced morning level of motor activation. Further studies on larger populations are needed to confirm these preliminary findings.

Circadian Activity Rhythm in Early Relapsing-Remitting Multiple Sclerosis.

While relapsing-remitting is the most prevalent course of multiple sclerosis, the prognostic/predictive markers of the worsening of symptomatology are still debated. With reference to other diseases, the study of the circadian activity rhythm, according to the theoretical framework of the two-process model of sleep regulation and applying functional linear modeling, proved to be useful to identify a possible marker. The usefulness of the study of circadian activity rhythm in multiple sclerosis is strengthened by recent findings indicating a potential involvement of circadian factors in the multifactorial etiopathology of the disorder. The aim of the present study was to verify whether circadian activity rhythm of early relapsing-remitting multiple sclerosis patients presents specific alterations, through functional linear modeling. Thirty-five relapsing-remitting multiple sclerosis patients (24 females; mean age ± SD = 31.51 ± 7.74) and 35 healthy controls (24 females; mean age ± SD = 31.29 ± 8.02) were enrolled. They wore an actigraph around the non-dominant wrist for one week. Relapsing-remitting multiple sclerosis patients showed a peak in motor activity around 5:00 a.m., higher than that of healthy controls. The timing of the peak in motor activity in the patients could be explained according to the hyperactive hypothalamus-pituitary-adrenal axis and higher cortisol awakening response reported in these patients.