Stereotactic arrhythmia radioablation: competitor or adjunct to catheter ablation?

Cardiology and Radiation Oncology working together—a new ‘STAR’ on the horizon? Until recently, most cardiologists associated radiation exposure to the heart with potential adverse effects, such as pericarditis, late coronary artery disease or potential damage to cardiac implantable devices. The landmark publication of 2017 reporting a case series of just five patients with recurrent ventricular tachycardia (VT) treated with stereotactic arrhythmia radioablation (STAR) changed this perception and introduced a new area for both cardiac electrophysiology and radiation oncology

Stereotactic body radiotherapy to defer systemic therapy in patients with oligorecurrent disease

Background Patients who develop oligorecurrent disease may be treated with metastasis-directed stereotactic body radiotherapy (SBRT) to defer the start of systemic therapy and delay its potential side effects. We report oncological outcomes and patterns of failure in patients with oligorecurrent disease treated with SBRT and determine which factors impact the interval to initiation of systemic therapy. Material/Methods This retrospective study included patients with oligorecurrent disease (≤5 lesions) from any solid organ malignancy, treated with SBRT to all metastases and no systemic therapy for a minimum one month after SBRT between 01/2014 and 12/2019. The Kaplan-Meier method was used to analyze overall survival (OS) and progression-free survival (PFS), and the cumulative incidence of initiation of systemic therapy was analyzed assuming death without systemic therapy as a competing risk. Univariable and multivariable analyses are used to assess predictors of the systemic therapy-free interval. Results Among 545 patients treated with SBRT for oligometastatic disease, 142 patients were treated with SBRT only for oligorecurrent disease. The most common primary tumors were lung and gastrointestinal cancer in 47 (33.1 %) and 28 (19.7 %) patients, respectively. After a median follow-up of 25 months, the median PFS and OS was 6.1 months and 48.9 months, respectively. Distant metastases were the most common first failure, and oligometastatic distant failure occured in 86 patients (60.6 %). New metastases were treated with repeat SBRT in 48 patients (33.8 %). The 1- and 2-year cumulative incidence of initiation of systemic therapy was 24.6 % and 36.8 %, respectively. In multivariable analysis, the number of previous lines of systemic therapy and the cumulative volume of metastases were significantly associated with the interval to initiation of systemic therapy. Conclusion Selected patients with oligorecurrence achieved favorable OS and low cumulative incidence of initiation of systemic therapy. Prospective studies are warranted to determine how the deferral of systemic therapy impacts OS compared with immediate systemic therapy in combination with SBRT

Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1

When a growing cell expands, lipids and proteins must be delivered to its periphery. Although this phenomenon has been observed for decades, it remains unknown how the secretory pathway responds to growth signaling. We demonstrate that control of Golgi phosphatidylinositol-4-phosphate (PI(4)P) is required for growth-dependent secretion. The phosphoinositide phosphatase SAC1 accumulates at the Golgi in quiescent cells and down-regulates anterograde trafficking by depleting Golgi PI(4)P. Golgi localization requires oligomerization of SAC1 and recruitment of the coat protein (COP) II complex. When quiescent cells are stimulated by mitogens, SAC1 rapidly shuttles back to the endoplasmic reticulum (ER), thus releasing the brake on Golgi secretion. The p38 mitogen-activated kinase (MAPK) pathway induces dissociation of SAC1 oligomers after mitogen stimulation, which triggers COP-I–mediated retrieval of SAC1 to the ER. Inhibition of p38 MAPK abolishes growth factor–induced Golgi-to-ER shuttling of SAC1 and slows secretion. These results suggest direct roles for p38 MAPK and SAC1 in transmitting growth signals to the secretory machinery

Repeat stereotactic body radiotherapy for oligometastatic disease

BACKGROUND Patients with oligometastatic disease (OMD) treated with metastasis-directed definitive local therapy such as stereotactic body radiotherapy (SBRT) are at risk of developing new metastases. Here, we compare characteristics and outcomes of patients treated with a single course and repeat SBRT. MATERIALS/METHODS OMD patients treated with SBRT to 1-5 metastases were included in this retrospective study, and classified as single course or repeat SBRT. Progression-free survival (PFS), widespread failure-free survival (WFFS), overall survival (OS), systemic therapy-free survival (STFS) and cumulative incidence of different first failures were analyzed. Patient and treatment characteristics predicting the use of repeat SBRT were investigated using univariable and multivariable logistic regression. RESULTS Among the 385 patients included, 129 and 256 received repeat or single course SBRT, respectively. The most common primary tumor and OMD state in both groups were lung cancer and metachronous oligorecurrence. Patients treated with repeat SBRT had shorter PFS (p < 0.0001), while WFFS (p = 0.47) and STFS (p = 0.22) were comparable. Distant failure, particularly with a single metastasis, was more frequently observed in repeat SBRT patients. Repeat SBRT patients had longer median OS (p = 0.01). On multivariable logistic regression, low distant metastases velocity and more previous lines of systemic therapy significantly predicted the use of repeat SBRT. CONCLUSION Despite shorter PFS and comparable WFFS and STFS, repeat SBRT patients had longer OS. The role of repeat SBRT for OMD patients warrants further prospective investigation, focussing on predictive factors to select patients that might derive a benefit

Stereotactic body radiotherapy for oligoprogression with or without switch of systemic therapy

BACKGROUND Oligoprogression is defined as cancer progression of a limited number of metastases under active systemic therapy. The role of metastasis-directed therapy, using stereotactic body radiotherapy (SBRT), is controversial as is the continuation versus switch of systemic therapy. We report outcomes of oligoprogressive patients after SBRT, and compare those patients that continued or switched their current line of systemic therapy. MATERIAL/METHODS We included patients who developed up to 5 progressive extracranial metastases under systemic therapy for any solid organ malignancy and were treated with SBRT to all lesions at our institution between 01/2014 and 12/2019. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method, and the interval to the next systemic therapy line determined using cumulative incidence functions. Multivariable Cox regression models were used to analyze the influence of baseline and post-progression variables on OS, PFS and survival with the next systemic therapy after SBRT. RESULTS Among 135 patients with oligoprogressive disease of which the most common primary tumor was lung cancer (n = 46, 34.1 %), 96 continued their current line of systemic therapy after oligoprogression. Among 39 who switched systemic therapy, 28 (71.8 %) paused or discontinued, while 11 (28.2 %) immediately started another systemic treatment. After a median follow-up of 27.2 months, patients that switched and those who continued systemic therapy after oligoprogression had comparable median OS (32.1 vs. 38.2 months, p = 0.47) and PFS (4.3 vs. 3.4 months, p = 0.6). The intervals to the next systemic therapy line were comparable between both cohorts (p = 0.6). An ECOG performance status of 2 and immediately starting a new systemic therapy after oligoprogression were associated with a poorer survival without next systemic therapy, while the de-novo OMD state was associated with better survival without next systemic therapy compared to the induced state. CONCLUSION Oncological outcomes of patients that continued or switched systemic therapy after SBRT for oligoprogression were comparable, potentially indicating that further lines of treatment may be safely delayed in selected cases

Inactivation of the phosphoinositide phosphatases Sac1p and Inp54p leads to accumulation of phosphatidylinositol 4,5-bisphosphate on vacuole membranes and vacuolar fusion defects

Phosphoinositides direct membrane trafficking, facilitating the recruitment of effectors to specific membranes. In yeast phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P-2) is proposed to regulate vacuolar fusion; however, in intact cells this phosphoinositide can only be detected at the plasma membrane. In Saccharomyces cerevisiae the 5-phosphatase, Inp54p, dephosphorylates PtdIns(4,5)P-2 forming PtdIns(4)P, a substrate for the phosphatase Sac1p, which hydrolyzes (PtdIns(4) P). We investigated the role these phosphatases in regulating PtdIns(4,5) P-2 subcellular distribution. PtdIns(4,5)P-2 bioprobes exhibited loss of plasma membrane localization and instead labeled a subset of fragmented vacuoles in Delta sac1 Delta inp54 and sac1(ts) Delta inp54 mutants. Furthermore, sac1(ts) Delta inp54 mutants exhibited vacuolar fusion defects, which were rescued by latrunculin A treatment, or by inactivation of Mss4p, a PtdIns(4)P 5-kinase that synthesizes plasma membrane PtdIns(4,5)P-2. Under these conditions PtdIns(4,5)P-2 was not detected on vacuole membranes, and vacuole morphology was normal, indicating vacuolar PtdIns(4,5)P-2 derives from Mss4p-generated plasma membrane PtdIns(4,5)P-2. Delta sac1 Delta inp54 mutants exhibited delayed carboxypeptidase Y sorting, cargo-selective secretion defects, and defects in vacuole function. These studies reveal PtdIns(4,5)P-2 hydrolysis by lipid phosphatases governs its spatial distribution, and loss of phosphatase activity may result in PtdIns(4,5)P-2 accumulation on vacuole membranes leading to vacuolar fragmentation/fusion defects

Evaluation of the prognostic value of the ESTRO EORTC classification of oligometastatic disease in patients treated with stereotactic body radiotherapy: A retrospective single center study

PURPOSE To explore the prognostic value of the oligometastatic disease (OMD) states as proposed by the European Society for Radiotherapy and Oncology (ESTRO) European Organisation for Research and Treatment of Cancer (EORTC) classification system. MATERIALS AND METHODS This retrospective single-institution study included patients with 1-5 extracranial metastases from any solid malignancy treated with SBRT to all metastases. OMD states were defined according to the ESTRO EORTC classification. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Discriminatory strength of the classification was assessed by Gönen & Heller's concordance probability estimate (CPE). Univariable and multivariable Cox regression models were used to assess predictors of OS and PFS. RESULTS In total, 385 patients were included. The median follow-up was 24.1 months. The most frequent OMD states were metachronous oligorecurrence (23.6%) and induced oligoprogression (18.7%). Induced OMD patients had significantly shorter median OS (28.1 months) compared with de-novo (46.3 months, p=0.002) and repeat OMD (50.3 months, p=0.002). Median PFS in de-novo OMD patients (8.8 months) was significantly longer than in repeat (5.4 months, p=0.002) and induced OMD patients (4.3 months, p<0.001). The classification system had moderate discriminatory strength for OS and PFS. Multivariable analyses confirmed that compared with induced OMD, de-novo was associated with longer PFS and repeat with longer OS. CONCLUSION All patients were successfully categorized according to the ESTRO EORTC classification system. The discriminatory strength of the classification was confirmed for OMD patients treated with metastases-directed SBRT. Larger multicenter trials are needed to validate the prognostic power for OMD patients irrespective of primary tumor and treatment approach

Dosimetric Analysis of Proximal Bronchial Tree Subsegments to Assess The Risk of Severe Toxicity After Stereotactic Body Radiation Therapy of Ultra-central Lung Tumors

Background and purpose Stereotactic body radiotherapy (SBRT) of ultra-central lung tumors (UCLT) is associated with an increased risk of severe toxicity. The aim of this study was to perform a detailed dosimetric analysis of the proximal bronchial tree (PBT) anatomical sub-segments to evaluate the safety of risk-adapted SBRT and to evaluate potential differences in radiation tolerance between PBT sub-segments. Material and methods Fifty-seven patients treated with SBRT for UCLT between 2014 and 2021 were included. UCLT were defined as tumor abutting or overlapping with the trachea, PBT, or esophagus. This study analyzed overall survival, local control, progression-free survival, and grade ≥3 toxicity events. Bayesian inference was used to build a dose-response model with upper limits for toxicity. Results Twenty-seven (47.4%) of the irradiated lesions were primary or locoregionally recurrent NSCLC and 30 (52.6%) oligometastases. All patients were treated with risk-adapted SBRT of median 45.0 Gy (range: 30.0-60.0 Gy) in 8 or 10 fractions. Grade ≥3 radiation pneumonitis was observed in two patients (3.5%), while no bronchial stenosis, hemorrhage or fistula were observed. The dose-response model predicted a grade ≥3 toxicity (stenosis, hemorrhage or fistula) limited to 4.9% (0 - 11.4%) when delivering EQD2$\_$3 = 100 Gy to any location of the PBT (D0.2cc). Detailed dosimetric analysis of PBT substructures showed no variation in the dose-response model between the anatomical PBT sub-segments. Conclusion Risk-adapted SBRT regimens delivered in 8 or 10 fractions for ultra-central lung tumors resulted in high rates of local tumor control with low toxicity rates, without differences in radiation tolerance between the anatomical PBT sub-segments

Dosimetric analysis of 17 cardiac Sub-structures, Toxicity, and survival in ultra central lung tumor patients treated with SBRT

•Data on cardiac toxicity after SBRT for ultra-central lung tumors remains limited.•We analyzed the dose to 18 cardiac sub-structures and cardiovascular toxicity.•A SBRT regimen of 45 Gy in 8-10 fractions yields good local control and low toxicity.•The highest cardiac doses were observed in the pulmonary artery and left atrium.•Higher doses to the base of the heart seem to be associated with non-cancer deaths