(1) Background: About 15% of the patients undergoing neoadjuvant chemoradiation for locally advanced rectal cancer exhibit pathological complete response (pCR). The surgical approach is associated with major risks as well as a potential negative impact on quality of life and has been questioned in the past. Still, there is no evidence of a reliable clinical or radiological surrogate marker for pCR. This study aims to replicate previously reported response predictions on the basis of non-contrast CT scans on an independent patient cohort. (2) Methods: A total of 169 consecutive patients (126 males, 43 females) that underwent neoadjuvant chemoradiation and consecutive total mesorectal excision were included. The solid tumors were segmented on CT scans acquired on the same scanner for treatment planning. To quantify intratumoral 3D spatial heterogeneity, 1819 radiomics parameters were derived per case. Feature selection and algorithmic modeling were performed to classify pCR vs. non-pCR cases. A random forest model was trained on the dataset using 4-fold cross-validation. (3) Results: The model achieved an accuracy of 87%, higher than previously reported. Correction for the imbalanced distribution of pCR and non-PCR cases (13% and 87% respectively) was applied, yielding a balanced accuracy score of 0.5%. An additional experiment to classify a computer-generated random data sample using the same model led to comparable results. (4) Conclusions: There is no evidence of added value of a radiomics model based on on-contrast CT scans for prediction of pCR in rectal cancer. The imbalance of the target variable could be identified as a key issue, leading to a biased model and optimistic predictions.
BackgroundSo far, glioblastomas cannot be cured by standard therapy and have an extremely poor median survival of about 15 months. The photodynamic therapy (PDT) with next generation photosensitizers, reaching a higher therapeutic depth, might offer a new, adjuvant treatment strategy in brain cancer therapy. Here, we investigated the effect of THPTS-PDT combined with ionizing irradiation (IR) on glioblastoma cells in vitro and in vivo.ResultsTHPTS colocalized to mitochondria and was not found in the nucleus. THPTS (2–20 μg/ml)-PDT significantly reduced the proliferation, metabolic activity and clonogenic survival and induced cell death mainly through apoptosis and autophagy. THPTS-PDT combined with IR decreased the clonogenicity significantly compared to single treatments. THPTS (≤ 300 μg/ml) alone showed no dark toxicity. The maximum therapeutic depth of THPTS-PDT in C6 glioblastomas was 13 mm.Materials and MethodsThree human glioblastoma cell lines (U-87 MG, A-172, DBTRG-05MG) were incubated with THPTS (1–300 μg/ml) 3–24 hours before laser treatment (760 nm, 30 J/cm2). THPTS localization and effects on metabolic activity, proliferation, cell death mechanisms and long-term reproductive survival were assessed. IR was conducted on an X-ray unit (0.813 Gy/min). Results were verified in vivo on a subcutaneous C6 glioblastoma model in Wistar rats.ConclusionsThis study demonstrated efficient THPTS-PDT in glioblastoma cells, in vitro and in vivo. The combinatorial effects of THPTS-PDT and IR are of specific clinical interest as enhanced eradication of infiltrating glioblastoma cells in the tumor surrounding tissue might possibly reduce the commonly occurring local relapses.
Supratentorial white matter is an important part of the brain and a major site of detrimental effects after whole brain radiotherapy (WBRT). It is not known if prevalence of metastases in white matter justifies standard inclusion of white matter in whole brain treatment. In this retrospective analysis we examined the frequency of metastasis in supratentorial deep cerebral white matter with cerebral magnetic resonance imaging (MRI). Deep white matter (DWM) was defined as white matter in corpus callosum with forceps anterior and posterior and centrum semiovale. Lesions extending from grey matter, gyrus or ventricles into white matter were not classified as DWM metastases. Brain MRI of 198 patients from two centres were analyzed. In total 1330 metastases were counted and only 4.6% were located in DWM. Metastases in DWM were small (median diameter 6 mm). Only 1/41 patients (2%) with a singular metastasis had a DWM metastasis, 2/35 patients (6%) with 2 metastases had a DWM metastasis, 14/79 patients (18%) with 3-9 metastases and 12/43 patients (28%) with >9 metastases had a single or more DWM metastases (p = 0.003). There appeared to be tumor related differences with renal cell carcinoma showing significantly more DWM metastasis (6/17, 35%), than NSCLC (11/85, 13%, p = 0.024), breast cancer (1/20, 5%, p = 0.019) or colorectal cancer (0/10, 0%, p = 0.033). Overall, relevant preservation of DWM from metastases, especially in oligometastatic disease, was shown. This implies that DWM in patients with only few brain metastases is unnecessarily damaged by conventional WBRT.
2048 Background: Standard of care (SOC) treatment achieves poor clinical outcomes in patients with glioblastoma (GBM), particularly in the absence of MGMT promoter hypermethylation. Preclinical models suggest that GBM recurrence is facilitated by CXCL12-mediated recruitment of bone marrow-derived cells capable of vasculogenesis after radiotherapy (RT). We have recently reported favorable safety and feasibility data of the phase I/II GLORIA trial, which combines RT and the CXCL12-neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) in patients with newly diagnosed, incompletely resected or unresected GBM lacking MGMT promoter hypermethylation (NCT04121455). Here we report on clinical outcomes and their correlation with potential biomarkers. Methods: 10 patients with newly diagnosed incompletely resected (n=8) or biopsied (n=2) GBM with ECOG≤2, age≥18 and without MGMT promoter hypermethylation were enrolled. All patients received standard RT (60 Gy in 30 fractions or 40.05 Gy in 15 fractions) and escalating dose levels of continuous (24/7) i.v. infusions of NOX-A12 for 26 weeks. While the previously reported primary endpoint was safety, secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Biomarker assessment was performed with a six-plex immunofluorescence staining (CODEX) of neuropathologically confirmed tumor areas of pretreatment tissues for CXCL12, CD31 (endothelial cells), GFAP (glioma cells), CD68 (macrophages, microglia), aSMA (pericytes), Ki-67 (proliferating cells) and a nuclear marker. An independent patient cohort treated with SOC (n=15) matched by clinical and histopathological features was used for comparisons of efficacy and biomarker assessment. Results: Median PFS of the GLORIA cohort was 5.7 (range 1.9–8.5) months and the median OS was 12.7 (4.7–18.4) months. Biomarker analyses revealed that a higher frequency of CXCL12 expressing endothelial and glioma cells (EG12 score) significantly correlated with PFS (r=0.87; p=0.005) in patients treated with RT and NOX-A12, but not with SOC (r=-0.10; p=0.724). GLORIA patients with a high EG12 score (median classifier) had a significantly longer PFS than those with lower scores (3.0 vs. 6.0 months; p=0.031) and a trend towards prolonged OS (11.1 vs. 15.8 months; p=0.075). These correlations were not seen in the reference cohort treated with SOC (PFS: 6.0 vs. 4.6 months; p=0.502; OS: 10.0 vs. 9.6 months; p=0.243). Conclusions: We show superior clinical efficacy of RT and NOX-A12 in patients with high frequency of CXCL12 expressing endothelial and glioma cells, suggesting the use of the EG12 score as a novel predictive biomarker for CXCL12-directed therapies in GBM. Clinical trial information: NCT04121455 .
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