Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study.

BACKGROUND AND PURPOSE: Patients with Ewing Sarcoma (EWS) are treated with multimodality therapy which includes radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) to the primary site for localized and metastatic EWS. MATERIALS AND METHODS: Forty-two children with EWS (33 localized, 9 metastatic) treated between 2007 and 2020 were enrolled on 2 prospective registry protocols for pediatric patients undergoing PRT. PRT was delivered by passive scatter (74 %), pencil-beam scanning (12 %) or mixed technique (14 %). Treated sites included the spine (45 %), pelvis/sacrum (26 %), skull/cranium (14 %), extraosseous (10 %), and chest wall (5 %). Median radiation dose was 54 Gy-RBE (range 39.6-55.8 Gy-RBE). Patients with metastatic disease received consolidative RT to metastatic sites (4 at the time of PRT to the primary site, 5 after completion of chemotherapy). Median follow-up time was 47 months after PRT. RESULTS: The 4-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83 %, 71 %, and 86 %, respectively. All local failures (n = 6) were in-field failures. Tumor size ≥ 8 cm predicted for inferior 4-year LC (69 % vs 95 %, p = 0.04). 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72 % vs 67 %, p = 0.70; 89 % vs 78 %, p = 0.38, respectively). CONCLUSION: In conclusion, LC for pediatric patients with EWS treated with PRT was comparable to that of historical patients who received photon-RT. Tumor size ≥ 8 cm predicted increased risk of local failure. Patients with metastatic disease, including non-pulmonary only metastases, received radiation therapy to all metastatic sites and had favorable survival outcomes.

Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.

Feasibility of a novel non-invasive swab technique for serial whole-exome sequencing of cervical tumors during chemoradiation therapy.

BACKGROUND: Clinically relevant genetic predictors of radiation response for cervical cancer are understudied due to the morbidity of repeat invasive biopsies required to obtain genetic material. Thus, we aimed to demonstrate the feasibility of a novel noninvasive cervical swab technique to (1) collect tumor DNA with adequate throughput to (2) perform whole-exome sequencing (WES) at serial time points over the course of chemoradiation therapy (CRT). METHODS: Cervical cancer tumor samples from patients undergoing chemoradiation were collected at baseline, at week 1, week 3, and at the completion of CRT (week 5) using a noninvasive swab-based biopsy technique. Swab samples were analyzed with whole-exome sequencing (WES) with mutation calling using a custom pipeline optimized for shallow whole-exome sequencing with low tumor purity (TP). Tumor mutation changes over the course of treatment were profiled. RESULTS: 216 samples were collected and successfully sequenced for 70 patients (94% of total number of tumor samples collected). A total of 33 patients had a complete set of samples at all four time points. The mean mapping rate was 98% for all samples, and the mean target coverage was 180. Estimated TP was greater than 5% for all samples. Overall mutation frequency decreased during CRT but mapping rate and mean target coverage remained at >98% and >180 reads at week 5. CONCLUSION: This study demonstrates the feasibility and application of a noninvasive swab-based technique for WES analysis which may be applied to investigate dynamic tumor mutational changes during treatment to identify novel genes which confer radiation resistance.

Sequential Diffusion Tensor Imaging and Magnetic Resonance Spectroscopy in Patients Undergoing Reirradiation for Progressive Diffuse Intrinsic Pontine Glioma.

PURPOSE: Diffusion tensor imaging for evaluation of white matter tracts is used with magnetic resonance spectroscopy (MRS) to improve management of diffuse intrinsic pontine glioma (DIPG). Changes in the apparent diffusion coefficient (ADC), fractional anisotropy (FA), and tumor metabolite ratios have been reported after initial radiation for DIPG, but these markers have not been studied sequentially in patients undergoing reirradiation for progressive DIPG. Here, we report a case series of 4 patients who received reirradiation for progressive DIPG on a prospective clinical trial in which we evaluated quantitative changes in FA, ADC, and tumor metabolites and qualitative changes in white matter tracts. METHODS AND MATERIALS: The median reirradiation dose was 25.2 Gy (24-30.8 Gy). Fiber tracking was performed using standard tractography analysis. The FA and ADC values for the corticospinal and medial lemniscus tracts were calculated before and after reirradiation. Multivoxel MRS was performed. Findings were correlated with clinical features and conventional MRI of tumors. RESULTS: All patients had an initial response to reirradiation as shown by a decrease in tumor size. In general, FA increased with disease response and decreased with progression, whereas ADC decreased with disease response and increased with progression. At second progression, the FA fold change relative to values during disease response decreased in both patients with available imaging at second progression. Visualization of tracts demonstrated robust reconstitution of previously disrupted paths during tumor response; conversely, there was increased fiber tract disruption and infiltration during tumor progression. The MRS analysis revealed a decrease in choline:creatinine and choline:N-acetylaspartate ratios during tumor response and increase during progression. CONCLUSIONS: Distinct changes in white matter tracts and tumor metabolism were observed in patients with DIPG undergoing reirradiation on a prospective clinical trial. Changes related to tumor response and progression were observed after 24 to 30.8 Gy reirradiation.

Analysis of pseudoprogression after proton or photon therapy of 99 patients with low grade and anaplastic glioma.

BACKGROUND AND PURPOSE: Proton therapy is increasingly used to treat primary brain tumors. There is concern for higher rates of pseudoprogression (PsP) after protons compared to photons. The purposes of this study are to compare the rate of PsP after proton vs. photon therapy for grade II and III gliomas and to identify factors associated with the development of PsP. MATERIALS AND METHODS: Ninety-nine patients age >18 years with grade II or III glioma treated with photons or protons were retrospectively reviewed. Demographic data, IDH and 1p19q status, and treatment factors were analyzed for association with PsP, progression free survival (PFS), and overall survival (OS). RESULTS: Sixty-five patients were treated with photons and 34 with protons. Among those with oligodendroglioma, PsP developed in 6/42 photon-treated patients (14.3%) and 4/25 proton-treated patients (16%, p = 1.00). Among those with astrocytoma, PsP developed in 3/23 photon-treated patients (13%) and 1/9 proton-treated patients (11.1%, p = 1.00). There was no difference in PsP rate based on radiation type, radiation dose, tumor grade, 1p19q codeletion, or IDH status. PsP occurred earlier in oligodendroglioma patients treated with protons compared to photons, 48 days vs. 131 days, p < .01. On multivariate analyses, gross total resection (p = .03, HR = 0.48, 95%CI = 0.25-0.93) and PsP (p = .04, HR = 0.22, 95% CI = 0.05-0.91) were associated with better PFS; IDH mutation was associated with better OS (p < .01, HR = 0.22, 95%CI = 0.08-0.65). CONCLUSIONS: Patients with oligodendroglioma but not astrocytoma develop PsP earlier after protons compared to photons. PsP was associated with better PFS.

Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity.

We previously isolated an IL-11-mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R-expressing tumors in vivo. This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high IL-11R expression levels in a large cohort of patients (n = 368). In matching surgical specimens (i.e., paired tumors and nonmalignant tissues), the cytoplasmic levels of IL-11R in tumor areas were significantly higher than in nonmalignant tissues (n = 36; P = 0.003). Notably, marked overexpression of IL-11R was observed in both tumor epithelial and vascular endothelial cell membranes (n = 301; P < 0.0001). BMTP-11 induced in vitro cell death in a representative panel of human lung cancer cell lines. BMTP-11 treatment attenuated the growth of subcutaneous xenografts and reduced the number of pulmonary tumors after tail vein injection of human lung cancer cells in mice. Our findings validate BMTP-11 as a pharmacologic candidate drug in preclinical models of lung cancer and patient-derived tumors. Moreover, the high expression level in patients with non-small cell lung cancer is a promising feature for potential translational applications.

A multifunctional streptococcal collagen-mimetic protein coating prevents bacterial adhesion and promotes osteoid formation on titanium.

The major barriers to the clinical success of orthopedic and dental implants are poor integration of fixtures with bone tissue and biomaterial-associated infections. Although multifunctional device coatings have long been considered a promising strategy, their development is hindered by difficulties in integrating biocompatibility, anti-infective activity and antithrombotic properties within a single grafting agent. In this study, we used cell adhesion assays and confocal microscopy of primary murine osteoblasts and human osteoblast cell lines MG-63 and Saos-2 to demonstrate that a streptococcal collagen-like protein engineered to display the α1 and α2 integrin recognition sequences enhances osteoblast adhesion and spreading on titanium fixtures. By measuring calcium deposition and alkaline phosphatase activity, we also showed that selective activation of α2ß1 integrin induces osteoblast differentiation, osteoid formation and mineralization. Moreover, cell adhesion assays and scanning electron microscopy of clinical isolates Staphylococcus aureus Philips and Staphylococcus epidermidis 9491 indicated that streptococcal collagen-mimetic proteins inhibit bacterial colonization and biofilm formation irrespective of their interaction with integrins. Given that streptococcal collagenous substrates neither interact with platelets nor trigger a strong immune response, this novel bioactive coating appears to have desirable multifaceted properties with promising translational applications.