Prognostic nomogram for bladder cancer with brain metastases: a National Cancer Database analysis.

BACKGROUND: This study aimed to establish and validate a nomogram for predicting brain metastasis in patients with bladder cancer (BCa) and assess various treatment modalities using a primary cohort comprising 234 patients with clinicopathologically-confirmed BCa from 2004 to 2015 in the National Cancer Database. METHODS: Machine learning method and Cox model were used for nomogram construction. For BCa patients with brain metastasis, surgery of the primary site, chemotherapy, radiation therapy, palliative care, brain confinement of metastatic sites, and the Charlson/Deyo Score were predictive features identified for building the nomogram. RESULTS: For the original 169 patients considered in the model, the areas under the receiver operating characteristic curve (AUC) were 0.823 (95% CI 0.758-0.889, P < 0.001) and 0.854 (95% CI 0.785-0.924, P < 0.001) for 0.5- and 1-year overall survival respectively. In the validation cohort, the nomogram displayed similar AUCs of 0.838 (95% CI 0.738-0.937, P < 0.001) and 0.809 (95% CI 0.680-0.939, P < 0.001), respectively. The high and low risk groups had median survivals of 1.91 and 5.09 months for the training cohort and 1.68 and 8.05 months for the validation set, respectively (both P < 0.0001). CONCLUSIONS: Our prognostic nomogram provides a useful tool for overall survival prediction as well as assessing the risk and optimal treatment for BCa patients with brain metastasis.

The Role of Genomic Techniques in Predicting Response to Radiation Therapy.

The understanding of the relationship between genetic variation and an individual patient's response to radiation therapy (RT) has gained significant ground over the past several years. Genetic markers have been identified that could ultimately serve as the foundation for predictive models in clinical practice, and that hold the potential to revolutionize the delivery of precision medicine in oncology. Single nucleotide polymorphisms, single genes, and/or gene signatures could ultimately serve as the basis for patient stratification in prospective clinical trials. Currently, molecular markers relevant to breast, lung, and head and neck cancers have been integrated into clinical practice and serve as predictive tools to guide systemic therapy. In the future, the use of predictive models based on genomic determinants may become standard practice in radiation oncology, offering the potential to further personalize the delivery of RT and optimize the therapeutic ratio.

Grains and grain boundaries in single-layer graphene atomic patchwork quilts.

The properties of polycrystalline materials are often dominated by the size of their grains and by the atomic structure of their grain boundaries. These effects should be especially pronounced in two-dimensional materials, where even a line defect can divide and disrupt a crystal. These issues take on practical significance in graphene, which is a hexagonal, two-dimensional crystal of carbon atoms. Single-atom-thick graphene sheets can now be produced by chemical vapour deposition on scales of up to metres, making their polycrystallinity almost unavoidable. Theoretically, graphene grain boundaries are predicted to have distinct electronic, magnetic, chemical and mechanical properties that strongly depend on their atomic arrangement. Yet because of the five-order-of-magnitude size difference between grains and the atoms at grain boundaries, few experiments have fully explored the graphene grain structure. Here we use a combination of old and new transmission electron microscopy techniques to bridge these length scales. Using atomic-resolution imaging, we determine the location and identity of every atom at a grain boundary and find that different grains stitch together predominantly through pentagon-heptagon pairs. Rather than individually imaging the several billion atoms in each grain, we use diffraction-filtered imaging to rapidly map the location, orientation and shape of several hundred grains and boundaries, where only a handful have been previously reported. The resulting images reveal an unexpectedly small and intricate patchwork of grains connected by tilt boundaries. By correlating grain imaging with scanning probe and transport measurements, we show that these grain boundaries severely weaken the mechanical strength of graphene membranes but do not as drastically alter their electrical properties. These techniques open a new window for studies on the structure, properties and control of grains and grain boundaries in graphene and other two-dimensional materials.

Softened elastic response and unzipping in chemical vapor deposition graphene membranes.

We use atomic force microscopy to image grain boundaries and ripples in graphene membranes obtained by chemical vapor deposition. Nanoindentation measurements reveal that out-of-plane ripples effectively soften graphene's in-plane stiffness. Furthermore, grain boundaries significantly decrease the breaking strength of these membranes. Molecular dynamics simulations reveal that grain boundaries are especially weakening when subnanometer voids are present in the lattice. Finally, we demonstrate that two graphene membranes brought together form membranes with higher resistance to breaking.

Transfer-free batch fabrication of single layer graphene transistors.

Full integration of graphene into conventional device circuitry would require a reproducible large scale graphene synthesis that is compatible with conventional thin film technology. We report the synthesis of large scale single layer graphene directly onto an evaporated copper film. A novel fabrication method was used to directly pattern these graphene sheets into devices by simply removing the underlying copper film. Raman and conductance measurements show that the mechanical and electrical properties of our single layer graphene are uniform over a large area, ( Ferrari, A. C. et al. Phys. Rev. Lett. 2006, 97, 187401.) which leads to a high device yield and successful fabrication of ultra long (>0.5 mm) graphene channels. Our graphene based devices present excellent electrical properties including a promising carrier mobility of 700 cm(2)/V.s and current saturation characteristics similar to devices based on exfoliated graphene ( Meric, I.. et al. Nat Nanotechnol. 2008, 3, 654-659).

Clinical Integration of Digital Solutions in Health Care: An Overview of the Current Landscape of Digital Technologies in Cancer Care.

Digital health constitutes a merger of both software and hardware technology with health care delivery and management, and encompasses a number of domains, from wearable devices to artificial intelligence, each associated with widely disparate interaction and data collection models. In this review, we focus on the landscape of the current integration of digital health technology in cancer care by subdividing digital health technologies into the following sections: connected devices, digital patient information collection, telehealth, and digital assistants. In these sections, we give an overview of the potential clinical impact of such technologies as they pertain to key domains, including patient education, patient outcomes, quality of life, and health care value. We performed a search of PubMed ( www.ncbi.nlm.nih.gov/pubmed ) and www.ClinicalTrials.gov for numerous terms related to digital health technologies, including digital health, connected devices, smart devices, wearables, activity trackers, connected sensors, remote monitoring, electronic surveys, electronic patient-reported outcomes, telehealth, telemedicine, artificial intelligence, chatbot, and digital assistants. The terms health care and cancer were appended to the previously mentioned terms to filter results for cancer-specific applications. From these results, studies were included that exemplified use of the various domains of digital health technologies in oncologic care. Digital health encompasses the integration of a vast array of technologies with health care, each associated with varied methods of data collection and information flow. Integration of these technologies into clinical practice has seen applications throughout the spectrum of care, including cancer screening, on-treatment patient management, acute post-treatment follow-up, and survivorship. Implementation of these systems may serve to reduce costs and workflow inefficiencies, as well as to improve overall health care value, patient outcomes, and quality of life.

Stereotactic radiosurgery practice patterns for brain metastases in the United States: a national survey.

BACKGROUND: Stereotactic radiosurgery (SRS) has emerged as an important modality for the treatment of intracranial metastases. There are currently few established guidelines delineating indications for SRS use and fewer still regarding plan evaluation in the treatment of multiple brain metastases. METHODS: An 18 question electronic survey was distributed to radiation oncologists at National Cancer Institute (NCI) designated cancer centers in the USA (60). Centers without radiation oncologists were excluded. Physicians who indicated that they do not prescribe SRS were excluded from the remaining survey questions. Sign test and Chi-square test were used to determine if responses differed significantly from random distribution. RESULTS: One hundred sixteen of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. Sixty-two percent reported treating patients with brain metastases using SRS. Radiation oncologists prescribing SRS most commonly treat CNS (66.2%) and lung (49.3%) malignancies. SRS was used more frequently for < 10 brain metastases (73.7%; p < 0.0001) and whole brain radiation therapy (WBRT) for > 10 brain metastases (82.5%; p < 0.0001). The maximum number of lesions physicians were willing to treat with SRS without WBRT was 1-4 (40.4%) and 5-10 (42.4%) (p < 0.0001 compared to 11-15, 16-20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p < 0.0001) and performance status (p = 0.016). The most common margin for SRS was 0 mm (49.1%; p = 0.0021). The most common dose constraints other than critical structure was conformity index (84.2%) and brain V12 (61.4%). The LINAC was the most common treatment modality (54.4%) and mono-isocenter technique for multiple brain metastases was commonly used (43.9%; p = 0.23). Most departments do not have a policy for brain metastases treatment (64.9%; p = 0.024). CONCLUSIONS: This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data highlight some clinical considerations for physicians treating brain metastases with SRS.

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases.

PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

Reirradiation for second primary or recurrent cancers of the head and neck: Dosimetric and outcome analysis.

BACKGROUND: The purpose of this study was to examine outcomes, toxicity, and dosimetric characteristics of patients treated with reirradiation for head and neck cancers. METHODS: Fifty patients underwent ≥2 courses of radiation therapy (RT) postoperatively or definitively with or without chemotherapy. Composite dose volume histograms (DVHs) for selected anatomic structures were correlated with grade ≥3 late toxicity. RESULTS: Median initial and retreatment radiation dose was 64 and 60 Gy, respectively. Median overall survival (OS), progression-free survival (PFS), and 1-year PFS rates were 18 months, 11 months, and 45%, respectively, with 13 months median follow-up. Thirty-four percent of patients experienced grade ≥3 late toxicity with 1 death from carotid blowout. The DVH corresponding to the carotid blowout fell above the third quartile compared with other patients. CONCLUSION: Our analysis is the first to systematically evaluate the dose to the carotid artery using composite dosimetry in head and neck reirradiation patients, and demonstrates a promising technique for evaluating the dose to other normal tissue structures. © 2015 Wiley Periodicals, Inc. Head Neck 38: E961-E969, 2016.

An interleukin 13 receptor α 2-specific peptide homes to human Glioblastoma multiforme xenografts.

Interleukin 13 receptor α 2 (IL-13Rα2) is a glioblastoma multiforme (GBM)-associated plasma membrane receptor, a brain tumor of dismal prognosis. Here, we isolated peptide ligands for IL-13Rα2 with use of a cyclic disulphide-constrained heptapeptide phages display library and 2 in vitro biopanning schemes with GBM cells that do (G26-H2 and SnB19-pcDNA cells) or do not (G26-V2 and SnB19-asIL-13Rα2 cells) over-express IL-13Rα2. We identified 3 peptide phages that bind to IL-13Rα2 in cellular and protein assays. One of the 3 peptide phages, termed Pep-1, bound to IL-13Rα2 with the highest specificity, surprisingly, also in a reducing environment. Pep-1 was thus synthesized and further analyzed in both linear and disulphide-constrained forms. The linear peptide bound to IL-13Rα2 more avidly than did the disulphide-constrained form and was efficiently internalized by IL-13Rα2-expressing GBM cells. The native ligand, IL-13, did not compete for the Pep-1 binding to the receptor and vice versa in any of the assays, indicating that the peptide might be binding to a site on the receptor different from the native ligand. Furthermore, we demonstrated by noninvasive near infrared fluorescence imaging in nude mice that Pep-1 binds and homes to both subcutaneous and orthotopic human GBM xenografts expressing IL-13Rα2 when injected by an intravenous route. Thus, we identified a linear heptapeptide specific for the IL-13Rα2 that is capable of crossing the blood-brain tumor barrier and homing to tumors. Pep-1 can be further developed for various applications in cancer and/or inflammatory diseases.