Radioresistance of Brain Tumors

Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation

Medically inoperable peripheral lung cancer treated with stereotactic body radiation therapy

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death in North America. There is wide variation between patients who are medically inoperable and those managed surgically. The use of stereotactic body radiotherapy (SBRT) has narrowed the gap in survival rates between operative and non-operative management for those with early stage disease. This retrospective study reports outcomes for the treatment of peripheral non-small cell lung carcinoma (NSCLC) with SBRT from a single community practice. METHODS: Sixty-seven consecutive patients (pts) with inoperable, untreated peripheral lung tumors were treated from 2010 through 2012 and included in this study. Stereotactic targeting was facilitated by either spine or lung-based image guidance, either with or without fiducial marker tracking with a frameless robotic radiosurgery system. Peripheral tumors received a median biological effective dose (BED) of 105.6 Gy10 or in terms of a median physical dose, 48 Gy delivered over 4 daily fractions. Survival was measured using the Kaplan-Meier method to determine rates of local control, progression of disease and overall survival. The Cox proportional hazards regression model was used to study the effects of tumor size, stage, histology, patient age, tumor location (lobe), tracking method, and BED on the survival distributions. RESULTS: The median follow-up for this cohort was 24.5 months (range: 2.4-50.3) with an overall (OS) 3-year survival of 62.4 % (95 % CI: 74.3-47.3). The median progression-free survival was 28.5 months (95 % CI: 15.8 months to not reached). Local control (LC), defined as a lack of FDG uptake on PET/CT or the absence of tumor growth was achieved in 60 patients (90.9 %) at the time of first follow-up (median 3 months, range: 1-6). Local control at one year for the entire cohort was 81.8 % (95 % CI, 67.3-90.3). The one-year OS probability among those who achieved local control at first follow-up was 86.2 % (95 % CI, 74.3-92.9) but no patients who did not achieve LC at first follow-up survived one year. Of the 60 pts that achieved initial LC, 16 have died. The rates of local control, progression-free survival and overall survival were not statistically different for patients treated using a fiducial target tracking system versus non-invasive guidance. (p = 0.44, p = 0.97 and p = 0.66, respectively). No National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE-4) grade 3 or greater toxicity was observed. CONCLUSION: SBRT is an effective treatment for medically inoperable NSCLC patients with peripherally located tumors. This therapy appears to be well tolerated with low toxicity, and patient outcomes when using non-invasive tumor tracking systems are not inferior to traditional fiducial-based techniques

Parasitic chytrids could promote copepod survival by mediating material transfer from inedible diatoms

Diatoms form large spring blooms in lakes and oceans, providing fuel for higher trophic levels at the start of the growing season. Some of the diatom blooms, however, are not grazed by filter-feeding zooplankton like Daphnia due to their large size. Several of these large diatoms are susceptible to chytrid infections. Zoospores of chytrids appeared to be excellent food for Daphnia, both in terms of size, shape, and quality (PUFAs and cholesterol). Thus, zoospores of chytrids can bridge the gap between inedible diatoms and Daphnia. In order to examine the effects of diatoms and chytrids on the survival of copepods, we performed one grazing and one survival experiment. The grazing experiment revealed that the diatom, Asterionella formosa, was not grazed by the copepod, Eudiaptomus gracilis, even after being infected by the chytrid Zygorhizidium planktonicum. However, carbon and nitrogen concentrations were significantly reduced by E. gracilis only when A. formosa was infected by Z. planktonicum, indicating that the chytrids might facilitate material transfer from inedible diatoms to the copepods. The survival experiment revealed that E. gracilis lived shorter with A. formosa than with the cryptophyta Cryptomonas pyrenoidifera. However, the survival of E. gracilis increased significantly in the treatment where A. formosa cells were infected by Z. planktonicum. Since E. gracilis could not graze A. formosa cells due to their large colonial forms, E. gracilis may acquire nutrients by grazing on the zoospores, and were so able to survive in the presence of the A. formosa. This provides new insights into the role of parasitic fungi in aquatic food webs, where chytrids may improve copepod survival during diatom blooms.

Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

<p>Abstract</p> <p>Background</p> <p>BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer.</p> <p>Case Presentation</p> <p>A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat.</p> <p>Conclusions</p> <p>Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.</p

Phase 1b Study of Batiraxcept in Combination With Durvalumab in Patients With Platinum-Resistant Ovarian Cancer

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71–2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10–24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC

Mutation detection in cholestatic patients using microarray resequencing of ATP8B1 and ABCB11

© 2013 McKay KE et al. Background: Neonatal cholestasis is a common presentation of childhood liver diseases and can be a feature of various conditions including disorders of bile acid biogenesis and transport, various inborn errors of metabolism and perinatal infections. Some inherited metabolic diseases can be easily screened using biochemical assays, however many can only be accurately diagnosed by DNA sequencing. Fluorescent capillary Sanger sequencing (FS) is the gold standard method used by clinical laboratories for genetic diagnosis of many inherited conditions; however, it does have limitations. Recently microarray resequencing (MR) has been introduced into research and clinical practice as an alternative method for genetic diagnosis of heterogeneous conditions. In this report we compared the accuracy of mutation detection for MR with FS in a group of patients with 'low-normal' gamma glutamyl transpeptidase (gGT) cholestasis without known molecular diagnoses. Methods: 29 patient DNA samples were tested for mutations in the ATP8B1 and ABCB11 genes using both FS and MR. Other known causes of "low gGT cholestasis such as ARC syndrome and bile acid biosynthesis disorders were excluded. Results: Mutations were identified in 13/29 samples. In 3/29 samples FS and MR gave discordant results: MR had a false positive rate of 3.4% and a false negative rate of 7%. Conclusions: The major advantage of MR over FS is that multiple genes can be screened in one experiment, allowing rapid and cost-effective diagnoses. However, we have demonstrated that MR technology is limited in sensitivity. We therefore recommend that MR be used as an initial evaluation, with FS deployed when genetic and clinical or histopathological findings are discordant

Responses to the 2017 ‘1 Million Gray Question’: ASTRO membership’s opinions on the most important research question facing radiation oncology

At the American Society for Radiation Oncology's (ASTRO's) 2017 annual meeting in San Diego, CA, attendees were asked, “What is the most important research question that needs to be answered in the next 3 to 5 years?” This request was meant to start a dialogue, promote thoughtful discussion within our professional community, and help inform topics for ASTRO workshops and focus meetings. Nearly 100 people responded while in attendance at the meeting, with questions that ranged from “How can we remove barriers so low- and middle-income countries can have radiation oncology facilities?” to “What is the exact role of radiation in stage IV disease in combination with immunotherapy or targeted agents to combat resistance development?” to “How can personalized care be better integrated into the oncology and radiation oncology clinical space?

Diagnosis of Anosmia and Hyposmia: A Systematic Review

BackgroundAnosmia and hyposmia have many etiologies, including trauma, chronic sinusitis, neoplasms, and respiratory viral infections such as rhinovirus and SARS-CoV-2. We aimed to systematically review the literature on the diagnostic evaluation of anosmia/hyposmia.MethodsPubMed, EMBASE, and Cochrane databases were searched for articles published since January 1990 using terms combined with Medical Subject Headings (MeSH). We included articles evaluating diagnostic modalities for anosmia, written in the English language, used original data, and had two or more patients.ResultsA total of 2065 unique titles were returned upon the initial search. Of these, 226 abstracts were examined, yielding 27 full-text articles meeting inclusion criteria (Level of evidence ranging from 1 to 4; most level 2). The studies included a total of 13,577 patients. The most utilized diagnostic tools were orthonasal smell tests (such as the Sniffin? Sticks and the UPSIT, along with validated abridged smell tests). Though various imaging modalities (including MRI and CT) were frequently mentioned in the workup of olfactory dysfunction, routine imaging was not used to primarily diagnose smell loss.ConclusionThe literature includes several studies on validity and reliability for various smell tests in diagnosing anosmia. Along with a thorough history and physical, validated orthonasal smell tests should be part of the workup of the patient with suspected olfactory dysfunction. The most widely studied modality was MRI, but criteria for the timing and sequence of imaging modalities was heterogenous

Patterns of patient-reported symptoms and association with sociodemographic and systemic sclerosis disease characteristics: a scleroderma Patient-centered Intervention Network (SPIN) Cohort cross-sectional study

Background Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals with similar anxiety, depression, fatigue, sleep disturbance, and pain symptoms and to evaluate associated sociodemographic and disease-related characteristics. Methods This multi-centre cross-sectional study used baseline data from Scleroderma Patient-centered Intervention Network Cohort participants enrolled from 2014 to 2020. Eligible participants completed the PROMIS-29 v2.0 measure. Latent profile analysis was used to identify homogeneous classes of participants based on patterns of anxiety, depression, fatigue, sleep disturbance, and pain scores. Sociodemographic and disease-related characteristics were compared across classes. Findings Among 2212 participants, we identified five classes, including four classes with “Low” (565 participants, 26%), “Normal” (651 participants, 29%), “High” (569 participants, 26%), or “Very High” (193 participants, 9%) symptom levels across all symptoms. Participants in a fifth class, “High Fatigue/Sleep/Pain and Low Anxiety/Depression” (234 participants, 11%) had similar levels of fatigue, sleep disturbance, and pain as in the “High” class but low anxiety and depression symptoms. There were significant and substantive trends in sociodemographic characteristics (age, education, race or ethnicity, marital or partner status) and increasing disease severity (diffuse disease, tendon friction rubs, joint contractures, gastrointestinal symptoms) across severity-based classes. Disease severity and sociodemographic characteristics of “High Fatigue/Sleep/Pain and Low Anxiety/Depression” class participants were similar to the “High” severity class. Interpretation Most people with systemic sclerosis can be classified by levels of patient-reported symptoms, which are consistent across symptoms and highly associated with sociodemographic and disease-related variables, except for one group which reports low mental health symptoms despite high levels of other symptoms and substantial disease burden. Studies are needed to better understand resilience in systemic sclerosis and to identify and facilitate implementation of cognitive and behavioural strategies to improve coping and overall quality of life