Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy.

BACKGROUND AND PURPOSE: Emerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both efficacy and toxicity. This manuscript characterizes factors associated with intracranial control and radiation necrosis in this group. MATERIALS AND METHODS: All patients had non-small cell lung cancer, renal cell carcinoma, or melanoma and were treated from 2013 to 2021 at two institutions with ICI and SRS/SRT. Univariate and multivariate analysis were used to analyze factors associated with local failure (LF) and grade 2+ (G2 + ) radiation necrosis. RESULTS: There were 179 patients with 549 metastases. The median follow up from SRS/SRT was 14.7 months and the median tumor size was 7 mm (46 tumors ≥ 20 mm). Rates of LF and G2 + radiation necrosis per metastasis were 5.8% (32/549) and 6.9% (38/549), respectively. LF rates for ICI +/- 1 month from time of radiation versus not were 3% (8/264) and 8% (24/285) (p = 0.01), respectively. G2 + radiation necrosis rates for PD-L1 ≥ 50% versus < 50% were 17% (11/65) and 3% (5/203) (p=<0.001), respectively. PD-L1 ≥ 50% remained significantly associated with G2 + radiation necrosis on multivariate analysis (p = 0.03). Rates of intracranial failure were 54% (80/147) and 17% (4/23) (p = 0.001) for those without and with G2 + radiation necrosis, respectively. CONCLUSIONS: PD-L1 expression (≥50%) may be associated with higher rates of G2 + radiation necrosis, and there may be improved intracranial control following the development of radiation necrosis. Administration of ICIs with SRS/SRT is overall safe, and there may be some local control benefit to delivering these concurrently.

Inhibition of Influenza Virus Replication by Oseltamivir Derivatives.

Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concentration (IC50). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200.

Abdominal imaging findings in patients with SARS-CoV-2 infection: a scoping review.

PURPOSE: This scoping review evaluated the currently available data related to abdominal imaging in the SARS-CoV-2 infection. METHOD: A systematic review of MEDLINE, EMBASE, SCOPUS, and Web of Science was performed from inception to July 15, 2020 using PRISMA-ScR guidelines. The review included case reports and series discussing radiologic manifestations of SARS-CoV-2 infection in abdominal imaging studies. Studies published from inception to March 31, 2020, were independently screened and reviewed by one author, and another author reviewed studies published after March 31 to July 15, 2020. Study screening and full-text review for publications before March 31, 2020, was performed by one author, and another author for publications after March 31 to July 15, 2020. RESULTS: Thirty-six studies were included in qualitative synthesis. The prevalence of gastrointestinal symptoms is roughly 18% and includes loss of appetite, nausea, vomiting, diarrhea, and abdominal pain. Sixteen percent of COVID-19 cases may only present with gastrointestinal symptoms. Many patients presenting this way demonstrate evidence of COVID-19 incidentally through abdominal CT imaging at the lung bases. Studies published to date have also reported abdominal imaging findings including small and large bowel wall thickening, fluid-filled colon, pneumatosis intestinalis, pneumoperitoneum, intussusception, and ascites. CONCLUSION: Gastrointestinal manifestations and imaging manifestations of SARS-CoV-2 infection are increasingly reported and warrant specific attention during abdominal imaging.

Diagnostic accuracy of dual-energy CT for the detection of bone marrow edema in the appendicular skeleton: a systematic review and meta-analysis.

OBJECTIVES: This meta-analysis evaluated the diagnostic accuracy of dual-energy CT (DECT) for detecting bone marrow edema (BME) in the appendicular skeleton. METHODS: A systematic review of MEDLINE, EMBASE, Scopus, the Cochrane Library, and gray literature from inception through January 31, 2020, was performed. Original articles with > 10 patients evaluating the accuracy of DECT for detecting BME in the appendicular skeleton with a reference standard of MRI and/or clinical follow-up were included. Study details were independently extracted by two reviewers. Meta-analysis was performed using a bivariate random-effects model with multivariable meta-regression. Risk of bias (RoB) was evaluated with QUADAS-2. RESULTS: Twenty studies evaluating 790 patients for BME in the appendicular skeleton were included in analysis. The summary sensitivity, specificity, and AUC values for BME in the appendicular skeleton were 86% (95% confidence interval [CI] 82-89%), 93% (95% CI 90-95%), and 0.95, respectively. Quantitative analysis had a higher sensitivity than qualitative analysis on meta-regression (p = 0.01), but no difference in specificity (p = 0.28). No other covariates contributed to variability in accuracy (etiology (trauma vs non-trauma); location (upper vs lower extremity); and RoB). Studies demonstrated generally low or unclear RoB and applicability. Eight studies included index tests with high RoB when quantitative assessments used a retrospective cut-off value. CONCLUSIONS: DECT demonstrates a higher specificity than sensitivity and AUC > 0.9. In scenarios where MRI availability is limited or contraindicated, DECT could be an alternative to MRI for detecting BME in the appendicular skeleton. However, limitations in sources of variability and RoB warrant continued study. KEY POINTS: • Twenty studies evaluating 790 patients for bone marrow edema in the appendicular skeleton with dual-energy CT were included in analysis. • The summary sensitivity, specificity, and AUC values for detecting bone marrow in the appendicular skeleton were 86% (95% confidence interval [CI] 82-89%), 93% (95% CI 90-95%), and 0.95, respectively. • In scenarios where MRI availability is limited or is contraindicated, DECT could be an alternative to MRI for detecting bone marrow edema in the appendicular skeleton.

Diagnostic accuracy of dual-energy CT for detecting bone marrow edema in patients with acute knee injuries: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis evaluated the diagnostic accuracy of dual-energy CT (DECT) for detecting bone marrow edema (BME) in adult patients with acute knee injuries. METHODS: A systematic review of MEDLINE, EMBASE, Scopus, the Cochrane Library, and gray literature was performed from inception to January 31, 2020, using PRISMA-DTA guidelines. The review included studies assessing the diagnostic accuracy of DECT for detecting BME in at least 10 adult patients with acute knee injuries and with an MRI reference standard. Study details were independently extracted by two reviewers. Meta-analysis was performed using a bivariate mixed-effects regression model with subgroup analysis performed to evaluate for sources of variability. Risk of bias (ROB) was evaluated using the QUADAS-2 tool. RESULTS: Eight studies evaluating 267 patients between the ages of 25-54 with acute knee injuries undergoing DECT and MRI were included in analysis. Summary sensitivity, specificity, and AUROC values for BME were 84% (95% confidence interval (CI) 74-91%), 96% (95% CI 93-98%), and 0.97 (95% CI 0.95-0.98), respectively. Bone-based characterization was found to have lower specificity than region-based characterization (83% (57-95%) versus 97 (96-98%), p < 0.05), but no difference in sensitivity. No other statistical differences were identified amongst study subgroups to account for presumed variability amongst studies. Most studies were rated low risk for bias and applicability concerns. CONCLUSION: DECT is specific and accurate for detecting BME in adult patients with acute knee injuries and can be used as an alternative to MRI, particularly when MRI is contraindicated or unavailable.

Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma.

Tumor-infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host antitumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 patients with primary melanoma to assess the association of absent, nonbrisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared with histology alone in 15% of the cohort. To assess for intergroup immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), nonbrisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (P=.025) and overall survival (P=.006) compared with patients with nonbrisk and absent TILs, for which there were no differences in recurrence-free survival (P=.40) or overall survival (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared with TIL grading on hematoxylin and eosin-stained sections. Melanomas with nonbrisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group, and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared with melanomas with nonbrisk or absent TILs.

Identification of a Novel Pathogenic Germline KDR Variant in Melanoma.

PURPOSE: The application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response. EXPERIMENTAL DESIGN: We analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody. RESULTS: Serum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells. CONCLUSIONS: Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.

FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

​Heat-shock factor 1 (​HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate ​HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase ​FBXW7α interacts with ​HSF1 through a conserved motif phosphorylated by ​GSK3ß and ​ERK1. ​FBXW7α ubiquitylates ​HSF1 and loss of ​FBXW7α results in impaired degradation of nuclear ​HSF1 and defective heat-shock response attenuation. ​FBXW7α is either mutated or transcriptionally downregulated in melanoma and ​HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. ​FBXW7α deficiency and subsequent ​HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the ​HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

Epidermal growth factor stimulates proton efflux from chondrocytic cells.

Proton efflux from chondrocytes alters the extracellular pH and ionic composition of cartilage, and influences the synthesis and degradation of extracellular matrix. Epidermal growth factor (EGF) promotes chondrocyte proliferation during skeletal development and accumulates in the synovial fluid in rheumatoid arthritis. The purpose of this study was to investigate the effect of EGF on proton efflux from chondrocytes. When monitored using a Cytosensor microphysiometer, EGF was found to rapidly activate proton efflux from CFK2 chondrocytic cells and rat articular chondrocytes. The actions of EGF were concentration-dependent with half-maximal effects at 0.3-0.7 ng/ml. Partial desensitization and time-dependent recovery of the response were observed following repeated exposures to EGF. EGF-induced proton efflux was dependent on extracellular glucose, and inhibitors of Na(+)/H(+) exchange (NHE) markedly attenuated the initial increase in proton efflux. The response was diminished by inhibitors of phosphatidylinositol 3-kinase and phospholipase C, but not by inhibitors of MEK (MAPK/ERK kinase) or protein kinase A or C. Thus, EGF-induced proton efflux involves glucose metabolism and NHE, and is regulated by a discrete subset of EGF-activated signaling pathways. In vivo, proton efflux induced by EGF may lead to an acidic environment, enhancing turnover of cartilage matrix during development and in rheumatoid arthritis.