A Multicenter Assessment of Interreader Reliability of LI-RADS Version 2018 for MRI and CT.

Background Various limitations have impacted research evaluating reader agreement for Liver Imaging Reporting and Data System (LI-RADS). Purpose To assess reader agreement of LI-RADS in an international multicenter multireader setting using scrollable images. Materials and Methods This retrospective study used deidentified clinical multiphase CT and MRI and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 to August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS version 2018 category was computed as a rescored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1, definitely benign; LR-2, probably benign; LR-3, intermediate probability of malignancy; LR-4, probably hepatocellular carcinoma [HCC]; LR-5, definitely HCC; LR-M, probably malignant but not HCC specific; and LR-TIV, tumor in vein) was computed using intraclass correlation coefficients (ICCs). Agreement was also computed for dichotomized malignancy (LR-4, LR-5, LR-M, and LR-TIV), LR-5, and LR-M. Agreement was compared between research-versus-research reads and research-versus-clinical reads. Results The study population consisted of 484 patients (mean age, 62 years ± 10 [SD]; 156 women; 93 CT examinations, 391 MRI examinations). ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.61, 0.73), 0.63 (95% CI: 0.55, 0.70), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs 0.62, respectively; P = .03) and for dichotomized malignancy (ICC, 0.63 vs 0.53, respectively; P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion There was moderate agreement for LI-RADS version 2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Johnson and Galgano and Smith in this issue.

Role of portable ultrasound during a short-term medical service trip to rural Guatemala: a collaborative mission of trainees and physicians.

INTRODUCTION: Access to health care in developing countries is scarce. One solution to this problem has been for doctors from the USA to provide single-visit care through short-term medical service trips. There is interest in using ultrasound imaging as a portable diagnostic tool; however, data describing its usefulness are scarce. Therefore, the goal of this study was to determine the usefulness of portable ultrasound imaging during a medical service trip to rural Guatemala. METHODS: A multidisciplinary team of physicians examined patients at a mobile clinic in Antigua, Guatemala. Patients with clinical indications for ultrasound had their suspected diagnoses recorded before ultrasound testing. After imaging, updated diagnoses were recorded and compared with the pre-test suspected diagnoses to determine how often ultrasound results changed the medical management of the patients and to assess the most common indications for ultrasound imaging. RESULTS: During the trip, 205 patients were seen. Of these, 24 (12%) were given ultrasound exams. The results of 13 (54%) exams altered their medical management, and the remaining 11 (46%) exams confirmed the pre-test suspected diagnoses. The most common indications for ultrasound testing were suspected cardiac (11 patients, 46%) and gastrointestinal (8 patients, 33%) diseases. CONCLUSION: Portable ultrasound imaging improved the medical team's ability to diagnose disease and clinically manage patients in a rural medical service trip. Ultrasound imaging may provide a low-cost solution to the growing demand for care in developing countries.

Li-Fraumeni Syndrome and Whole-Body MRI Screening: Screening Guidelines, Imaging Features, and Impact on Patient Management.

OBJECTIVE: Li-Fraumeni syndrome (LFS) is a rare autosomal-dominant inherited syndrome containing a germline mutation in the TP53 gene, which predisposes to oncogenesis. Leukemia and tumors of the brain, soft tissues, breasts, adrenal glands, and bone are the most common cancers associated with this syndrome. Patients with LFS are very susceptible to radiation, therefore the use of whole-body MRI is recommended for regular cancer screening. It is important to recognize the common tumors associated with LFS on MRI, and it is also important to be aware of the high rate of false-positive lesions. CONCLUSION: Whole-body MRI is useful for the detection of cancer in patients who come for regular screening; however, it is associated with pitfalls about which the radiologist must remain aware.

The Lesser Sac and Foramen of Winslow: Anatomy, Embryology, and CT Appearance of Pathologic Processes.

OBJECTIVE. This article reviews the embryologic development, relevant anatomy, and imaging features, on CT, of pathologic processes involving the lesser sac and foramen of Winslow. CONCLUSION. The lesser peritoneal sac is an intricate anatomic region involved in many disease processes. It is a significant conduit for the spread of disease within the peritoneal cavity. The spectrum of pathologic processes pertaining to the lesser sac can be classified on the basis of the type of involvement, such as a fluid collection (e.g., transudate, exudate, bile, and blood), a mass (e.g., neoplastic or nonneoplastic conditions and lymphadenopathy), or an internal hernia into the lesser sac.

Morison's pouch: anatomical review and evaluation of pathologies and disease spread on cross-sectional imaging.

The peritoneum is a complex structure. Having a better understanding of this complex anatomy will enable the radiologist to accurately assess and diagnose the wide range of intra-abdominal pathologies. In this article, we review the anatomy, boundaries, and connections of Morison's pouch. In addition, we discuss the incidence and development of common pathological conditions within Morison's pouch and the role of multiple imaging modalities in assessment and diagnosis of these conditions.

Angiogenesis in Hepatocellular Carcinoma; Pathophysiology, Targeted Therapy, and Role of Imaging.

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, usually occurring on a background of liver cirrhosis. HCC is a highly vascular tumor in which angiogenesis plays a major role in tumor growth and spread. Tumor-induced angiogenesis is usually related to a complex interplay between multiple factors and pathways, with vascular endothelial growth factor being a major player in angiogenesis. In the past decade, understanding of tumor-induced angiogenesis has led to the emergence of novel anti-angiogenic therapies, which act by reducing neo-angiogenesis, and improving patient survival. Currently, Sorafenib and Lenvatinib are being used as the first-line treatment for advanced unresectable HCC. However, a disadvantage of these agents is the presence of numerous side effects. A major challenge in the management of HCC patients being treated with anti-angiogenic therapy is effective monitoring of treatment response, which decides whether to continue treatment or to seek second-line treatment. Several criteria can be used to assess response to treatment, such as quantitative perfusion on cross-sectional imaging and novel/emerging MRI techniques, including a host of known and emerging biomarkers and radiogenomics. This review addresses the pathophysiology of angiogenesis in HCC, accurate imaging assessment of angiogenesis, monitoring effects of anti-angiogenic therapy to guide future treatment and assessing prognosis.

Feasibility of Automated Volumetric Assessment of Large Hepatocellular Carcinomas' Responses to Transarterial Chemoembolization.

Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy and the leading cause of death in patients with cirrhosis. Various treatments for HCC are available, including transarterial chemoembolization (TACE), which is the commonest intervention performed in HCC. Radiologic tumor response following TACE is an important prognostic factor for patients with HCC. We hypothesized that, for large HCC tumors, assessment of treatment response made with automated volumetric response evaluation criteria in solid tumors (RECIST) might correlate with the assessment made with the more time- and labor-intensive unidimensional modified RECIST (mRECIST) and manual volumetric RECIST (M-vRECIST) criteria. Accordingly, we undertook this retrospective study to compare automated volumetric RECIST (A-vRECIST) with M-vRECIST and mRESIST for the assessment of large HCC tumors' responses to TACE. Methods:We selected 42 pairs of contrast-enhanced computed tomography (CT) images of large HCCs. Images were taken before and after TACE, and in each of the images, the HCC was segmented using both a manual contouring tool and a convolutional neural network. Three experienced radiologists assessed tumor response to TACE using mRECIST criteria. The intra-class correlation coefficient was used to assess inter-reader reliability in the mRECIST measurements, while the Pearson correlation coefficient was used to assess correlation between the volumetric and mRECIST measurements. Results:Volumetric tumor assessment using automated and manual segmentation tools showed good correlation with mRECIST measurements. For A-vRECIST and M-vRECIST, respectively, r = 0.597 vs. 0.622 in the baseline studies; 0.648 vs. 0.748 in the follow-up studies; and 0.774 vs. 0.766 in the response assessment (P < 0.001 for all). The A-vRECIST evaluation showed high correlation with the M-vRECIST evaluation (r = 0.967, 0.937, and 0.826 in baseline studies, follow-up studies, and response assessment, respectively, P < 0.001 for all). Conclusion:Volumetric RECIST measurements are likely to provide an early marker for TACE monitoring, and automated measurements made with a convolutional neural network may be good substitutes for manual volumetric measurements.

Preresection Radiologic Assessment and Imaging Features of 156 Pathologically Proven Adrenal Adenomas.

PURPOSE: The aims of the study were to assess the typical and atypical radiologic features of pathologically proven adrenal adenomas and to determine the relationship between the radiologic and histopathologic classification. METHODS: We retrospectively studied 156 pathologically proven adrenal adenomas in 154 patients from our institutional databases who have computed tomography (CT) and/or magnetic resonance imaging (MRI) examinations before intervention. We determined the histopathologic diagnosis (typical or atypical) using Weiss scoring and classified the adenomas radiologically into typical, atypical, or indeterminate based on lesion size, precontrast CT attenuation, absolute percentage washout, calcification, and necrosis. The κ statistic was used to assess the agreement between radiologists. The Fisher exact test was used to compare the radiologic and pathological classifications. RESULTS: In consensus, there were 83 typical, 42 atypical, and 31 indeterminate adrenal lesions. Logistic regression model showed that radiologically atypical adenoma was significantly associated with larger size, lobulated shape, higher unenhanced CT attenuation, heterogeneous appearance, nonfunctioning status, absolute percentage washout of less than 60%, and a signal intensity index of less than 16.5%.Pathologically, 147 adenomas were pathologically typical (Weiss 0), and 9 adenomas were pathologically atypical (Weiss 1-2). Radiologically, there was substantial agreement between both readers, with Cohen κ at 0.71. Approximately 98% of radiologically typical adenomas were pathologically typical. Only 17% of radiologically atypical adenomas were pathologically atypical. All radiologically indeterminate adenomas were pathologically typical. However, some of the radiologically indeterminate and typical adenomas still had an atypical component on pathologic analysis, such as necrosis, nuclear atypia, or oncocytic features. CONCLUSIONS: Radiologically atypical lesion was significantly associated with larger size and higher unenhanced CT attenuation. Approximately 27% of the cases demonstrated atypical features on imaging. Most radiologically atypical adrenal adenomas are pathologically typical.

Calcified Adrenal Lesions: Pattern Recognition Approach on Computed Tomography With Pathologic Correlation.

Incidental adrenal lesions are found in 2% to 10% of the population. The presence and pattern of calcifications, in conjunction with other clinical and imaging features, such as soft tissue attenuation, enhancement, and laterality, can aid in narrowing a differential diagnosis, thereby preventing unnecessary biopsies and avoiding delays in management. Calcified adrenal lesions can be categorized under the clinical and laboratory headings of normal adrenal function, hyperfunctioning adrenal tissue, and adrenal insufficiency. In this review, we provide an algorithmic approach to assessing calcified adrenal nodules with correlative radiologic findings.

Adrenal cortical carcinoma: pathology, genomics, prognosis, imaging features, and mimics with impact on management.

Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Most tumors are either metastatic or locally invasive at the time of diagnosis. Differentiation between ACC and other adrenal masses depends on clinical, biochemical, and imaging factors. This review will discuss the genetics, pathological, and imaging feature of ACC.

Comparison of Abdominal Computed Tomographic Enhancement and Organ Lesion Depiction Between Weight-Based Scanner Software Contrast Dosing and a Fixed-Dose Protocol in a Tertiary Care Oncologic Center.

OBJECTIVE: This study aimed to evaluate the quality of enhancement and solid-organ lesion depiction using weight-based intravenous (IV) contrast dosing calculated by injector software versus fixed IV contrast dose in oncologic abdominal computed tomographic (CT) examinations. METHODS: This institutional review board-exempt retrospective cohort study included 134 patients who underwent single-phase abdominal CT before and after implementation of weight-based IV contrast injector software. Patient weight, height, body mass index, and body surface area were determined. Two radiologists qualitatively assessed examinations (4 indicating markedly superior to -4 indicating markedly inferior), and Hounsfield unit measurements were performed. RESULTS: Enhancement (estimated mean, -0.05; 95% confidence interval [CI], -0.19 to 0.09; P = 0.46) and lesion depiction (estimated mean, -0.01; 95% CI, -0.10 to 0.07; P = 0.79) scores did not differ between CT examinations using weight-based IV contrast versus fixed IV contrast dosing when a minimum of 38.5 g of iodine was used. However, the scores using weight-based IV contrast dosing were lower when the injector software calculated and delivered less than 38.5 g of iodine (estimated mean, -0.81; 95% CI, -1.06 to -0.56; P < 0.0001). There were no significant differences in measured Hounsfield units between the CT examinations using weight-based IV contrast dosing versus fixed IV contrast dosing. CONCLUSIONS: Oncologic CT image quality was maintained or improved with weight-based IV contrast dosing using injector software when using a minimum amount of 38.5 g of iodine.

Computed tomography in ventral hernia diagnosis: have we improved? A quality improvement initiative.

BACKGROUND: Previous studies suggest that agreement between readers of computed tomography (CT) scans for the diagnosis of a ventral hernia (VH) is poor (32% agreement, κ = 0.21). Recommendations were developed by surgeons and radiologists after determining common reasons for disagreement among CT reviewers; however, the long-term effect of adoption of these recommendations has not been assessed. The aim of this quality improvement (QI) project was to determine whether the incorporation of recommendations developed by surgeons and radiologists improves agreement among reviewers of CT scans in diagnosing a VH. METHODS: A prospective cohort of patients, with a CT scan of the abdomen and pelvis in the past 1 y, attending a surgery clinic at a single institution was enrolled. Enrolled subjects underwent a standardized physical examination by a trained hernia surgeon to determine the likelihood of a clinical VH (no, indeterminate, or yes). The QI intervention was the distribution and implementation of previously described recommendations. After a year of intervention, independent radiologists assessed patients' CT scans for the presence or absence of a VH. Percent agreement and kappa were calculated to determine interobserver reliability. In-person discussion on scans with disagreement was held, and the results were used as a "gold standard" to calculate sensitivity, specificity, positive, and negative predictive values for CT scan diagnosis of a VH. RESULTS: A total of 79 patients were included in the study. After QI intervention, seven radiologists agreed on 43% of the scans, and κ was 0.50 (P < 0.001). Agreement was highest among patients with a high clinical likelihood of a VH and lowest among patients with an indeterminate clinical likelihood. Sensitivity and specificity were 0.369 and 0.833, respectively. CONCLUSIONS: After the implementation of recommendations, there is improved agreement among radiologists reading CT scans for the diagnosis of a VH. However, there is substantial room for improvement, and CT scans for the diagnosis of VH is not ready for widespread use.

Utility of CT oral contrast administration in the emergency department of a quaternary oncology hospital: diagnostic implications, turnaround times, and assessment of ED physician ordering.

PURPOSE: To compare studies with and without oral contrast on performance of multidetector computed tomography (CT) and the order to CT examination turnaround time in cancer patients presenting to the emergency department (ED). To the best of our knowledge, oral contrast utility has not previously been specifically assessed in cancer patients presenting to the emergency department. MATERIALS & METHODS: Retrospective review of CT abdomen examinations performed in oncology patients presenting to the emergency department during one month. CT examinations performed with and without oral contrast were rated by two consensus readers for degree of confidence and diagnostic ability. Correlations were assessed for primary cancer type, age, sex, chief complaint/examination indication, body mass index, intravenous contrast status, repeat CT examination within 4 weeks, and disposition. Turnaround times from order to the start of the CT examination were calculated. RESULTS: The studied group consisted of 267 patients (127 men and 140 women) with a mean age of 56 years and a mean body mass index of 27.8 kg/m2. One hundred sixty CT examinations were performed without oral contrast, and 107 CT examinations were performed with oral contrast. There was no significant difference between cases with oral contrast and cases without oral contrast in the number of cases rated as "improved confidence" (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.23-1.31, P = 0.17), "improved diagnosis" (OR 0.58, 95% CI 0.20-1.64, P = 0.3), "impaired confidence" (OR 3.92, 95% CI 0.46-33.06, P = 0.21), or "impaired diagnosis" (OR 2.63, 95% CI 0.29-23.89, P = 0.39). The turnaround time in the group receiving oral contrast (mean, 141 min; standard deviation, 49.8 min) was significantly longer than that in the group not receiving oral contrast (mean, 109.2 min; standard deviation, 64.8 min) with a mean difference of 31.8 min (P < 0.0001). CONCLUSION: On the basis of our findings and prior studies, targeted rather than default use of oral contrast shows acceptable diagnostic ability in the emergency setting for oncology patients. Benefit from oral contrast use is suggested in scenarios such as suspected fistula/bowel leak/abscess, hypoattenuating peritoneal disease, prior bowel surgery such as gastric bypass, and the absence of intravenous contrast administration. Improvement through the use of targeted oral contrast administration also supports the emergency department need for prompt diagnosis and disposition.

Comparison of ordinal versus Agatston coronary calcification scoring for cardiovascular disease mortality in community-living individuals.

Coronary artery calcification (CAC) by the Agatston method predicts cardiovascular disease (CVD), but requires cardiac gated computed tomography (CT) scans, a procedure not covered by most insurance providers. An ordinal CAC score (scored 0-12 based on artery number and extent of calcification involvement) can be measured on standard chest CTs. However, the correlation of ordinal and Agatston CAC scores and their relative association with CVD mortality is uncertain, which we sought to determine. Nested case-control study. Community-living individuals undergoing "whole body" CT scans for preventive medicine. 4,544 consecutive patients with CT scans, were followed from 2000 to 2009. We selected cases who died of CVD (n = 57) and age, sex, and CT slice-thickness matched each case to three controls (N = 171). Cardiac gated 3 mm chest CTs and non-gated 6 mm standard chest CTs. CVD death over 9 years follow-up. The intra- and inter-reader kappa for the ordinal CAC score was 0.90 and 0.76 respectively. The correlation of Agatston and ordinal CAC scores was 0.72 (p < 0.001). In models adjusted for traditional CVD risk factors, the odds of CVD death per 1 SD greater CAC was 1.66 (1.03-2.68) using the ordinal CAC score and 1.57 (1.00-2.46) using the Agatston score. A simple ordinal CAC score is reproducible, strongly correlated with Agatston CAC scores, and provides similar prediction for CVD death in predominantly Caucasian community-living individuals.

Macular hole: a rare complication of ocular bartonellosis.

A 37-year-old woman presented with an anterior optic neuropathy related to Bartonella henselae. Twenty-nine days after symptom onset, a partial thickness macular hole developed in the involved eye. Fundus photography and optical coherence tomography confirmed the conversion to a full-thickness macular hole in 2 months. Macular hole as a complication of cat scratch disease is a rare entity, with 2 prior reported cases in children. The development of a macular hole following cat scratch disease can appear without the clinical picture of multiple white chorioretinal lesions, macular star, or vitritis.

Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt.

BACKGROUND: Cancer stem cells (CSC) are believed to play a crucial role in cancer recurrence due to their resistance to conventional chemotherapy and capacity for self-renewal. Recent studies have reported that salinomycin, a livestock antibiotic, selectively targets breast cancer stem cells 100-fold more effectively than paclitaxel. In our study we sought to determine the effects of salinomycin on head and neck squamous cell carcinoma (HNSCC) stem cells. METHODS: MTS and TUNEL assays were used to study cell proliferation and apoptosis as a function of salinomycin exposure in JLO-1, a putative HNSCC stem cell culture. MTS and trypan blue dye exclusion assays were performed to investigate potential drug interactions between salinomycin and cisplatin or paclitaxel. Stem cell-like phenotype was measured by mRNA expression of stem cell markers, sphere-forming capacity, and matrigel invasion assays. Immunoblotting was also used to determine expression of epithelial-mesenchymal transition (EMT) markers and Akt phosphorylation. Arrays by Illumina, Inc. were used to profile microRNA expression as a function of salinomycin dose. RESULTS: In putative HNSCC stem cells, salinomycin was found to significantly inhibit cell viability, induce a 71.5% increase in levels of apoptosis, elevate the Bax/Bcl-2 ratio, and work synergistically with cisplatin and paclitaxel in inducing cell death. It was observed that salinomycin significantly inhibited sphere forming-capability and repressed the expression of CD44 and BMI-1 by 3.2-fold and 6.2-fold, respectively. Furthermore, salinomycin reduced invasion of HNSCC stem cells by 2.1 fold. Contrary to expectations, salinomycin induced the expression of EMT markers Snail, vimentin, and Zeb-1, decreased expression of E-cadherin, and also induced phosphorylation of Akt and its downstream targets GSK3-ß and mTOR. CONCLUSIONS: These results demonstrate that in HNSCC cancer stem cells, salinomycin can cause cell death and decrease stem cell properties despite activation of both EMT and Akt.

EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells.

Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of "stemness" in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.

Recombinant human erythropoietin promotes the acquisition of a malignant phenotype in head and neck squamous cell carcinoma cell lines in vitro.

BACKGROUND: Recent studies indicate an increase in tumor progression and recurrence in head and neck squamous cell carcinomas (HNSCC) of cancer patients taking recombinant human erythropoietin (rhEpo) for anemia. This study was undertaken to investigate the potential role of rhEpo in invasion, proliferation, and cisplatin-induced cell death in HNSCC cell lines. METHODS: The following experiments were performed with two HNSCC cell lines, UMSCC-10B and UMSCC-22B. Presence of EpoR in both cell lines was determined by western blot and quantitative PCR. Colorimetric MTS assays and clonogenic assays were used to study the effect of rhEpo at pharmacologically relevant doses on cell proliferation. Matrigel invasion assays were performed in order to determine effects of exogenous rhEpo on invasive abilities. Clonogenic assays were also used to study potential cytoprotective effects of rhEpo against cisplatin. Immunoblotting was done to analyze the effect of rhEpo on Akt phosphorylation. Finally, MTS and TUNEL assays were performed to test our hypothesis that Akt activation by PI3K was involved in rhEpo-mediated cisplatin resistance. RESULTS: HNSCC cell lines were shown to express Epo receptor (EpoR). RhEpo increased invasion 1.8-fold in UMSCC-10B and 2.6-fold in UMSCC-22B compared to control. RhEpo at 10 U/ml increased cell proliferation by 41% and 53% in UMSCC-10B and UMSCC-22B, respectively, and colony formation by 1.5-fold and 1.8-fold. UMSCC-10B treated with cisplatin and exposed to rhEpo at 1 and 10 U/ml resulted in a 1.7-fold and 3.0-fold increase in colony number compared to control, respectively. UMSCC-22B treated with cisplatin and rhEpo at 1 or 10 U/ml resulted in ~2.5-fold increase in colony number. A TUNEL assay demonstrated a 30.5% and 76.5% increase in survival in UMSCC-10B and UMSCC-22B cells, respectively, in cisplatin and rhEpo-treated cells compared to cisplatin alone. MTS assay showed similar cytoprotective effects. Western blot revealed increased phosphorylation of Akt upon exposure of HNSCC cell lines to rhEpo. MTS assay and TUNEL analyses implicate Akt as a likely contributor to regulation of rhEpo-mediated cytoprotection. CONCLUSIONS: The results demonstrate that, in HNSCC cells expressing functional EpoR, rhEpo promotes invasion, cell proliferation, and induces resistance to cisplatin, which may contribute to tumor progression.

EGF and bFGF promote invasion that is modulated by PI3/Akt kinase and Erk in vestibular schwannoma.

OBJECTIVES: Vestibular schwannomas (VSs) are slow-growing benign tumors but, on rare occasion, can invade adjacent cranial nerves, causing significant morbidity, especially in association with neurofibromatosis 2 (NF2). We aimed to determine the role of the growth factors EGF, bFGF, and the hormone, Epo, in promoting such invasive behavior in VS, as well as their mechanisms of action. METHODS: Immunohistochemical staining showed expression of EGFR, bFGF, Epo, EpoR in archived VS tissue. Western blots and immunofluorescence showed expression of EGFR, EpoR and FGF in HEI-193, an immortalized cell line derived from human NF2-related VS. Matrigel invasion assays were used to study the effect of Epo, FGF and bFGF on invasive behavior in HEI-193. Western blotting showed levels of phospho-Akt and phospho-Erk in HEI-193 upon addition of growth factors plus PI3K or MEK inhibitors. Quantitative RT-PCR was performed to determine the expression of MMP2 and MMP9 after treatment with growth factors. RESULTS: EGFR, bFGF, Epo and EpoR were expressed in VS tissue and HEI193. Addition of EGF and bFGF increased cellular invasion by 10 and 3.5-fold, respectively. Epo had minimal effect on invasion. Results indicated that Erk is involved in bFGF but not EGF-induced invasion, while Akt is involved in both pathways. EGF treatment moderately induced MMP9, but is unlikely to account for the observed invasion. CONCLUSION: Activation of EGFR and FGFR may promote invasive behavior in VS through ERK and Akt signaling pathways. Further investigation will be necessary to elucidate their potential as useful targets in the treatment of VS.