5-Aminolevulinic acid fluorescence in brain non-neoplastic lesions: a systematic review and case series.

Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) is used to assist brain tumor resection, especially for high-grade gliomas but also for low-grade gliomas, metastasis, and meningiomas. With the increasing use of this technique, even to assist biopsies, high-grade glioma-mimicking lesions had misled diagnosis by showing 5-ALA fluorescence in non-neoplastic lesions such as radiation necrosis and inflammatory or infectious disease. Since only isolated reports have been published, we systematically review papers reporting non-neoplastic lesion cases with 5-ALA according with the PRISMA guidelines, present our series, and discuss its pathophysiology. In total, 245 articles were identified and 12 were extracted according to our inclusion criteria. Analyzing 27 patients, high-grade glioma was postulated as preoperative diagnosis in 48% of the cases. Microsurgical resection was performed in 19 cases (70%), while 8 patients were submitted to biopsy (30%). We found 4 positive cases in demyelinating disease (50%), 4 in brain abscess (80%), 1 in neurocysticercosis (33%), 1 in neurotoxoplasmosis, infarction, and hematoma (100%), 4 in inflammatory disease (80%), and 3 in cortical dysplasia (100%). New indications are being considered especially in benign lesion biopsies with assistance of 5-ALA. Using fluorescence as an aid in biopsies may improve procedure time, number of samples, and necessity of intraoperative pathology. Further studies should include this technology to encourage more beneficial uses.

Head-to-head comparison between 18F-FDOPA PET/CT and MR/CT angiography in clinically recurrent head and neck paragangliomas.

PURPOSE: Head and neck paragangliomas (HNPGLs) can relapse after primary treatment. Optimal imaging protocols have not yet been established for posttreatment evaluation. The aim of the present study was to assess the diagnostic value of 18F-FDOPA PET/CT and MR/CT angiography (MRA/CTA) in HNPGL patients with clinical relapse during their follow-up. METHODS: Sixteen consecutive patients presenting with local pain, tinnitus, dysphagia, hoarse voice, cranial nerve involvement, deafness, or retrotympanic mass appearing during follow-up after the initial treatment of HNPGLs were retrospectively evaluated. Patients underwent both 18F-FDOPA PET/CT and MRA (15 patents) or CTA (1 patent). Both methods were first assessed under blinded conditions and afterwards correlated. Head and neck imaging abnormalities without histological confirmation were considered true-positive results based on a consensus between radiologists and nuclear physicians and on further 18F-FDOPA PET/CT and/or MRA. RESULTS: 18F-FDOPA PET/CT and MRA/CTA were concordant in 14 patients and in disagreement in 2 patients. 18F-FDOPA PET/CT and MRA/CTA identified, respectively, 12 and 10 presumed recurrent HNPGLs in 12 patients. The two lesions diagnosed by PET/CT only were confirmed during follow-up by otoscopic examination and MRA performed 29 and 17 months later. 18F-FDOPA PET/CT images were only slightly influenced by the posttreatment sequelae, showing a better interobserver reproducibility than MRA/CTA. Finally, in 2 of the 16 studied patients, 18F-FDOPA PET/CT detected two additional synchronous primary HNPGLs. CONCLUSION: 18F-FDOPA PET/CT is highly sensitive in posttreatment evaluation of patients with HNPGLs, and also offers better interobserver reproducibility than MRA/CTA and whole-body examination. We therefore suggest that 18F-FDOPA PET/CT is performed as the first diagnostic imaging modality in symptomatic patients with suspicion of HNPGL relapse after primary treatment when 68Ga-labeled somatostatin analogues are not available.

Mixed Mesonephric Adenocarcinoma and High-grade Neuroendocrine Carcinoma of the Uterine Cervix: Case Description of a Previously Unreported Entity With Insights Into Its Molecular Pathogenesis.

Human papillomavirus (HPV)-negative cervical carcinomas are uncommon and typically encompass unusual histologic subtypes. Mesonephric adenocarcinoma is one such subtype. Mesonephric tumors in the female genital tract are thought to arise from Wolffian remnants, and are extremely rare tumors with widely variable morphology. Sarcomatoid dedifferentiation has been previously described in a few cases, but other forms of dedifferentiation have not been reported. Neuroendocrine carcinoma of the cervix (e.g. small cell carcinoma) is associated with HPV infection, typically HPV 18. These tumors often arise in association with a conventional epithelial component such as squamous cell carcinoma or usual-type endocervical adenocarcinoma. We describe a case of mesonephric adenocarcinoma of the uterine cervix associated with an HPV-negative high-grade neuroendocrine carcinoma at the morphologic and immunophenotypic level, for which we performed targeted massively parallel sequencing analysis of the 2 elements. Both components shared identical mutations in U2AF1 p.R156H (c.467G>A) and GATA3 p.M422fs (c.1263dupG), as well as MYCN amplification. In addition, the neuroendocrine carcinoma harbored TP53 and MST1R mutations not present in the mesonephric carcinoma. Our data suggest a clonal origin of the 2 components of this rare entity, rather than a collision tumor.

Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma.

Immune checkpoint blockade targeting the programmed death-1 (PD-1) pathway has shown efficacy in several types of cancers including mismatch-repair-deficient colorectal carcinoma. In some tumor types, programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry has shown utility as a predictive marker for response to anti-PD-1 therapies. This utility, however, remains to be determined in colorectal carcinoma. In addition, although tumor-infiltrating lymphocytes have been associated with better prognosis in colorectal carcinoma, the prognostic value of PD-1 expression in these lymphocytes and its interaction with PD-L1 expression still await investigation. To address these questions, we performed a pilot study to evaluate the patterns of PD-L1 and PD-1 immunohistochemical expression on colorectal carcinoma cells and their tumor-infiltrating lymphocytes, respectively. Using tissue microarray, we found that 5% (19/394) of colorectal carcinomas exhibited high tumor PD-L1 expression, and 19% (76/392) had elevated numbers of PD-1-positive tumor-infiltrating lymphocytes. PD-L1 levels correlated with PD-1 levels (P<0.001), and mismatch-repair-deficient tumors had significantly higher rates of high PD-L1 and PD-1 expression when compared with mismatch-repair-proficient tumors (18% vs 2% and 50% vs 13%, respectively; P<0.001 for both). Staining intensity was also stronger for both markers in mismatch-repair-deficient tumors. Furthermore, we observed that among patients with mismatch-repair-deficient colorectal carcinoma, PD-1/PD-L1 expression stratified recurrence-free survival in an inter-dependent manner: an association between high PD-1-positive tumor-infiltrating lymphocytes and improved recurrence-free survival (P=0.041) was maintained only when the tumors had low-level PD-L1 expression (P=0.006); patients whose tumors had both high PD-1-positive tumor-infiltrating lymphocytes and high PD-L1 expression had a significantly worse recurrence-free survival (P<0.001). Thus, our results not only provide a foundation for further assessment of PD-L1 immunohistochemistry as a predictive marker for anti-PD-1 therapy in colorectal carcinoma, they also shed light on the prognostic impact of tumor-infiltrating lymphocytes in different subsets of mismatch-repair-deficient colorectal carcinomas.

Ki67 Index Correlates with Tumoral Volumetry and 5-ALA Residual Fluorescence in Glioblastoma.

BACKGROUND: Malignant gliomas are the most prevalent primary malignant cerebral tumors. Preoperative imaging plays an important role, and the prognosis is closely related to surgical resection and histomolecular aspects. Our goal was to correlate Ki67 indexes with tumoral volumetry in semiautomatic segmentation on preoperative magnetic resonance images and residual fluorescence in a 5-ALA-assisted resection cohort. METHODS: We included 86 IDH-wildtype glioblastoma patients with complete preoperative imaging submitted to 5-ALA assisted resections. Clinical, surgical, and histomolecular findings were also obtained. Preoperative magnetic resonance studies were preprocessed and segmented semiautomatically on Visualization and Analysis for whole tumor (WT) on 3D FLAIR, enhancing tumor (ET), and necrotic core on 3D postgadolinium T1. We performed a linear regression analysis for Ki67 and a multivariate analysis for surgical outcomes. RESULTS: Higher Ki-67 indexes correlated positively with higher WT (P = 0.048) and ET (P = 0.002). Lower Ki67 correlated with 5-ALA free margins (P = 0.045). WT and ET volumes correlated with the extent of resection (EOR; P = 0.002 and 0.002, respectively). Eloquence did not impact EOR (P = 0.14). CONCLUSIONS: There is a correlation between Ki67, the metabolically active tumoral volumes (WT and ET), and 5-ALA residual fluorescence. Methodological inconsistencies are probably responsible for contradictory literature findings, and further prospective studies are needed to validate and reproduce these findings.

Fast growth rate of a right atrial myxoma.

Primary cardiac tumors are rare, with an incidence between 0.0017 and 0.19%, and are asymptomatic in up to 72% of cases. Approximately 75% of tumors are benign, and nearly 50% of these are myxomas. Concerning location, 75% of myxomas are in the left atrium, 15 to 20% in the right atrium, and more rarely in the ventricles. The finding of cardiac myxomas usually implies immediate surgical excision to prevent embolic events and sudden cardiac death. Reports with documented growth rate are rare, and the actual growth rate remains a controversial issue. We report the rapid growth rate of a right atrial myxoma in an oligosymptomatic 69-year-old patient, with negative previous echocardiographic history in the last two years, who refused surgery upon diagnosis, enabling monitoring of myxoma growth.

Retroperitoneal castleman disease mimicking lymph node spread from clear renal cell carcinoma. A case report.

Renal Cell Carcinoma (RCC) corresponds to 3% of the neoplasms in the adults. Surgery is the main mode of treatment, which can be associated toretroperitoneal lymphadenectomy in the presence of clinically tumor positive lymph nodes. Castleman Disease (CD) is a rare lymphoproliferative disorder, with little-known etiopathogenesis. It rarely affects the retroperitoneum. Thorax, neck, and abdomen are more frequently affected. Therefore, CD can simulate lymphatic spread from RCC to the retroperitoneum, also leading to a possible misdiagnosis, or diagnosis concerning a paraneoplastic syndrome due to RCC.

Burden and cost of multiple sclerosis in Brazil.

BACKGROUND: The objective of this study was to estimate costs to society and patients' quality of life (QoL) at all levels of disease severity (measured with the Expanded Disability Status Scale, EDSS) in Brazil. METHODS: The study was part of an international, cross-sectional burden-of-illness study carried out in collaboration with national MS patient organizations. All information was collected directly from patients using a validated questionnaire. Direct costs were estimated both from societal and payer perspectives, while total costs are presented as societal costs. RESULTS: The survey included 694 patients (response rate 21%; mean age 40.8 years). 95% of patients were of working age, and around half were working. The mean EDSS score was 3.2 (62.5% of patients with EDSS <3). Relapses were reported by 18.9% of patients. Fatigue affected almost all patients (94%) regardless of EDSS level, and cognitive difficulties were reported by 69.1% of patients. Mean utility ranged from 0.77 at EDSS 0 to negative values at EDSS 9, with a mean score of 0.58; utility was affected by relapses. Total mean annual cost was R$33,872 (€ 8,000) per patient in the societal perspective, with direct costs representing 81% (R$ 27,355, € 6,500). Direct costs for the payer amounted to R$ 16,793 (€ 4,000)/patient. CONCLUSIONS: This study included a population with relatively mild and early disease, with a majority of patients with relapsing disease and thus on DMD treatment. It is not possible to conclude directly on the total cost of MS in Brazil. Nevertheless, resource quantities used, QoL and MS symptoms are very similar to what was seen in the European survey.

Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype.

Primary intraosseous rhabdomyosarcomas (RMSs) are extremely rare. Recently 2 studies reported 4 cases of primary intraosseous RMS with EWSR1/FUS-TFCP2 gene fusions, associated with somewhat conflicting histologic features, ranging from spindle to epithelioid. In this study we sought to further investigate the pathologic and molecular abnormalities of a larger group of intraosseous RMSs by a combined approach using targeted RNA sequencing analysis and fluorescence in situ hybridization (FISH). We identified 7 cases, 3 males and 4 females, all in young adults, age range 20 to 39 years (median, 27 y). Three cases involved the pelvis, 2 involved the femur and 1 each involved the maxilla and the skull. Molecular studies identified recurrent gene fusions in all 7 cases tested, including: a novel MEIS1-NCOA2 fusion in 2 cases, EWSR1-TFCP2 in 3 cases, and FUS-TFCP2 gene fusions in 1 case. One case showed a FUS gene rearrangement, without a TFCP2 gene abnormality by FISH. The MEIS1-NCOA2-positive cases were characterized by a more primitive and fascicular spindle cell appearance, while the EWSR1/FUS rearranged tumors had a hybrid spindle and epithelioid phenotype, with more abundant eosinophilic cytoplasm and mild nuclear pleomorphism. Immunohistochemically, all tumors were positive for desmin and myogenin (focal). In addition, 4 tumors with TFCP2-associated gene fusions also coexpressed ALK and cytokeratin. In conclusion, our results suggest a high incidence of gene fusions in primary RMSs of bone, with 2 molecular subsets emerging, defined by either MEIS1-NCOA2 or EWSR1/FUS-TFCP2 fusions, showing distinct morphology and immunophenotype. Additional studies with larger numbers of cases and longer follow-up data are required to definitively evaluate the biological behavior of these tumors and to establish their relationship to other spindle cell RMS genetic groups.

Comparison between red wine and isolated trans-resveratrol on the prevention and regression of atherosclerosis in LDLr (-/-) mice.

Moderate consumption of red wine has been widely associated with reduced cardiovascular risk, mainly due to its composition in phenolic compounds with antioxidant activity, such as resveratrol. The objective of this study was to compare the effect of red wine vs. trans-resveratrol consumption on the prevention and regression of atherosclerosis in LDLr (-/-) mice. This study consisted of two protocols: "Prevention" (PREV) and "Regression" (REGR). Both protocols included four groups: red wine (WINE), dealcoholized red wine (EXT), trans-resveratrol (RESV), and control (CONT). In PREV protocol, animals received a regular diet for 8 weeks and then switched to an atherogenic diet for the following 8 weeks, while the opposite was performed in REGR. Animals that received atherogenic diet after an initial period of standard diet (PREV) gained more body weight (39.25±2.30%) than the opposite (29.27±1.91%, P=.0013), suggesting an interaction between age and weight gain. Trans-resveratrol showed the highest hypocholesterolemic effect during PREV, reducing total cholesterol, LDL-C, VLDL-C and HDL-C. Supplementation with trans-resveratrol and dealcoholized red wine changed the fatty acids profile in the liver in both protocols, leading to an increase of MDA concentrations and SOD activity in the PREV protocol. In conclusion, supplementation with trans-resveratrol, red wine and the same wine without alcohol altered biomarkers of oxidative stress and lipidemia but had no effect on the prevention or regression of fatty streaks. These data suggest that cardiovascular protection associated with the "French Paradox" may be a result of synergistic effects between wine and the Mediterranean diet.

Poorly Differentiated Clusters Predict Colon Cancer Recurrence: An In-Depth Comparative Analysis of Invasive-Front Prognostic Markers.

This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.

Fast growth rate of a right atrial myxoma

ABSTRACT Primary cardiac tumors are rare, with an incidence between 0.0017 and 0.19%, and are asymptomatic in up to 72% of cases. Approximately 75% of tumors are benign, and nearly 50% of these are myxomas. Concerning location, 75% of myxomas are in the left atrium, 15 to 20% in the right atrium, and more rarely in the ventricles. The finding of cardiac myxomas usually implies immediate surgical excision to prevent embolic events and sudden cardiac death. Reports with documented growth rate are rare, and the actual growth rate remains a controversial issue. We report the rapid growth rate of a right atrial myxoma in an oligosymptomatic 69-year-old patient, with negative previous echocardiographic history in the last two years, who refused surgery upon diagnosis, enabling monitoring of myxoma growth.

The ENETS/WHO grading system for neuroendocrine neoplasms of the gastroenteropancreatic system: a review of the current state, limitations and proposals for modifications.

The understanding of neuroendocrine neoplasms has evolved significantly since their initial descriptions in the 1800s to early 1900s. In the gastroenteropancreatic system, this group of malignant tumors is subdivided into well and poorly differentiated neuroendocrine neoplasms based on morphologic, proliferative and biologic differences. However, it has become increasingly apparent that well-differentiated neuroendocrine tumors are not a homogeneous group. Attempting to better predict outcome of these tumors has been the motivation behind numerous proposed classification systems, the evolution of which culminated with the currently used system, the ENETS/WHO classification. Herein, we review the genesis of this classification system and some of its shortcomings. In addition, we discuss some of the most recent proposals that suggest modifications to the current system.

Clinicopathologic Features of Colorectal Carcinoma in HIV-Positive Patients.

BACKGROUND: Emerging evidence suggests differences in colorectal cancer in HIV-infected patients (HIV(+)) compared with HIV(-) patients. Microsatellite instability (MSI), occurring in a subset of colorectal cancer, is present at a higher rate in certain cancers in HIV(+) patients. Colorectal cancer with MSI share some characteristics with those reported for HIV(+) colorectal cancer. On this premise, we studied clinical and pathologic features of HIV(+) colorectal cancer and evaluated for MSI using matched HIV(-) colorectal cancer controls. METHODS: Two nested, matched cohorts were identified from a hospital-based cohort of colorectal cancer patients. HIV(+) colorectal cancers were identified and random control patients were matched for selected characteristics. Mismatch repair protein (MMR) IHC was performed as the detection method for MSI. Variables were compared between cases and controls using fixed-effects logit modeling to account for matching. RESULTS: We included 184 colorectal cancer samples (38 HIV(+), 146 HIV(-) control). Median patient age at colorectal cancer onset was 55. When compared with HIV(-) colorectal cancer, HIV(+) patients were more likely to have smoked (P = 0.001), have right-sided colorectal cancer (37% vs. 14%; P = 0.003), and tumor-infiltrating lymphocytes (TIL) above 50/10 high-power fields (21% vs. 7%). There was no difference in MMR protein expression (P = 0.6). HIV(+) colorectal cancer patients had reduced overall survival (P = 0.02) but no difference in progression-free survival. CONCLUSIONS: HIV(+) patients developed colorectal cancer at a lower median age than population estimates, had a higher frequency of right-sided disease, and increased TILs, suggesting potential biologic differences compared with uninfected patients. IMPACT: Clinicopathologic differences in colorectal cancer of HIV(+) persons may have implications for tumor pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(7); 1098-104. ©2016 AACR.

West Nile Virus Central Nervous System Infection in Patients Treated With Rituximab: Implications for Diagnosis and Prognosis, With a Review of Literature.

The spectrum of West Nile virus (WNV) infection continues to be elucidated. Many cases of WNV are asymptomatic; however, in immunocompromised patients, symptoms are more likely to be severe. We describe fatal WNV central nervous system disease in lymphoma patients who received rituximab, blunting the inflammatory response and complicating diagnosis.