More than 85% of patients with uveal melanoma (UM) carry a GNAQ or GNA11 mutation at a hotspot codon (Q209) that encodes G protein α subunit q/11 polypeptides (Gα_q/11). GNAQ/11 relies on palmitoylation for membrane association and signal transduction. Despite the palmitoylation of GNAQ/11 was discovered long before, its implication in UM remains unclear. Here, results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells. Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^Q209L-induced malignant transformation in NIH3T3 cells. Importantly, the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells, which are much more dependent on Gα_q/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gα_q/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.
Humans ; Mice ; Animals ; Lipoylation ; NIH 3T3 Cells ; Uveal Neoplasms/genetics* ; Melanoma/genetics* ; Cell Proliferation ; Proto-Oncogene Proteins c-bcl-2 ; GTP-Binding Protein alpha Subunits, Gq-G11/genetics*

Choroid plexus tumors are uncommon brain tumors that primarily occur in children. Most of these tumors originate from the intraventricular area, and the most common clinicalpresentation is increased intracranial pressure. Dissemination through the cerebrospinal fluid space is the inevitable natural course of the disease. Here, we present 2 rare cases of adult choroid plexus carcinoma (CPC), each with distinct clinical presentation and progression. The first case was a 40-year-old male who presented with multiple intraventricular masses. After surgical biopsy, radiation and intrathecal chemotherapy failed to elicit any response. The patient progressed with spinal cord dissemination and expired 1 year later. The second case presented with visual disturbance, and brain MRI revealed a large ovoid juxtaventricular mass with peritumoral edema. This 49-year-old female patient underwent craniotomy for what was thought to be a high-grade glioma; however, the mass was connected to the choroid plexus at the operative field. Her pathology specimen was diagnosed as CPC, and adjuvant systemic chemotherapy was administered. She has now been free of recurrence for 10 months. The description of the presentation and progression of these rare adult-onset CPC provides insight for the diagnosis and treatment of other rare instances of choroid plexus tumors.
Adult ; Biopsy ; Brain ; Brain Neoplasms ; Cerebrospinal Fluid ; Child ; Choroid Plexus Neoplasms ; Choroid Plexus ; Choroid ; Craniotomy ; Diagnosis ; Drug Therapy ; Edema ; Female ; Fourth Ventricle ; Glioma ; Humans ; Intracranial Pressure ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Pathology ; Recurrence ; Spinal Cord

PURPOSE: To report a case of extensive choroidal effusion following the Valsalva maneuver under consecutive general anesthesia. CASE SUMMARY: A 41-year-old man who underwent panretinal photocoagulation with proliferative diabetic retinopathy had pars plana vitrectomy and endolaser photocoagulation under general anesthesia due to vitreous hemorrhage. Urology cooperated as the patient had hematuria; the day after the operation, he was transferred to the urology department. Two days after vitrectomy, the patient had an urgent transurethral bladder tumor resection under general anesthesia with suspicion of bladder tumor. At 6 days postoperatively, extensive choroidal effusion was observed from 8 to 10 o'clock on fundus examination and ultrasonography. On day 23 after urological surgery, the choroidal effusion had disappeared without treatment. CONCLUSIONS: Consecutive general anesthesia requires caution, as it is not only burdensome to the body as a whole but may also cause choroidal effusion in the eye.
Adult ; Anesthesia, General ; Choroid ; Diabetic Retinopathy ; Hematuria ; Humans ; Light Coagulation ; Ultrasonography ; Urinary Bladder Neoplasms ; Urology ; Valsalva Maneuver ; Vitrectomy ; Vitreous Hemorrhage

Background: Decision-making concerning the treatment of choroid plexus tumor (CPT) in pediatric patients remains a topic of considerable debate. The aim of this work was to describe clinical features and prognostic risk factors of CPT in the pediatric population and to provide theoretical opinions regarding clinical decisions for CPT. Methods: The data of 96 patients with CPT and younger than 14 years were retrospectively analyzed. Clinical characteristics such as pathological type of CPTs, rate and severity of hydrocephalus, treatment and outcome, and recurrence were investigated. For categorical variables, the Pearson's Chi-square test was performed. The Mann-Whitney U-test was used for comparisons between nonnormally distributed parameters. Log-rank test was used for progression-free survival (PFS). Results: The study included 70 choroid plexus papilloma (CPP) cases, 17 atypical choroid plexus papilloma (aCPP) cases, and 9 choroid plexus carcinoma (CPC) cases. Compared with patients with CPP or aCPP, patients with CPC had a shorter disease course (median: CPP, 4 months; aCPP, 2 months; CPC, 1 month; H: 23.5, P < 0.001), higher rate of acute hydrocephalus (CPP, 27.1%; aCPP, 52.9%; CPC, 77.8%; χ = 10.9, P < 0.05), and lower incidence of cure rate (CPP, 85.7%; aCPP, 70.5%; CPC, 33.3%; χ = 13.5, P < 0.05). The severity of hydrocephalus with tumor in the lateral or third ventricle was significantly higher than that with tumors in the fourth ventricle (severe hydrocephalus: lateral ventricle, 51.7%; third ventricle, 47.0%; fourth ventricle, 11.1%; χ = 26.0, P < 0.001). Patients with gross total surgical resection had no better PFS than those with partial resection because of the use of adjuvant therapy in the latter (χ = 4.0, P > 0.05). Patients with CPC experienced shorter time for recurrence than those with CPP or aCPP (χ = 40.1, P < 0.0001). Conclusions Our results indicated that CPP in the fourth ventricle could trigger serious clinical symptoms at an early stage, requiring early intervention. Adjuvant treatment might be necessary for patients with partially resected CPP, aCPP, and CPC to achieve a favorable outcome.
Child ; Child, Preschool ; Choroid Plexus Neoplasms ; mortality ; pathology ; surgery ; Female ; Humans ; Hydrocephalus ; etiology ; Infant ; Male ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Prognosis ; Risk Factors

Gastric cancer with double metastasis to the orbit and duodenum is extremely rare. We report the case of a patient with gastric adenocarcinoma who presented with synchronous orbital and duodenal metastases at the time of initial diagnosis. A 60-year-old man presented with a 1-month history of visual disorder and pain in his right eye. He underwent ophthalmological examinations. The biopsy results suggested intraocular metastatic carcinoma. We conducted a systemic evaluation to identify primary malignancy. Finally, a diagnosis of advanced gastric adenocarcinoma with multi-organ metastasis was made. He planned to be treated with systemic chemotherapy.
Adenocarcinoma ; Biopsy ; Choroid ; Diagnosis ; Drug Therapy ; Duodenum ; Humans ; Middle Aged ; Neoplasm Metastasis ; Orbit ; Stomach Neoplasms ; Vision Disorders

ObjectiveThe objective of the study was to summarize the role of DNA methylation in the development and metastasis of uveal melanoma (UM).

Data SourcesThe relevant studies in MEDLINE were searched.

Study SelectionIn this review, we performed a comprehensive literature search in MEDLINE using "uveal melanoma" AND ("DNA methylation" OR "epigenetics") for original research/review articles published before February 2018 on the relationship between DNA methylation and UM. References of the retrieved studies were also examined to search for potentially relevant papers.

ResultsPrevious studies on the relationship between DNA methylation and UM covered many genes including tumor suppressor genes (TSGs), cyclin-dependent kinase genes, and other genes. Among them, the TSG genes such as RASSF1A and p16INK4a, which encodes a cyclin-dependent kinase inhibitor, are relatively well-studied genes. Specifically, a high percentage of promoter methylation of RASSF1A was observed in UM cell lines and/or patients with UM. Promoter methylation of RASSF1A was also associated with the development of metastasis. Similarly, a high percentage of promoter hypermethylation of p16INK4a was found in UM cell lines. DNA promoter methylation can control the expression of p16INK4a, which affect cell growth, migration, and invasion in UM. Many other genes might also be involved in the pathogenesis of UM such as the Ras and EF-hand domain containing (RASEF) gene, RAB31, hTERT, embryonal fyn-associated substrate, and deleted in split-hand/split-foot 1.

ConclusionsOur review reveals the complex mechanisms underlying the tumorigenesis of UM and highlights the great needs of future studies to discover more genes/5'-C-phosphate-G-3' sites contributing to the development/metastasis of UM and explore the mechanisms through which epigenetic changes exert their function in UM.

Cell Transformation, Neoplastic ; genetics ; DNA Methylation ; genetics ; Epigenesis, Genetic ; genetics ; Humans ; Melanoma ; genetics ; Promoter Regions, Genetic ; genetics ; Uveal Neoplasms ; genetics

PURPOSE: Uveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood of recurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters. MATERIALS AND METHODS: Prognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy. RESULTS: Forty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)–negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter ≥ 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival. CONCLUSION: Risk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes.
Disease-Free Survival ; Humans ; Liver ; Male ; Melanoma* ; Metastasectomy ; Multivariate Analysis ; Prognosis* ; Radiotherapy ; Recurrence ; Risk Factors ; Uveal Neoplasms

OBJECTIVE: Choroidal metastases (CMs) are the most common intraocular tumor. Management is mainly radiation therapy with goals of pain control and visual improvement. However, many radiation-related complications are reported. Since gamma knife radiosurgery (GKS) for CM was first reported in 1995, few cases have been reported. We report 7 cases of CMs treated with GKS.METHODS: From April 2011 to November 2014, 7 patients with CM underwent GKS. Their median age at treatment was 64 years (range, 51–71 years). Four males and three females were treated. Lung cancer was the most common primary pathology, followed by renal cell carcinoma and stomach cancer. Four patients had multiple cerebral lesions and were treated simultaneously for choroidal lesions. The median marginal dose of 20 Gy (range, 15–25 Gy) was administered at the 50% isodose line.RESULTS: Median follow-up period after GKS was 8 months (range, 2–38.3 months). Four patients expired due to underlying malignancy progression. Except for two patients who were not followed with magnetic resonance image after GKS, all patients showed size reduction in the treated lesions, but a new choroidal lesion appeared in one patient and one recurred. Six of seven patients reported subjectively improved visual symptoms. Visual acuity improved in 2 patients, and 2 were stable upon objective examination. One patient showed no improvement in visual acuity, but ocular pain was relieved; another patient showed improved vision and tumor remission, but visual deterioration recurred.CONCLUSION: GKS was shown to be safe and effective and should be considered for CM treatment.
Carcinoma, Renal Cell ; Choroid ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; Male ; Neoplasm Metastasis ; Orbit ; Pathology ; Radiosurgery ; Stomach Neoplasms ; Visual Acuity

Down syndrome (DS, trisomy 21) is associated with neuroanatomical abnormalities, including choroid plexus cysts and various types of brain tumors. Trisomy 21 is associated with oncogenic factor, especially in brain tumor. The brain of DS patients had a smaller volume of gray and white matter and an unbalanced cerebellum volume, indicating a smaller volume overall than normal. We report a case of a DS male patient who had an incidentally discovered neuroglial cyst in left cerebellar vermis. He visited our hospital with gait disturbance and fatigue. But, the neurologic exam was normal. To the best of our knowledge, this is the first reported case of a neuroglial cyst in a trisomy 21 patient. As the developmental mechanisms of a cyst and the choroid plexus are related, more research is needed.
Brain ; Brain Neoplasms ; Central Nervous System Cysts ; Cerebellar Vermis ; Cerebellum ; Choroid Plexus ; Down Syndrome* ; Fatigue ; Gait ; Humans ; Male ; Neuroglia ; Trisomy ; White Matter

PURPOSE: To report a case of choroidal metastasis caused by lung cancer in a young female who had no history. CASE SUMMARY: A 31-year-old female presented with decreased vision for 1 week. Fundus examination revealed an orange colored choroidal tumor and serous retinal detachment at superotemporal area of the optic disc on the left eye. On chest X-ray, atypical pneumonia or hematogenous metastasis was shown. Additionally, mammography, chest-abdomen computed tomography, lumbar magnetic resonance imaging, and transbronchial lung biopsy were performed and the patient was finally diagnosed with adenocarcinoma. The patient started systemic chemotherapy and visual acuity improved after 1 month. Tumor size and subretinal fluid also decreased. The tumor disappeared 2 months later and there was no recurrence. CONCLUSIONS: There are only few cases in which choroidal metastasis was observed in a young female patient with no history who had decreased visual acuity and was later diagnosed with lung cancer. Authors report this case because a satisfactory result was obtained from chemotherapy alone.
Adenocarcinoma ; Adult ; Biopsy ; Choroid* ; Citrus sinensis ; Drug Therapy ; Female ; Humans ; Lung Neoplasms* ; Lung* ; Magnetic Resonance Imaging ; Mammography ; Neoplasm Metastasis* ; Pneumonia ; Recurrence ; Retinal Detachment ; Subretinal Fluid ; Thorax ; Visual Acuity