Although identified as the key environmental driver of common cutaneous melanoma, the role of ultraviolet radiation (UVR)-induced DNA damage in mucosal melanoma is poorly defined. We analyze 10 ...mucosal melanomas of conjunctival origin by whole genome sequencing and our data shows a predominance of UVR-associated single base substitution signature 7 (SBS7) in the majority of the samples. Our data shows mucosal melanomas with SBS7 dominance have similar genomic patterns to cutaneous melanomas and therefore this subset should not be excluded from treatments currently used for common cutaneous melanoma.
To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a ...first-line treatment of primary CNS lymphoma (PCNSL).
Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m
day (D) 1, methotrexate 3 g/m
D1; D15, VP16 100 mg/m
D2, BCNU 100 mg/m
D3, prednisone 60 mg/kg/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m
D1, cytarabine 3 g/m
D1 to D2). Intensive chemotherapy consisted of thiotepa (250 mg/m
/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial.
Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT.
WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.
Summary The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In ...2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.
Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated ...with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.
Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B‐cell lymphoma and most frequently develops in elderly ...populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%–90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin‐10 levels in ocular fluids and detection of IgH or T‐cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.
摘要
原发性玻璃体视网膜淋巴瘤(PVRL),又称原发性眼内淋巴瘤,是一种罕见的恶性肿瘤,通常被归为弥漫性大B细胞淋巴瘤,老年人多见。PVRL仅发生于视网膜和中枢神经系统,常被误认为后色素层炎。超过15%的原发性中枢神经系统淋巴瘤患者发生眼内淋巴瘤,通常发生在视网膜和/或玻璃体。相反,65%~90%的PVRL患者发生中枢神经系统淋巴瘤。由于PVRL最终与中枢神经系统相关联,因此往往是致命的。目前的PVRL动物模型有局限性,需进一步开发。典型临床表现为在散瞳眼底镜检查、荧光血管造影和 光学相干断层扫描 下可见玻璃体细胞浸润(淋巴瘤和炎症细胞)和视网膜下肿瘤浸润。目前,PVRL最常用的诊断方法是通过组织学确定玻璃体或视网膜的淋巴瘤细胞、以及免疫组化提示单克隆性。其他PVRL辅助诊断方法包括眼内液白介素‐10增高、恶性细胞中检测出IgH 或T细胞受体基因重排。PVRL的最佳治疗方案尚未确定,需要肿瘤科医生和眼科医生通力合作。PVRL对放疗敏感,并对玻璃体内注射甲氨蝶呤或利妥昔单抗具有高反应性。虽然PVRL采用全身化疗缓解率较高,但复发率也较高。由于本病罕见,因此需要国际性多中心的协作努力,才能更透彻地了解PVRL的生物学特性和发病机制,确定其诊断标记物和最佳疗法。
A symposium on primary vitreoretinal lymphoma held at the Fifth Annual, National Cancer Institute–sponsored International Primary Central Nervous System Lymphoma Collaborative Group conference, a multidisciplinary meeting, is summarized herein. Tumor biology, nomenclature, epidemiology and prognosis, biology and pathogenesis, animal models, clinical manifestations, diagnosis, therapeutics, and future investigations are reviewed.
Cataract and uveitis are rare in newborns but potentially blinding. Three newborns with cataract and severe anterior uveitis underwent cataract surgery. Spiroplasma ixodetis was detected in lens ...aspirates using bacterial 16S-rRNA PCR and transmission electron microscopy. These findings, which suggest maternal-fetal infection, are consistent with previous experimental Spiroplasma-induced cataract and uveitis.
Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our ...prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation‐specific bidirectional pyrophosphorolysis‐activated polymerization (bi‐PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch® technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1–20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4–11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression‐free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.
What's new?
In some cancers, tumor cells and tumor DNA find their way into the bloodstream and circulate around the body. These circulating markers present the tantalizing possibility of an easily performed test for disease prognosis. In this study, the authors sought to detect circulating tumor cells and DNA from metastatic uveal melanoma. They found that the two were highly correlated with each other, but not necessarily of strong prognostic value. Circulating tumor DNA, they report, was more frequently detected, and in patients with known mutations, might prove more useful for prognosis.
Disruption of splicing patterns due to mutations of genes coding splicing factors in tumors represents a potential source of tumor neoantigens, which would be both public (shared between patients) ...and tumor-specific (not expressed in normal tissues). In this study, we show that mutations of the splicing factor
in uveal melanoma generate such immunogenic neoantigens. Memory CD8
T cells specific for these neoantigens are preferentially found in 20% of patients with uveal melanoma bearing
-mutated tumors. Single-cell analyses of neoepitope-specific T cells from the blood identified large clonal T-cell expansions, with distinct effector transcription patterns. Some of these expanded T-cell receptors are also present in the corresponding tumors. CD8
T-cell clones specific for the neoepitopes specifically recognize and kill
-mutated tumor cells, supporting the use of this new family of neoantigens as therapeutic targets. SIGNIFICANCE: Mutations of the splicing factor
in uveal melanoma generate shared neoantigens that are uniquely expressed by tumor cells, leading to recognition and killing by specific CD8 T cells. Mutations in splicing factors can be sources of new therapeutic strategies applicable to diverse tumors.
.
It has been accepted for many years that tumor cells spread
via
the circulation to distant sites. The latency period between treatment and tumor recurrence has been attributed to dormant cells in ...distant organs that emerge and grow as metastatic tumors. These processes are accepted with an incomplete demonstration of their existence. Challenging such a well-established accepted paradigm is not easy as history as shown. An alternative or co-existing mechanism involving tumor cell migration along the outside of the vessels and co-option of the blood vessel has been studied for over 25 years and is presented. Several lines of data support this new mechanism of tumor spread and metastatic growth and is termed angiotropic extravascular migratory metastasis or EVMM. This slow migration along the outside of the vessel wall may explain the latency period between treatment and metastatic tumor growth. The reader is asked to be open to this possible new concept in how tumors spread and grow and the reason for this latency period. A full understanding of how tumors spread and grow is fundamental for the targeting of new therapeutics.
Abstract Introduction We aimed to confirm the diagnostic value and to evaluate the pre- and post-therapeutic prognostic value of cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and ...IL-6 in patients with diffuse large B-cell primary central nervous system lymphoma (PCNSL). Patients and methods IL-10 and IL-6 concentrations were measured in 79 patients with PCNSL at diagnosis and in 40 control individuals. Fifty-four PCNSL patients underwent repeat assessments starting at diagnosis. Results The IL-10 concentration distinguished PCNSL from other neurologic diseases with a sensitivity of 88.6% and a specificity of 88.9% with a cutoff of 4 pg/ml. In a multivariate analysis of PCNSL patients, CSF involvement was associated with a higher IL-10 concentration (mean log (IL-10) of 4.4 versus 2.5 pg/ml, respectively, p = 0.0004). The pre-therapeutic IL-10 concentration had no prognostic impact on outcome. The IL-10 concentration decreased after treatment for most patients tested. Among patients with complete remission or partial remission, as evaluated by magnetic resonance imaging (MRI), a persistent detectable IL-10 level in the CSF at the end of treatment was associated with a negative impact on progression-free survival (PFS) (1-year PFS: 15%, 95% confidence interval CI: 2.5–38% versus 59%, 95% CI: 32–78%, respectively, p = 0.0004). Conclusion Our study confirmed that IL-10 is a useful biomarker for the diagnosis of PCNSL. We highlight new findings showing that the IL-10 level in the CSF could be used as a surrogate marker for CSF involvement and that the post-treatment IL-10 concentration could complement standard MRI for therapeutic response assessment in PCNSL.