Chromogenic in situ hybridization reveals specific expression pattern of long non-coding RNA DRAIC in formalin-fixed paraffin-embedded specimen.

Long non-coding RNA (lncRNA) plays an important role in the regulation of gene expression in normal and cancer cells. We previously discovered a novel tumor-suppressive lncRNA, DRAIC, in prostate cancer cells. Subsequent studies have demonstrated that DRAIC is dysregulated in various malignancies and exhibits a tumor-suppressive or pro-oncogenic function. However, details regarding its expression pattern in normal and cancerous tissues remain largely unknown. In this study, we performed chromogenic in situ hybridization (CISH) using RNAscope technology to assess DRAIC expression in formalin-fixed paraffin-embedded (FFPE) specimens. In the neuroendocrine-differentiated cancer cell line VMRC-LCD, CISH revealed a diffuse localization of DRAIC in the cytoplasm as well as specific accumulation in the nuclear compartment. DRAIC expression was comprehensively analyzed using tissue microarrays containing 89 normal and 155 tumor tissue samples. DRAIC was weakly expressed in normal epithelial cells of the colon, bronchiole, kidney, prostate, and testis. Conversely, DRAIC was moderately to highly expressed in some cancer tissues, including prostate adenocarcinoma, invasive ductal carcinoma of the breast, neuroendocrine carcinoma of the esophagus, lung adenocarcinoma, and small cell lung carcinoma. While DRAIC knockdown did not affect VMRC-LCD cellular viability and invasive ability, gene expression related to the neuroendocrine and cancer-related pathways was altered. Our expression analysis revealed the specific expression pattern of DRAIC in normal and cancerous FFPE tissues. The results presented here may lead to the elucidation of additional novel functions of DRAIC.

SEGA-like circumscribed astrocytoma in a non-NF1 patient, harboring molecular profile of GBM. A case report.

Subependymal giant cell astrocytoma (SEGA) is a low-grade periventricular tumor that is closely associated with tuberous sclerosis complex (TSC). SEGA typically arises during the first two decades of life and rarely arises after the age of 20-25 years. Nevertheless, it has also been reported that glioma histologically resembling SEGA, so-called SEGA-like astrocytoma, can arise in neurofibromatosis type 1 (NF1) patients, even in the elderly. Herein, we report a case of SEGA-like circumscribed astrocytoma arising in the lateral ventricle of a 75-year-old woman. Whole-exome sequencing revealed a somatic variant of NF1. Methylation array analysis led to a diagnosis of "methylation class glioblastoma, IDH-wildtype, mesenchymal-type (GBM, MES)" with a high calibrated score (0.99). EGFR amplification, CDKN2A/B homozygous deletion, chromosomal +7/-10 alterations, and TERT promoter mutation, typical molecular abnormalities usually found in GBM, were also observed. While most reported cases of SEGA-like astrocytoma have arisen in NF1 patients, the patient was neither TSC nor NF1. Near total removal was accomplished with endoscopic cylinder surgery. At the 36-month follow-up, there was no tumor recurrence without adjuvant therapies. This clinical behavior did not match GBM. SEGA-like astrocytoma of the elderly is rare, and this is the oldest case reported so far. In addition, high-grade molecular features found in circumscribed tumor remain unclear. Further investigations among larger series are needed for clarifying the underlying molecular mechanisms.

Early detection of genotoxic hepatocarcinogens in rats using γH2AX and Ki-67: prediction by machine learning.

Direct DNA double-strand breaks result in phosphorylation of H2AX, a variant of the histone H2 protein. Phosphorylated H2AX (γH2AX) may be a potential indicator in the evaluation of genotoxicity and hepatocarcinogenicity. In this study, γH2AX and Ki-67 were detected in the short-term responses (24 h after chemical administration) to classify genotoxic hepatocarcinogens (GHs) from non-GH chemicals. One hundred and thirty-five 6-week-old Crl: CD(SD) (SPF) male rats were treated with 22 chemicals including 11 GH and 11 non-GH, sacrificed 24 h later, and immunostained with γH2AX and Ki-67. Positivity rates of these markers were measured in the 3 liver ZONEs 1-3; portal, lobular, and central venous regions. These values were input into 3 machine learning models-Naïve Bayes, Random Forest, and k-Nearest Neighbor to classify GH and non-GH using a 10-fold cross-validation method. All 11 and 10 out of 11 GH caused significant increase in γH2AX and Ki-67 levels, respectively (P < .05). Of the 3 machine learning models, Random Forest performed the best. GH were identified with 95.0% sensitivity (76/80 GH-treated rats), 90.9% specificity (50/55 non-GH-treated rats), and 90.0% overall correct response rate using γH2AX staining, and 96.2% sensitivity (77/80), 81.8% specificity (45/55), and 90.4% overall correct response rate using Ki-67 labeling. Random Forest model using γH2AX and Ki-67 could independently predict GH in the early stage with high accuracy.

Utility of cerebrospinal fluid liquid biopsy in distinguishing CNS lymphoma from cerebrospinal infectious/demyelinating diseases.

BACKGROUND: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. METHODS: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. RESULTS: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days). CONCLUSIONS: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

Future Perspective for ALK-Positive Anaplastic Large Cell Lymphoma with Initial Central Nervous System (CNS) Involvement: Could Next-Generation ALK Inhibitors Replace Brain Radiotherapy for the Prevention of Further CNS Relapse?

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments.

Three-Dimensional Amide Proton Transfer-Weighted Imaging for Differentiating between Glioblastoma, IDH-Wildtype and Primary Central Nervous System Lymphoma.

Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1-100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width1-100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses.

Totally laparoscopic resection using delta-shaped anastomosis of jejunal leiomyosarcoma with intussusception at the angle of Treitz: a case report.

BACKGROUND: A leiomyosarcoma of the gastrointestinal tract is extremely rare. We report a case of jejunal leiomyosarcoma with intestinal intussusception at the angle of Treitz that was successfully treated with laparoscopic resection followed by intracorporeal reconstruction using a delta-shaped anastomosis. CASE PRESENTATION: A 54-year-old man was referred to our hospital due to fatigue and loss of appetite. Blood tests showed anemia. Enteroscopy and subsequent enterography using meglumine sodium amidotrizoate showed easily hemorrhagic tumor (10 cm in diameter) in the jejunum just beyond the angle of Treitz. Contrast-enhanced computed tomography revealed jejunojejunal intussusception. Histopathological examination of a biopsy specimen revealed a leiomyosarcoma. Laparoscopic resection of the tumor without reduction of the intussusception was performed. The resected line of the proximal intestine was very close to the ligament of Treitz in the present case. Intracorporeal jejunojejunostomy was completed using a delta-shaped anastomosis, wherein anastomosis was performed between the posterior walls of the proximal and distal jejunums after minimal mobilization around the ligament of Treitz. The patient's postoperative course was uneventful, and he was discharged at 10 days postoperatively. No recurrence has been observed within 2 years after surgery. CONCLUSIONS: We present a case in which a totally laparoscopic surgery for leiomyosarcoma located at the angle of Treitz with jejunojejunal intussusception was performed successfully.

Morphologic Analysis of M2 Macrophage in Glioblastoma: Involvement of Macrophage Extracellular Traps (METs).

Macrophages are classified into two phenotypes, M1 and M2, based on their roles. M2 macrophages suppress inflammation and increase in proportion to the malignancy of brain tumors. Recently, macrophage extracellular traps (METs), which change into a network, have been reported as a unique form of macrophage cell death. In this study, immunohistochemical analysis of macrophages in METs in human glioblastoma was performed. To distinguish between M1 and M2 macrophages, multiple immunostainings with Iba1 combined with CD163 or CD204 were performed. M2 macrophages were present in small amounts in normal and borderline areas but showed an increasing trend as they shifted to tumor areas, and most of them were the activated- or phagocytic-type. We also successfully detected METs coexisting with fibrin and lactoferrin near the border between the tumor and necrotic area. M2 macrophages not only suppressed inflammation but also were involved in the formation of METs. This study found that M2 macrophages play various roles in unstable situations.

DNA methylation array analysis for diffuse leptomeningeal glioneuronal tumor with conspicuous hypothalamic mass. A case report.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioneuronal neoplasm newly included in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Owing to the wide spectrum of its histopathological and radiological features, accurate diagnosis can be challenging. Recently, molecular testing including DNA methylation array has been introduced with the possibility of improving diagnostic accuracy and contributing to the subtyping especially for brain tumors with ambiguous histology. Two molecularly distinct subtypes of DLGNT have been reported: methylation class-1 (MC-1) with an indolent clinical course and MC-2, the latter aggressive. Herein, we report a case of a 14-year-old girl with a conspicuous hypothalamic mass lesion and diffuse leptomeningeal enhancement on magnetic resonance imaging. Biopsy specimens obtained from the hypothalamic lesion endoscopically were mainly composed of oligodendrocyte-like cells. However, it was difficult to make a definite diagnosis from these non-specific histological findings. Thus, DNA methylation array analysis was performed additionally by using formalin-fixed, paraffin-embedded tissue, resulting in a diagnosis of "MC-1 subtype of DLGNT" with a high calibrated score (0.99). Consequently, she was treated conservatively, with neither progression of the tumor nor aggravation of symptoms for the next 12 months. It was concluded that DNA methylation array analysis for DLGNT, a rare glioneuronal tumor, could be a powerful tool not only for accurate diagnosis but also decision-making in selecting the best treatment.

Intraoperative Real-Time Near-Infrared Image-Guided Surgery to Identify Intracranial Meningiomas via Microscope.

Meningiomas are a common pathology in the central nervous system requiring complete surgical resection. However, in cases of recurrence and post-irradiation, accurate identification of tumor remnants and a dural tail under bright light remains challenging. We aimed to perform real-time intraoperative visualization of the meningioma and dural tail using a delayed-window indocyanine green (ICG) technique with microscopy. Fifteen patients with intracranial meningioma received 0.5 mg/kg ICG a few hours before observation during the surgery. We used near-infrared (NIR) fluorescence to identify the tumor location. NIR fluorescence could visualize meningiomas in 12 out of 15 cases. Near-infrared visualization during the surgery ranged from 1 to 4 h after the administration of ICG. The mean signal-to-background ratio (SBR) of the intracranial meningioma in delayed-window ICG (DWIG) was 3.3 ± 2.6. The ratio of gadolinium-enhanced T1 tumor signal to the brain (T1BR) (2.5 ± 0.9) was significantly correlated with the tumor SBR (p = 0.016). K trans , indicating blood-brain barrier permeability, was significantly correlated with tumor SBR (p < 0.0001) and T1BR (p = 0.013) on dynamic contrast-enhanced magnetic resonance imaging (MRI). DWIG demonstrated a sensitivity of 94%, specificity of 38%, positive predictive value (PPV) of 76%, and negative predictive value (NPV) of 75% for meningiomas. This is the first pilot study in which DWIG fluorescence-guided surgery was used to visualize meningioma and dural tail intraoperatively with microscopy. DWIG is comparable with second-window ICG in terms of mean SBR. Gadolinium-enhanced T1 tumor signal may predict NIR fluorescence of the intracranial meningioma. Blood-brain barrier permeability as shown by K trans on dynamic contrast-enhanced MRI can contribute to gadolinium enhancement on MRI and to ICG retention and tumor fluorescence by NIR.

A rare case of pancreatic neuroendocrine neoplasm causing Cushing's syndrome.

Pancreatic neuroendocrine neoplasms (PNENs) are relatively rare with a reported incidence of 1-2/100,000 and generally thought to originate from the precursor of the neuroendocrine cells including the islet and the pancreatic duct cells. About 65% of PNENs are non-functional. While insulinomas and gastrinomas are the most common functional PNENs, ACTH-producing PNENs are extremely rare. We herein present an extremely rare case of a patient with Cushing's syndrome caused by PNEN. A 46-year-old woman with edema in bilateral lower extremities and moon face was admitted with a suspicious pancreatic tumor. Enhanced computed tomography and endoscopic ultrasonography revealed a pancreatic tumor. The final diagnosis of ACTH-producing PNEN with Cushing's syndrome was based on clinical and biochemical test results and endocrinological studies. The symptoms associated Cushing's syndrome improved after pancreaticoduodenectomy for PNEN.

Primary central nervous system lymphomas with massive intratumoral hemorrhage: Clinical, radiological, pathological, and molecular features of six cases.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

Myoinositol to Total Choline Ratio in Glioblastomas as a Potential Prognostic Factor in Preoperative Magnetic Resonance Spectroscopy.

Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.

Association of preoperative seizures with tumor metabolites quantified by magnetic resonance spectroscopy in gliomas.

Seizures are common in patients with gliomas; however, the mechanisms of epileptogenesis in gliomas have not been fully understood. This study hypothesized that analyzing quantified metabolites using magnetic resonance spectroscopy (MRS) might provide novel insights to better understand the epileptogenesis in gliomas, and specific metabolites might be indicators of preoperative seizures in gliomas. We retrospectively investigated patient information (gender, age at diagnosis of tumor, their survival time) and tumor information (location, histology, genetic features, and metabolites according to MRS) in patients with gliomas. The data were correlated with the incidence of seizure and analyzed statistically. Of 146 adult supratentorial gliomas, isocitrate dehydrogenase (IDH) mutant tumors significantly indicated higher incidence of preoperative seizures than IDH wild-type gliomas. However, MRS study indicated that glutamate concentration in IDH wild-type gliomas was higher than that in IDH mutant gliomas. Glutamate was not associated with high frequency of preoperative seizures in patients with gliomas. Instead, increased total N-acetyl-L-aspartate (tNAA) was significantly associated with them. Moreover, multivariable analysis indicated that increased level of tNAA was an independent predictor of preoperative seizures. According to MRS analysis, tNAA, rather than glutamate, might be a useful to detect preoperative seizures in patient with supratentorial gliomas.

Superficial Siderosis of the Central Nervous System Caused by Glioneuronal Tumor: A Case Report and Literature Review.

Superficial siderosis is a rare disease resulting from the deposited hemosiderin owing to repeated subarachnoid hemorrhage. It has been reported that hemosiderin deposits on the brain surface and brain parenchyma causes nerve disorder, resulting in progressive and irreversible hearing loss, cerebellar ataxia and pyramidal disorder. The brain tumor is one of the cause of superficial siderosis. A 16-year-old female present a nearby hospital with complaints of absence seizure. A magnetic resonance imaging (MRI) revealed a heterogeneously enhanced mass at the right temporal lobe. Susceptibility-weighted imaging revealed diffuse and extensive superficial siderosis on the brain surface. The tumor was gross totally removed and diagnosed as glioneuronal tumor. The patient had been well, although susceptibility-weighted imaging performed one year after the surgery showed superficial siderosis remained. Early diagnosis and prevention of bleeding sources are recommended to prevent symptom progression associated with superficial siderosis. Susceptibility-weighted imaging is considered useful for early detection of superficial siderosis.

Primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation: a similar cytological appearance as its soft tissue counterpart but no lobulation in association with desmoplastic stroma.

The CIC-DUX4 translocation is the most common genetic alteration of small round cell sarcomas without EWSR1 rearrangement. These "Ewing-like sarcomas" usually occur in peripheral soft tissues, and rare primary central nervous system (CNS) tumors have been described. We report a rare case of primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation. A 23-year-old man presented with weakness in the extremities. Magnetic resonance imaging revealed a large intramedullary tumor spanning C3-C5 with heterogeneous enhancement following gadolinium administration. Histologically, most of the tumor displayed dense myeloid proliferation composed of medium- to slightly small-sized primitive cells. Postoperatively, he received local adjuvant radiation therapy without tumor progression for 10 months. Target RNA sequencing analysis revealed the CIC-DUX4 fusion gene. Methylation array analysis resulted in a diagnosis of "methylation class CNS Ewing sarcoma family tumor with CIC alteration". Although this tumor lacked characteristic histological features such as lobular structures in association with desmoplastic stroma, relatively uniform nuclei with prominent nucleoli and eosinophilic cytoplasm, which are often found in CIC-rearranged sarcomas of soft tissue, were identified. Recently, many CNS and soft tissue tumors require genetic analysis for precise diagnosis. To consider certain molecular testing, careful histological examination is essential.

Correlation between IDH, ATRX, and TERT promoter mutations in glioma.

According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.

Treatment outcomes of patients with adenocarcinoma of the uterine cervix after definitive radiotherapy and the prognostic impact of tumor-infiltrating CD8+ lymphocytes in pre-treatment biopsy specimens: a multi-institutional retrospective study.

The current study aimed to evaluate the outcomes of patients with adenocarcinoma (AC) of the uterine cervix after definitive radiotherapy (RT) and to evaluate prognostic factors, including immunity-related molecules. A total of 71 patients with AC of the uterine cervix from multiple Japanese institutions were retrospectively analysed. Histological subtypes were diagnosed according to the 2014 World Health Organization classification. All patients underwent definitive RT comprising external beam RT and intracavitary brachytherapy with or without concurrent chemotherapy. Immunohistochemical studies were performed to detect the expression of programmed cell death-ligand 1(PD-L1) and CD8. The 5-year locoregional control (LC), overall survival (OS) and progression-free survival (PFS) rates for all patients were 61.8, 49.7 and 36.1%, respectively. The LC, OS and PFS rates were not significantly different among the histological subtypes. Membranous PD-L1 expression was not significantly associated with prognosis. Patients with CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) in the tumor nests had significantly better OS than patients without CD8+TILs in the tumor nests (5-year OS: 53.8 vs 23.8%, P = 0.038). As expected, the International Federation of Gynecology and Obstetrics (FIGO) stage (2008) III-IVA and maximum tumor diameter > 40 mm were significantly associated with worse prognosis. In summary, the presence of CD8+TILs in the tumor nests has the potential to be an independent favorable prognostic factor for patients with AC of the uterine cervix after definitive RT.

The Correlation of Fluorescence of Protoporphyrinogen IX and Status of Isocitrate Dehydrogenase in Gliomas.

BACKGROUND: The extent of resection has been reported to be associated with overall survival in gliomas. The use of 5-aminolevulinic acid (5-ALA) has been recognized to increase the extent of tumor resection. OBJECTIVE: To evaluate what factors affect the intraoperative fluorescence after administration of 5-ALA in gliomas. METHODS: Correlation of intraoperative fluorescence and several clinical, radiographic, molecular biologic, and histopathologic characters was retrospectively evaluated in 104 patients (53 males and 51 females; mean age 54.2 yr) with gliomas at our institution. To clarify the mechanisms that mutant isocitrate dehydrogenase (IDH) affect the intraoperative fluorescence, in Vitro experiments using genetically engineered glioma cells harboring mutant IDH1 were performed. RESULTS: Intraoperative fluorescence was observed in 82 patients (78.8%). In addition to age, magnetic resonance imaging enhancement, World Health Organization grades, and MIB-1 index, the status of IDH was revealed to be correlated with intraoperative fluorescence. In Vitro assay revealed that mutant IDH indirectly reduced the amount of exogenous 5-ALA-derived protoporphyrinogen IX in glioma cells by increasing activity of ferrochelatase and heme oxygenase 1. CONCLUSION: Mutant IDH1/2-induced metabolite changes of exogenous 5-ALA were suggested to contribute to the lesser intraoperative fluorescence in gliomas with mutant IDH1/2 than in those without.