Prognostic impact of clinical and radiological factors on leptomeningeal metastasis from solid cancers.

PURPOSE: The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types. METHODS: We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021. RESULTS: The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results. CONCLUSIONS: This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.

Qualitative MR features to identify non-enhancing tumors within glioblastoma's T2-FLAIR hyperintense lesions.

PURPOSE: To identify qualitative MRI features of non-(contrast)-enhancing tumor (nCET) in glioblastoma's T2-FLAIR hyperintense lesion. METHODS: Thirty-three histologically confirmed glioblastoma patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11C-methionine positron emission tomography (Met-PET) were available were included in this study. Met-PET was utilized as a surrogate for tumor burden. Imaging features for identifying nCET were searched by qualitative examination of 156 targets. A new scoring system to identify nCET was established and validated by two independent observers. RESULTS: Three imaging features were found helpful for identifying nCET; "Bulky gray matter involvement", "Around the rim of contrast-enhancement (Around-rim)," and "High-intensity on T1WI and low-intensity on T2WI (HighT1LowT2)" resulting in an nCET score = 2 × Bulky gray matter involvement - 2 × Around-rim + HighT1LowT2 + 2. The nCET score's classification performances of two independent observers measured by AUC were 0.78 and 0.80, with sensitivities and specificities using a threshold of four being 0.443 and 0.771, and 0.916 and 0.768, respectively. The weighted kappa coefficient for the nCET score was 0.946. CONCLUSION: The current investigation demonstrated that qualitative assessments of glioblastoma's MRI might help identify nCET in T2/FLAIR high-intensity lesions. The novel nCET score is expected to aid in expanding treatment targets within the T2/FLAIR high-intensity lesions.

[Astrocytoma, IDH-Mutant].

Astrocytoma, IDH-mutant is defined as infiltrative diffuse glioma harboring IDH1/2 mutation without accompanying 1p/19q codeletion in the current diagnostic system based on the 5th edition of the World Health Organization Classification of Tumors of the Central Nervous System. This revision delineates this neoplasm as a molecularly and clinically relevant tumor type. The evidence for the clinical management of patients with glioma has been largely established based on the results of clinical studies using the diagnostic criteria before the molecular classification. Many clinical studies investigated astrocytoma, IDH-mutant in combination with IDH-wildtype gliomas or oligodendrogliomas. The aim of the present study was to discuss the optimal management of astrocytoma, IDH-mutant based on the growing number of recent clinical studies incorporating molecular analyses. Particularly, the significance of the extent of surgical removal has increased after the definition of this tumor type in comparison with other types of gliomas.

Eribulin prolongs survival in an orthotopic xenograft mouse model of malignant meningioma.

Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (P < .0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas.

TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma.

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM.

Characteristics and outcomes of elderly patients with diffuse gliomas: a multi-institutional cohort study by Kansai Molecular Diagnosis Network for CNS Tumors.

INTRODUCTION: This study investigates the current state of clinical practice and molecular analysis for elderly patients with diffuse gliomas and aims to elucidate treatment outcomes and prognostic factors of patients with glioblastomas. METHODS: We collected elderly cases (≥ 70 years) diagnosed with primary diffuse gliomas and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and pathological characteristics were analyzed retrospectively. Various factors were evaluated in univariate and multivariate models to examine their effects on overall survival. RESULTS: Included in the study were 140 elderly patients (WHO grade II: 7, III: 19, IV: 114), median age was 75 years. Sixty-seven patients (47.9%) had preoperative Karnofsky Performance Status score of ≥ 80. All patients underwent resection (gross-total: 20.0%, subtotal: 14.3%, partial: 39.3%, biopsy: 26.4%). Ninety-six of the patients (68.6%) received adjuvant treatment consisting of radiotherapy (RT) with temozolomide (TMZ). Seventy-eight of the patients (75.0%) received radiation dose of ≥ 50 Gy. MGMT promoter was methylated in 68 tumors (48.6%), IDH1/2 was wild-type in 129 tumors (92.1%), and TERT promoter was mutated in 78 of 128 tumors (60.9%). Median progression-free and overall survival of grade IV cases was 8.2 and 13.6 months, respectively. Higher age (≥ 80 years) and TERT promoter mutated were associated with shorter survival. Resection and adjuvant RT + TMZ were identified as independent factors for good prognosis. CONCLUSIONS: This community-based study reveals characteristics and outcomes of elderly glioma patients in a real-world setting. Elderly patients have several potential factors for poor prognosis, but resection followed by RT + TMZ could lengthen duration of survival.

Glioblastomas with IDH1/2 mutations have a short clinical history and have a favorable clinical outcome.

OBJECTIVE: Glioblastomas with isocitrate dehydrogenase 1/2 mutations comprise a biologically distinct subgroup of glioblastomas. We studied isocitrate dehydrogenase 1/2 mutant glioblastomas at the clinical, molecular and radiological levels to define their clinical features, including the prognostic value of isocitrate dehydrogenase 1/2 mutations compared with isocitrate dehydrogenase 1/2 wild-type glioblastomas. METHODS: We investigated 128 newly diagnosed glioblastoma patients who were treated at our institute between January 2005 and May 2013. Isocitrate dehydrogenase 1/2 mutation status was determined using pyrosequencing. O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation and 1p/19q co-deletions were also analyzed using pyrosequencing and multiplex ligation-dependent probe amplification, respectively. RESULTS: Isocitrate dehydrogenase 1/2 mutations were detected in 10 of 128 patients (7.8%). Isocitrate dehydrogenase 1/2 mutations were correlated with a younger age, the presence of an oligodendroglial component and 1p/19q co-deletions and a longer survival time. The interval from initial symptom to initial operation did not differ according to isocitrate dehydrogenase 1/2 mutation status (median interval: 2.3 versus 1.2 months; P = 0.13). Two of three isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions had an oligodendroglial component and were associated with a prolonged survival time. Multivariate analysis of 90 patients treated with temozolomide-based chemoradiotherapy indicated that age, extent of resection, postoperative Karnofsky performance score and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation were correlated with better survival. Isocitrate dehydrogenase 1/2 mutations showed a trend for improved survival (P = 0.068). CONCLUSIONS: Most isocitrate dehydrogenase 1/2 mutant glioblastomas have a short clinical history, and some isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions behave like oligodendroglial tumors. Isocitrate dehydrogenase 1/2 mutations may have a positive prognostic impact on the Japanese population.

Human chorionic gonadotropin is expressed virtually in all intracranial germ cell tumors.

Human chorionic gonadotropin (hCG) production has been utilized as a diagnostic marker for germinoma with syncytiotrophoblastic giant cells (STGC) and choriocarcinoma. Elevated hCG in germinoma is considered to predict less favorable prognosis, and an intensive treatment strategy may accordingly be applied. However, there is some evidence that any germinoma may produce hCG to varying extent. We investigated mRNA expression of the hCG ß subunit (hCGß) using real time quantitative polymerase chain reaction in 94 germ cell tumors (GCTs). Most (93.3 %) GCTs showed higher expression levels compared with that of normal brain tissue (1.09 × 10(0)-1.40 × 10(5) fold). The expression was the highest in GCTs which harbor choriocarcinoma or STGC components. The expression level of hCGß in germinoma was highly variable (1.09 × 10(0)-5.88 × 10(4) fold) in linear but not bimodal distribution. hCG concentrations in serum and CSF correlated with gene expression, especially when GCTs with single histological component were analyzed separately. The expression was not significantly associated with recurrence in pure germinoma. These results suggest that the serum/CSF hCG levels may need to be interpreted with caution as most GCTs appear to have the capacity of producing hCG irrespective of their histology. The clinical significance of ubiquitous hCG expression in GCTs needs further investigation.

Gsp mutation in acromegaly and its influence on TRH-induced paradoxical GH response.

OBJECTIVE: We recently reported that paradoxical GH response to TRH administration reflects biological characteristics in patients with acromegaly. The aim of this study is to elucidate the relationship between gsp mutations and the paradoxical GH response to TRH. PATIENTS: Sixty-seven patients with acromegaly were included for analysis. Paradoxical increase in serum GH level to TRH, GH suppression by octreotide and bromocriptine, radiological profiles and histopathological findings were analysed with respect to tumour gsp-mutation status. RESULTS: Twenty-six (38·8%) gsp mutations were detected, and the number of paradoxical GH responders to TRH, defined as an increase of 100% or more in GH after TRH, was 49 (73·1%). Among the paradoxical GH responders to TRH, 21 patients (42·9%) had a gsp mutation and 28 patients (57·1%) did not. The percentage of paradoxical GH responders to TRH in gsp-positive and gsp-negative patients was not significantly different (80·8% and 68·3%, respectively). The gsp-positive group showed a significantly higher paradoxical increase in serum GH level by TRH administration (1830% vs 650% GH increase, P = 0·045) and greater GH suppression by octreotide (88·7% vs 75·4% GH decrease, P = 0·003) than the gsp-negative group. CONCLUSION: Paradoxical GH response to TRH was observed regardless of gsp mutation, although the rate of increase was significantly higher in gsp-positive patients. These results suggest that gsp mutation is not sufficient to cause the paradoxical GH response to TRH, while other unidentified factors have a strong influence on paradoxical GH response to TRH in patients with acromegaly.

Risk factors for early death after surgery in patients with brain metastases: reevaluation of the indications for and role of surgery.

Surgical resection remains an important option for the treatment of brain metastases despite recent advancements in radiotherapy and systemic therapy. When selecting surgical candidates, it is important to exclude terminal cases who will receive neither a survival benefit nor an improvement in their quality of life. We reviewed a total of 264 surgical cases of brain metastases and analyzed the clinical characteristics of early death in order to clarify the indication for and the role of surgery. The median survival time (MST) after surgery in all cases was 12.4 months. Early death was defined as death within 6 months, and 23% (62 cases) of this series were succumbed to this. A decrease in postoperative Karnofsky performance status (KPS) (<70) (P = 0.041), lack of systemic therapy after surgery (P < 0.0001), and uncontrolled extracranial malignancies (P = 0.0022) were significantly related to early death in multivariate analysis, while preoperative KPS (<70) and recursive partitioning analysis (RPA) class were related to early death only in univariate analysis (P < 0.05). When analyzing patients with uncontrolled extracranial malignancies and those with a postoperative KPS score of 70 or greater (who were generally candidates for systemic therapy), the MST was significantly longer in the systemic therapy (+) group compared with the systemic therapy (-) group (12.5 vs. 5.6 months; P = 0.0026). Our data indicate that the postoperative RPA class and treatment strategy were associated with early death. Deterioration of patients by surgery should be avoided in the treatment of brain metastases.

Prediction of MGMT promotor methylation status in glioblastoma by contrast-enhanced T1-weighted intensity image.

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (p = .015, odds ratio = 2.44) and for the validation cohort (p = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.

Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss.

Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55 %). The frequency of mutation was particularly high among primary glioblastomas (70 %) and pure oligodendroglial tumors (74 %), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25 %, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98 %). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92 %) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.

Prevalence of cerebral aneurysm in patients with acromegaly.

The prevalence of cerebral aneurysm was retrospectively investigated in 208 patients with acromegaly relative to the rate of cerebral aneurysm in a group of control subjects. Neuroradiological examinations of the cerebral vascular system were conducted in 208 acromegaly patients (101 men; mean age, 48.8 years). The prevalence of cerebral aneurysm in the acromegaly patients was compared to that in a control group consisting of 7,390 subjects who underwent "brain checkup" between 2006 and 2008 (mean age, 51.6 years). In the acromegaly group, cerebral aneurysm was detected in 4.3 % of patients. By sex, the prevalence was 6.9 % in males, a significantly proportion than that in the control group with an odds ratio of 4.40. The prevalence in females did not differ between the two groups. In the acromegaly group, the rate of hypertension was significantly higher in the patients with aneurysm compared to those without aneurysm. Multiple logistic regression identified acromegaly as a significant factor related to the prevalence of cerebral aneurysm in all male subjects; other factors, such as age, hypertension and smoking, were not found to be significant. A significantly higher prevalence of cerebral aneurysm was detected in male patients with acromegaly. This finding indicates that excess growth hormone or insulin-like growth factor 1 affects the cerebral vascular wall, resulting in aneurysm formation. In addition to known systematic complications in the cardiovascular, respiratory, metabolic, and other systems, the risk of cerebral aneurysm should be considered in the management of acromegaly.

Management of glioblastoma in an NF1 patient with moyamoya syndrome: a case report.

INTRODUCTION: Glioma and moyamoya syndrome are both potential complications of neurofibromatosis type 1 (NF1). Here, we report the first case of NF1 concomitantly presenting with glioblastoma 10 years after surgical treatment of moyamoya syndrome. CASE REPORT: A 14-year-old boy with NF1 was incidentally diagnosed by magnetic resonance imaging (MRI) with a thalamic tumor during a follow-up for moyamoya syndrome, which had been treated with surgery 10 years earlier. After observation for 36 months, he developed left hemiparesis, and MRI revealed an increase in tumor size and obstructive hydrocephalus due to the tumor. Needle biopsy was performed through small craniotomy, and the histological diagnosis was glioblastoma. After concurrent chemoradiotherapy with 23 cycles of temozolomide, partial response of the tumor was observed. However, 24 months after the start of the initial therapy, the tumor showed regrowth, and the patient died 30 months after the initial therapy. No cerebrovascular events associated with moyamoya syndrome and chemoradiotherapy were observed during the clinical course of glioblastoma. DISCUSSION: Glioblastoma is a fatal disease in children, and our patient successfully received chemoradiotherapy with temozolomide despite the diagnoses of NF1 and moyamoya syndrome. Although radiotherapy or chemotherapy potentially causes cerebrovascular complications, chemoradiotherapy might be feasible for glioblastoma treatment in patients with moyamoya syndrome and NF1. The following issues are discussed in the management of the present case: the indication of biopsy in NF1 cases, the method of surgery, and the treatment protocol for tumors concomitant with moyamoya disease or syndrome.

Linear accelerator-based stereotactic radiotherapy for brain metastases, including multiple and large lesions, carries a low incidence of acute toxicities: a retrospective analysis.

BACKGROUND: Data on acute toxicities after stereotactic radiotherapy (SRT) for brain metastases, including multiple and large lesions, are lacking. We aimed to evaluate the incidence and nature of toxicities immediately after SRT using a linear accelerator. METHODS: This retrospective study reviewed the medical records of 315 patients with brain metastases treated with SRT at our institution between May 2019 and February 2022. In total, 439 SRT sessions were performed for 2161 brain metastases. The outcome of interest was immediate side effects (ISEs), defined as new or worsening symptoms occurring during SRT or within 14 days after the end of SRT. RESULTS: Grade ≥ 2 and ≥ 3 ISEs occurred in 16 (3.6%) and 7 (1.6%) cases, respectively. Among 63 treatments for 10 or more lesions (range: 10-40), 1 (1.6%) ISE occurred. Among 22 treatments for lesions with a maximum tumor volume of > 10 cc, 2 (9.1%) ISEs occurred. Grade ≥ 3 ISEs included 1, 4, 1, and 1 cases of grade 3 nausea, grade 3 new-onset partial and generalized seizures, grade 3 obstructive hydrocephalus, and grade 5 intracranial hemorrhage, respectively. ISEs were more common in patients with a larger maximum tumor volume, primary sites other than lung and breast cancer, and pre-treatment neurological symptoms. CONCLUSION: SRT using a linear accelerator for brain metastases, including multiple and large lesions, is safe, with a low incidence of ISEs. Serious complications immediately after SRT are rare but possible; therefore, careful follow-up is necessary after treatment initiation.

Nonbrain metastases seen on magnetic resonance imaging during metastatic brain tumor screening.

Although metastases found during head magnetic resonance imaging (MRI) are not limited to metastatic brain tumors, the MRI is a very common method for "brain metastasis screening," a modality that is being increasingly performed. In this review, we describe MRI findings of nonbrain metastases and discuss ways to avoid missing these lesions. Metastatic cranial bone tumors are among the most common nonbrain metastatic lesions found on head MRI, followed by leptomeningeal carcinomatosis. The other less-frequent metastatic lesions include those in the ventricle/choroid plexus, the pituitary gland and stalk, and the pineal gland. Metastases in the head and neck area, as well as cranial and intracranial lesions, should be carefully evaluated. Furthermore, direct geographical invasion, perineural spread, and double cancers should also be considered. While it is important to recognize these metastatic lesions on MRI, because they may necessitate a change in treatment strategy that could lead to an improvement in prognosis due to early introduction of therapy, nonbrain lesions should also be given greater attention, given the increasing survival of patients with cancer and advances in MRI technology, such as contrast-enhanced-3D T1-weighted imaging.

WT1 Trio Peptide-Based Cancer Vaccine for Rare Cancers Expressing Shared Target WT1.

No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers.

¹¹C-methionine uptake and intraoperative 5-aminolevulinic acid-induced fluorescence as separate index markers of cell density in glioma: a stereotactic image-histological analysis.

BACKGROUND: The extent of tumor resection is acknowledged as 1 of the prognostic factors for glioma. 5-Aminolevulinic acid (5-ALA)-induced fluorescence guidance and neuronavigation integrated with (11) C-methionine positron emission tomography (PET) are widely utilized under the expectation of improving the extent of resection. These 2 novel approaches are beneficial for glioma resections, and the combination of these approaches appears rational. However, biological characteristics reflecting 5-ALA-induced fluorescence and (11) C-methionine uptake have not been clearly elucidated, and studies about the relationship between 5-ALA-induced fluorescence and (11) C-methionine uptake have been limited. The present study aimed to clarify this issue. METHODS: Data from 11 consecutive patients harboring astrocytic tumors were analyzed: 2 grade II and 2 grade III, and 7 grade IV tumors were included. Thirty samples from these patients were obtained from the relative periphery of each tumor. Relationships among histology, 5-ALA-induced fluorescence and (11) C-methionine uptake were analyzed by stereotactic sampling and image analysis. RESULTS: Uptake of (11) C-methionine correlated with cell density (R(2) = 0.322, P = .0059). Cell density was higher in fluorescence-positive areas than in negative areas (2760 ± 1080 vs 1450 ± 1380/mm(2) , P = .0132). Although both (11) C-methionine uptake and fluorescence seemed to correlate with cell density, no significant difference in (11) C-methionine uptake was seen between fluorescence-positive and -negative areas (P = .367). Multiple linear regression analysis revealed (11) C-methionine uptake and 5-ALA-induced fluorescence as independent indices for tumor cell density. CONCLUSIONS: These results indicate that 5-ALA fluorescence and (11) C-methionine PET image are separate index markers for cytoreduction surgery of gliomas.

Imaging ¹8F-fluorodeoxy glucose/¹¹C-methionine uptake decoupling for identification of tumor cell infiltration in peritumoral brain edema.

Discriminating tumor infiltrative and vasogenic brain edema in malignant gliomas is important although challenging in clinical settings. This study challenged this issue by performing voxel-wise analysis of (18)F-fluorodeoxy glucose (FDG) and (11)C-methionine positron emission tomography (PET) in peritumoral brain edemas. The authors studied ten malignant glioma and nine meningioma patients with peritumoral brain edema. A voxel-wise analysis of FDG and (11)C-methionine PET was performed in order to quantify the correlation between uptake of these tracers in normal brain tissue and peritumoral brain edema. Decoupling score of the uptake of two tracers was calculated as the z-score from the estimated correlation between uptake of the two tracers in normal brain tissue. The decoupling score was also converted into images for visual inspection. Average decoupling score in the peritumoral brain edema was calculated and compared between those obtained from malignant gliomas and meningiomas. FDG and (11)C-methionine uptake showed a reproducible linear correlation in normal brain tissue. This correlation was preserved in peritumoral edema of meningioma, but not in that of malignant gliomas. In malignant gliomas, higher (11)C-methionine uptake compared to that estimated by the FDG uptake in normal brain tissue was observed, thus suggesting that decoupling was caused by tumor infiltration. Visual inspection of the decoupling score enabled discrimination of tumor infiltrative and vasogenic edema. The average decoupling scores of the peritumoral brain edema in malignant gliomas were significantly higher than those in meningiomas (2.9 vs. 0.7, P = 0.0003). As a conclusion, FDG/(11)C-methionine uptake decoupling score can be used for the discrimination of tumor infiltrative and vasogenic brain edema. The proposed method also suggests the possibility of accurately detecting tumor infiltration into brain tissues in gliomas, providing significant information for treatment planning and follow-up.

Clinical characteristics of meningiomas assessed by ¹¹C-methionine and ¹8F-fluorodeoxyglucose positron-emission tomography.

The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including (11)C-methionine and (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on (11)C-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and (11)C-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, (11)C-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of (11)C-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of (11)C-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of (11)C-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P < 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that (11)C-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.