Evaluation of children with craniopharyngioma using carbon-11 methionine PET prior to proton therapy

Background

Fluorine-18 (¹⁸F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is limited in its evaluation of brain tumors due to the high basal activity of the cerebral cortex and white matter. Carbon-11 methionine (¹¹C MET) has little uptake under normal conditions. We prospectively investigated the uptake of ¹⁸F FDG and ¹¹C MET PET in patients with craniopharyngioma prior to proton therapy.

Methods

Ten patients newly diagnosed with craniopharyngioma underwent PET imaging using ¹⁸F FDG and ¹¹C MET. PET and MRI studies were registered to help identify tumor volume. Measurements of maximum standardized uptake value (SUV_max) were taken of the tumor and compared with noninvolved left frontal background white matter using a paired t-test. Uptake was graded using a 4-point scale.

Results

Median patient age was 9 years (range 5–19). Seven patients were diagnosed by pathology, 1 by cyst fluid aspiration, and 2 by neuroimaging. Median FDG SUV_max for tumor and background were 2.65 and 3.2, respectively. Median MET SUV_max for tumor and background were 2.2 and 1, respectively. There was a significant difference between MET tumor SUV_max and MET background SUV_max (P = .0001). The difference between FDG tumor SUV_max and FDG background SUV_max was not significant (P = .3672).

Conclusion

¹¹C MET PET uptake is significantly greater within the tumor compared with noninvolved background white matter, making it more useful than FDG PET in identifying active tumor in patients with craniopharyngioma. Future work will focus on using ¹¹C MET PET to discriminate between active and inactive tumor after irradiation.     

Preoperative [11C]methionine PET to personalize treatment decisions in patients with lower-grade gliomas

BackgroundPET with radiolabeled amino acids is used in the preoperative evaluation of patients with glial neoplasms. This study aimed to assess the role of [¹¹C]methionine (MET) PET in assessing molecular features, tumor extent, and prognosis in newly diagnosed lower-grade gliomas (LGGs) surgically treated.MethodsOne hundred and fifty-three patients with a new diagnosis of grade 2/3 glioma who underwent surgery at our Institution and were imaged preoperatively using [¹¹C]MET PET/CT were retrospectively included. [¹¹C]MET PET images were qualitatively and semi-quantitatively analyzed using tumor-to-background ratio (TBR). Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and Cox proportional-hazards regression was used to test the association of clinicopathological and imaging data to PFS.ResultsOverall, 111 lesions (73%) were positive, while thirty-two (21%) and ten (6%) were isometabolic and hypometabolic at [¹¹C]MET PET, respectively. [¹¹C]MET uptake was more common in oligodendrogliomas than IDH-mutant astrocytomas (87% vs 50% of cases, respectively). Among [¹¹C]MET-positive gliomas, grade 3 oligodendrogliomas had the highest median TBR_max (3.22). In 25% of patients, PET helped to better delineate tumor margins compared to MRI only. In IDH-mutant astrocytomas, higher TBR_max values at [¹¹C]MET PET were independent predictors of shorter PFS.ConclusionsThis work highlights the role of preoperative [¹¹C]MET PET in estimating the type of suspected LGGs, assessing tumor extent, and predicting biological behavior and prognosis of histologically confirmed LGGs. Our findings support the implementation of [¹¹C]MET PET in routine clinical practice to better manage these neoplasms.     

Detection of histological anaplasia in gliomas with oligodendroglial components using positron emission tomography with 18F-FDG and 11C-methionine: report of two cases

Gliomas are regionally heterogeneous tumors. Positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) and ¹¹C-methionine (MET) evaluates the heterogeneity of histological malignancy within the tumor. We present two patients with oligodendrocytic tumors that showed discrepancies in the highest uptake areas with these two tracers. PET studies with MET and FDG were performed on the same day, 2 weeks before surgery. In both cases, biopsy specimens were separately obtained from the highest MET and FDG uptake areas guided by intraoperative neuronavigation. Histological examinations demonstrated that the specimens from the highest MET uptake area revealed low-grade oligoastrocytoma or oligodendroglioma, whereas histological anaplasias were contained in the specimens from the highest FDG uptake area. With gliomas with oligodendroglial components, the MET uptake ratio does not always correspond to histological anaplasia, which can be detected only by FDG PET. Sole application of MET PET for preoperative evaluation may lead to misunderstanding of histological heterogeneity in gliomas, especially those with oligodendroglial components. FDG and MET tracers play complementary roles in preoperative evaluation of gliomas.     

TP53 and p53 statuses and their clinical impact in diffuse low grade gliomas

TP53 is a pivotal gene frequently mutated in diffuse gliomas and particularly in astrocytic tumors. The majority of studies dedicated to TP53 in gliomas were focused on mutational hotspots located in exons 5–8. Recent studies have suggested that TP53 is also mutated outside the classic mutational hotspots reported in gliomas. Therefore, we have sequenced all TP53 coding exons in a retrospective series of 61 low grade gliomas (LGG) using high throughput sequencing technology. In addition, TP53 mutational status was correlated with: (i) p53 expression, (ii) tumor type, (iii) chromosome arms 1p/19q status and (iv) clinical features of patients. The cohort included 32 oligodendrogliomas (O), 21 oligoastrocytomas (M) and 8 astrocytomas (A). TP53 mutation was detected in 52.4 % (32/61) of tumors (34 % of O, 71.4 % of M and 75 % of A). All mutations (38 mutations in 32 samples) were detected in exons 4, 5, 6, 7, 8 and 10. Missense and non-missense mutations, including seven novel mutations, were detected in 42.6 and 9.8 % of tumors respectively. TP53 mutations were almost mutually exclusive with 1p/19q co-deletion and were associated with: (i) astrocytic phenotype, (ii) younger age, (iii) p53 expression. Using a threshold of 10 % p53-positive tumor cells, p53 expression is an interesting surrogate marker for missense TP53 mutations (Se = 92 %; Sp = 79.4 %) but not for non-missense mutation (18.4 % of mutations). TP53 and p53 statuses were not prognostic in LGG. In conclusion, we have identified novel TP53 mutations in LGG. TP53 mutations outside exons 4–8 are rare. Although it remains imperfect, p53 expression with a threshold of 10 % is a good surrogate marker for missense TP53 mutations and appears helpful in the setting of LGG phenotype diagnosis.     

Gastric cancers with microsatellite instability exhibit high fluorodeoxyglucose uptake on positron emission tomography

Background

Gastric cancers exhibit various degrees of ¹⁸F-fluorodeoxyglucose (FDG) uptakes on positron emission tomography/computed tomography (PET/CT) imaging. The aim of this study was to evaluate whether FDG uptake in gastric cancer varies according to the microsatellite instability (MSI) status.

Methods

Consecutive gastric cancer patients who underwent PET/CT imaging and MSI analysis were included in the study. The maximum standardized uptake value (SUV_max) of gastric cancer was assessed using PET/CT imaging.

Results

Of 131 gastric cancers, 16 exhibited a high incidence of MSI (MSI-H) and 3 exhibited a low incidence of MSI (MSI-L). In 29 subjects who showed no uptake on PET/CT imaging the gastric cancers were all microsatellite stable (MSS). Gastric cancers with MSI were related to age older than 60 years (p = 0.002), cancer volume larger than 10 cm³ (p = 0.015), and the presence of FDG uptake on PET/CT imaging (p = 0.001). A higher SUV_max of gastric cancer was linked to the presence of MSI (p < 0.001).

Conclusion

The presence of MSI is related to FDG uptake in gastric cancer. Care should be taken with MSS gastric cancers, because they show lower SUV_max on PET/CT imaging than MSI gastric cancers.     

Diffusion abnormalities of the corpus callosum in patients receiving bevacizumab for malignant brain tumors: suspected treatment toxicity

Bevacizumab has been reported to cause diffusion restriction in the tumor bed of patients with malignant gliomas. This study evaluated prolonged diffusion restriction, in the corpus callosum (CC), of patients with malignant brain tumors treated with bevacizumab. We retrospectively reviewed our database of patients treated with bevacizumab for malignant brain tumors looking for those with restricted diffusion in the CC. CC ADC ratio measurements were obtained prior to and following treatment. Correlation was made with biopsy (n = 3) and MR perfusion (n = 7) and PET (n = 4). The temporal evolution of these changes relative to therapy was examined with mixed effects regression analysis. Nine patients (eight malignant gliomas, one malignant meningioma) out of 146 patients were found to have developed areas of diffusion restriction in the CC. These areas tended to enlarge and coalesce over serial MRIs and persisted for up to 22 months. Hypoperfusion was demonstrated in MR perfusion in 7/7. PET was hypometabolic in all 4. Biopsy of the CC showed no tumor in 3/3. ADC ratio measurements indicated a significant overall effect of time (F(16,60) = 11.2; p < 0.0001), consistent with persistent diffusion restriction over the measured time periods. Bevacizumab causes prolonged diffusion restriction in the CC. The negative MR perfusion, FDG PET and histopathology suggest this is a toxicity of bevacizumab and not active tumor. Awareness of these changes can assist in patient care.     

The value of primary tumor <Superscript>18</Superscript>F-FDG uptake on preoperative PET/CT for predicting intratumoral lymphatic invasion and axillary nodal metastasis

Background

The preoperative evaluation of axillary lymph node (LN) status is important for prognostic prediction of breast cancer. We investigated the ability of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) to predict intratumoral lymphatic invasion and axillary LN metastasis.

Methods

The preoperative ¹⁸F-FDG PET/CT images and pathologic reports for 428 breast cancer patients between January 2003 and December 2008 were evaluated retrospectively. The maximum standardized uptake value (SUV_max) of the primary tumor on ¹⁸F-FDG PET/CT, the degree of lymphatic invasion, and axillary LN metastasis identified by pathologic reports were assessed. Univariate and multivariate logistic regression analyses were performed to identify the significant features of the primary tumor that were associated with pathologically confirmed axillary LN metastasis.

Results

The mean SUV_max of primary tumors with lymphatic invasion was higher than that of tumors without lymphatic invasion (5.13 ± 3.49 vs. 3.00 ± 2.47; p < 0.0001). The mean SUV_max of primary tumors with pathologically confirmed axillary LN metastasis was higher than that of tumors without LN metastasis (4.93 ± 3.32 vs. 3.22 ± 2.78; p < 0.0001). The degree of lymphatic invasion correlated strongly with axillary LN metastasis (p = 0.0001). Multiple logistic regression analysis showed that the high SUV_max of the primary tumor (>2.8), the high SUV_max of the axillary LN (>0.72) and the degree of lymphatic invasion were significant predictive factors of the development of axillary LN metastasis.

Conclusion

Breast cancer patients with higher primary tumor ¹⁸F-FDG uptake are at higher risk of concurrent intratumoral lymphatic invasion and axillary LN metastasis.

     

Nitrosourea-based chemotherapy for low grade gliomas failing initial treatment with temozolomide

There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.     

磁共振灌注加权成像鉴别脑胶质瘤术后放疗后复发的价值

目的 评价磁共振灌注加权成像(PWMRI)对脑胶质瘤术后放疗后复发的鉴别价值。方法 对 35例脑胶质瘤术后放疗后疑似肿瘤复发者(真复发 20例、假复发 15例)同时行MRI和PWMRI检查。在局部脑血容量(rCBV)图上对应病变强化区、近侧水肿区及对侧半球正常脑白质区选择感兴趣区测量rCBV值,计算标准化rCBV比值,记录每一病变区最大rCBV (rCBV_max)比值。比较二者间平均rCBV_max比值差异并行成组t检验,对病变强化区rCBV_max比值行受试者工作特征(ROC)曲线分析。     

Differential kinetics of α-[<Superscript>11</Superscript>C]methyl-<Emphasis Type="SmallCaps">l</Emphasis>-tryptophan on PET in low-grade brain tumors

Increased tryptophan metabolism via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[¹¹C]Methyl-l-tryptophan (AMT) is a positron emission tomography (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and determined if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and volume of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates (k^￠₃ k^{\prime}_{3} ) were also calculated. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher k^￠₃ k^{\prime}_{3} tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic analysis of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.     

Prognostic value of maximum standardized uptake value measured by pretreatment 18F-FDG PET/CT in locally advanced head and neck squamous cell carcinoma

Purpose/objectives

To evaluate the prognostic impact of maximum standardized uptake value (SUV_max) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing pretreatment [F-18] fluoro-d-glucose-positron emission tomography/computed tomography (FDG PET/CT) imaging.

Materials/methods

Fifty-eight patients undergoing FDG PET/CT before radical treatment with definitive radiotherapy (±concomitant chemotherapy) or surgery + postoperative (chemo)radiation were analyzed. The effects of clinicopathological factors (age, gender, tumor location, stage, Karnofsky Performance Status (KPS), and treatment strategy) including primary tumor SUV_max and nodal SUV_max on overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) were evaluated. Kaplan–Meier survival curves were generated and compared with the log-rank test.

Results

Median follow-up for the whole population was 31 months (range 2.3–53.5). Two-year OS, LRC, DFS and DMFS, for the entire cohort were 62.1, 78.3, 55.2 and 67.2%, respectively. Median pretreatment SUV_max for the primary tumor and lymph nodes was 11.85 and 5.4, respectively. According to univariate analysis, patients with KPS < 80% (p < 0.001), AJCC stage IVa or IVb vs III (p = 0.037) and patients undergoing radiotherapy vs surgery (p = 0.042) were significantly associated with worse OS. Patients with KPS < 80% (p = 0.003) or age ≥65 years (p = 0.007) had worse LRC. The KPS < 80% was the only factor associated with decreased DFS (p = 0.001). SUV_max of the primary tumor or the lymph nodes were not associated with OS, DFS or LRC. The KPS < 80% (p = 0.002), tumor location (p = 0.047) and AJCC stage (p = 0.025) were associated with worse cancer-specific survival (CSS). According to Cox regression analysis, on multivariate analysis KPS < 80% was the only independent parameter determining worse OS, DFS, CSS. Regarding LRC only patients with IK < 80% (p = 0.01) and ≥65 years (p = 0.01) remained statistically significant. Nodal SUV_max was the only factor associated with decreased DMFS. Patients with a nodal SUV_max > 5.4 presented an increased risk for distant metastases (HR, 3.3; 95% CI 1.17–9.25; p = 0.023).

Conclusions

The pretreatment nodal SUV_max in patients with locally advanced HNSCC is prognostic for DMFS. However, according to our results primary tumor SUV_max and nodal SUV_max were not significantly related to OS, DFS or LRC. Patients presenting KPS < 80% had worse OS, DFS, CSS and LRC.

     

Gliomas of the posterior fossa in adults

Infratentorial gliomas are relatively rare tumors compared to their supratentorial counterparts. As such they have not been extensively characterized as a group and are usually excluded from clinical studies. Using our database we aimed to characterize adult gliomas involving the posterior fossa with respect to their clinical behavior and prognostic factors. We reviewed our neurosurgical and neuro-oncological data bases for adult patients diagnosed with gliomas involving the posterior fossa between 1996 and 2010. Of 1,283 glioma patients, 57 patients with gliomas involving the posterior fossa were identified (4.4 %). Tumors were further classified by location as primary brainstem (n = 21) and primary cerebellar (n = 18) tumors. On univariate analysis survival was correlated to tumor grade and KPS. In addition we have identified a unique group of patients (n = 18) with previously diagnosed supratentorial gliomas who subsequently developed noncontiguous secondary infratentorial extension of their tumors with subsequent rapid clinical deterioration. Gliomas of the posterior fossa comprise a heterogeneous group of tumors. Histological grade of the tumor was found to be the main prognostic factor. Survival of primary cerebellar gliomas is comparable to supra-tentorial gliomas, while brainstem gliomas in adults fare better than in the pediatric population. Secondary extension of supratentorial gliomas to the posterior fossa signifies a grave prognosis.     

MiR-21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas

High-grade gliomas are some of the most lethal forms of human cancer, and new clinical biomarkers and therapeutic targets are highly needed. MicroRNAs (miRNAs), a group of short noncoding RNAs, hold great potential as new biomarkers and targets as they are commonly deregulated in a variety of diseases including gliomas. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several cancers including gliomas and is therefore very promising as a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in gliomas, paraffin-embedded glioma tissue samples from 193 patients with grade I, II, III, and IV tumors were analyzed by in situ hybridization (ISH) using LNA-DNA chimeric probes. We found miR-21 expression in tumor cells and tumor-associated blood vessels, whereas no expression was seen in adjacent normal brain parenchyma. Using advanced image analysis we obtained quantitative estimates reflecting the miR-21 expression levels in each of these compartments. The miR-21 levels correlated significantly with grade [p = 0.027, r _s = 0.161, 95 % confidence interval (CI), 0.015–0.301] with the highest levels measured in glioblastomas. Only tumor cell miR-21 was associated with poor prognosis when adjusting for known clinical parameters (age, grade, and sex) in a multivariate analysis [p = 0.049, hazard ratio (HR) = 1.545, 95 % CI, 1.002–2.381]. In conclusion, we have shown that miR-21 is located in both tumor cells and tumor blood vessels and that its level in the tumor cell compartment holds unfavorable prognostic value in gliomas.     

Evaluation of [<Superscript>89</Superscript>Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer

Purpose

To evaluate whether tumor uptake of [⁸⁹Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer.

Methods

Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 ± 2 days following [⁸⁹Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [⁸⁹Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUV_max), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [⁸⁹Zr]trastuzumab uptake was evaluated.

Results

On a per-patient basis, [⁸⁹Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2-positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUV_max was not significantly different in patients with HER2-positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUV_max was significantly higher in HER2-positive compared to HER2-negative patients (p = 0.003). A cutoff SUV_max of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2-positive from HER2-negative lesions. There was intrapatient heterogeneity of [⁸⁹Zr]trastuzumab uptake in 20% of patients with multiple lesions.

Conclusions

[⁸⁹Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.

     

Evaluation of <Superscript>11</Superscript>C-methionine PET as a surrogate endpoint after treatment of grade 2 gliomas

The aim of the present study was to assess the usefulness of positron emission tomography (PET) as a surrogate endpoint by analysing the uptake variability of ¹¹C-methionine (MET) in follow-up scans.A total of 96 PET MET scans were re-evaluated in 32 patients with histologically confirmed supratentorial grade 2 gliomas.In untreated patients, all follow-up PET scans showed an increased tumour volume after median 68 weeks, but only 46% of cases had an increased hot spot uptake. An improved outcome was observed in patients with stable hot spot uptake per se (P=0.07) and in combinations with minor increase in tumour volume (P=0.02). After conventional therapy, 52% of PET scans showed a reduced hot spot uptake the first year and 43% were reduced after more than a year. Successful MET decline after therapy did not correlate with outcome.PET MET may be a promising surrogate endpoint after treatment of grade 2 gliomas. Evaluation of both hot spot activity and uptake volume on PET may strengthen the association with clinical outcome.     

The prognostic value of volume-based parameters using <Superscript>18</Superscript>F-FDG PET/CT in gastric cancer according to HER2 status

Background

We aimed to find the clinical value of metastatic tumor burden evaluated with F18-FDG PET/CT in gastric cancer patients, considering the human epidermal growth factor receptor 2 (HER2) status.

Methods

We retrospectively reviewed 124 patients with locally advanced or metastatic gastric cancer at Yonsei Cancer Center between January 2006 and December 2014 who had undergone baseline FDG PET/CT before first-line chemotherapy. We measured the maximum standardized uptake value from the primary tumor (SUV_max) and whole-body (WB) PET/CT parameters, including WB SUV_max, WB SUV_mean, WB metabolic tumor volume (WB MTV), and WB total lesion glycolysis (WB TLG), in all metabolically active metastatic lesions (SUV threshold ≥2.5 or 40% isocontour for ≤2.5), and we determined their association with patient survival outcomes.

Results

SUV_max was higher in HER2-positive gastric cancers (median 12.1, range 3.4–34.6) compared to HER-2 negative (7.4, 1.6–39.1, P < 0.001). Among all patients, WB TLG > 600, which is indicative of a high metastatic tumor burden, showed worse progression-free survival (PFS) [hazard ratio (HR), 2.003; 95% CI, 1.300–3.086; P = 0.002] and overall survival (OS) (HR, 3.001; 95% CI, 1.950–4.618; P < 0.001) than did WB TLG ≤ 600. Among HER2-positive gastric cancer patients treated with trastuzumab, higher metabolic tumor burden predicted worse OS, but not PFS.

Conclusions

HER2-positive gastric cancers had higher SUV_max compared to HER2-negative gastric cancers. In both HER2-negative patients and -positive patients receiving trastuzumab, FDG PET/CT volume-based parameters may have a role in further stratifying the prognosis of stage IV gastric cancer.

     

Prognostic Significance of 18F-FDG PET/CT Metabolic Parameters and Tumor Galectin-1 Expression in Patients With Surgically Resected Lung Adenocarcinoma

PurposeTo study the prognostic significance of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) metabolic parameters and tumor galectin-1 (Gal-1) expression in patients surgically treated for lung adenocarcinoma.Patients and MethodsThe medical records of 96 patients with primary lung adenocarcinoma who underwent surgery after ¹⁸F-FDG PET/CT were retrospectively reviewed. The maximal standardized uptake value (SUV_max), metabolic tumor volume, and total lesion glycolysis of the primary tumor were measured through PET/CT imaging. The expression of tumor Gal-1, glucose transporter 1 (GLUT-1), and hexokinase II (HK-II) were examined through immunohistochemistry.ResultsThere were significant positive correlations between tumor Gal-1 and SUV_max, tumor Gal-1 and metabolic tumor volume, tumor Gal-1 and total lesion glycolysis, tumor Gal-1 and GLUT-1 expression, tumor Gal-1 and HK-II expression, and SUV_max and tumor GLUT-1 and HK-II expression (P < .0001 in all cases). SUV_max was the only independent predictor of tumor Gal-1 expression. On receiver operating characteristic analysis, the optimal cutoff value of SUV_max for predicting tumor Gal-1 expression was 5.1. Progression-free and overall survival were significantly shorter in patients with Gal-1–positive tumors than in those with Gal-1–negative tumors (P ≤ .001). On multivariate analysis, advanced tumor stage (P = .001) and tumor Gal-1 expression (P < .0001) were independent prognostic indicators of poor progression-free survival, while advanced tumor stage (P < .0001) and SUV_max (P = .024) were independent prognostic indicators of poor overall survival.Conclusion¹⁸F-FDG PET/CT has the potential to be used as a noninvasive imaging modality to assess tumor Gal-1 status and prognosis in lung adenocarcinoma.     

Correlation of <Emphasis Type="SmallCaps">l</Emphasis>-methyl-<Superscript>11</Superscript>C-methionine (MET) uptake with <Emphasis Type="SmallCaps">l</Emphasis>-type amino acid transporter 1 in human gliomas

l-Type amino acid transporter 1 (LAT1) is a neutral amino acid transport system and is a major route for the transport of large neutral amino acids, including methionine, through the plasma membrane. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional expression. Positron emission tomography (PET) with l-[methyl-¹¹C] methionine (MET) provides information about amino acid metabolism in brain tumors. We conducted a clinicopathologic study to elucidate the correlation of LAT1 and 4F2hc expression with MET uptake in patients with newly diagnosed human gliomas. Thirty-three newly diagnosed glioma patients were enrolled in this study. Uptake of MET in the tumor was evaluated with the maximum standardized uptake value (SUVmax). Expression of the LAT1, 4F2hc, and CD34, and Ki-67 labeling index of the tumor were analyzed by immunohistochemical staining, and the correlation with the SUVmax in the tumors was examined. Expression of LAT1 and 4F2hc was higher in high-grade gliomas than in low-grade gliomas. The grade of LAT1 immunostaining increased with glioma grade. LAT1 was mainly expressed in the tumor cytoplasm and vascular endothelium and 4F2hc was mainly expressed in the tumor cytoplasm and plasma membrane. Expression of LAT1 but not 4F2hc was significantly correlated with MET SUVmax. Expression of LAT1 in the tumor vascular endothelium is significantly correlated with CD34 positive microvessel density. In conclusion, MET SUVmax correlates with LAT1 expression in the tumor in newly diagnosed gliomas. MET transport may be increased by an increased number of microvessels combined with a higher density or activity of LAT1 in the tumor endothelial cells in high-grade gliomas. Use of MET-PET as a molecular target combined with anti-angiogenesis in glioma therapy should be addressed in future studies.     

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model

Background

Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood–brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.

Methods

Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.

Results

After dosing of oral TMZ only, ECF-TMZ mean-C _max and area under the concentration curve(AUC_0–∞) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C _max and AUC_0–∞ were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C _max and AUC_0–∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB “normalization” profile following cediranib treatment.

Conclusions

In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.     

Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [18F]FET-PET imaging in intracranial WHO grade II and III gliomas

Oligodendroglial components (OC) and loss of heterozygosity on chromosomes 1p and 19q (LOH 1p/19q) are associated with better outcome in patients with glioma. We aimed to assess the fitness of [¹⁸F]fluoroethyltyrosine positron-emission-tomography (FET-PET) for noninvasively identifying these important prognostic/predictive factors. One hundred forty-four patients with MRI-suspected WHO grade II and III glioma underwent FET-PET scans prior to histological diagnosis. FET-PET analyses included maximal tumoral uptake (SUV_max/BG), biological tumor volume (BTV), mean tumoral uptake (SUV_mean/BG), total tumoral uptake (SUV_total/BG), and kinetic analysis. Suspicion of OC was based on static and dynamic FET-uptake parameters. PET results were correlated with histology and 1p/19q status. OC tumors exhibited significantly higher uptake values, compared with astrocytomas (AC) (SUV_max/BG 3.1 vs 2.3, BTV 15.5 mL vs 7.2 mL, SUV_total/BG 38.5 vs 17.4, P < .01 each; SUV_mean/BG 2.2 vs 2.1, P < .05). These differences were more pronounced in WHO grade II gliomas. Comparable results were found with respect to 1p/19q status. Kinetic analysis misclassified 18 of 34 low-grade OC tumors as high-grade glioma but misclassified only 5 of 45 of the low-grade ACs. FET-based suspicion of OC resulted in concordance rates of both 76% for the prediction of OC and LOH 1p/19q. FET-uptake was significantly higher in gliomas with OC, compared with AC, and likewise in 1p/19q codeleted, compared with noncodeleted tumors. However, FET-PET analysis did not reliably predict the presence of OC/LOH 1p/19q in the individual patient, mostly because of an overlap in PET characteristics of OC tumors and high-grade AC. Histological examination is still required for an accurate diagnosis.