Single-Dose Cisplatin Pre-Treatment Enhances Efficacy of ROBO1-Targeted Radioimmunotherapy.

We previously reported that radioimmunotherapy (RIT) using 90Y-labeled anti-ROBO1 IgG (90Y-B5209B) achieved significant anti-tumor effects against small-cell lung cancer (SCLC) xenografts. However, subsequent tumor regrowth suggested the necessity for more effective therapy. Here, we evaluated the efficacy of combination 90Y-B5209B and cisplatin therapy in NCI-H69 SCLC xenograft mice. Mice were divided into four therapeutic groups: saline, cisplatin only, RIT only, or combination therapy. Either saline or cisplatin was administered by injection one day prior to the administration of either saline or 90Y-B5209B. Tumor volume, body weight, and blood cell counts were monitored. The pathological analysis was performed on day seven post injection of 90Y-B5209B. The survival duration of the combination therapy group was significantly longer than that of the group treated with RIT alone. No significant survival benefit was observed following the isolated administration of cisplatin (relative to saline). Pathological changes following combination therapy were more significant than those following the isolated administration of RIT. Although combination therapy was associated with an increase of several adverse effects such as weight loss and pancytopenia, these were transient. Thus, cisplatin pre-treatment can potentially enhance the efficacy of 90Y-B5209B, making it a promising therapeutic strategy for SCLC.

One-by-One Comparison of Lymph Nodes Between 18F-FDG Uptake and Pathological Diagnosis in Esophageal Cancer.

PURPOSE: Esophagectomy with extended lymph node (LN) dissection is a standard treatment for resectable esophageal cancer to prevent recurrence, but severe, potentially life-threatening postoperative complications are still important issues. Accurate diagnosis of LN metastases would enable the decision to dissect or leave the LNs in regions with high risk of complications. Advancements in intraoperative gamma probe and radioactivity detectors have made intraoperative navigation surgery possible using a radiotracer as a marker. F-FDG is one such candidate markers, and the diagnostic power of FDG through counting the radioactivity close to each LN should be elucidated. MATERIALS AND METHODS: In 20 patients, 1073 LNs including 38 metastatic LNs were prospectively investigated. Preoperative FDG PET was performed on the same day before esophagectomy and visually surveyed in each LN station to identify abnormal uptake. The FDG radioactivity of each individual dissected LN was measured by a well-type counter, and the pathological diagnosis was compared with LN radioactivity on a one-by-one basis and with the preoperative FDG PET findings for each LN station. RESULTS: Lymph node station-based analysis showed a sensitivity and specificity of 28.6% and 96.7%, respectively. One-by-one LN-based analysis using a cutoff value obtained from the receiver operating characteristic curve showed a sensitivity and specificity of 94.7% and 78.7%, respectively, demonstrating higher accuracy compared with the use of LN weight or the shortest diameter. CONCLUSIONS: The FDG uptake by each LN is a potentially useful marker for navigation surgery in esophageal cancer and has higher accuracy than LN weight or diameter.

Value of FDG-PET/CT Volumetry After Chemoradiotherapy in Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by an optimal surgery is the standard treatment for patients with locally advanced rectal cancer. FDG-PET/CT is commonly used as the modality for assessing the effect of chemoradiotherapy. OBJECTIVE: The purpose of this study was to investigate whether PET/CT-based volumetry could contribute to the prediction of pathological complete response or prognosis after neoadjuvant chemoradiotherapy. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a single research center. PATIENTS: Ninety-one consecutive patients with locally advanced rectal cancer were enrolled between January 2005 and December 2015. INTERVENTION: Patients underwent PET/CT before and after neoadjuvant chemoradiotherapy. MAIN OUTCOME MEASURES: Maximum standardized uptake value and total lesion glycolysis on PET/CT before and after neoadjuvant chemoradiotherapy were calculated using isocontour methods. Correlations between these variables and clinicopathological factors and prognosis were assessed. RESULTS: PET/CT-associated variables before chemoradiotherapy were not correlated with either clinicopathological factors or prognosis. Maximum standardized uptake value was associated with pathological complete response, but total lesion glycolysis was not. Maximum standardized uptake value correlated with ypT, whereas total lesion glycolysis correlated with both ypT and ypN. High total lesion glycolysis was associated with a considerably poorer prognosis; the 5-year recurrence rate was 65% and the 5-year mortality rate 42%, whereas in lesions with low total lesion glycolysis, these were 6% and 2%. On multivariate analysis, high total lesion glycolysis was an independent risk factor for recurrence (HR = 4.718; p = 0.04). LIMITATIONS: The gain in fluoro-2-deoxy-D-glucose uptake may differ between scanners, thus the general applicability of this threshold should be validated. CONCLUSIONS: In patients with locally advanced rectal cancer, high total lesion glycolysis after neoadjuvant chemoradiotherapy is strongly associated with a worse prognosis. Total lesion glycolysis after chemoradiotherapy may be a promising preoperative predictor of recurrence and death. See Video Abstract at http://links.lww.com/DCR/A464.

An automated voxel-based method for calculating the reference value for a brain tumour metabolic index using 18F-FDG-PET and 11C-methionine PET.

OBJECTIVE: The tumour-to-normal ratio (T/N) is a representative index reflecting brain tumour activity by 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) PET. We proposed a new automated method of calculating the normal reference value (N-value) for use as the denomination of T/N. This method uses voxel-based analysis of FDG- and MET-PET images. We compared the results of this method with those of the standard region-of-interest (ROI) method. METHODS: Data sets were obtained from 32 patients with newly diagnosed glioma and 13 patients with recurrent brain tumour. Our methods were as follows: (1) FDG-PET and MET-PET images were co-registered. (2) The areas where the FDG uptake was higher than a set threshold were selected. (3) For the corresponding areas of MET-PET images, mode and mean voxel values were calculated as tentative MET N-values. (4) Applying the same coordinates to FDG-PET, the voxel values were averaged and used as tentative FDG N-values. (5) The threshold of FDG-PET and whether to use the mode or the mean voxel values were computationally optimized using learning data sets. (6) Applying the optimal threshold and either the mode or mean, N-values of FDG and MET were finally determined. RESULTS: N-values determined by our automated method showed excellent agreement with those determined by a manual ROI method (ICC(2,1) > 0.78). These values were significantly correlated with mean manual N-values (p < 0.001). CONCLUSIONS: Our new method shows sufficiently good agreement with the standard method and can provide a more objective metabolic index.

Evaluation of 18F-FDG uptake for detecting lymph node metastasis of gastric cancer: a prospective pilot study for one-to-one comparison of radiation dose and pathological findings.

BACKGROUND: Gastric cancer exhibits various degrees of fluorine F-18 fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). We evaluated the relationship between (18)F-FDG uptake and the presence/absence of metastasis in individual lymph nodes (LN) on a one-to-one basis. METHODS: We analyzed 21 patients with gastric cancer. We injected (18)F-FDG intravenously in the morning, and gastrectomy with LN dissection was performed in the afternoon of the same day. Radiation doses were measured at each LN using a well-type counter, and we then compared (18)F-FDG uptake, the shortest diameter, and pathological examination results for each LN. RESULTS: In our study, 906 LNs were analyzed, including 115 metastatic LNs. Metastatic LNs showed significantly higher (18)F-FDG uptake (P < 0.0001), and were significantly enlarged (P < 0.0001). The receiver operating characteristics (ROC) curve had a larger area under the curve (0.71) for (18)F-FDG uptake than for the shortest LN diameter (0.60). Considering histology, the ROC curve for intestinal type adenocarcinoma had a larger area under the curve than that for diffuse type (0.75 vs 0.61). CONCLUSIONS: F-FDG uptake is potentially a more useful variable than LN diameter for discriminating between LN with and without metastasis, especially in intestinal type gastric cancer cases.

Preoperative evaluation of renal cell carcinoma by using 18F-FDG PET/CT.

PURPOSE: This study aimed to characterize the FDG uptake of renal cell carcinoma (RCC) by the pathological subtype and nuclear grade. PATIENTS AND METHODS: We retrospectively identified patients who underwent F-FDG PET and subsequent partial or radical nephrectomy for renal tumors. The relationships of the SUV of renal tumor with subtypes, nuclear grade, and clinicopathological variables were investigated. RESULTS: Ninety-two tumors were analyzed, including 52 low-grade (G1 and G2) and 18 high-grade (G3 and G4) clear cell RCC; 7 chromophobe, 5 papillary, and 1 unclassified RCC; and 9 benign tumors (7 angiomyolipoma and 2 oncocytoma). The SUVs of high-grade clear cell RCC (mean ± SD, 6.8 ± 5.1) and papillary RCC (6.6 ± 3.7) were significantly higher than that of the controls (2.2 ± 0.3). The SUV of high-grade clear cell RCC was higher than that of low-grade tumors (median, 4.0 vs. 2.2; P < 0.001). The optimal SUV cutoff value of 3.0 helped to differentiate high-grade from low-grade clear cell RCC, with 89% sensitivity and 87% specificity. On multiple regression analysis, a high grade was the most significant predictor of SUV for clear cell RCC. CONCLUSIONS: FDG uptake higher than that observed in normal kidney tissues suggests a high-grade clear cell RCC or papillary RCC subtype. FDG-PET using SUV may have a role in prediction of pathological grade of renal tumor.

90Y-Labeled Anti-ROBO1 Monoclonal Antibody Exhibits Antitumor Activity against Small Cell Lung Cancer Xenografts.

INTRODUCTION: ROBO1 is a membrane protein that contributes to tumor metastasis and angiogenesis. We previously reported that 90Y-labeled anti-ROBO1 monoclonal antibody (90Y-anti-ROBO1 IgG) showed an antitumor effect against ROBO1-positive tumors. In this study, we performed a biodistribution study and radioimmunotherapy (RIT) against ROBO1-positive small cell lung cancer (SCLC) models. METHODS: For the biodistribution study, 111In-labeled anti-ROBO1 monoclonal antibody (111In-anti-ROBO1 IgG) was injected into ROBO1-positive SCLC xenograft mice via the tail vein. To evaluate antitumor effects, an RIT study was performed, and SCLC xenograft mice were treated with 90Y-anti-ROBO1 IgG. Tumor volume and body weight were periodically measured throughout the experiments. The tumors and organs of mice were then collected, and a pathological analysis was carried out. RESULTS: As a result of the biodistribution study, we observed tumor uptake of 111In-anti-ROBO1 IgG. The liver, kidney, spleen, and lung showed comparably high accumulation of 111In-labeled anti-ROBO1. In the RIT study, 90Y-anti-ROBO1 IgG significantly reduced tumor volume compared with baseline. Pathological analyses of tumors revealed coagulation necrosis and fatal degeneration of tumor cells, significant reduction in the number of Ki-67-positive cells, and an increase in the number of apoptotic cells. A transient reduction of hematopoietic cells was observed in the spleen, sternum, and femur. CONCLUSIONS: These results suggest that RIT with 90Y-anti-ROBO1 IgG is a promising treatment for ROBO1-positive SCLC.

Dynamic metabolic changes during the first 3 months after 90Y-ibritumomab tiuxetan radioimmunotherapy.

OBJECTIVE: To elucidate the time course of tumor metabolism during the first 3 months after (90)Y-ibritumomab tiuxetan radioimmunotherapy (RIT) in patients with refractory malignant lymphoma. MATERIALS AND METHODS: Seven patients with recurrent follicular lymphoma underwent FDG-PET imaging before and after 1-, 4-, and 12-week RIT with (90)Y-ibritumomab tiuxetan. Tumor metabolic activity on FDG-PET scans was assessed as the maximum standard uptake value (SUVmax). RESULTS: Decrease in metabolism was detected 1 week after RIT. In the most decreased lesion, SUVmax decreased to 20% of the baseline value during the first week. Most lesions continued to decrease for up to 4 weeks. Some lesions showed increased metabolism from 4 to 12 weeks, while the level of FDG accumulations at 12 weeks was still lower than the baseline. CONCLUSIONS: Tumor response to RIT could be observed as early as 1 week after the administration of RIT. After tumor activity decreases, the metabolism may increase at least between 4 and 12 weeks. It suggests that the metabolic changes should be carefully evaluated during this period.

A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy.

BACKGROUND: ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models. METHODS: ROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with (111)In and (90)Y. To study biodistribution, the (111)In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the (90)Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out. RESULTS: The tumour uptake of (111)In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection. Immunotherapy with cold-anti-ROBO1 MAb (70 µg) did not cause a significant antitumour effect. RIT with 6.7 MBq of (90)Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow. CONCLUSIONS: These results suggest that RIT with (90)Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular carcinoma.