Phase I/IIa trial of 18F-prostate specific membrane antigen (PSMA) 1007 PET/CT in healthy volunteers and prostate cancer patients.

OBJECTIVE: 18F-PSMA 1007 is a promising PET tracer for prostate cancer. We aimed to examine the safety, biodistribution, radiation dosimetry, and clinical effectiveness in Japanese healthy volunteers and patients with prostate cancer. METHODS: Part A evaluated the pharmacokinetics and exposure doses in three healthy volunteers. Part B evaluated the diagnostic accuracy in patients with untreated preoperative prostate cancer (Cohort 1, n = 7) and patients with biochemical recurrence (Cohort 2, n = 3). All subjects received a single dose of 3.7 MBq/kg 18F-PSMA 1007. Results: 18F-PSMA 1007 was found to be safe and well tolerated in all subjects. No serous AEs or drug-related AEs were identified during the present study. The average blood radioactivity concentration reached a maximum of 47.87 ± 1.05 (percentage of injected dose [%ID]/ml) at 5 min and then decreased to 1.60 ± 0.78 in 6 h. The systemic radioactivity reached a maximum of 211.05 ± 6.77 (%ID$\times$103) at 5 min and decreased to 7.18 ± 3.91 in 6 h. The sensitivity and positive predictive value were 100% and 100% based on both pathologic and imaging confirmation as gold standard. In Cohort 1, 15 primary foci (11.9%) were >5 mm in the largest diameter and identified in 39 of 126 segments (30.1%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 60 min uptake time acquisition were 80.0, 96.5, 91.4, 91.2 and 91.3%, respectively. CONCLUSIONS: Our study revealed that 18F-PSMA 1007 was safe, well tolerated and showed high accuracy in the diagnosis of prostate cancer.

Nuclear Receptor and Stress Response Pathways Associated with Antineoplastic Agent-Induced Diarrhea.

In severe cases, antineoplastic agent-induced diarrhea may be life-threatening; therefore, it is necessary to determine the mechanism of toxicity and identify the optimal management. The mechanism of antineoplastic agent-induced diarrhea is still unclear but is often considered to be multifactorial. The aim of this study was to determine the molecular initiating event (MIE), which is the initial interaction between molecules and biomolecules or biosystems, and to evaluate the MIE specific to antineoplastic agents that induce diarrhea. We detected diarrhea-inducing drug signals based on adjusted odds ratios using the Food and Drug Administration Adverse Event Reporting System. We then used the quantitative structure-activity relationship platform of Toxicity Predictor to identify potential MIEs that are specific to diarrhea-inducing antineoplastic agents. We found that progesterone receptor antagonists were potential MIEs associated with diarrhea. The findings of this study may help improve the prediction and management of antineoplastic agent-induced diarrhea.

Comprehensive Analysis of Chemotherapeutic Agents That Induce Infectious Neutropenia.

Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring.

Evaluation of the Expression Profile of Irinotecan-Induced Diarrhea in Patients with Colorectal Cancer.

Irinotecan (CPT-11) is widely used for the treatment of unresectable colorectal cancer in combination with fluoropyrimidines, such as 5-fluorouracil and S-1. Diarrhea is one of the adverse effects associated with CPT-11 and frequently reported by patients treated with CPT-11-containing regimens combined with oral fluoropyrimidines. However, the mechanisms involved in this process, as well as whether fluctuations in the frequency and differences in the onset time of diarrhea with each CPT-11-containing regimen are caused by drug interactions remain unclear. Therefore, we examined the incidence of diarrhea caused by each CPT-11-containing regimen in patients with colorectal cancer using data from the large voluntary reporting Japanese Adverse Drug Event Report (JADER) database. Firstly, we searched for suspected drugs related to the occurrence of diarrhea using reported odds ratio and calculated the signal score to assess drug-drug interactions. Subsequently, we conducted a time-to-onset analysis using Weibull distribution. The results showed that the combination of CPT-11 with S-1 increased the frequency of diarrhea due to a pharmacological interaction but delayed its onset. The present results may contribute to the appropriate management of drug-induced adverse effects by healthcare professionals.

Visualization of Low-Level Gamma Radiation Sources Using a Low-Cost, High-Sensitivity, Omnidirectional Compton Camera.

We present experimental protocols for visualizing various low-level gamma radiation sources in the ambient environment. Experiments were conducted by using a low-cost, high-sensitivity, omnidirectional, gamma-ray imaging Compton camera. In the laboratory, the position of a sub-MeV gamma radiation source such as 137Cs can easily be monitored via omnidirectional gamma-ray imaging obtained by the Compton camera. In contrast, a stationary, wall-mounted dose rate monitor cannot always successfully monitor such a source. Furthermore, we successfully demonstrated the possibility of visualizing the radioactivity movement in the environment, for example, the movement of a patient injected with 18F-fluorodeoxyglucose (18F-FDG) in a nuclear medicine facility. In the Fukushima field, we easily obtained omnidirectional gamma-ray images concerned with the distribution on the ground of low-level radioactive contamination by radioactive cesium released by the Fukushima Daiichi nuclear power plant accident in 2011. We demonstrate clear advantages of using our procedure with this camera to visualize gamma-ray sources. Our protocols can further be used to discover low-level gamma radiation sources, in place of stationary dose rate monitors and/or portable survey meters used conventionally.

Imaging peritoneal metastasis of gastric cancer with 18F-fluorothymidine positron emission tomography/computed tomography: a proof-of-concept study.

OBJECTIVE: Peritoneal metastasis (PM) is the most frequent form of metastasis in gastric cancer (GC). The sensitivity of detecting PM by pre-operative imaging modalities is low. Utility of positron emission tomography (PET) with 18F-fluodeoxyglucose (FDG) for GC is limited, because diffuse-type tumors are not FDG-avid. 18F-fluothymidine ([F-18]FLT) is a radiotracer that reflects cellular proliferation and the utility of [F-18]FLT-PET in GC has been reported. In this proof-of-concept study, we explored the ability of [F-18]FLT-PET/CT to detect PM of GC previously identified by other imaging modalities. METHODS: The key eligibility criteria were as follows; (i) histologically proven gastric adenocarcinoma; (ii) evident PM detected by CT performed within 4 weeks prior to registration; (iii) no prior treatment of PM within 4 weeks before registration. [F-18]FLT-PET/CT was performed at National Cancer Center Hospital, and [F-18]FLT-PET/CT images were evaluated independently by two radiologists. Safety assessments were carried out before and after [F-18]FLT-PET/CT. The primary end point was the detection sensitivity of PM. RESULTS: A total of 19 eligible patients were analyzed, of which 15 (78.9%) had diffuse-type histology. Detection sensitivity of PM, primary lesion, and lymph node metastasis were 73.7% [maximum standardized uptake value (SUVmax): 1.697-13.21], 100% (SUVmax: 2.71-22.01), and 72.7% (SUVmax: 2.079-12.61), respectively. No patients experienced adverse events during or after [F-18]FLT-PET/CT. CONCLUSION: This proof-of-concept study shows that [F-18]FLT-PET/CT is a sensitive method for detecting PM in GC, and paves the way for future studies investigating the clinical utility of this approach for the detection of clinically non-evident PM in GC. Advances in knowledge: This proof-of-concept study found that [F-18]FLT-PET/CT is a sensitive method for detecting peritoneal metastases in GC.

Relationship between tumor volume and quantitative values calculated using two-dimensional bone scan images.

The bone scan index (BSI) is calculated from a whole-body bone scan image; it shows the tumor burden in bone as a percentage of total skeletal mass. It has been used to determine the prognosis and to assess treatment effects; however, little has been reported on whether the BSI calculated using a two-dimensional image can accurately evaluate the three-dimensional spread in tumor volume. We investigated the relationship between tumor volume and BSI using Monte Carlo simulation (MCS). We simulated a gamma camera and constructed a voxel phantom based on an anthropomorphic phantom computed tomography (CT) image and gamma rays emitted from each part according to technetium-99m-labeled methylene diphosphonate (99mTc-MDP) uptake (bone 1, soft tissue 0.2, tumor 2-32). We constructed bone scan images from the obtained counts and analyzed them using the BSI calculation software. The BSI increased with increased tumor uptake (two- to 32-fold). However, there was not always a significant difference between change in BSI and tumor uptake of eight times or greater than that of bone. When BSI was calculated with a tumor having an uptake of four-to-eight times higher than that of bone, the BSI was consistent with tumor volume, but decreased to about half the tumor volume when tumors were in the thoracic spine (Th-spine) segment. The BSI can be a good indicator of tumor volume in most segments, even though it is affected by the tumor's 99mTc-MDP uptake. Nevertheless, values calculated from the Th-spine should be interpreted carefully.

Comparison of DWIBS/T2 image fusion and PET/CT for the diagnosis of cancer in the abdominal cavity.

Fusion images of diffusion-weighted whole-body imaging with background body signal suppression and T2-weighted image (DWIBS/T2) demonstrate a strong signal for malignancies, with a high contrast against the surrounding tissues, and enable anatomical analysis. In the present study, DWIBS/T2 was compared with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for diagnosing cancer in the abdomen. Patient records, including imaging results of examination conducted between November 2012 and May 2014, were analyzed retrospectively. In total, 10 men (age, 73.6±9.6 years) and 8 women (age, 68.9±7.1 years) were enrolled into the current study. Of the enrolled patients, 2 were diagnosed with hepatocellular carcinoma, 1 with cholangiocellular carcinoma, 1 with liver metastasis, 2 with pancreatic ductal adenocarcinoma, 1 with renal cell carcinoma and 1 with malignant lymphoma. Benign lesions were also analyzed, including adenomyomatosis of the gallbladder (5 patients), intraductal papillary mucinous neoplasm (4 patients) and right adrenal adenoma (1 case). All the patients with cancer showed positive results on DWIBS/T2 images. However, only 7 out of 8 patients were positive with PET/CT. One patient with right renal cellular carcinoma was positive with DWIBS/T2, but negative with PET/CT. All the patients with benign lesions were negative with DWIBS/T2 and PET/CT. In conclusion, DWIBS/T2 was more sensitive in diagnosing cancer of organs in the abdominal cavity compared with PET/CT. Furthermore, negative results with DWIBS/T2 and PET/CT were useful for the diagnosis of benign lesions, such as adenomyomatosis of the gallbladder and intraductal papillary mucinous neoplasm.

Diagnostic accuracy of diffusion-weighted whole-body imaging with background body signal suppression/T2-weighted image fusion for the detection of abdominal solid cancer.

Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) images show significant contrast for cancer tissues against non-cancerous tissues. Fusion of a DWIBS and a T2-weighted image (DWIBS/T2) can be used to obtain functional, as well as anatomic, information. In the present study, the performance of DWIBS/T2 in the diagnosis of abdominal solid cancer was evaluated. The records of 14 patients were retrospectively analyzed [5 patients with hepatocellular carcinoma (HCC), 4 with metastatic liver cancer, 3 with pancreatic cancer, 1 with renal cellular carcinoma and 1 with malignant lymphoma of the para-aortic lymph node]. T1WI and T2WI scans did not detect pancreatic cancer in certain cases, whereas DWIs and DWIBS/T2 clearly demonstrated pancreatic cancer in all cases. In addition, metastatic liver cancer and HCC were successfully detected with abdominal US and CECT; however, US did not detect pancreatic cancer in 1 case, while CECT and DWIBS/T2 detected pancreatic cancer in all cases. In conclusion, the diagnostic performance of DWIBS/T2 was the same as that of abdominal US and CECT in detecting primary and metastatic liver cancer. DWIBS/T2 enabled the diagnosis of pancreatic cancer in cases where it was not detected with US, T1WI or T2WI.

Diffusion-weighted whole-body imaging with background body signal suppression/T2 image fusion for the diagnosis of colorectal polyp and cancer.

Diffusion-weighted whole-body imaging with background body signal suppression/T2 image fusion (DWIBS/T2) is useful for the diagnosis of cancer as it presents a clear contrast between cancerous and non-cancerous tissue. The present study investigated the limitations and advantages of DWIBS/T2 with regards to the diagnosis of colorectal polyp (CP) or cancer (CRC). The current study included patients diagnosed with CP or CRC following colonoscopy, who were subjected to DWIBS/T2 between July 2012 and March 2015. Patient records were analyzed retrospectively. Patients were subjected to DWIBS/T2 when they presented with abdominal cancers or inflammation. Colonoscopy was performed as part of screening, or if patients had suspected colon cancer or inflammatory bowel disease. A total of 8 male and 7 female patients were enrolled in the present study. All patients, with the exception of one who had been diagnosed with CRC following colonoscopy, had positive results and all patients diagnosed with CP following a colonoscopy, with the exception of one, had negative results on DWIBS/T2. Thus, CRC was detected by DWIBS/T2, while CP was not (P=0.0028). The diameter of CRC lesions was significantly larger than that of CP (P<0.0001) and that of lesions positive on DWIBS/T2 was significantly larger than that of negative lesions (P=0.0004). The depth of invasion tended to be greater for lesions positive on DWIBS/T2 compared with that of negative ones. This indicated that DWIBS/T2 may be suitable for the detection of CRC but not for detection of CP. The results of DWIBS/T2 may also be affected by lesion diameter and depth of invasion.

Diffusion-weighted whole-body imaging with background body signal suppression/T2-weighted image fusion of gastrointestinal cancers.

Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) yields positive results for cancer against the surrounding tissues. The combination of DWIBS and T2-weighted images (DWIBS/T2) in the diagnosis of gastrointestinal tract cancers was retrospectively analyzed in the present study. Patients were subjected to magnetic resonance imaging after cancer was diagnosed through specimens obtained via biopsy or endoscopic mucosal resection. Sixteen patients were assessed between July, 2012 and June, 2013 and the correlation between detection with DWIBS/T2 and T staging was analyzed. Regarding patients who underwent surgery, the correlation between detection with DWIBS/T2 and the diameter or depth of invasion was analyzed. All cancers that had advanced to >T2 stage were detectable by DWIBS/T2, whereas all cancers staged as T2) or invading beyond the muscularis propria.

Negative signals for adenomyomatosis of the gallbladder upon diffusion-weighted whole body imaging with background body signal suppression/T2-weighted image fusion analysis.

Differentiation between adenomyomatosis (ADM) and cancer of the gallbladder is necessary during diagnosis. Diffusion-weighted whole body imaging with background body signal suppression (DWIBS) images are able to indicate cancer and inflammation. The fusion of a DWIBS with a T2 weighted image (DWIBS/T2) facilitates both functional and anatomical investigations. In the present study, patient records and images from patients with surgically confirmed ADM from April 2012 to October 2014 were analyzed retrospectively. The enrolled patients, including 6 men (64.2±13.1 years) and 4 women (57.3±12.4 years) were subjected to DWIBS/T2 during routine clinical practice. The diagnosis of ADM was based on magnetic resonance cholangiopancreatography, transabdominal ultrasonography, and endoscopic ultrasonography; ADM was diagnosed definitively when cystic lesions were observed, indicating the Rokitansky-Aschoff sinus. A single patient was indicated to be positive by DWIBS/T2 imaging. The Rokitansky-Aschoff sinus revealed a relatively high signal intensity; however, it was not as strong as that of the spleen. The signal intensity was also high on an apparent diffusion coefficient map, suggesting T2 shine-through. The thickened wall displayed low signal intensity. The aforementioned results indicate that ADM may be negative upon DWIBS/T2 imaging; one false positive case was determined to be ADM, accompanied by chronic cholecystitis. The majority of patients with ADM displayed negative findings upon DWIBS/T2 imaging, and chronic cholecystitis may cause false positives.

Comparative study of the value of dual tracer PET/CT in evaluating breast cancer.

The present study was conducted to assess the relationship between tumor uptake and pathologic findings using dual-tracer PET/computed tomography (CT) in patients with breast cancer. Seventy-four patients with breast cancer (mean age 54 years) who underwent (11)C-choline and 2-[(18)F]fluoro-2-deoxy-d-glucose ((18)F-FDG) PET/CT prior to surgery on the same day were enrolled in the present study. Images were reviewed by a board-certified radiologist and two nuclear medicine specialists who were unaware of any clinical information and a consensus was reached. Uptake patterns and measurements of dual tracers were compared with the pathologic findings of resected specimens as the reference standard. Mean (±SD) tumor size was 5.9 ± 3.2 cm. All primary tumors were identified on (18)F-FDG PET/CT and (11)C-choline PET/CT. However, (18)F-FDG PET/CT demonstrated focal uptake of the primary tumor with (n = 38; 51%) or without (n = 36; 49%) diffuse background breast uptake. Of the pathologic findings, multiple logistic regression analysis revealed an independent association between fibrocystic change and diffuse background breast uptake (odds ratio [OR] 8.57; 95% confidence interval [CI] 2.86-25.66; P < 0.0001). Tumors with higher histologic grade, nuclear grade, structural grade, nuclear atypia, and mitosis had significantly higher maximum standardized uptake values (SUV(max)) and tumor-to-background ratios (TBR) for both tracers. Multiple logistic regression analysis revealed that only the degree of mitosis was independently associated with a high SUV(max) (OR 7.45; 95%CI 2.21-25.11; P = 0.001) and a high TBR (OR 5.41; 95%CI 1.13-25.96; P = 0.035) of (11)C-choline PET/CT. In conclusion, (11)C-choline may improve tumor delineation and reflect tumor aggressiveness on PET/CT in patients with breast cancer.

Role of carbon-11 choline PET/CT in the management of uterine carcinoma: initial experience.

PURPOSE: The present study was conducted to clarify the role of carbon-11 choline ((11)C-choline) positron emission tomography (PET)/computed tomography (CT) in the management of uterine carcinoma. MATERIALS AND METHODS: Twenty-two patients who underwent (11)C-choline PET/CT and pelvic MRI were evaluated retrospectively. The images were reviewed by a board-certified radiologist and a nuclear medicine specialist who were unaware of any clinical information, and a consensus was reached. Diagnostic accuracy of PET/CT was evaluated for staging. The reference standard consisted of histological examination (n = 17) and follow-up conventional CT (n = 5). In five patients with cervical carcinoma, (11)C-choline PET/CT was performed before and after treatment that consisted of cisplatin infusion and subsequent radiotherapy. Standardized uptake value (SUV) was compared with uni-dimensional and volumetric measurements that were made on magnetic resonance images (MRI) before and after treatment. RESULTS: Based on PET/CT interpretations, the reviewers correctly classified T stage in 8 patients (47%), N stage in 21 patients (96%), M stage in 20 patients (91%), and TNM stage in 15 patients (88%). Tumor size, volume, and SUV decreased after treatment in five patients with cervical carcinoma. Using the Pearson correlation test, a significant correlation was found between the reduction rate of SUV and reduction rate of tumor volume. CONCLUSIONS: (11)C-choline PET/CT is an accurate means for the management of patients with uterine carcinoma. The combination of (11)C-choline PET/CT and MRI increases the accuracy of staging in patients with uterine carcinoma.