Assessing Therapeutic Response to Radium-223 with an Automated Bone Scan Index among Metastatic Castration-Resistant Prostate Cancer Patients: Data from Patients in the J-RAP-BSI Trial.

To evaluate the usefulness of change in the automated bone scan index (aBSI) value derived from bone scintigraphy findings as an imaging biomarker for the assessment of treatment response and survival prediction in metastatic castration-resistant prostate cancer (mCRPC) patients treated with Ra-223. This study was a retrospective investigation of a Japanese cohort of 205 mCRPC patients who received Ra-223 in 14 hospitals between July 2016 and August 2020 and for whom bone scintigraphy before and after radium-223 treatment was available. Correlations of aBSI change, with changes in the serum markers alkaline phosphatase (ALP) and prostate-specific antigen (PSA) were evaluated. Additionally, the association of those changes with overall survival (OS) was assessed using the Cox proportional-hazards model and Kaplan-Meier curve results. Of the 205 patients enrolled, 165 (80.5%) completed six cycles of Ra-223. Following treatment, ALP decline (%ALP < 0%) was noted in 72.2% (148/205), aBSI decline (%aBSI < 0%) in 52.7% (108/205), and PSA decline (%PSA < 0%) in 27.8% (57/205). Furthermore, a reduction in both aBSI and ALP was seen in 87 (42.4%), a reduction in only ALP was seen in 61 (29.8%), a reduction in only aBSI was seen in 21 (10.2%), and in both aBSI and ALP increasing/stable (≥0%) was seen in 36 (17.6%) patients. Multiparametric analysis showed changes in PSA [hazard ratio (HR) 4.30, 95% confidence interval (CI) 2.32-8.77, p < 0.0001], aBSI (HR 2.22, 95%CI 1.43-3.59, p = 0.0003), and ALP (HR 2.06, 95%CI 1.35-3.14, p = 0.0008) as significant prognostic factors for OS. For mCRPC patients treated with Ra-223, aBSI change is useful as an imaging biomarker for treatment response assessment and survival prediction.

Novel nomogram developed for determining suitability of metastatic castration-resistant prostate cancer patients to receive maximum benefit from radium-223 dichloride treatment-Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial.

PURPOSE: To develop a novel nomogram for determining radium-223 dichloride (Ra-223) treatment suitability for metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: This Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial was a retrospective multicenter investigation enrolled 258 mCRPC patients in Japan with Ra-223 treatment between June 2016 and August 2020, with bone scintigraphy findings before treatment, clinical data, and survival outcome available. A nomogram was constructed using prognostic factors for overall survival (OS) based on a least absolute shrinkage and selection operator Cox regression model. A sub-analysis was also conducted for patients meeting European Medicines Agency (EMA) guidelines. RESULTS: Within a median of 17.4 months after initial Ra-223 treatment, 124 patients (48.1%) died from prostate cancer. Predictive factors included (1) sum of prior treatment history (score 0, never prior novel androgen receptor-targeted agents (ARTA) therapy, never prior taxane-based chemotherapy, and ever prior bisphosphonate/denosumab treatment), (2) Eastern Cooperative Oncology Group (ECOG) performance status, (3) prostate-specific antigen doubling time (PSADT), (4) hemoglobin, (5) lactate dehydrogenase (LDH), and (6) alkaline phosphatase (ALP) levels, and (7) automated bone scan index (aBSI) value based on bone scintigraphy. The nomogram using those factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.748 and 0.734, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.771, 0.818, and 0.771, respectively. In 227 patients meeting EMA recommendation, the nomogram with seven factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.722 and 0.704, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.747, 0.790, and 0.759, respectively. CONCLUSION: This novel nomogram including aBSI to select mCRPC patients to receive Ra-223 with significantly prolonged OS possibility was found suitable for assisting therapeutic decision-making, regardless of EMA recommendation.

Predicting pathological highly invasive lung cancer from preoperative [18F]FDG PET/CT with multiple machine learning models.

PURPOSE: The efficacy of sublobar resection of primary lung cancer have been proven in recent years. However, sublobar resection for highly invasive lung cancer increases local recurrence. We developed and validated multiple machine learning models predicting pathological invasiveness of lung cancer based on preoperative [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and computed tomography (CT) radiomic features. METHODS: Overall, 873 patients who underwent lobectomy or segmentectomy for primary lung cancer were enrolled. Radiomics features were extracted from preoperative PET/CT images with the PyRadiomics package. Seven machine learning models and an ensemble of all models (ENS) were evaluated after 100 iterations. In addition, the probability of highly invasive lung cancer was calculated in a nested cross-validation to assess the calibration plot and clinical usefulness and to compare to consolidation tumour ratio (CTR) on CT images, one of the generally used diagnostic criteria. RESULTS: In the training set, when PET and CT features were combined, all models achieved an area under the curve (AUC) of ≥ 0.880. In the test set, ENS showed the highest mean AUC of 0.880 and smallest standard deviation of 0.0165, and when the cutoff was 0.5, accuracy of 0.804, F1 of 0.851, precision of 0.821, and recall of 0.885. In the nested cross-validation, the AUC of 0.882 (95% CI: 0.860-0.905) showed a high discriminative ability, and the calibration plot indicated consistency with a Brier score of 0.131. A decision curve analysis showed that the ENS was valid with a threshold probability ranging from 3 to 98%. Accuracy showed an improvement of more than 8% over the CTR. CONCLUSION: The machine learning model based on preoperative [18F]FDG PET/CT images was able to predict pathological highly invasive lung cancer with high discriminative ability and stability. The calibration plot showed good consistency, suggesting its usefulness in quantitative risk assessment.

Clinical value of PET/CT with carbon-11 4DST in the evaluation of malignant and benign lung tumors.

OBJECTIVES: The aim of this study was to assess the clinical value of [11C]4DST uptake in patients with lung nodules, including benign and malignant tumors, and to assess the correlation between [11C]4DST uptake and proliferative activity of tumors in comparison with [18F]FDG uptake. METHODS: Twenty-six patients (22 males and 4 females, mean age of 65.5-year-old) were analyzed in this prospective study. Patients underwent [11C]4DST and [18F]FDG PET/CT imaging on the same day. Diagnosis of each lung nodule was confirmed by histopathological examination of tissue specimens at surgery, or during clinical follow-up after the PET/CT studies. To assess the utility of the semi-quantitative evaluation method, the SUVmax was calculated of [11C]4DST and [18F]FDG uptake by the lesion. Proliferative activities of each tumor as indicated by the immunohistochemical Ki-67 index was also estimated using surgical specimens of patients. Then the relationship between the SUVmax of both PET/CT and the Ki-67 index was examined. Furthermore, the relationship between the uptake of [11C]4DST or [18F]FDG and the histopathological findings, the clinical stage, and the clinical outcome of patients were also assessed. RESULTS: There was a positive linear relationship between the SUVmax of [11C]4DST images and the Ki-67 index (Correlation coefficients = 0.68). The SUVmax of [11C]4DST in the 26 lung nodules were 1.65 ± 0.40 for benign lesions, 3.09 ± 0.83 for adenocarcinomas (P < 0.001 between benign and adenocarcinoma), and 2.92 ± 0.58 for SqCCs (P < 0.001 between benign and SqCC). Whereas, the SUVmax of [18F]FDG were 2.38 ± 2.27 for benign lesions, 6.63 ± 4.24 for adenocarcinomas (n.s.), and 7.52 ± 2.84 for SqCCs (n.s.). The relationship between TNM tumor stage and the SUVmax of [11C]4DST were 2.54 ± 0.37 for T1, 3.48 ± 0.57 for T2, and 4.17 ± 0.72 for T3 (P < 0.005 between T1 and T2, and P < 0.001 between T1 and T3). In comparison with the TNM pathological stage, SUVmax of [11C]4DST were 2.63 ± 0.49 for stage I, 3.36 ± 0.23 for stage II, 3.40 ± 1.12 for stage III, and 4.65 for stage IV (P < 0.05 between stages I and II). In comparison of the clinical outcome, the SUVmax of [11C]4DST were 2.72 ± 0.56 for the no recurrence (No Rec.) group, 3.10 ± 0.33 for the recurrence-free with adjuvant chemotherapy after the surgery (the No Rec. Adjv. CTx. group) and 4.66 ± 0.02 for the recurrence group (Rec. group) (P < 0.001 between the No Rec and Rec. groups, and P < 0.005 between the No Rec. Adjv. CTx. and Rec. groups). CONCLUSIONS: PET/CT with [11C]4DST is as feasible for imaging of lung tumors as [18F]FDG PET/CT. For diagnosing lung tumors, [11C]4DST PET is useful in distinguishing benign nodules from malignancies. [11C]4DST uptake in lung carcinomas is correlated with the proliferative activity of tumors, indicating a promising noninvasive PET imaging of DNA synthesis in malignant lung tumors.

Comparison of vascularized supraclavicular lymph node transfer and lymphaticovenular anastomosis for advanced stage lower extremity lymphedema.

BACKGROUND: Vascularized lymph node transfer has become a popular surgical option to improve lower extremity lymphedema (LEL), although potential donor sites are limited. The free supraclavicular flap with deep cervical lymph nodes has been recently associated with a minimal risk of secondary lymphedema caused by donor site dissection. However, the effectiveness of this procedure has not yet been evaluated. METHODS: Vascularized supraclavicular lymph node transfer (VSLNT) was performed for patients with International Society of Lymphology late stage II or more severe LEL. The results were compared with lymphaticovenular anastomosis (LVA) performed for patients with the same stages of severity. To evaluate improvement in lymphatic function, indocyanine green lymphography and lymphoscintigraphy were performed. RESULTS: Vascularized supraclavicular lymph node transfer was performed in 13 limbs of 13 patients. The results were compared with 43 limbs of 33 patients who underwent multiple LVA. No severe complications were observed in either group. Improvement in lymphatic function, as measured by the LEL index, was 26.5 ± 4.4 and 21.2 ± 2.0 in the VSLNT and LVA groups, respectively. Lymphatic function was improved in 7 cases in the VSLNT group and 10 cases in the LVA group. CONCLUSIONS: Vascularized supraclavicular lymph node transfer is an effective technique for the treatment of advanced stage LEL. Lymphaticovenular anastomosis is also effective, but to a lesser degree than VSLNT. However, LVA is less invasive and requires a shorter hospital stay.

Correlation between angiogenesis and reduction ratio measured using 201Tl chloride single photon emission computed tomography in patients with oral cavity squamous cell carcinoma.

OBJECTIVE: The aim of this study is to examine the correlation between tumor angiogenesis and response to preoperative radiotherapy evaluated using 201Tl single photon emission computed tomography (Tl SPECT) in oral cavity squamous cell carcinoma (SCC). METHODS: Tl SPECTs before and after preoperative radiotherapy were obtained from 11 patients diagnosed with SCC in oral cavity. Regions of interest were set around the tumor and scalp respectively, and the ratio of mean counts in the tumor to those in the scalp was calculated (T/N). Immunohistochemical staining for investigating microvessel density of pre-treatment biopsy specimen was performed using CD31 monoclonal antibody. We compared microvessel density with semi-quantitative parameters obtained using Tl SPECT (T/N at pre- an post-treatment, reduction ratio) and prognosis. RESULTS: The subgroup with higher microvessel density showed a significantly higher reduction ratio than the one with lower microvessel density. Regarding prognosis, the subgroup with locoregional recurrent disease exhibited a significantly higher microvessel density than the one without recurrence. CONCLUSIONS: In SCC of the oral cavity, there was a significant correlation between microvessel density and response to preoperative radiotherapy. Namely, it was revealed that change of 201Tl uptake after preoperative radiotherapy correlated with tumor angiogenesis of oral cavity SCC.

Evaluation of mandibular invasion by head and neck cancers using 99mTc-methylene diphosphonate or 99mTc-hydroxymethylene diphosphonate and 201Tl chloride dual isotope single photon emission computed tomography.

Whether a patient with head and neck cancer has mandibular invasion or not is important in determining the method of resection surgery. But, no modality is adequately reliable when used alone in the evaluation of mandibular invasion. Therefore, to more accurately diagnose mandibular invasion in head and neck cancer, we used a new modality, namely, 99mTc methylene diphosphonate (MDP) or 99mTc hydroxymethylene diphosphonate (HMDP) and 201Tl chloride dual isotope single photon emission computed tomography (Tc/Tl SPECT). The aim of this study is to disclose the usefulness of Tc/Tl SPECT in the assessment of mandibular invasion by head and neck cancers. 99mTc-MDP or -HMDP SPECT (Tc SPECT)s and 201Tl chloride SPECT (Tl SPECT)s were performed in 34 patients with suspected mandibular involvement of head and neck cancer. Thirty of 34 cases underwent both TcMTl SPECT and CT examination. Tc/Tl SPECT fusion images were obtained using the Automatic Registration Tool (ART, TOSHIBA, Japan) system. In the diagnosis of mandibular invasion on Tc/Tl SPECT fusion images, a problem was that the range of Tc and Tl uptake was changed by the condition of display used in the reconstruction and expression of the images. Then, prior to clinical evaluation, to reveal the most appropriate upper window level for display, a phantom study was performed. In a clinical study, the upper window level was set at 40 or 50%, which were verified to be the proper values in the preliminary study. The diagnostic accuracy obtained using Tc SPECT, TcMTl SPECT and CT was compared with the histopathological findings. Tc/Tl SPECT at 40 and 50% upper window level had higher specificity, accuracy, and positive predictive value (73.3%, 85.3%, 81.8%) than Tc SPECT alone (21.4%, 67.6%, 64.5%) and higher sensitivity and negative predictive value (94.7%, 91.7%) than CT (70.6%, 72.2%) for detecting mandibular invasion. Tc/Tl SPECT was a useful diagnostic procedure for the assessment of mandibular invasion by head and neck cancers.

Semi-quantitative assessment of oral cavity squamous cell carcinoma using 201Tl SPECT for evaluating effectiveness of preoperative radiotherapy.

The aim of this study is to reveal the usefulness of semi-quantitative assessment using 201Tl chloride (Tl) single photon emission computed tomography (SPECT) (Tl SPECT) to evaluate the effectiveness of radiotherapy in 15 patients with oral cavity squamous cell carcinma (SCC). Fifteen patients were diagnosed with SCC by biopsy. All 15 patients enrolled in this study were planned to undergo preoperative radiotherapy with or without chemotherapy using carboplatin (CBDCA) and received reduction operation. Tl SPECTs were performed 15 minutes after intravenous administration of 111 MBq 201Tl chloride. Regions of Interest (ROI) were set up around tumor (T), and non-lesion (N) at the part of contralateral scalp at the height of the cerebellum. The ratios of mean counts in ROI of the tumor to those in non-lesion were measured as pre- and post-treatment T/N ratios (pre T/N, post T/N). Furthermore, reduction rate (RR) was obtained by calculating [(pre T/N - post T/N)/(pre T/ N)] x 100%. Each parameter (pre T/N, post T/N, and RR) was compared to histopathological grade of surgical specimen based on the Oboshi and Shimosato classification (grade I-IV). RR showed significantly higher values in grade III and IV than in grade I and II (p = 0.0008). In conclusion, semi-quantitative assessment using Tl SPECT, especially calculating RR, is useful to evaluate the effectiveness of preoperative radiotherapy.

Extraosseous accumulation of bone scanning agents in malignant brain tumors: comparison to semi-quantitative evaluation with 99mTc SPECT/201Tl SPECT and histological findings.

Although 201Tl chloride (Tl) SPECT has been used in the differential diagnosis between recurrence of malignant brain tumor and necrosis after treatment, it is not generally recognized as a definite modality to distinguish them. We conducted a preliminary study using Tl SPECT and 99mTc-MDP or 99mTc-HMDP (Tc) SPECT because it has been said that extraosseous accumulation was caused by calcium deposits in necrotic tissues. In our study, for the purposes of clarifying the mechanism of extraosseous uptake and the correlation between extraosseous accumulation of bone-scanning agent and tumor viability in malignant brain tumors, we compared whether Tc uptake was correlated with the histopathological findings and further performed semi-quantitative evaluation between Tc SPECT and Tl SPECT. The correlation coefficients between the ratio of tumor to normal skull count obtained from Tc SPECT (Tc-T/N) and those of tumor to normal brain count (T/N) and to normal scalp count (T/S) both obtained from Tl SPECT were calculated. Using contrast enhanced CT (CE-CT) or contrast enhanced MRI (CE-MRI), 8 of 10 cases showed intensely ring-enhanced tumor with necrotic lesion. Histopathologically, 7 of 8 cases whose tumor had been resected before treatment had necrosis with increased vascularity or bleeding. Of the remaining 2 cases one case, malignant lymphoma had only hypervascularity by biopsy, while the other one was excluded for resection after treatment. Three of these 8 cases whose CE-CT or CE-MRI showed necrotic lesions exhibited Tc and Tl accumulations in the area corresponding to necrosis. In contrast, 2 showed no Tc nor Tl uptake. Tc-T/N had no significant correlation with any of early-, delayed-T/N or T/S. In conclusion, there was no significant correlation between Tc and Tl uptakes by malignant brain tumors in semi-quantitative evaluation.

Can initial prostate specific antigen determinations eliminate the need for bone scans in patients with newly diagnosed prostate carcinoma? A multicenter retrospective study in Japan.

BACKGROUND: The objective of the current study was to assess rigorously whether serum prostate specific antigen (PSA) determination can eliminate the need for bone scans in Japanese patients with newly diagnosed prostate carcinoma with serum PSA levels < or = 10 ng/mL. METHODS: A retrospective assessment of 1294 patients with newly diagnosed, untreated prostate carcinoma was conducted at the authors' institutions. All patients underwent a bone scan, serum PSA measurement, and core needle biopsy of the prostate. The receiver operating characteristic curve for identifying a positive bone scan based on serum PSA levels and a decision tree were analyzed to determine the expected 10-year cumulative cost and disease specific survival rate. Two competing strategies were used: PSA alone and PSA plus baseline bone scan. For the PSA-alone strategy, a baseline bone scan was performed only when the patient had a serum PSA level > 10 ng/mL. RESULTS: The proportion of positive bone scans in patients with serum PSA levels < or = 10.0 ng/mL was 1.33%. The area under the receiver operating characteristic curve was 0.870. Patients with a Gleason Grade > or = 3 tumors or with a Gleason score > or = 7 had a higher proportion of positive bone scans. The 10-year disease specific survival rates with the PSA-alone strategy and the PSA-plus-bone-scan strategy were the same. The PSA-alone strategy was minimally cost effective, with a savings of $16.00 (U.S.) in the cumulative net cost per patient over the PSA-plus-bone-scan strategy. CONCLUSIONS: The current results suggest that baseline bone scans can be eliminated in patients with newly diagnosed prostate carcinoma in Japan who have serum PSA levels < or = 10 ng/mL. Apparently, it is possible to omit baseline bone scans for patients with a Gleason Grade < or = 2 tumors or with a Gleason score < or =6.

Extraosseous accumulation of 99mTc phosphonate complexes in primary brain tumor evaluated with SPECT.

Although extraosseous accumulations of 99mTc phosphate complexes are phenomena which can often be seen, no case showing extraosseous accumulation to brain tumor on SPECT has been reported. We report here two cases of primary brain tumor showing extraosseous accumulation of 99mTc phosphate in bone SPECT. 201Tl SPECT also showed increased 201Tl uptake by the tumor. Comparing bone SPECT with 201Tl SPECT, the regions of abnormality of both SPECTs were very similar in the case of glioblastoma, but in the case of malignant lymphoma the region showing intense uptake of 99mTc-MDP was smaller than that on 201Tl SPECT. It was revealed that bone SPECT is more useful in the assessment of extraosseous accumulation to a primary brain tumor than conventional bone scintigraphy.