Early evaluation of CAR-T cell therapy response in R/R DLBCL patients using 18F-FDG PET/CT.

OBJECTIVE: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. SUBJECTS AND METHODS: Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. RESULTS: Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. CONCLUSION: Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.

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.

Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention.

BACKGROUND: Treatment of recurrent malignant pleural mesothelioma (MPM) remains challenging. Our study examined the efficacy, tolerability, and safety of nivolumab with ipilimumab treatment for recurrent MPM after primary curative-intent surgery. METHODS: Treatment comprised 360 mg nivolumab every 3 weeks and 1 mg/kg of ipilimumab every 6 weeks, both administered intravenously. Both were discontinued for progressive disease or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), post-treatment survival, progression-free survival (PFS), and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Survival analysis was estimated using a Kaplan-Meier plot. Feasibility analysis was performed using the National Cancer Institute Common Terminology Criteria for AEs version 5.0. RESULTS: Forty-one patients received nivolumab with ipilimumab for recurrent MPM after primary curative-intent surgery (median follow-up, 10.4 months; median treatment, 5.1 months). Overall, 18 patients exhibited partial response, 13 exhibited stable disease, and 10 had documented progressive disease. ORR and DCR were 43.9 and 75.6%, respectively. The 12-month post-treatment survival rate and PFS rate were 74.2 and 40.0%, respectively (median survival, not calculated; median PFS, 7.3 months). Further, 47 AEs were reported in 29 patients (70.7%), including grade 3-4 AEs in 14 patients (34.1%). Grade 4 hepatobiliary disorders were observed in 2 patients and grade 4 neutropenia was observed in 1. CONCLUSION: Nivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.

Effects of CT-based attenuation correction on quantitative SPECT/CT of jawbone.

OBJECTIVE: With single photon emission computed tomography (SPECT)/computed tomography (CT) quantitative examinations, CT-based attenuation correction (CTAC) is considered necessary, though its effect on the quantitative values of an examined area close to the body surface, such as the jawbone, has not been elucidated. We performed an investigation to determine whether quantitative evaluation using a bone SPECT standalone device without CT is possible. SUBJECTS AND METHODS: The calculated indices were maximum standardized uptake value (SUVmax) and SUVpeak. Grouping was performed based on the presence or absence of CTAC. The CTAC group underwent CTAC, while the noAC group did not.Validation was performed using clinical data of patients who underwent a jawbone SPECT/CT examination. Becquerel calibration factor (BCF) is required for calculation of SUV, and was determined with values obtained with both phantom and syringe methods. The index for the uptake areas in each group was assessed using a paired t-test. RESULTS: Using BCF obtained with the phantom method, both SUVmax and SUVpeak were higher in the noAC group. In contrast, BCF obtained with the syringe method showed no significant difference between the CTAC and noAC groups in regard to SUVmax and SUVpeak. This tendency was found regardless of the device used. Also, a high correlation was observed between the groups for both devices (r=0.95 and 0.93). CONCLUSION: Our findings show that BCF obtained with a syringe method should be used when performing quantitative evaluation without CTAC. They also indicate that quantitative evaluation using a SPECT standalone device may be possible for jawbone SPECT/CT examinations.

The usefulness of the total metabolic tumor volume for predicting the postoperative recurrence of thoracic esophageal squamous cell carcinoma.

BACKGROUND: Induction or adjuvant therapies are not always beneficial for thoracic esophageal squamous cell carcinoma (ESCC) patients, and it is thus important to identify patients at high risk for postoperative ESCC recurrence. We investigated the usefulness of the total metabolic tumor volume (TMTV) for predicting the postoperative recurrence of thoracic ESCC. METHODS: We retrospectively analyzed the cases of 163 thoracic ESCC patients (135 men, 28 women; median age of 66 [range 34-82] years) treated at our hospital in 2007-2012. The TMTV was calculated from the fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the primary lesion and lymph node metastases. The optimal cut-off values for relapse and non-relapse were obtained by the time-dependent receiver operating curve analyses. Relapse-free survival (RFS) was evaluated by the Kaplan-Meier method, and between-subgroup differences in survival were analyzed by log-rank test. The prognostic significance of metabolic parameters and clinicopathological variables was assessed by a Cox proportional hazard regression analysis. The difference in the failure patterns after surgical resection was evaluated using the χ2-test. RESULTS: The optimal cut-off value of TMTV for discriminating relapse from non-relapse was 3.82. The patients with a TMTV ≥3.82 showed significantly worse prognoses than those with low values (p < 0.001). The TMTV was significantly related to RFS (model 1 for preoperative risk factors: TMTV: hazard ratio [HR] =2.574, p = 0.004; model 2 for preoperative and postoperative risk factors: HR = 1.989, p = 0.044). The combination of the TMTV and cN0-1 or pN0-1 stage significantly stratified the patients into low-and high-risk recurrence groups (TMTV cN0-1, p < 0.001; TMTV pN0-1, p = 0.004). The rates of hematogenous and regional lymph node metastasis were significantly higher in the patients with TMTV ≥3.82 than those with low values (hematogenous metastasis, p < 0.001, regional lymph node metastasis, p = 0.011). CONCLUSIONS: The TMTV was a more significantly independent prognostic factor for RFS than any other PET parameter in patients with resectable thoracic ESCC. The TMTV may be useful for the identifying thoracic ESCC patients at high risk for postoperative recurrence and for deciding the patient management.

Evaluation of 11 C-choline positron emission tomography/computed tomography for determining treatment response in castration-resistant prostate cancer patients.

OBJECTIVE: The utility of 11 C-choline positron emission tomography/computed tomography for determining treatment response as compared with prostate-specific antigen response and prognosis prediction in castration-resistant prostate cancer patients was investigated. METHODS: Eighty-four 11 C-choline-positron emission tomography/computed tomography scans before/after treatments with abiraterone (n = 12 patients), enzalutamide (n = 3), docetaxel (n = 9), cabazitaxel (n = 5), radiation therapy alone (n = 3), radiation therapy, enzalutamide, and/or abiraterone (n = 5), radium-223 (n = 4), and radiofrequency ablation (n = 1) in 42 castration-resistant prostate cancer patients were retrospectively examined. Prostate-specific antigen values were determined before and after treatment. Using the Kaplan-Meier method, the correlation of Positron Emission Tomography Response Criteria In Solid Tumors with prostate-specific antigen response and prognostic impact was evaluated. RESULTS: Pretreatment 11 C-choline-positron emission tomography/computed tomography findings identified local, lymph node, bone, and visceral metastasis in 12, 12, 29, and five patients, respectively. Following treatments, complete metabolic response was noted in one, partial metabolic response in eight, stable metabolic disease in 13, and progressive metabolic disease in 20. Mean prostate-specific antigen change for complete metabolic response, partial metabolic response, stable metabolic disease and progressive metabolic disease was -48.9%, -55.0% (range -92.4% to -19.1%), -4.2% (-33.2% to 35.1%), and 142.7% (30.7% to 373.8%), respectively, significantly greater in the progressive metabolic disease cases (P < 0.01). Positron Emission Tomography Response Criteria In Solid Tumors was well correlated with prostate-specific antigen change. Patients with no progression (complete metabolic response/partial metabolic response/stable metabolic disease) showed significantly longer cancer-specific survival than progressive metabolic disease (P < 0.005). Using pretreatment 11 C-choline-positron emission tomography/computed tomography results to divide into three groups; (a) local and/or lymph node metastasis without bone metastasis (n = 10), (b) <6 bone metastasis sites (n = 16), (c) ≥6 bone metastasis sites and/or visceral metastasis (n = 16), cancer-specific survival showed significant stratification (P < 0.001). CONCLUSIONS: 11 C-choline-positron emission tomography/computed tomography may reflect castration-resistant prostate cancer metastatic lesion activity for treatment response and prognosis evaluations.

Early assessment of tumor response using 18F-FDG PET/CT after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer.

OBJECTIVE: This study was conducted to evaluate the usefulness of early assessment of tumor response using fluorine-18-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer. SUBJECT AND METHODS: Thirty-three patients with recurrent or metastatic breast cancer underwent 18F-FDG PET/CT before and after one cycle of systemic therapy. Based on the European Organization for Research and Treatment of Cancer (EORTC) criteria, the maximum standardized uptake value (SUVmax) of the same lesions (up to a total of five) noted in the baseline and follow-up scans were summed (maximum of two per organ) as target lesions, and therapeutic response was evaluated. Log-rank and Cox methods were employed to determine progression-free survival (PFS) and overall survival (OS). RESULTS: Complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) was seen in 2, 16, 11, and 4 patients, respectively. The mean reduction rates of SUVmax between 84 target lesions in 18 responders (CMR/PMR) and 75 target lesions in 15 non-responders (SMD/PMD) were -55.8% (range, -100%- -1.2%) and 0.47% (range, -48.7%- +209.4%), respectively, with a significant difference (P<0.0001). Every lesion site (local lesion, lymph node metastasis, bone metastasis, lung metastasis, and liver metastasis) showed a similar tendency. Thirty patients showed progression, and 17 died due to breast cancer after a median of 38.5 months. Responders showed significantly longer PFS than non-responders (P=0.0038). CONCLUSION: Fluorine-18-FDG PET/CT after one cycle of systemic therapy was able to reflect early metabolic changes regardless of the lesion site, and showed accuracy for early response evaluation and prediction of progression in patients with recurrent or metastatic breast cancer.

Clinical value of the threshold derived from bone single-photon emission computed tomography/computed tomography in differentiating sternoclavicular arthritis.

OBJECTIVE: With the recent improvements in the quantitative accuracy of single-photon emission computed tomography (SPECT)/ computed tomography (CT), the value of using standardized uptake value (SUV) in bone SPECT/CT for quantitative assessment has been reported.We established a threshold for inflamed and normal areas of the sternoclavicular joint and examined the clinical value of bone SPECT/CT. SUBJECTS AND METHODS: The threshold between the inflamed and normal areas of the sternoclavicular joint was initially calculated. The diagnostic performance of the calculated threshold was subsequently compared with the visual assessment of the whole-body image. The clinical value of the threshold was examined in cases of ambiguous visual assessment and a sub-analysis with pustuloticarthro-osteitis (PAO) patients was done. RESULTS: The threshold between the inflamed and the normal area in the 93 sternoclavicular joints of 51 patients was 4.46. The area under the ROC curve (AUC), accuracy, sensitivity, and specificity of SUVmax for differentiating sternoclavicular arthritis were 0.92, 0.86, 0.88, and 0.85, respectively. Similarly, the AUC of visual assessment were 0.87, and the difference was not significant (P=0.11). In 25 patients with PAO, the AUC, accuracy, sensitivity, and specificity of SUVmax were 0.94, 0.90, 0.96, and 0.84, respectively with a significant higher AUC of visual assessment (0.82, P=0.032). Furthermore, for cases where there was ambiguous uptake upon visual assessment, the accuracy, sensitivity, and specificity of SUVmax were 0.84, 1.00, and 0.71, respectively, which was useful to judge regarding the initiation of treatment. CONCLUSION: Quantitative assessment using SUVmax and the threshold found using bone SPECT/CT for the presence of sternoclavicular arthritis is clinically useful and can be a useful tool for the initiation of treatment, especially in PAO patients.

Effectiveness of quantitative bone SPECT/CT for bone metastasis diagnosis.

OBJECTIVE: This study was conducted to investigate the utility of standardized uptake value (SUV) derived from bone single photon emission tomography/computed tomography (SPECT/CT) for diagnosing bone metastasis. SUBJECTS AND METHODS: One hundred forty-seven patients with malignant cancer (breast or prostate cancer), joint disorders, primary skeletal disease, or cartilaginous bone neoplasms who underwent skeletal quantitative SPECT/CT were retrospectively investigated. Acquired data were classified as normal fourth lumbar vertebra, skeletal degenerative changes, or bone metastasis. Receiver operating characteristic (ROC) curves were used to determine the optimum cut-off value for SUVmax to distinguish among these diagnoses. RESULTS: Mean SUVmax values for the normal L4 bone (n=101), skeletal degenerative changes (n=47) and bone metastasis (n=64) groups were 4.47±1.66 (range 1.01-11.25), 6.99±2.58 (2.21-14.6), and 25.4±15.7 (3.88-98.87), respectively. Compared to the other two groups, SUVmax for the bone metastasis group was significantly higher (P<0.001). In the normal bone group, sensitivity, specificity and accuracy for discriminating bone metastasis were 96.3%, 95.1%, and 95.7% respectively, with a best SUVmax cut-off value of 7.40. For the skeletal degenerative changes group sensitivity, specificity and accuracy were 87.5%, 93.6%, and 90.4% respectively, with a best SUVmax cut-off value of 11.26. CONCLUSION: Quantitative bone SPECT/CT may be useful for bone metastasis diagnosis.

Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

BACKGROUND: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. METHODS: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. RESULTS: patients' median age was 65 years (range 50-79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. CONCLUSIONS: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Predicting tumor response and prognosis to neoadjuvant chemotherapy in esophageal squamous cell carcinoma patients using PERCIST: a multicenter study in Japan.

PURPOSE: To investigate the usefulness of the positron emission tomography response criteria in solid tumors 1.0 (PERCIST1.0) for predicting tumor response to neoadjuvant chemotherapy and prognosis and determine whether PERCIST improvements are necessary for esophageal squamous cell carcinoma (ESCC) patients. PATIENTS AND METHODS: We analyzed the cases of 177 ESCC patients and examined the association between PERCIST and their pathological responses. Associations of whole-PERCIST with progression-free survival (PFS) and overall survival (OS) were evaluated by a Kaplan-Meier analysis and Cox proportional hazards model. To investigate potential PERCIST improvements, we used the survival tree technique to understand patients' prognoses. RESULTS: There were significant correlations between the pathologic response and PERCIST of primary tumor (p < 0.001). The optimal cutoff value of the primary tumors' SULpeak response to classify pathologic responses was -50.0%. The diagnostic accuracy of SULpeak response was 87.3% sensitivity, 54.1% specificity, 68.9% accuracy, positive predictive value 60.5%, and negative predictive value 84.1%. Whole-PERCIST was significantly associated with PFS and OS. The survival tree results indicated that a high reduction of the whole SULpeak response was significantly correlated with the patients' prognoses. The cutoff values for the separation of prognoses were - 52.5 for PFS and - 47.1% for OS. CONCLUSION: PERCIST1.0 can help predict tumor responses and prognoses. However, 18F-FDG-PET/CT tends to underestimate residual tumors in histopathological response evaluations. Modified PERCIST, in which the partial metabolic response is further classified by the SULpeak response (-50%), might be more appropriate than PERCIST1.0 for evaluating tumor responses and stratifying high-risk patients for recurrence and poor prognosis.

Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition.

Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.

Quantitative bone SPECT/CT applications for primary bone neoplasms.

OBJECTIVE: To evaluate the clinical utility of quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT) for primary bone neoplasms. SUBJECTS AND METHODS: Bone SPECT/CT scans of 23 patients with 19 benign bone neoplasms (5 osteoid osteomas, 4 bone giant cell tumor, 4 osteofibrous dysplasia, 3 intraosseous ganglion, 2 aneurysmal bone cyst, 1 intraosseous hemangioma) and 5 malignant bone neoplasms (2 osteosarcoma, 1 periosteal osteosarcoma, 1 malignancy in bone giant cell tumor, 1 Ewing sarcoma) were retrospectively analyzed with maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), metabolic bone volume (MBV), and total bone uptake (TBU) of primary lesions. RESULTS: Mean SUVmax of 19 benign and 5 malignant primary bone neoplasms were 6.89±3.26 (range 3.9-15.13) and 10.31±3.19 (5.0-13.45) respectively, with statistically significant difference (P=0.048). Mean SUVpeak of those were 5.87±2.83 (range 3.5-13.63) and 9.18±3.05 (4.09-12.03) respectively, with statistically significant difference (P=0.032). Mean SUVmean of those were 4.43±2.11 (range 2.59-9.37) and 7.13±2.90 (3.3-10.42) respectively, with statistically significant difference (P=0.027). Mean MBV of those were 22.0±30.0 (range 2.47-110.61) and 27.8±39.94 (8.59-99.24) respectively, with no statistically significant difference (P=0.72). Mean TBU of those were 80.64±94.57 (range 10.50-373.57) and 166.60±203.97 (28.68-528.13) respectively, with no statistically significant difference (P=0.17). CONCLUSION: Quantitative values obtained with bone SPECT/CT may serve as osteoblastic biomarkers for primary bone neoplasm.

The utility of 68F-FDG PET/CT for evaluation of tumor response to immune checkpoint inhibitor therapy and prognosis prediction in patients with non-small-cell lung cancer.

OBJECTIVE: To compare three fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) (EORTC criteria and PERCIST) and computed tomography (CT) (RECIST1.1) for response evaluation and prognosis prediction in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI) monotherapy. SUBJECTS AND METHODS: Forty NSCLC patients underwent 18F-FDG PET/CT scans at baseline and after 4 to 8 cycles of nivolumab or pembrolizumab. Therapeutic response was evaluated according to EORTC criteria, PERCIST, and RECIST1.1,then concordance among those was assessed using Cohen's κ coefficient. Progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods. RESULTS: The number of complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) were 8/10/4/18 for EORTC criteria and 9/9/4/18 for PERCIST. Using RECIST1.1, those of CR/PR/SD/PD were 4/10/12/14. Although there was high concordance between PERCIST and EORTC (92.5% of patients; κ=0.924), that between PERCIST and RECIST1.1 was substantial (65.0%; κ=0.560) and that between EORTC and RECIST1.1 (65.0%; κ=0.574). After a median 23.2 months (range 7.2 to 51.8 months), 32 patients had documented progression and 24 patients died from NSCLC. According to both PET and CT, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and OS than PMD or PD patients (EORTC: P<0.0001 and P<0.0001, respectively, PERCIST: P<0.0001 and P=0.0001, respectively, RECIST1.1: P<0.0001 and P<0.0001, respectively). In a univariate analysis total MTV (P=0.042) on pre-ICI treatment 18F-FDGPET/CT scans was significantly associated with progression. Highest SUVmax (P<0.0001), total MTV (P=0.0062), total TLG (P<0.0001), highest SULpeak (P<0.0001), and total TLGL (P<0.0001) on post-ICI treatment 18F-FDG PET/CT scans were also were significantly associated with progression. Moreover, the change rate of highest SUVmax (P<0.0001), total metabolic tumor volume (MTV) (P<0.0001), total lesion glycolysis(TLG) (P<0.0001), highest SULpeak (P<0.0001), total TLGL (P<0.0001), size (P=0.0012), EORTC (P<0.0001), PERCIST (P<0.0001), and RECIST 1.1 (P<0.0001) on two PET/CT scans were significantly associated with progression. A multivariate analysis confirmed the change rate of total MTV (P=0.034), and total TLGL (P=0.0027), EORTC (P=0.018), PERCIST (P=0.045), and RECIST1.1 (P=0.0037) as independent negative PFS predictors. CONCLUSION: Both 18F-FDG PET (EORTC criteria and PERCIST) and CT (RECIST1.1) after 4 to 8ICI monotherapy cycles are accurate for evaluation of tumor response and predicting prognosis in NSCLC patients.

Quantitative 67Ga-citrate SPECT/CT for evaluating disease activity in patients with interstitial lung disease.

OBJECTIVE: To determine whether results of a standardized uptake value (SUV)-based semi-quantitative analytic method for gallium-67 (67Ga)-citrate single photon emission tomography/computed tomography (SPECT/CT) reflects disease activity in patients with interstitial lung disease. SUBJECTS AND METHODS: Gallium-67-citrate SPECT/CT was used to evaluate disease activity in 24 patients with interstitial pneumoniaon clinical grounds at a single institution from June 2018 to August 2020. SUV in a given volume of interest over the bilateral pulmonary parenchyma was calculated using a dosimetry software package. Correlations of maximum SUV (SUVmax) and mean SUV (SUVmean) with clinical factors, including KL-6, lactate dehydrogenase (LDH), and C-reactive protein (CRP), were evaluated in all 24, as well as in 15 patients with spirometry results using Pearson's rank correlation test. RESULTS: The mean bilateral pulmonary SUVmax value showed a moderately significant correlation with KL-6 (Pearson's correlation coefficient r=0.51, P=0.012) and LDH (r=0.51, P=0.010), a weak non-significant correlation with DLCO% (r=-0.26, P=0.34), and no correlation with CRP (r=-0.01, P=0.94), FVC% (r=0.11, P=0.71), or FEV1.0% (r=0.14, P=0.62). Eleven patients with high KL-6 (≥1000U/mL) were defined as having disease activity. Maximum SUV sensitivity, specificity, and accuracy for predicting interstitial lung disease activity were 72.7%, 76.9%, and 75.0%, respectively, with a best cut-off value of 3.78. CONCLUSION: Semi-quantitative values obtained with 67Ga-citrate SPECT/CT showed a moderate correlation with KL-6 and moderate diagnostic performance for predicting disease activity of interstitial lung disease. It is rather unlikely that quantitative 67Ga-citrate SPECT/CT will have a role into the algorithm of interstitial lung disease.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1ß in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1ß, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1ß/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma.

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.

Quantitative bone SPECT/CT applications for cartilaginous bone neoplasms.

OBJECTIVE: To evaluate the ability of quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT) to differentiate benign from malignant cartilaginous bone neoplasms. SUBJECTS AND METHODS: Bone SPECT/CT scans of 10 patients with 8 benign cartilaginous bone neoplasms (4 enchondromas, 1 periosteal chondroma, 1 osteochondroma, 1 bizarre parosteal osteochondromatous proliferation, 1 chondroblastoma) and 2 malignant cartilaginous bone neoplasms (1 periosteal chondrosarcoma, 1 chondrosarcoma) were retrospectively analyzed with maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic bone volume (MBV), and total bone uptake (TBU) of primary lesions. RESULTS: Mean SUVmax of 8 benign and 2 malignant cartilaginous bone neoplasms were 1.93±1.02 (range 0.59-3.41) and 6.07±0.86 (5.46-6.67), respectively with no overlap (P=0.028). Mean SUVmean of those were 1.24±0.71 (range 0.36-2.36) and 4.05±0.30 (3.84-4.26), respectively with no overlap (P=0.00036). Mean MBV of those were 7.17±4.19 (range 3.17-13.77) and 10.29±10.05 (3.19-17.4), respectively with no significant difference (P=0.74). Mean TBU of those were 9.22±8.31 (range 1.15-23.61) and 43.19±43.7 (12.26-74.13), respectively with no significant difference (P=0.47). CONCLUSION: Standardized uptake value obtained with bone SPECT/CT may be useful to differentiate benign from malignant cartilaginous bone neoplasms, thus helping the orthopedic surgeon towards the most appropriate treatment procedure.

Harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters for stage IV breast cancer prognosis. Multicenter study in Japan.

OBJECTIVE: The prognostic value of harmonized pretreatment volume-based quantitative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters in metastatic breast cancer patients was investigated. SUBJECTS AND METHODS: Records of 65 stage IV breast cancer patients, including 29 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 23 HER2-positive, and 13 triple-negative cases, from four different institutions were retrospectively reviewed. Harmonized standardized uptake value (SUVmax) of the primary tumor (pSUVmax), highest SUVmax of all malignant lesions (wSUVmax), whole-body metabolic tumor volume (WB MTV), and whole-body total lesion glycolysis (WB TLG) shown by pretreatment 18F-FDG PET/CT imaging were calculated. Cox proportional hazards model and log-rank test results were used to evaluate relationships among clinicopathological factors, volume-based quantitative 18F-FDG PET/CT parameters, progression-free survival, and overall survival (OS). RESULTS: Disease progression occurred in 54 patients and 28 died during a median follow-up period of 52.5 months (range 2.6-133.6 months). Univariate analysis of all cases showed associations of negative ER and progesterone receptor (PR) status (P=0.0025), and high T/N stage (P=0.037/P=0.019), pSUVmax (P=0.049), WB MTV (P=0.021), and WB TLG (P=0.0010) with significantly shorter OS. Multivariate analysis confirmed negative ER and PR status (hazard ratio [HR]: 6.42, 95% confidence interval [CI]: 2.27-19.38; P=0.0054), high T stage (HR: 5.10, 95% CI:1.96-18.61, P=0.0064) and WB TLG (HR: 4.69, 95% CI:1.67-12.79, P=0.049) as independent negative OS predictors. In two groups of ER-positive/HER2-negative and triple-negative, WB TLG had a significant association with death (P=0.021 and P=0.037, respectively) on univariate analysis. In a HER2-positive group, no independent negative OS predictors were observed. CONCLUSION: In metastatic breast cancer patients, harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters, especially whole-body TLG, are potential surrogate markers for prognosis.

Diffusion-weighted MRI, 11C-choline PET/CT, and 18F-FDG PET/CT for predicting the Gleason score in prostate cancer.

OBJECTIVE: To evaluate diffusion-weighted magnetic resonance imaging (DWI), 11C-choline positron emission tomography (PET), and fluorine-18-fluorodeoxyglucose (18F-FDG) PET for predicting Gleason score in prostate cancer patients. SUBJECTS AND METHODS: The study cohort included 11 patients with biopsy-proven prostate cancer who underwent DWI, 11C-choline PET, and 18F-FDG PET examinations before treatment. The correlations of Gleason score with those findings were determined using Spearman's test. Multi-technique imaging performance for separating higher Gleason score (≥8) cases was also examined. RESULTS: Both diffusion coefficient (ADC) map and 11C-choline PET/computed tomography (CT) findings showed prostate cancer in all 11 patients, while 18F-FDG PET/CT was only successful in 6 (54.5%) cases, thus no further evaluations of that modality were performed. A moderately negative correlation was observed between Gleason score and ADC value for the primary tumor shown by DWI, though the difference was not significant (r=-0.49, P=0.13). In contrast, a strongly significant positive correlation was observed between Gleason score and maximum standardized uptake value (SUVmax) for the primary tumor in 11C-choline PET findings (r=0.85, P=0.0010). Sensitivity, specificity, and accuracy for separating higher (≥8) from lower (≤7) Gleason score were 87.5%, 33.3%, and 72.7%, respectively, with a best cut-off value of 0.78 for ADC map, and 87.5%, 100%, and 90.9%, respectively, with a best cut-off value of 6.0 for 11C-choline PET. CONCLUSION: Carbon-11-choline PET was found have a greater correlation with Gleason score than DWI and is considered to be more useful to predict a higher score in patients with prostate cancer. Fluorine-18-FDG PET was limited because of low sensitivity.