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Objective: Radium-223 is a first alpha-emitting radionuclide treatment for metastatic castration-resistant prostate cancer (mCRPC) patients with bone metastases. Although the spread-based bone scan index (BSI) and novel index of the intensity-based two-dimensional total bone uptake (2D-TBU) from bone scintigraphy may provide useful input in radium-223 treatment, they have not been evaluated in detail yet. This study aimed to fill this gap by evaluating BSI and 2D-TBU in patients treated with radium-223., Methods: Twenty-seven Japanese patients with mCRPC treated with radium-223 were retrospectively analyzed. The patients were evaluated via blood tests and bone scans at baseline and 3 cycles intervals of treatment. BSI and 2D-TBU were analyzed via VSBONE BSI in terms of correlations, response to radium-223 treatment, association with treatment completion, and the Kaplan-Meier survival analysis was performed., Results: Nineteen patients (70.4%) completed six cycles of radium-223 treatment, whereas eight patients (29.6%) did not complete the treatment regimen. A significant difference in baseline BSI and 2D-TBU was observed between these groups of patients. Both BSI and 2D-TBU were highly correlated (r = 0.96, p < 0.001). Univariate analysis showed an association between radium-223 completion in median BSI and 2D-TBU values (p = 0.015) and completion percentage differences (91.7% vs. 45.5%; p = 0.027). The Kaplan-Meier product limit estimator showed that the median overall survival was 25.2 months (95% CI 14.0-33.6 months) in the completion group and 7.5 months (95% CI 3.3-14.2 months) in the without completion group (p < 0.001). The overall survival based on median cutoff levels showed a significant difference in 2D-TBU (p = 0.007), but not in BSI (p = 0.15)., Conclusions: The 2D-TBU may offer advantages over BSI in classifying patients towards radium-223 treatment based on the degree of progression of bone metastases. This study supports the importance of preliminary assessment of bone metastasis status using BSI and 2D-TBU extracted from VSBONE BSI for radium-223 treatment decisions., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Objective: There is no good response evaluation method for skeletal metastasis. We aimed to develop a novel quantitative method to evaluate the response of skeletal metastasis, especially lytic lesions, for treatment., Methods: A method to measure active bone metastatic burden quantitatively using F-18 fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) in breast cancer patients, whole skeletal total lesion glycolysis (WS-TLG), a summation of each skeletal lesion's TLG, was developed. To identify active bone lesions, a tentative cutoff value was decided using FDG-PET/CT in 85 breast cancer patients without skeletal metastasis and 35 with skeletal metastasis by changing the cutoff value. Then, the WS-TLG method was evaluated by comparing to PET Response Criteria in Solid Tumor (PERCIST) or European Organization for Research and Treatment of Cancer (EORTC) criteria for only bone in 15 breast cancer patients with skeletal metastasis who were treated., Results: A cutoff value of the standardized uptake value (SUV) = 4.0 gave 91% (77/85) specificity and 97% (34/35) sensitivity. We decided on SUV = 4.0 as a tentative cutoff value. Skeletal metastases of lytic and mixed types showed higher WS-TLG values than those of blastic or intertrabecular types, although statistical significance was not tested. All 15 patients showed agreement with PERCIST or EORTC in the therapeutic bone response., Conclusion: This quantitative WS-TLG method appears to be a good biomarker to evaluate skeletal metastasis in breast cancer patients, especially lytic or mixed types. Further clinical studies are warranted to assess the clinical values of this new WS-TLG method.

Objectives: To establish a new three-dimensional quantitative evaluation method for bone metastasis, we applied bone single photon emission tomography with computed tomography (SPECT/CT). The total bone uptake (TBU), which measures active bone metastatic burden, was calculated as the sum of [mean uptake obtained as standardized uptake value (SUV) above a cut-off level] × (the volume of the lesion) in the trunk using bone SPECT/CT. We studied the threshold value and utility of TBU in prostate cancer patients treated with radium-223 (Ra-223) therapy., Methods: To establish the threshold value of TBU, we compared bone metastatic and non-metastatic regions in 61 prostate cancer patients with bone metastasis and 69 without. Five fixed sites in each patient were selected as evaluation points and divided into bone metastatic and non-metastatic sites. Sensitivity and specificity analysis was applied to establish the threshold level. Using the obtained threshold value, we then calculated the TBU in nine prostate cancer patients who received Ra-223 therapy, and compared the results with the bone scan index (BSI) by BONENAVI ® and visual evaluation of bone scintigraphy., Results: Uptake was significantly lower in non-metastatic sites in patients with bone metastasis than in patients without metastasis. Sensitivity and specificity analysis revealed SUV = 7.0 as the threshold level. There was a discrepancy between TBU and BSI change in two of the nine patients, in whom TBU change correlated with visual judgement, but BSI change did not. In two patients, BSI was nearly 0 throughout the course, but the TBU was positive and changed, although the change was not large. These results suggest that TBU may be more accurate and sensitive than BSI for quantitative evaluation of active bone metastatic burden., Conclusion: We established a threshold value (SUV > 7.0) for three-dimensional TBU for evaluating active bone metastatic burden in prostate cancer patients using bone SPECT/CT. Despite the small number of patients, we expect the change in TBU could be more accurate and sensitive than the change in BSI among patients who received Ra-223.

Monoclonal gammopathy of undetermined significance does not overexpress cluster of differentiation (CD) 56, but plasma cell myeloma frequently overexpressed it. However, plasma cell leukemia and extramedullary plasmacytoma usually down-regulate CD56 expression. Plasmacytoma, especially 'solitary plasmacytoma of bone', is difficult to diagnose as plasma cell neoplasm, because it occasionally appears similar to other bone tumors, both clinically and pathologically, and is rarely accompanied by monoclonal protein in the serum or urine. The present case was a patient with an osteolytic 'small round cell tumor' of the iliac bone, which also invaded the femora. An immunohistopathological finding of CD56 expression played a key role in making a diagnosis. The definitive diagnosis of plasmacytoma was made based on the electron microscopic findings. The plasma cells which infiltrated her sternum showed the same restriction to kappa light chain expression in their cytoplasms as that of the iliac bone tumor cells, but did not express CD56. Locally infiltrating osteolytic bone tumors should be examined for surface immunoglobulin light chains as well as CD56 expression when plasmacytoma is suspected.

Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant neoplasm. Despite a consensus for the distinct clinicopathologic entity of EMC, its clinical features remain controversial. In addition, most studies have contained a small number of patients who underwent definitive surgical treatment., Methods: Forty-two cases of EMC, which had been identified from files of eight affiliated hospitals and confirmed for histologic diagnosis at the Pathology Center, were analyzed for histologic grade, demographics, treatments, outcomes, and prognostic factors. The average follow-up period was 7.4 years., Results: Included in the study were 20 men and 22 women with a mean age at diagnosis of 52.1 years. The tumors were located mainly in the lower extremities (69%). Thirty-three tumors (79%) were classified as Grade 1 and nine as Grade 2 according to the modified French System. Overall survival was 100% at 5 years and 88% at 10 years. Disease-free survival was 45% at 5 years and 36% at 10 years. Inadequate initial surgery was defined as a significant risk factor for local recurrence by univariate analysis of all 42 patients but not by the analysis of those 30 patients who had undergone wide tumor excision or amputation. Wide excision led to the recurrence rate of 14%., Conclusions: These findings supported the role of wide excision in the local control of EMC, irrespective of the previous excision procedure or recurrence. The protracted clinical course of the tumors and the presence of patients who had distant metastasis develop after definitive surgery of the primary tumor represented EMC as intermediate malignancy., (Copyright 2003 American Cancer Society.)

The prognosis for malignant pelvic bone tumors is worse than that for malignant bone tumors of the extremities because definitive surgery in the pelvis is often difficult to accomplish. The results for eight patients who were treated consecutively with a multidisciplinary approach, from 1990, were analyzed. The histologic diagnosis was osteosarcoma in five patients, chondrosarcoma in two, and Ewing's sarcoma in one. Five lesions arose in the ilium and three in the pubis. The extraosseous tumors decreased in size and/or were encapsulated as a result of preoperative chemotherapy in six patients, four of these achieving a wide surgical margin. With respect to tumor location and surgical margin, all five lesions in the ilium involved the sacrum, four of these being resected with an inadequate margin. The three lesions in the pubis were resected with an adequate margin. Local recurrence was observed in two patients who had been treated with an inappropriate margin. During the period between 18 and 57 months after the first operation, five patients were continuously free of disease and one was still alive but had lung metastases. Our results indicate that a patient's chances of definitive surgery may be enhanced by a multidisciplinary approach, although the management of sacroiliac involvement remains challenging.

A review of 135 patients with pelvic chondrosarcoma who had been treated at 58 institutions in Japan between 1989 and 1998. In this series ablative surgery was necessary in 14 patients, and a limb salvage procedure performed in 121 patients. The surgical margins were "intra-lesional" in 27 patients, "marginal" in 30, "wide" in 77 and "unspecified" in 1. Local recurrence occurred in 33 patients and distant metastases in 25. Post-operative infection occurred in 25 patients. Revision was performed in 10 patients. The oncological outcome was "disease free" in 92 patients, "alive with disease" in 17 and "dead because of the disease" in 26. The cumulative prospective 10-year survival rate for all patients was 65%. The 6 statistically significant prognostic factors that determined the outcome were: - surgical stage, site of tumour, size of tumour, surgical margin, functional mobility and activity level after surgery. Excision of the tumour with a wide margin, or with a wide margin with partly marginal areas, and subsequent stable reconstruction are essential for improving the results of pelvic chondrosarcoma treatment.

Bone is one of the most common sites of recurrence of breast cancer. Therefore, it would be clinically very useful if breast cancers with a high probability of bone metastasis (BM) could be identified by histopathological examination of the primary lesions. To elucidate histological characteristics associated with predisposition to initial BM, we examined nine histopathological parameters in the primary lesions of 110 invasive ductal carcinomas (IDCs) of the breast with 0 to 3 regional node metastases. These cases had recurrence between 4 months and 10.1 years after the initial radical surgery. The first metastatic site was bone in 24 cases, whereas other sites were involved in 86 cases. IDCs growing in a strand growth pattern or with fibrotic focus (FF) had a significantly higher frequency of initial BM than those growing in a non-strand growth pattern or without FF, respectively. Strand growth pattern was a significant predictor of the initial BM in multivariate analysis. In all 54 IDCs that developed BM during the follow-up period, osteolytic metastasis was significantly more frequent in the group with FF than in that without FF. This study demonstrated that strand growth pattern and the presence of FF are significant histopathological factors associated with initial BM. The combination of those predictive factors along with prognostic factors may provide a useful approach to identify patients at high risk for initial BM, enabling early treatment for the recurrent cancer.

Palliative operations for various bone metastases are being performed more frequently than before with the improvement of surgical technique and the development of new instruments. However, anesthesia in advanced cancer patients who are under palliative care accompanies inherent risks which are uncommon in general orthopaedic populations. Thus, we made a retrospective analysis of the medical records of 59 patients scheduled for palliative operation against metastatic bone lesions during the last 4 years. The survey revealed 5 cases of perioperative lethal events. Two of them died preoperatively from the hepatic failure and unexpected cerebral tumor embolism. An intraoperative cardiac arrest secondary to pulmonary embolism occurred in a patient during intramedullary nailing. There was a patient who developed disseminated intravascular coagulation and acute renal failure after posterior fixation of the lumbar vertebrae. The remaining one patient with superior vena cava syndrome developed life-threatening airway obstruction during general anesthesia with endotracheal intubation. We conclude that the exact evaluation of the patient's condition and the careful management of vital organ functions are mandatory during the perioperative period. In this regard, the anesthesiologists should be involved not only in the intraoperative anesthetic management but also in the perioperative care of the patients with bone metastasis.

From January 1990 to December 1995 we treated 35 patients (pts) with bone and soft tissue sarcoma with ifosfamide (IFM). Sixteen patients had measurable metastatic pulmonary lesion and 9 had primary lesion. Histology of the tumor included osteosarcoma in 13 pts, Ewing sarcoma in 5 pts, malignant fibrous histiocytoma of bone in 2 pts, synovial sarcoma in 7pts, primitive neuroectodermal tumor in 2 pts, and other in 7 pts. The IFM at the dose of 12-18g/m2 (mean 15. 4g/m2) for 5 to 8 days continuous infusion was administered to patients in each treatment course. The uroprotector, mesna, was also given concomitantly in 60-100% dose of IFM. Eighteen pts received one course of IFM treatment. Other pts received 2 to 8 courses of IFM treatment at three to four week intervals. The overall response rate was 40% (PR in 14 pts, NC in 18 pts, and PD in 3 pts). The response rate of 13 pts with osteosarcoma was 54% (PR in 7 pts) and 30% in 15 pts with soft tissue sarcoma (PR in 5 pts).

Primary Hodgkin's disease in the bone is extremely rare. We report the case of a 41-year-old woman with Hodgkin's disease, who had complained of left coxalgia 17 months prior to nodal involvement becoming evident clinically. She received combination chemotherapy with doxorubicin, bleomycin, vincristine and dacarbazine as well as radiotherapy to the pelvic lesion. Although the lymphadenopathy responded well to this treatment, the bone lesion was never in remission. The large mass of the bone lesion and its pelvic origin may explain the poor response to the cytotoxic therapies this patient received. The 22 cases reviewed showed that: 1, bony pain was the most frequent initial symptom; 2, nodal disease appeared in their clinical course in most cases; 3, the bones most commonly involved were pelvis, femur or tibia, and spine.

A total of 64 courses of ifosfamide (IFM) treatments for sarcoma patients were evaluated for toxic effects. A dose of 100 ml of 1/2 diluted Maalox by normal saline was instilled into urinary bladder with clump of catheter for 15 min for uroprotection instead of Mesna that was not available in Japan at that time. Forty-six courses of ifosfamide treatment in 12-16 g/m2 doses with daily Maalox instillation resulted only one hemorrhagic cystitis, while 18 courses at a dose of 6-10 g/m2 of IFM without Maalox eventuated in 5 cases of hemorrhagic cystitis. Forty-six courses of ifosfamide treatment at a dose of 12-16 g/m2 (mean dose of 14.4 g/m2) for 5 to 6 day continuous infusion were evaluated also for myelosuppression, nephrotoxicity, neurotoxicity, and other toxicities. Myelosuppression was acceptable, although the absolute neutrophil count of the 80% course was below 500. No patient showed neurotoxicity characterized by confusion or somnolence. No course resulted in abnormal serum creatinine elevation, although two of 46 courses caused an abnormal decrease of creatinine clearance. One patient had arrhythmia that required medical treatment after 5 courses of IFM treatment.

Serum levels of various hydrolytic enzymes in prostatic cancer patients with or without bone metastasis were compared with those in patients with prostatic hypertrophy and in the control subjects. The enzymes tested included 11 aminopeptidases, 2 endopeptidases, dipeptidyl carboxypeptidase, esterase, acetyl cholinesterase, and RNase. Although most of the enzymatic levels tended to be decreased in the cancer patients without bone metastasis, they tended to be increased in those with metastasis as well as in the patients with prostatic hypertrophy. Thus, bone metastasis is an important factor affecting the serum levels of hydrolytic enzymes in cancer patients. Of the enzymes tested, RNase was unique in that its serum levels were significantly increased regardless of the existence of bone metastasis. This enzyme may become a marker of malignancy.

Single photon emission computed tomography using newly designed whole body imaging system which was composed of opposing dual gamma cameras, a rotating gantry and a sliding table was clinically evaluated for bone imaging. Two hundred and seventeen portions of various bone diseases were performed single photon emission computed tomography following conventional bone imaging with 99mTc-MDP (methylen diphosphonate) or -HMDP (hydroxymethylene diphosphonate) and the results were discussed. Transaxial images were sometimes superior than conventional images in the diagnosis of the tumor localization and extension of the facial bone. Combination of emission computed tomography to conventional methods also presented more exact informations for the diagnosis of the vertebral change. Separation of the overlapped radioactivities of the bone and the soft tissue is another advantage of the tomographic image, and cross-sectional images with enoughly high qualities were available in early time after administration of 99mTc-phosphate compounds. Useful diagnostic informations could be obtained by tomographic bone imaging combined with conventional imagings.

Preoperative radiotherapy and systemic chemotherapy are effective for reducing the size of a tumor and rendering it resectable. The results achieved with systemic chemotherapy are ultimately reflected in improved survival. Moreover, limb-saving procedure in the treatment of osteosarcoma has become possible with rationality in carefully selected patients. Since 1975, 38 patients with osteosarcoma within an age range of 5 to 56 years, (average 17.9 years) have been treated by fast neutron radiotherapy, systemic chemotherapy and limb-salvage surgery. Twenty-two of these 38 patients underwent en bloc resection of the femur, eight resection of the proximal tibia and five resection of the proximal humerus. Only one of the 38 patients had evidence of local tumor recurrence and overall, 31 patients are currently alive without distant metastasis after 9 to 120 months follow-up. Preoperative fast neutron radiotherapy was employed and it was suggested that fast neutrons had a higher relative biological effectiveness and a greater therapeutic gain factor in comparison with X-rays. Fast neutron radiotherapy thus seems capable of playing a significant role in the treatment of osteosarcoma and is specifically useful for preservation of the affected limb.

Severe toxicity associated with high-dose methotrexate (HD-MTX) combined with citrovorum factor rescue (CR-Rescue) was evaluated in the 365 courses in 54 patients with osteosarcoma. Anaphylactoid reaction developed in 8 patients (14.8%), 8 courses (2.2%). The mean age was 14 years old. The total dose given was 85770mg in mean and 1840 mg per body weight (kg). The occurrence was proportional to the dose and the number of the course. Plasma MTX concentration remained under 10(-7) mol/l during the episode. Delayed clearance of MTX from plasma was treated with massive CF-Rescue in 10 patients (19%) (the mean age of 13.6), in 12 courses (3.3%), which was observed on an average at the 7th course when the total dose reached to 59530 mg, or 1390 mg per body weight (kg). Neurotoxicity was observed in only one patient (1.9%), one course (0.3%). Severe toxicity associated with HD-MTX therapy tended to occur according to dose escalation and the number of administration. To overcome severe toxicity careful observation of clinical symptoms and signs as well as adequate treatment of side effects without delay are of importance.

The pre-operative radiotherapy and systemic chemotherapy is effective in reducing the size of tumor and making the tumor resectable. The results achieved with systemic chemotherapy are ultimately reflected in improved survival. Moreover, limb-saving procedure in the treatment of osteosarcoma has become possible with rationality in carefully selected patients. Sixty-seven patients with osteosarcoma within a range of 5 to 27 years of age were treated at Chiba Cancer Center Hospital in the recent 12 year-duration. Seventeen of 67 patients underwent en bloc resection for osteosarcoma of the femur, (12 patients) and the tibia (5 patients). No patients had evidence of local recurrence of the tumor and overall 15 patients are alive without distant metastasis after 9 to 120 months follow-up. Based on the effective chemotherapy schedule, the limb salvation in the treatment of osteosarcoma is most desirable if it is indicated without risk of decreased radicality of the treatment.

Whole body distribution and accumulation of radionuclide for diagnostic purpose such as 99mTc-MDP (methylene diphosphonate), 67Ga-citrate (67Ga) and 201Tl-chloride (201Tl) in implanted osteosarcoma of human origin were evaluated by macroautoradiography of Balb/c nude mouse. 3H-thymidine of which uptake has a close relation to growth pattern of tumors was used for a partner of target nuclide in double tracer technique to examine the distribution characteristics. Separated distribution pattern of coupled nuclides was imaged by a difference both of half life and energy of radiation between radionuclides. The distribution pattern of each target nuclide and 3H-thymidine were compared to clarify distribution characteristics respectively in specimen. 67Ga and 201Tl were taken around the tumor and the mode of their distribution was identical to that of 3H-thymidine. Uptake of 67Ga in tumor was much higher. 99mTc-MDP accumulated in the central zone of the tumor and its pattern was quite different from that of 3H-thymidine. From above result it was demonstrated that the accumulation mechanism of 67Ga, 201Tl and 99mTc-MDP are quite different in the tumor each other. So we concluded that our method of double tracer technique was useful for evaluation of distribution pattern of radionuclides for diagnostic purpose.

A total of 31 patients with malignant bone and soft tissue tumors were evaluated for toxic effects after receiving cisplatin (104 courses) at doses of 2.0-3.0 mg/kg with aggressive hydration. Nausea was common and in 86% of cisplatin courses severe vomiting was observed. Nephrotoxicity was observed in less than 10% of all courses but ototoxicity, especially tinnitis, developed in 5 of 6 patients whose total doses of cisplatin were over 500mg, and one of them showed hearing disorder in the upper frequency above 5,000 Hz. There were no other toxic effects such as severe myelosuppression, allergic reaction or peripheral neuropathy.