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We encountered a case of metastatic renal cell carcinoma in which the serum level of KL-6, a therapeutic marker, was exceptionally high and fluctuated with the progression of treatment. A 74-year-old man was diagnosed with right renal cystic cancer and multiple metastases in October 2022. The KL-6 level was 27490 U/mL. He started treatment with lenvatinib and pembrolizumab. KL-6 decreased to 3885 U/mg in February 2023. The patient’s proteinuria worsened, leading to the discontinuation of lenvatinib. KL-6 increased to 25950 U/mL in April. He discontinued pembrolizumab and started taking cabozantinib. In September, drug-induced bilateral inflammatory pneumonitis developed. He discontinued cabozantinb and began taking axitinib. KL-6 decreased; however, he suffered from severe diarrhea and subsequent renal insufficiency. He discontinued axitinib in November. KL-6 increased to 29640 U/mL in December.

A 65-year-old man was diagnosed with bladder cancer invading the prostate and penis and multiple bone metastases. He underwent palliative radiation (30 Gy/10 fr) through vertebral bones (Th3 and Th12-L5) and pelvic bones for pain control. The patient received pembrolizumab therapy after three courses of gemcitabine and cisplatin therapy. CT four weeks after starting pembrolizumab therapy showed that both the primary and metastatic lesions had notably reduced in size, and no new lesion was detected. He subsequently fell, resulting in a femoral neck pathological fracture, and underwent hemiarthroplasty. Pathological examination of the pathological fracture site revealed no residual tumor tissue.

Abstract Background Near-falls should be detected to prevent falls related to the earlier ambulation after Total knee arthroplasty (TKA). The quadriceps weakness with femoral nerve block (FNB) has led to a focus on adductor canal block (ACB). We purposed to examine the risk of falls and the earlier ambulation in each continuous infusion nerve block. Methods Continuous infusion nerve block (FNB or ACB) was performed until postoperative day (POD) 2 or 3. Pain levels and falls/near-falls with knee-buckling were monitored from POD 1 to POD 3. The score on the manual muscle test, MMT (0 to 5, 5 being normal), of the patients who could ambulate on POD 1, was investigated. Results A total of 73 TKA cases, 36 FNB and 37 ACB, met the inclusion criteria. No falls were noted. But episodes of near-falls with knee-buckling were witnessed in 14 (39%) cases in the FNB group and in 4 (11%) in the ACB group (p = 0.0068). In the ACB group, 81.1% of patients could ambulate with parallel bars on POD 1, while only 44.4% of FNB patients could do so (p = 0.0019). The quadriceps MMT values in the ACB group was 2.82, significantly higher than 1.97 in the FNB group (p = 0.0035). There were no significant differences in pain as measured with a numerical rating scale (NRS) and rescue analgesia through POD 3. Conclusion ACB was associated with significantly less knee-buckling and earlier ambulation post-TKA, with better quadriceps strength. Our study indicated the incidence of falls and near-falls with continuous infusion nerve blocks, and support the use of ACB to reduce the risk of falls after TKA. It is suggested that a certain number of the patients even with continuous ACB infusion should be considered with the effect of motor branch to prevent falls.

Schwannomas consist of both high‐cellularity regions (Antoni A area) and hypocellular regions (Antoni B area) in histopathological findings. Neurofibromas characteristically consist of CD34 positive spindle cells with thin, wavy, nuclei and wavy collagen bands. Previous reports have described segments of schwannomas with neurofibroma features as hybrid tumors, although hybrid tumors were diagnosed based on partial CD34 positivity in many previous reports. On the other hand, the Antoni B area of some schwannomas was reported to be positive for CD34. Therefore, the definition of a hybrid tumor has not been clear. The objective of this study was to determine whether only CD34 positive findings in schwannomas could be used to define a hybrid tumor. In the analysis of our patient with schwannomatosis caused by a novel LZTR1 germline mutation, part of the tumor had CD34 positive hypocellular regions. These regions contained no thin, wavy, nuclei, indicating an Antoni B area. Laser microdissection was used to investigate the genetic background and differences in molecular mechanisms between CD34 positive and CD34 negative regions. All mutations identified in CD34 positive regions were also found in CD34 negative regions. Our data could not clear the genetic background of Antoni B which was CD34 positive area. We then reviewed the pathologies of 66 sporadic schwannomas. Histopathological examinations of all schwannomas revealed the absence of thin, wavy, nuclei and wavy collagen bands, and no hybrid tumors were found in any of the cases. Ten of 66 patients were randomly selected for CD34 immunostaining and positivity was found in all cases. Our data suggest that it is difficult to distinguish schwannomas by staining for CD34 alone, as Antoni B areas can also be positive for CD34. Therefore, CD34 staining alone should not be used to diagnose hybrid tumors in patients with schwannomas. [ABSTRACT FROM AUTHOR]

We encountered a case of metastatic renal cell carcinoma in which the serum level of KL‐6, a therapeutic marker, was exceptionally high and fluctuated with the progression of treatment. A 74‐year‐old man was diagnosed with right renal cystic cancer and multiple metastases in October 2022. The KL‐6 level was 27490 U/mL. He started treatment with lenvatinib and pembrolizumab. KL‐6 decreased to 3885 U/mg in February 2023. The patient's proteinuria worsened, leading to the discontinuation of lenvatinib. KL‐6 increased to 25950 U/mL in April. He discontinued pembrolizumab and started taking cabozantinib. In September, drug‐induced bilateral inflammatory pneumonitis developed. He discontinued cabozantinb and began taking axitinib. KL‐6 decreased; however, he suffered from severe diarrhea and subsequent renal insufficiency. He discontinued axitinib in November. KL‐6 increased to 29640 U/mL in December. [ABSTRACT FROM AUTHOR]

Background: T-cell receptor-engineered T-cell therapies have achieved promising response rates against synovial sarcoma in clinical trials, but their applicability is limited owing to the HLA matching requirement. Chimeric antigen receptor (CAR) can redirect primary T cells to tumor-associated antigens without requiring HLA matching. However, various obstacles, including the paucity of targetable antigens, must be addressed for synovial sarcoma. Ligands for natural killer (NK) cell-activating receptors are highly expressed by tumor cells. Methods: The surface expression of ligands for NK cell-activating receptors in synovial sarcoma cell lines was analyzed. We analyzed RNA sequencing data deposited in a public database to evaluate NKp44-ligand expression. Primary T cells retrovirally transduced with CAR targeting NKp44 ligands were evaluated for their functions in synovial sarcoma cells. Alterations induced by various stimuli, including a histone deacetylase inhibitor, a hypomethylating agent, inflammatory cytokines, and ionizing radiation, in the expression levels of NKp44 ligands were investigated. Results: : Ligands for NKp44 and NKp30 were expressed in all cell lines. NKG2D ligands were barely expressed in a single cell line. None of the cell lines expressed NKp46 ligand. Primary synovial sarcoma cells expressed the mRNA of the truncated isoform of MLL5, a known cellular ligand for NKp44. NKp44-based CAR T cells specifically recognize synovial sarcoma cells, secrete interferon-γ, and exert suppressive effects on tumor cell growth. No stimulus altered the expression of NKp44 ligands. Conclusion: NKp44-based CAR T cells can redirect primary human T cells to synovial sarcoma cells. CAR-based cell therapies may be an option for treating synovial sarcomas.

Abstract Background and aim The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management. Methods We investigated the effect of administering a low dose (1000 μM or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived 2-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS). Results Low-dose NAC (1000 μM) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 μM of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 μM) to RA-FLS suppressed MMP-3. Conclusions We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies.

Background: Synovial sarcoma is a rare malignant soft-tissue tumor that is prevalent in adolescents and young adults, and poor prognosis has been reported in patients with metastatic lesions. Chimeric antigen receptor (CAR) T-cell therapy is an emerging novel therapy for solid tumors; however, its application in synovial sarcoma has not yet been explored. Methods: A novel human epidermal growth factor receptor 2 (HER2)-targeted CAR containing scFv-FRP5, CD8α hinge and transmembrane domains as well as 4-1BB costimulatory and CD3ζ signaling domains was developed. Three synovial sarcoma cell lines that expressed the fusion transcript SS18-SSX1/2/4 were used in the study. Cytokine secretion assay, cytotoxicity assay, and real-time cell analysis experiments were conducted to confirm the function of T cells transduced with the CAR gene. Results: High cell-surface expression of HER2 was observed in all the cell lines. HER2-targeted/4-1BB-costimulated CAR T cells specifically recognized the synovial sarcoma cells, secreted interferon gamma and tumor necrosis factor alpha, and exerted cytotoxic effects in these cells. Conclusion: To the best of our knowledge, this is the first study to indicate that HER2-targeted CAR T cells are directly effective against molecularly defined synovial sarcoma cells. Furthermore, our findings might set the basis for developing improved CAR T cell-based therapies for chemo-refractory or relapsed synovial sarcoma.

A 65‐year‐old man was diagnosed with bladder cancer invading the prostate and penis and multiple bone metastases. He underwent palliative radiation (30 Gy/10 fr) through vertebral bones (Th3 and Th12‐L5) and pelvic bones for pain control. The patient received pembrolizumab therapy after three courses of gemcitabine and cisplatin therapy. CT four weeks after starting pembrolizumab therapy showed that both the primary and metastatic lesions had notably reduced in size, and no new lesion was detected. He subsequently fell, resulting in a femoral neck pathological fracture, and underwent hemiarthroplasty. Pathological examination of the pathological fracture site revealed no residual tumor tissue. [ABSTRACT FROM AUTHOR]

Abstract Background A solitary fibrous tumour (SFT) is an unusual neoplasm typically found in soft tissues. Although SFTs can arise in the bones, they very rarely arise in the vertebral arch. Here, we describe a case of a SFT that arose in the vertebral arch of the first lumbar (L1) spinal vertebrae and mimicked osteosarcoma. Case presentation A 49-year-old woman presented with a 2-month history of lower back pain and a lumbar region mass. Magnetic resonance imaging demonstrated a heterogeneously enhanced mass in the L1 vertebral arch. The patient received neoadjuvant chemotherapy, followed by a surgical procedure comprising an anterior spinal fusion and en bloc resection. Histologically, our initial diagnosis was osteosarcoma. The postoperative course was uneventful, and the patient received adjuvant chemotherapy. However, the tumour metastasised to the lung 5 years after the first surgery, and a second surgery was performed for lung tumour resection. The histology of the metastatic lung tumour appeared similar to that of the malignant SFT, and the specimen from the first surgery was re-examined. Immunohistochemically, the tumour was positive for STAT6. Reverse transcription-polymerase chain reaction revealed a NAB2-STAT6 fusion gene, thus confirming our final diagnosis of malignant SFT. The patient died of disease progression 8 years after the first surgery; however, there was no evidence of local recurrence. Conclusions Malignant SFT in the vertebral arch is extremely rare and very difficult to distinguish histologically an osteoid from lace-like collagen. STAT6 immunostaining is useful for distinguishing malignant SFTs from other neoplasms. Although it is difficult to completely resect a SFT arising from the spine, we demonstrated the feasibility of an en bloc resection of spinal tumours arising from posterior elements, without local recurrence.

The natural history of asymptomatic retroperitoneal schwannomas is poorly understood. This study aimed at investigating the natural history of incidental retroperitoneal schwannomas. The medical charts and imaging studies of 22 asymptomatic patients under observation for at least 12 months for retroperitoneal schwannomas were reviewed. The duration of follow-up ranged between 13 and 176 months (mean 48 months). In the 22 patients managed by the "wait and see" approach, the average tumor size at initial presentation was 51 mm, which increased to 57 mm at final follow-up. During the final follow-up, 2 patients required surgical treatment for tumor enlargement, while the remaining patients remained asymptomatic without surgery. The average growth rate of the tumors was 1.9 mm/year (range: -1.9 to 8.7 mm/year). The majority of asymptomatic retroperitoneal schwannomas demonstrate minimal growth and may be suitable for management with the "wait and see" approach.

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.