Efficacy and safety of denosumab de­escalation in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a locally aggressive intermediate bone tumor. Denosumab has shown effectiveness in GCTB treatment; however, the benefits of denosumab de-escalation for unresectable GCTB have not been well discussed. The present study investigated the efficacy and safety of denosumab de-escalation for GCTB. The medical records of 9 patients with unresectable GCTB or resectable GCTB not eligible for resection, who received de-escalated denosumab treatment at Okayama University Hospital (Okayama, Japan) between April 2014 and December 2021, were retrospectively reviewed. The denosumab treatment interval was gradually extended to every 8, 12 and 24 weeks. The radiographic changes and clinical symptoms during standard and de-escalated denosumab therapy were assessed. The denosumab interval was de-escalated after a median of 12 months of a standard 4-weekly treatment. Imaging showed that the re-ossification of osteolytic lesions obtained with the 4-weekly treatment were sustained with 8- and 12-weekly treatments. The extraskeletal masses reduced significantly with standard treatment, while tumor reduction was sustained during de-escalated treatment. During the 24-weekly treatment, 2 patients remained stable, while 2 patients developed local recurrence. The clinical symptoms improved significantly with standard treatment and remained improved during de-escalated treatment. There were severe adverse events including osteonecrosis of the jaw (2 patients), atypical femoral fracture (1 patient) and malignant transformation of GCTB (1 patient). In conclusion, 12-weekly de-escalated denosumab treatment showed clinical benefits as a maintenance treatment in patients with unresectable GCTB, in addition to sustained stable tumor control and improved clinical symptoms with standard treatment. A 24-weekly treatment can also be administered, with careful attention paid to detecting local recurrence.

Changes in Spinal Instability After Conventional Radiotherapy for Painful Vertebral Bone Metastases.

OBJECTIVE: Precise assessment of spinal instability is critical before and after radiotherapy (RT) for evaluating the effectiveness of RT. Therefore, we retrospectively evaluated the efficacy of RT in spinal instability over a period of 6 months after RT, utilizing the spinal instability neoplastic score (SINS) in patients with painful spinal metastasis. We retrospectively evaluated 108 patients who received RT for painful vertebral metastasis in our institution. Mechanical pain at metastatic vertebrae, radiological responses of irradiated vertebrae, and spinal instability were assessed. Follow-up assessments were done at the start of and at intervals of 1, 2, 3, 4, and 6 months after RT, with the pain disappearing in 67%, 85%, 93%, 97%, and 100% of the patients, respectively. The median SINS were 8, 6, 6, 5, 5, and 4 at the beginning and after 1, 2, 3, 4, and 6 months of RT, respectively. Multivariate analysis revealed that posterolateral involvement of spinal elements (PLISE) was the only risk factor for continuous potentially unstable/unstable spine at 1 month. In conclusion, there was improvement of pain, and recalcification results in regaining spinal stability over time after RT although vertebral body collapse and malalignment occur in some irradiated vertebrae. Clinicians should pay attention to PLISE in predicting continuous potentially unstable/unstable spine.

PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumours.

BACKGROUND: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. METHODS: PRRX1 expression in human Malignant peripheral nerve sheath tumours (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA-seq and structural prediction were used to identify proteins interacting with PRRX1. RESULTS: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2 A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumour malignancy-related gene sets including mTORC1, KRAS and SRC signalling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. CONCLUSION: Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through ß2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

Results of resection of forearm soft tissue sarcoma.

PURPOSE: Soft tissue sarcomas (STS) of the forearm are rare. We aim to assess their oncological and functional outcomes. METHODS: We retrospectively evaluated 34 patients who underwent surgical excision for forearm STS at our institution between 1993 and 2020. We analyzed postoperative Musculoskeletal Tumor Society rating scale (MSTS) and local recurrence-free survival (LRFS), metastasis-free survival, and overall survival (OS) rates. The significance of the following variables was determined: age, sex, histology, tumor size, Fédération Nationale des Centres de Lutte contre le Cancer grade, American Joint Committee on Cancer stage, surgical margin, unplanned excision, metastases upon initial presentation, receipt of chemotherapy, and radiotherapy (RT). RESULTS: The postoperative median MSTS score was 28. Bone resection or major nerve palsy was the only factor that influenced MSTS scores. The median MSTS scores in patients with or without bone resection or major nerve palsy were 24 and 29, respectively (P < 0.001). The 5-year LRFS rates was 87%. Univariate analysis revealed that the histological diagnosis of myxofibrosarcoma was the only factor that influenced LRFS (P = 0.047). The 5-year MFS rates was 71%. In univariate analysis, no factors were associated with MFS. The 5-year OS rates was 79%. Age was the only factor that influenced OS (P = 0.01). CONCLUSION: In the treatment of forearm STS, reconstruction of the skin and tendon can compensate for function, while bone resection and major nerve disturbance cannot. Careful follow-up is important, especially in patients with myxofibrosarcoma, due to its likelihood of local recurrence.

Vertebral body collapse after radiotherapy for spinal metastases.

Spinal metastases are common in patients with advanced stages of cancer and frequently cause vertebral body collapse (VBC). Although conventional radiotherapy (RT) is used for spinal metastases, the rates of occurrence of new VBC and progression of VBC at RT initiation have not been fully investigated. The present retrospective study assessed VBC and its associated risk factors after RT over time and evaluated new VBC and progression of VBC in patients who presented with VBC at RT initiation. The study evaluated 177 patients who received RT for vertebral metastases without paralysis between July 2012 and November 2016. Radiological responses of the irradiated vertebrae were assessed using computed tomography. Follow-up assessments were performed at RT initiation and 1, 2, 3, 4 and 6 months after RT. New VBC occurred in 12% of patients with no prior VBC within 1 month of RT. Multivariate analysis revealed that numeric rating scale (NRS) score (≥4) [relative risk (RR), 27.1; 95% confidence interval (CI), 1.86 to 394.9; P=0.016] was associated with the occurrence of new VBC at the 1 month follow-up time point. VBC progression occurred in 51% of the patients with collapse at RT initiation. Multivariate analysis revealed that bone quality (lytic metastases) (RR, 3.1; 95% CI, 1.28 to 7.70; P=0.013), NRS score (≥4) (RR, 3.0; 95% CI, 1.18 to 7.45; P=0.021) and tumor involvement of posterolateral elements of the spine (RR, 2.7; 95% CI, 1.03 to 7.29; P=0.04) were associated with the progression of VBC at the 1 month follow-up time point. The current study findings suggested that clinicians should pay attention to the factors that predict the occurrence of new VBC and VBC progression to ensure proper evaluation of conservative treatment effectiveness and facilitate the determination of patients who need close monitoring.

Effect of bacterium in the malignant wounds of soft tissue sarcoma.

Malignant wounds (MWs) are rare skin lesions, which accompany ulceration, necrosis and infection caused by infiltration or damage by malignant tumor. The present study aimed to investigate the bacterial etiology implicated in MW in soft tissue sarcoma (STS), and the effectiveness of culture-guided perioperative antibacterial administration. A retrospective evaluation was conducted on medical records of patients who presented with MW between 2006 and 2020. A total of seven patients were included in the present study, in whom all tumors were relatively large (>5 cm) and high-grade. Subsequently, five patients underwent limb-sparing surgery, and three patients had distant metastases with a 5-year overall survival of 71%. Preoperative microbiological sampling from the wound identified 11 different bacterial strains in five patients. The infections were polymicrobial with an average of 2.6 strains isolated per patient (1 aerobic, 1.6 anaerobic bacteria). They were predominantly methicillin-sensitive Staphylococcus aureus. Patients with MWs from STS reported symptoms, including bleeding (71%), exudation (71%) and malodorous wound (43%) at the initial presentation; these completely resolved after surgery. All but one patient reported pain at the MW site with an average numeric rating scale of 4.4 at presentation that decreased to 1.4 (P=0.14) and 0.6 (P=0.04) one and two weeks after surgery, respectively. The patients had elevated C-reactive protein (71%), anemia (57%), low albumin (86%) and renal/liver dysfunction (14-29%). One patient was diagnosed with sepsis. Surgical resection afforded symptomatic relief and resolution of abnormal laboratory values. Although selected antibiotics were administered in four patients based on the preoperative antibiotic sensitivity test, surgical site infection (SSI) occurred in three patients. Therefore, the effectiveness of the selected antibiotics based on the results of the preoperative culture in preventing SSI needs to be investigated in the future. In conclusion, physicians should keep in mind that although surgical resection can improve the symptoms and abnormal values in laboratory examination form MW, it is accompanied with a high rate of SSI and poor prognosis.

Clinicopathological and histological analysis of secondary malignant giant cell tumors of bone without radiotherapy.

Giant cell tumor of bone (GCTB) is an intermediate bone tumor that rarely undergoes malignant transformation. Secondary malignant GCTB (SMGCTB) is defined as a lesion in which high-grade sarcoma occurs at the site of previously treated GCTB. The present study retrospectively reviewed the medical records of patients with GCTB treated at Okayama University Hospital between April 1986 and April 2020. The clinicopathological and histological features of patients with SMGCTB without prior radiotherapy were investigated. A total of three patients (4%) with SMGCTB were detected, and the tumor sites were the distal ulna, distal femur and sacrum. Two of the patients had been treated with curettage and bone graft, and one had been treated with denosumab. In all cases, the lesions were made up of two components, the conventional GCTB component and the malignant component. The Ki67 labeling index was higher in the malignant components of SMGCTB and metastatic lesions compared with that in primary and recurrent conventional GCTB, or the conventional GCTB component of SMGCTB. Moreover, p53 expression was higher in these same components in patients who underwent curettage and bone grafting; however, there was no difference in the patient that received denosumab treatment. In this patient, clinical cancer genomic profiling revealed loss of CDKN2A, CDKN2B and MTAP expression. All three patients developed distant metastasis. The patients with SMGCTB in the ulna and femur died 13 and 54 months after detection of malignant transformation, respectively. The patient with SMGCTB in the sacrum received carbon-ion radiotherapy to the sacrum and pazopanib; the treatment was effective and the patient was alive at the last follow-up 3 years later. In conclusion, p53 may be associated with malignant transformation in GCTB. Future studies should investigate the association of between denosumab treatment and malignant transformation, as well as molecular targeted therapy to improve the clinical outcomes of SMGCTB.