Bilateral Upper Arm Granulomas Induced by Leuprorelin Acetate Injection Mimicking Malignant Soft Tissue Tumors: A Case Report.

Leuprorelin acetate is a common anticancer medication used for prostate cancer treatment. One of the local adverse reactions after leuprorelin injection is the development of reactive granulomas, typically presenting as subcutaneous nodules. In this case report, we describe a 73-year-old patient with prostate cancer who developed unusually large sized intramuscular reactive granulomas, which mimicked malignant soft tissue tumors. The patient, who had been receiving leuprorelin acetate treatment for the past 12 months, noticed painful masses in both upper arms. Based on the findings of magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography/computed tomography, a diagnosis of malignant soft tissue tumor was strongly suggested. However, further investigation through needle biopsy ultimately led us to the final diagnosis of reactive granuloma. The masses spontaneously resolved after discontinuation of leuprorelin injection. While reactive granulomas after leuprorelin injections are not rare, intramuscular cases are relatively uncommon. Despite using imaging studies as a rational initial approach in the diagnostic process, as we did in our case, their results turned out to be indistinguishable from those of malignant soft tissue tumors, thus highlighting the importance of pathological examination in confirming diagnosis, especially when a patient presents with atypical clinical manifestations.

What Are the Complication Rates and Factors Associated With Total Femur Replacement After Tumor Resection? Findings From the Japanese Musculoskeletal Oncology Group.

BACKGROUND: Patients undergoing massive tumor resection and total femur replacement (TFR) face a substantial risk of hip dislocation and infection, often resulting in multiple implant revisions or hip disarticulation. These complications can impact their independence and prognosis. Additionally, their shorter life expectancy is influenced by challenges in achieving local radical resection and controlling metastases. Identifying suitable candidates for TFR is vital, necessitating investigations into dislocation, infection, implant failure rates, local recurrence, overall survival, and associated factors. QUESTIONS/PURPOSES: (1) What is the postsurgical complication (hip dislocation and infection) rate and factors associated with postsurgical complications in patients who underwent TFR after tumor resection? (2) What is the local recurrence rate, implant failure rate, overall survival rate, and factors associated with local recurrence and implant failure? METHODS: We retrospectively evaluated 42 patients (median [range] age 47 years [10 to 79 years]) who underwent TFR and tumor resection at the time of the same surgical procedure between 1990 and 2020 at 12 registered institutions that specialized in tumor treatment in Japan. A total of 55% (23) of the patients were men, and 79% (33) had bone sarcoma. The median (range) follow-up period was 36.5 months (2 to 327 months). Of the 42 patients, 12% (5) were lost to follow-up before 2 years without meeting a study endpoint (postsurgical complications, revision, or amputation), and another 19% (8) died before 2 years with implants intact, leaving 69% (29) of the original group who had either follow-up of at least 2 years or met a study endpoint before the minimum surveillance duration. Another 10% (4) had a minimum of 2 years of follow-up but had not been seen in the past 5 years. Infection was defined as deep-seated infection involving soft tissues, bones, joints, and the area around the implant. We did not consider superficial infections. Implant failure was defined when a patient underwent reimplantation or amputation. The complication and implant failure rates were assessed by the cumulative incidence function method, considering competing events. The Kaplan-Meier method was used to estimate the overall survival rate. RESULTS: The 1-month, 6-month, 1-year, and 2-year dislocation rates were 5%, 12%, 14%, and 14%, respectively. The 1-month, 6-month, 1-year, and 2-year infection rates were 5%, 7%, 10%, and 15%, respectively. Multivariable analyses for hip dislocation and infection revealed that resection of the abductor muscles and large tumor size were positively associated with hip dislocation. The 6-month, 1-year, and 2-year local recurrence rates were 5%, 15%, and 15%, respectively. The 6-month, 1-year, 2-year, and 5-year implant failure rates were 5% (95% confidence interval 1% to 15%), 7% (95% CI 2% to 18%), 16% (95% CI 6% to 29%), and 16% (95% CI 6% to 29%), respectively. Multivariable analyses of local recurrence and implant failure that led to reimplantation or amputation revealed that a positive surgical margin was positively associated with local recurrence. The 1-year, 2-year, and 5-year overall patient survival rates were 95% (95% CI 87% to 102%), 77% (95% CI 64% to 91%), and 64% (95% CI 48% to 81%), respectively. CONCLUSION: Hip dislocation, infection, and local recurrence were frequently observed in patients who received massive tumor resection and TFR in our study, eventually leading to reimplantation or amputation. Preserving the abductor muscles and resecting the tumor with a wide margin can prevent postoperative dislocation and local recurrence. Future research should focus on patient selection criteria, prevention of hip dislocation, and innovative treatments. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Multiple Recurrent Atypical Lipomatous Tumors/Well-Differentiated Liposarcomas and Dedifferentiated Liposarcomas Treated with Multiple Surgical Resections: A Case Report.

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS) is usually a solitary adipocytic tumor. ALT/WDLPS shows no potential for metastasis unless it undergoes dedifferentiation. No case of multiple ALT/WDLPS has been reported in recent years. We present a rare case of multiple recurrent liposarcomas. A 71-year-old man with a history of scrotal ALT/WDLPS at 61 years presented with multiple large tumors spread throughout the body. The patient was bedridden and severely limited in his activities of daily living (ADL) due to multiple large tumors in the trunk and lower extremities. Radiological examination revealed multiple adipocytic tumors, mainly in the soft tissues of the trunk and extremities, with several visceral lesions. Tumors were resected in stages, starting with large tumors directly related to disability. Repeated palliative resections improved the patient's ADL; he regained ambulation and was discharged 18 months after admission. Twelve surgeries were performed to remove 44 adipocytic tumors from the testis, left chest wall, perigastric area, ileum, left inguinal region, both buttocks, thighs, and lower legs. Histological examination revealed dedifferentiated components in five tumors, while 39 tumors were diagnosed as ALT/WDLPS. At the age of 76 years, the patient developed an unresectable dedifferentiated liposarcoma between the heart and aorta, leading to fatality at 79 years. The patient's clinical course suggested multiple metastases of ALT/WDLPS of scrotal origin or ALT/WDLPS of multicentric origin. Although multicentric ALT/WDLPS or ALT/WDLPS metastases are rare, they should be considered when multiple large adipocytic tumors are found throughout the body. Despite the presence of numerous large malignant tumors, surgical treatments of the lesions can improve ADL and prolong life if the tumors are of low-grade malignancy.

Additional Wide Resection of Infantile Dermatofibrosarcoma Protuberans after Unplanned Excision: A Case Report.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive intermediate soft tissue neoplasm that occurs in the dermis. DFSP generally occurs in young to middle-aged adults and rarely in infancy. Because of its extreme rarity, DFSP is difficult to diagnose and treat, especially when it occurs in infancy. In this paper, we reported a case of infantile DFSP in which we performed additional wide resection with a 3-cm horizontal margin for a mass that had previously undergone unplanned excision. No tumor recurrence has been seen for 3 years postoperatively. We suggest that the possibility of DFSP should always be considered when an enlarging superficial mass is identified on the trunk, even in an infant. Additionally, radical local treatment is as important for DFSP in infancy as it is for DFSP in adults, even after unplanned excision.

Intramedullary osteoid osteoma in the humerus of a toddler-A case report and review of the literature.

Osteoid osteoma (OO) is a benign osteoblastic tumor characterized by nocturnal pain that responds well to non-steroidal anti-inflammatory drugs. This condition commonly affects adolescents and young adults, and patients between 5 and 24 years of age account for 85% of all OO cases; it occurs very rarely in patients under 5 years old. Tumors often occur in the cortical bone in the diaphysis and metaphysis of the appendicular skeleton and are more common in the lower extremities than upper extremities. Here, we present an extremely rare case of intramedullary OO that arose in the proximal metaphysis of the humerus in a 2-year-old boy, which mimicked subacute osteomyelitis on imaging studies. We also conducted a retrospective literature review and found that the intramedullary location was fairly common in very young patients (<6 years old) with OO.

Recurrent malignant peripheral nerve sheath tumor presenting as an asymptomatic intravenous thrombus extending to the heart: a case report.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma mainly treated via surgical resection. Herein, we report a case of MPNST wherein a massive tumor thrombus extended to the major veins and heart. CASE PRESENTATION: A 39-year-old female with a history of neurofibromatosis type 1 developed MPNST from the right radial nerve. In addition to adjuvant chemotherapy, she underwent wide tumor resection and concomitant radial nerve resection, followed by postoperative radiotherapy. Histological evaluation revealed marked venous invasion. The 2-year follow-up CT revealed an asymptomatic recurrent tumor thrombus extending from the right subclavian vein to the heart. An urgent life-saving operation was performed to ligate the base of the right subclavian vein and remove the entire intravenous thrombus that extended to the right ventricle. The remaining tumor in the right subclavian vein increased in size 3 months after thrombectomy. After confirming the absence of any metastatic lesions, the patient underwent extended forequarter amputation to achieve surgical remission. One year later, a new metastasis to the right diaphragm was safely resected. The patient remains alive without any evidence of disease 2 years after the extended forequarter amputation. CONCLUSIONS: In cases of a previous history of microscopic venous invasion, recurrence can occur as a massive tumor thrombus that extends to the great vessels.

Multiple myeloma cells induce lipolysis in adipocytes and uptake fatty acids through fatty acid transporter proteins.

Adipocytes occupy 70% of the cellular volume within the bone marrow (BM) wherein multiple myeloma (MM) originates and resides. However, the nature of the interaction between MM cells and adipocytes remains unclear. Cancer-associated adipocytes support tumor cells through various mechanisms, including metabolic reprogramming of cancer cells. We hypothesized that metabolic interactions mediate the dependence of MM cells on BM adipocytes. Here we show that BM aspirates from precursor states of MM, including monoclonal gammopathy of undetermined significance and smoldering MM, exhibit significant upregulation of adipogenic commitment compared with healthy donors. In vitro coculture assays revealed an adipocyte-induced increase in MM cell proliferation in monoclonal gammopathy of undetermined significance/smoldering MM compared with newly diagnosed MM. Using murine MM cell/BM adipocyte coculture assays, we describe MM-induced lipolysis in adipocytes via activation of the lipolysis pathway. Upregulation of fatty acid transporters 1 and 4 on MM cells mediated the uptake of secreted free fatty acids (FFAs) by adjacent MM cells. The effect of FFAs on MM cells was dose dependent and revealed increased proliferation at lower concentrations vs induction of lipotoxicity at higher concentrations. Lipotoxicity occurred via the ferroptosis pathway. Exogenous treatment with arachidonic acid, a very-long-chain FFA, in a murine plasmacytoma model displayed a reduction in tumor burden. Taken together, our data reveal a novel pathway involving MM cell-induced lipolysis in BM adipocytes and suggest prevention of FFA uptake by MM cells as a potential target for myeloma therapeutics.

Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation.

MYC upregulation is associated with multidrug refractory disease in patients with multiple myeloma (MM). We, isolated patient-derived MM cells with high MYC expression and discovered that NCOR2 was down-regulated in these cells. NCOR2 is a transcriptional coregulatory protein and its role in MM remains unknown. To define the role of NCOR2 in MM, we created NCOR2 knockout human myeloma cell lines and demonstrated that NCOR2 knockout led to high MYC expression. Furthermore, NCOR2 knockout conferred resistance to pomalidomide, BET and HDAC inhibitors, independent of Cereblon (CRBN), indicating high MYC expression as a cause of multidrug resistance. Moreover, NCOR2 interacted with the nucleosome remodeling and deacetylase (NuRD) complex and repressed the expression of CD180 by directly binding to its promoter and inducing MYC expression. Next, we generated lenalidomide-resistant and pomalidomide-resistant human myeloma cell lines. Whole-exome sequencing revealed that these cell lines acquired the same exonic mutations of NCOR2. These cell lines showed NCOR2 downregulation and MYC upregulation independent of CRBN and demonstrated resistance to BET and HDAC inhibitors. Our findings reveal a novel CRBN independent molecular mechanism associated with drug resistance. Low NCOR2 expression can serve as a potential biomarker for drug resistance and needs further validation in larger prospective studies.

Necessity of Flanking Repeats R1' and R8' of Human Pumilio1 Protein for RNA Binding.

Human Pumilio (hPUM) is a structurally well-analyzed RNA-binding protein that has been used recently for artificial RNA binding. Structural analysis revealed that amino acids at positions 12, 13, and 16 in the repeats from R1 to R8 each contact one specific RNA base in the eight-nucleotide RNA target. The functions of the N- and C-terminal flanking repeats R1' and R8', however, remain unclear. Here, we report how the repeats contribute to overall RNA binding. We first prepared three mutants in which R1' and/or R8' were deleted and then analyzed RNA binding using gel shift assays. The assays showed that all deletion mutants bound to their target less than the original hPUM, but that R1' contributed more than R8', unlike Drosophila PUM. We next investigated which amino acid residues of R1' or R8' were responsible for RNA binding. With detailed analysis of the protein tertiary structure, we found a hydrophobic core in each of the repeats. We therefore mutated all hydrophobic amino residues in each core to alanine. The gel shift assays with the resulting mutants revealed that both hydrophobic cores contributed to the RNA binding: especially the hydrophobic core of R1' had a significant influence. In the present study, we demonstrated that the flanking R1' and R8' repeats are indispensable for RNA binding of hPUM and suggest that hydrophobic R1'-R1 interactions may stabilize the whole hPUM structure.

Genome sequence analysis of new plum pox virus isolates from Japan.

OBJECTIVE: To find mutations that may have recently occurred in Plum pox virus (PPV), we collected six PPV-infected plum/peach trees from the western part of Japan and one from the eastern part. After sequencing the full-length PPV genomic RNAs, we compared the amino acid sequences with representative isolates of each PPV strain. RESULTS: All new isolates were found to belong to the PPV-D strain: the six isolates collected from western Japan were identified as the West-Japan strain while the one collected from eastern Japan as the East-Japan strain. Amino acid sequence analysis of these seven isolates suggested that the 1407th and 1529th amino acid residues are characteristic of the West-Japan and the East-Japan strains, respectively. Comparing them with the corresponding amino acid residues of the 47 non-Japanese PPV-D isolates revealed that these amino acid residues are undoubtedly unique. A further examination of the relevant amino acid residues of the other 210 PPV-D isolates collected in Japan generated a new hypothesis regarding the invasion route from overseas and the subsequent diffusion route within Japan: a PPV-D strain might have invaded the western part of Japan from overseas and spread throughout Japan.

Establishment and characterization of novel patient-derived cell lines from giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a locally aggressive and rarely metastasizing tumor. GCTB is characterized by the presence of unique giant cells and a recurrent mutation in the histone tail of the histone variant H3.3, which is encoded by H3F3A on chromosome 1. GCTB accounts for ~ 5% of primary bone tumors. Although GCTB exhibits an indolent course, it has the potential to develop aggressive behaviors associated with local recurrence and distant metastasis. Currently, complete surgical resection is the only curative treatment, and novel therapeutic strategies are required. Patient-derived cancer cell lines are critical tools for basic and pre-clinical research. However, only a few GCTB cell lines have been reported, and none of them are available from public cell banks. Therefore, we aimed to establish novel GCTB cell lines in the present study. Using curetted tumor tissues of GCTB, we established two cell lines and named them NCC-GCTB2-C1 and NCC-GCTB3-C1. These cells harbored a typical mutation in histones and exhibited slow but constant growth, formed spheroids, and had invasive capabilities. We demonstrated the utility of these cell lines for high-throughput drug screening using 214 anticancer agents. We concluded that NCC-GCTB2-C1 and NCC-GCTB3-C1 cell lines were useful for the in vitro study of GCTB.

Development of a method to rapidly assess resistance/susceptibility of Micro-Tom tomatoes to Tomato yellow leaf curl virus via agroinoculation of cotyledons.

OBJECTIVE: Tomato yellow leaf curl virus (TYLCV) is one of the pathogens severely damaging tomato crops. Therefore, methods to treat or prevent TYLCV infection need to be developed. For this purpose, a method to conveniently and quickly assess infection of tomatoes by TYLCV is desired. In the present study, we established a quick method to evaluate TYLCV infection using cotyledons of Micro-Tom, a miniature tomato cultivar. RESULTS: First, we constructed a binary plasmid harboring 1.5 copies of the TYLCV genome and transformed Agrobacterium with the plasmid. By injecting agroinoculum from the resulting transformant into the branches of Micro-Tom, we confirmed the susceptibility of Micro-Tom to TYLCV. To shorten the evaluation process of TYLCV infection further, we agroinoculated cotyledons of Micro-Tom 10 days after sowing seeds. We consistently observed typical symptoms of TYLCV infection on true leaves 10 days after agroinoculation. Molecular analysis detected TYLCV progeny DNA in all leaves demonstrating symptoms 6 days after agroinoculation. Therefore, our new protocol enabled assessment of TYLCV infection within 20 days after sowing seeds. Thus, agroinoculation of Micro-Tom cotyledons will accelerate the process of screening TYLCV-resistant Micro-Toms and enable screening of larger numbers of plants more quickly, contributing to the development of TYLCV-resistant tomatoes.

Prognostic factors of metastatic myxoid liposarcoma.

BACKGROUND: Myxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis. METHODS: This retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined. RESULTS: Lung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED. CONCLUSIONS: This is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.

A multidisciplinary approach to soft-tissue sarcoma of the extremities.

INTRODUCTION: Soft-tissue sarcoma (STS) denotes a group of rare and highly heterogeneous malignant tumors of mesenchymal origin. Accurate histological diagnosis is critical for selecting appropriate treatment. Complete tumor resection is the primary treatment for STS, and the efficacies of radiotherapy and chemotherapy have been tested in the adjuvant setting to improve oncological outcomes. Because most STS lesions arise in the extremities, preserving limb function and managing limb impairment after radical local treatment represent significant challenges. AREAS COVERED: This article reviews the current front-line treatments for patients with extremity STS and discusses the multidisciplinary team-based efforts needed to improve oncological outcomes and survivorship. EXPERT OPINION: Given the rarity, variety, and complexity of STS, a multidisciplinary approach involving experts in various disciplines is vital for improving outcomes in patients ranging from diagnosis to survivorship. A major challenge is building a sustainable system in each region permitting all patients with extremity STS to be treated at high-volume centers with multidisciplinary teams dedicated to this rare and complex disease.

A Rare Case of Elongated Styloid Process Fracture.

BACKGROUND An elongated styloid process occurs with Eagle syndrome and causes a variety of symptoms. Fracture of the elongated styloid process is a rare condition. With spontaneous fractures, appropriate treatment cannot be performed in many cases due to unexplained symptoms and indefinite complaints that are not thoroughly examined. CASE REPORT We encountered a case of fractured elongate styloid process reaching the hyoid bone. Based on the findings from cervical 3-dimensional computed tomography (3D-CT), we chose surgery using the transcervical approach instead of the intraoral approach. Symptoms resolved following surgery. CONCLUSIONS A fractured styloid process is a rare event, but it needs to be recognized. If drug therapy does not work, surgical treatment is needed and has been shown to be effective. Surgical therapies include an intraoral approach and a transcervical approach. In the case presented here, 3D-CT was very useful for diagnosis and surgery selection.