Effects of selective cyclooxygenase-2 inhibitor robenacoxib on primary cells derived from feline injection-site sarcoma.

Feline injection-site sarcomas (FISSs) are highly invasive malignant mesenchymal neoplasms that arise from injection sites in cats. Although the tumorigenesis of FISSs is still uncertain, there is a consensus that FISS is associated with chronic inflammation caused by irritation of injection-related trauma and foreign chemical substances. Chronic inflammation can provide a proper microenvironment for tumour development, which has been known as one of the risk factors of tumorigenesis in many tumours. To investigate the tumorigenesis of FISS and screen for its potential therapeutic targets, cyclooxygenase-2 (COX-2), an inflammation-enhancing enzyme, was selected as a target for this study. In vitro experiments using FISS- and normal tissue-derived primary cells and robenacoxib, a highly selective COX-2 inhibitor, were performed. The results demonstrated that expression of COX-2 could be detected in formalin-fixed and paraffin-embedded FISS tissues and FISS-derived primary cells. Cell viability, migration and colony formation of FISS-derived primary cells were inhibited, and cell apoptosis was enhanced by robenacoxib in a dose-dependent manner. However, susceptibility to robenacoxib varied in different lines of FISS primary cells and was not completely correlated with COX-2 expression. Our results suggest that COX-2 inhibitors could be potential adjuvant therapeutics against FISSs.

Investigating the role of signal transducer and activator of transcription 3 in feline injection site sarcoma.

BACKGROUND: Feline injection-site sarcomas (FISSs) are malignant mesenchymal tumors of different histotypes. The pathogenesis of FISS has been correlated with chronic inflammation, resulting in neoplastic transformation. Activation of the Janus kinase-signal transducer and activator of transcription 3 (STAT3) have been demonstrated to play a critical role in tumor development by regulating signaling pathways involved in cell proliferation, survival, metastasis, and angiogenesis in human medicine. To characterize the role of STAT3 in FISS, we first detected STAT3 and phosphorylated STAT3 in formalin-fixed and paraffin-embedded (FFPE) FISS tissues using immunohistochemical staining. RESULTS: STAT3 was detected in 88.9% (40/45) of FISS cases, and phosphorylated STAT3 was detected in 53.3% (24/45) of cases. However, the expression levels of both forms of STAT3 were not correlated with tumor grade. To study the role of STAT3 in tumor survival, two primary cells derived from FISSs of two cats exhibiting consistent immunophenotypes with their parental FFPE tissues were established. A dose-dependent inhibitory effect on cell proliferation was observed in both primary FISS cells treated with the STAT3 inhibitor, 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide. CONCLUSIONS: The STAT 3 may play an important role in the tumorigenesis of FISS and be a potential molecular therapeutic target for FISS.

The Risk of Tumor Contamination Associated With Thoracic Instrumentation in Patients With Osteosarcoma: 2 Case Reports and a Literature Review.

Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteosarcoma. However, tumor contamination in patients with osteosarcoma associated with thoracic instrumentation is not well described. The authors summarize 2 reported cases in addition to the 2 cases at their institution of this phenomenon. Knowledge of tumor contamination and preventative measures against tumor contamination is sparse in the literature, especially pertaining to patients with osteosarcoma undergoing thoracic instrumentation. In this report, the authors hope to increase awareness of these cases and suggest preventative measures to mitigate against tumor contamination in patients with osteosarcoma. The authors report that the median time between thoracic instrumentation and the visible detection of tumor migration to local sites was 5 months. They conclude that tumor contamination associated with thoracic instrumentation is characterized by patients with multiple sites of relapse and aggressive, fatal disease.

Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience.

BACKGROUND: The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context. METHODS: Here, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019. RESULTS: Median progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6-16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD. CONCLUSIONS: This single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS.

Fluorescence-guided resection in bone and soft tissue infiltrating meningiomas.

BACKGROUND: Bone infiltration of the tumour is common in meningioma surgery. This may also affect patients without indicative signs of bone infiltration on preoperative imaging. Unrecognized bone invasion may lead to higher recurrence rates. 5-ALA fluorescence-guided resection (5-ALA-fg) could be a promising tool to help recognize possible bone invasion and/or tumour remnants. However, there is still little data about 5-ALA-fg resection in bone and soft tissue infiltrating meningiomas. METHODS: We performed a retrospective study of 11 patients who were operated with the aid of 5-ALA due to bone and soft tissue infiltrating meningiomas at the University Hospital of St. Poelten between 2013 and 2019. RESULTS: Strong and homogeneous fluorescence of the meningioma was observed in 9 cases (81.8%) and vague and heterogeneous fluorescence in 2 cases (18.2%). Hyperostosis on computerized tomography was evident in 3 of 6 cases (50%) and bone infiltration was visible in preoperative magnetic resonance imaging in 7 of 11 patients (63.6%). All eleven patients showed positive fluorescence of the bone infiltrating part. In all 7 cases where tissue could be collected, histopathological testing verified tumour infiltration (100%). There was also fluorescence of the periosteum in 3 cases and histopathological testing verified tumour infiltration in 100%. CONCLUSION: There is growing evidence that 5-ALA-fg resection can help to identify bone infiltration in meningioma surgery. Therefore, it may help to improve extent of resection. However, further studies are necessary to investigate the rate of false-negative fluorescence and its effect on progression free survival. If 5-ALA-fg resection of meningioma is performed, the attending surgeon should also consider investigating the adjacent periosteum under blue light for detection of possible fluorescence.

Best Practice Approach for Assessment of Microchip-associated Tumors in Preclinical Safety Studies: Position of the Registry of Industrial Toxicology Animal-data (RITA).

Microchip (passive radio-frequency identification device) implantation is a common and widely employed means of animal identification in laboratory animal facilities. However, these devices have been associated with tumors of the skin and subcutis in rodents. While microchip-associated tumors are rare, they pose a challenge for accurate diagnosis and documentation in preclinical toxicity studies. Documentation of these tumors should differentiate microchip-associated lesions with spontaneously occurring or test article-induced tumors. Standardizing criteria for microchip-associated lesions will aid the diagnostic process and allow for preclinical regulatory standardization. To this end, the Registry of Industrial Toxicology Animal-data have developed clear recommendations for diagnosis and documentation of microchip-associated lesions.

Symptomatic Neuroma Following Initial Amputation for Traumatic Digital Amputation.

PURPOSE: We tested the null hypothesis that no factors are independently associated with the development of symptomatic neuroma after traumatic digital amputation. METHODS: We performed a retrospective review of 1,083 patients who underwent revision amputation for traumatic digital amputation; we excluded those undergoing replantation or revascularization. Patients who developed a painful neuroma during follow-up were identified with a minimum follow-up of 1 week and a median of 3.3 months. We calculated the rate of developing a painful neuroma as a proportion of the total number of patients and performed multivariable logistic regression analysis to identify factors independently associated with its development. RESULTS: Of 1,083 patients, 71 (6.6%) developed a symptomatic neuroma. Mean time to diagnosis was 6.4 months. A total of 47 patients (66%) underwent surgery for painful neuroma. Mean time to surgical intervention was 11 months. Index finger injury and avulsion injury mechanism were significantly associated with a higher risk for symptomatic neuroma. CONCLUSIONS: Approximately 1 in 15 patients will develop a symptomatic neuroma after traumatic digital amputation and more than half of these patients will undergo revision surgery for neuroma, with a mean time to operative intervention of 11 months. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Current Concepts in Upper-Extremity Amputation.

Advances in motor vehicle safety, trauma care, combat body armor, and cancer treatment have enhanced the life expectancy and functional expectations of patients with upper-extremity amputations. Upper-extremity surgeons have multiple surgical options to optimize the potential of emerging prosthetic technologies for this diverse patient group. Targeted muscle reinnervation is an evolving technique that improves control of myoelectric prostheses and can prevent or treat symptomatic neuromas. This review addresses current strategies for the care of patients with amputations proximal to the wrist with an emphasis on recent advancements in surgical techniques and prostheses.

Treatment of cutaneous and/or soft tissue manifestations of corticosteroids refractory chronic graft versus host disease (cGVHD) by a total nodal irradiation (TNI).

The management of corticosteroids refractory chronic graft versus host disease (cGVHD) remains controversial. Retrospective analysis of patients treated at the Integrated Center of Oncology by total nodal irradiation (TNI) was performed to evaluate its therapy potency. TNI delivers a dose of 1 Gy in a single session. The delimitation of the fields is clinical (upper limit: external auditory meatus; lower limit: mid-femur). No pre-therapeutic dosimetry scanner was necessary. Evaluation of the efficacy was by clinical measures at 6 months after the treatment. Twelve patients were treated by TNI between January 2010 and December 2013. TNI was used in second-line treatment or beyond. The median time between allograft and TNI was 31.2 months, and the median time between the first manifestations of cGVHD and TNI was about 24.2 months. Of the 12 patients, nine had a clinical response at 6 months (75%), including five complete clinical responses (41.6%). Five patients could benefit from a reduction of corticosteroid doses. Three patients had hematologic toxicity. TNI could be considered as an option for the treatment of a cutaneous and/or soft tissues corticosteroids refractory cGVHD. However, prospective randomized and double-blind trials remain essential to answer the questions about TNI safety and effectiveness.

Traumatic Facial Myopericytoma: A Differential to Consider.

Myopericytoma is a slow-growing, benign soft tissue neoplasm that arises from perivascular smooth muscle cells. This tumor is a rare entity itself, but it is only scarcely mentioned in the literature occurring secondary to trauma. The authors report a 21-year-old male patient who presented with a pulsatile mass in the medial canthal area where he had experienced previous trauma from a car accident 1-year prior. The mass was excised and histopathology revealed myopericytoma. This clinical report adds to the limited body of evidence supporting trauma as an etiology for this rare tumor.

The animal-dependent risk factors in canine osteosarcomas.

Canine osteosarcoma (OSA) is a malignant neoplastic tumor, which develops from the primitive mesenchymal stem cell, that has or can acquire the capacity to produce neoplastic osteoid with possible neoplastic bone formation. Predisposition of some dog breeds to OSA indicates genetic background of oncogenesis. The aim of the study was to characterize animal-dependent risk factors for canine osteosarcoma development in Poland. The study was conducted on canine patients diagnosed cytologically or histopathologically as having OSA, and data on age, breed, sex, as well as tumor location and character were recorded. No sex predisposition to OSA was observed, mongrels were significantly underrepresented. Large and giant dogs accounted for 47% and 35% of all pedigree dogs, respectively, and both proved predisposed to OSA. A vast majority of OSA developed in the skeleton (appendicular skeleton was more commonly affected than axial skeleton), soft tissues were affected less often. Rottweiler dogs are strongly predisposed to OSA, suggesting that the genetic background is involved in the tumor development, and indicates that dogs of this breed are a promising object for further studies on OSA pathogenesis.

Pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia of the left lower extremity in a 14-year-old female: a case report.

BACKGROUND: Pseudomyogenic hemangioendothelioma is a rare soft tissue tumor usually found in young adults, predominantly males. Fibrous dysplasia is a common benign bone tumor, which accounts for 5~7 % of all the primary benign bone tumors. However, pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia is extremely rare. To the best of our knowledge, this is the first case of pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia. CASE PRESENTATION: This study describes a case of a 14-year-old female who suffered from pseudomyogenic hemangioendothelioma secondary to fibrous dysplasia of the left lower extremity. The patient underwent two operations successively due to pathological fractures in the left femur and tibia in a local hospital. She was diagnosed with fibrous dysplasia according to the postoperative pathological examinations. However, less than 1 year later, she was diagnosed with a recurrence of fibrous dysplasia in her left femur during a follow-up in our hospital. She underwent a curettage and grafting in the left femur. Postoperative pathological examinations demonstrated the diagnosis of fibrous dysplasia. Nevertheless, she presented to our clinic with a chief complaint of pain and swelling in her left tibia and calcaneus 4 months later. The patient underwent fine-needle aspiration in her left tibia. According to the histological and immunohistochemical findings, the diagnosis of pseudomyogenic hemangioendothelioma was confirmed by an expert pathology consultant. Finally, the patient had to undergo an amputation of the left thigh. Postoperative pathological examinations confirmed the diagnosis of pseudomyogenic hemangioendothelioma. Postoperative follow-up at 3 months disclosed no evidence of recurrent disease and no residual side effects from therapy. CONCLUSIONS: Pseudomyogenic hemangioendothelioma is a rare endothelial neoplasm which often mimics myoid and epithelioid tumors morphologically. For the diagnosis, the immunostaining is very important but not decisive and enough. Analysis based on any single factor or incomplete information may easily lead to arbitrary conclusion. Clinical information including age, gender, tumor location, disease course, and recurrence is important for appropriate diagnosis, and full understanding of the tumor is indispensable.

Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma.

BACKGROUND: We previously determined that radiation could be safely administered using a mouse-flank in vivo model to both alveolar (Rh30) and embryonal (Rh18) rhabdomyosarcoma xenografts. Mice from both tumor lines in this experiment developed metastases, an event not previously described with these models. We sought to determine if radiation-induced changes in gene expression underlie an increase in the metastatic behavior of these tumor models. PROCEDURE: Parental Rh18 and Rh30 xenografts, as well as tumor that recurred locally after radiotherapy (Rh18RT and Rh30RT), were grown subcutaneously in the flanks of SCID mice and then subjected to either fractionated radiotherapy or survival surgery alone. Metastasis formation was monitored and recorded. Gene expression profiling was also performed on RNA extracted from parental, recurrent, and metastatic tissue of both tumor lines. RESULTS: Rh30 and Rh30RT xenografts demonstrated metastases only if they were exposed to fractionated radiotherapy, whereas Rh18 and Rh18RT xenografts experienced significantly fewer metastatic events when treated with fractionated radiotherapy compared to survival surgery alone. Mean time to metastasis formation was 40 days in the recurrent tumors and 73 days in the parental xenografts. Gene expression profiling noted clustering of Rh30 recurrent and metastatic tissue that was independent of the parental Rh30 tissue. Rh18RT xenografts lost radiosensitivity compared to parental Rh18. CONCLUSION: Radiation therapy can significantly decrease the formation of metastases in radio-sensitive tumors (Rh18) and may induce a more pro-metastatic phenotype in radio-resistant lines (Rh30).

Epidemiological and morphological analysis of feline injection site sarcomas.

Feline injection site sarcomas (FISS) are malignant neoplasms of mesenchymal origin which arise in sites of injections in cats. The prevalence is estimated between 1 in 1000 and 1 in 10 000 vaccinations in the United Kingdom. The aim of this study was to estimate the incidence of FISS in Poland and to analyse clinical aspects and histological and cytological features of injection site sarcomas. In our study the prevalence of FISS was 0.16% (16 FISS on 10.000 of cats) in feline patients in one of a veterinary surgery which conducts the general practice and 85 on 10.000 cats in a practice focused on veterinary oncology. The most typical microscopic features of FISS found in the present analysis were: the presence of perilesional scarring and inflammation, aggregates of lymphocytes at the tumour periphery, moderate but usually marked cellular pleomorphism and intralesional necrosis. The most typical cytologic features of FISS found in present study were: the presence of neutrophils, marked cellular pleomorphism, the presence of lymphocytes and macrophages, the presence of extremely large nuclei in the neoplastic cells, and high sample cellularity.

Syndrome-associated soft tissue tumours.

Soft tissue neoplasms may be associated with a variety of genetic disorders and malformation syndromes, especially when they arise in children, adolescents and early adulthood. This review summarizes the principal histopathological types of soft tissue tumours which occur in various syndromes, with an emphasis on pathological features, genetic aspects and considerations for the diagnostic pathologist.

Sirolimus for non-progressive NF1-associated plexiform neurofibromas: an NF clinical trials consortium phase II study.

BACKGROUND: Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamycin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity. PROCEDURE: We conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry. RESULTS: No subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus. CONCLUSIONS: This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes.

Pachydermodactyly: a review.

Synovitis is the characteristic feature of inflammatory joint disease. If synovitis is localized to interphalangeal joints, rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis are among the most common differential diagnoses. The absence of pain, tenderness, and limitation of function despite progressive swelling of proximal interphalangeal joints suggests an alternative diagnosis, for example pachydermodactyly (PDD). This is a benign disease, associated with asymptomatic, progressive swelling of periarticular soft tissue, which usually occurs in young males. PDD is probably the result of repetitive mechanical stimulation. One hundred and twenty-one cases have been reported in the literature. Some of these were initially misdiagnosed and treated for inflammatory arthritis. We provide a comprehensive review of the literature on pachydermodactyly to promote awareness of this rare but important differential diagnosis of arthritis.

Symptomatic Neuroma Development following En Bloc Resection of Skeletal and Soft-Tissue Tumors: A Retrospective Analysis of 331 Cases.

BACKGROUND: Although symptomatic neuroma formation has been described in other patient populations, these data have not been studied in patients undergoing resection of musculoskeletal tumors. This study aimed to characterize the incidence and risk factors of symptomatic neuroma formation following en bloc resection in this population. METHODS: The authors retrospectively reviewed adults undergoing en bloc resections for musculoskeletal tumors at a high-volume sarcoma center from 2014 to 2019. The authors included en bloc resections for an oncologic indication and excluded non-en bloc resections, primary amputations, and patients with insufficient follow-up. Data are provided as descriptive statistics, and multivariable regression modeling was performed. RESULTS: The authors included 231 patients undergoing 331 en bloc resections (female, 46%; mean age, 52 years). Nerve transection was documented in 87 resections (26%). There were 81 symptomatic neuromas (25%) meeting criteria of Tinel sign or pain on examination and neuropathy in the distribution of suspected nerve injury. Factors associated with symptomatic neuroma formation included age 18 to 39 [adjusted OR (aOR), 3.6; 95% CI, 1.5 to 8.4; P < 0.01] and 40 to 64 (aOR, 2.2; 95% CI, 1.1 to 4.6; P = 0.04), multiple resections (aOR, 3.2; 95% CI, 1.7 to 5.9; P < 0.001), preoperative neuromodulator requirement (aOR, 2.7; 95% CI, 1.2 to 6.0; P = 0.01), and resection of fascia or muscle (aOR, 0.5; 95% CI, 0.3 to 1.0; P = 0.045). CONCLUSION: The authors' results highlight the importance of adequate preoperative optimization of pain control and intraoperative prophylaxis for neuroma prevention following en bloc resection of tumors, particularly for younger patients with a recurrent tumor burden. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma.

We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer.