Complete clinical remission of malignant peritoneal mesothelioma with systemic pemetrexed and bevacizumab in a patient with a BAP1 mutation.

Malignant peritoneal mesothelioma (MPeM) is a rare malignancy with historically poor prognosis. Recent research has started to reveal increasingly prevalent genetic mutations seen in this malignancy. Here, we report a case of complete clinical remission of unresectable, metastatic MPeM with systemic chemotherapy. Immunohistochemistry of our patient's malignant cytology sample showed loss of Breast Cancer Gene 1-associated protein-1 expression (BAP1). The patient had synchronous diagnoses of primary squamous cell carcinoma of the anus, benign schwannoma and meningioma. Following the completion of 18 cycles of pemetrexed and bevacizumab, the patient has remained in clinical remission for 8 months. We examine the unusual susceptibility of unresectable MPeM to systemic chemotherapy and attribute susceptibility to the molecular milieu created by mutations in multiple DNA repair pathways. We encourage increased testing for and analysis of mutations in DNA repair pathways to improve future treatment outcomes in this rare malignancy.

Gene partners of the EWSR1 fusion may represent molecularly distinct entities.

EWSR1 fusions are highly promiscuous and are associated with unique malignancies, clinical phenotypes, and molecular subtypes. However, rare fusion partners (RFP) of EWSR1 has not been well described. Here, we conducted a cross-sectional, retrospective study of 1,140 unique tumors harboring EWSR1 fusions. We identified 64 unique fusion partners. RFPs were identified more often in adults than children. Alterations in cell cycle control and DNA damage response genes as driving the differences between fusion partners. Potentially clinically actionable genomic variants were more prevalent in tumors harboring RFP than common fusions. While the data presented here is limited, tumors harboring RFP of EWSR1 may represent molecularly distinct entities and may benefit from further molecular testing to identify targeted therapeutic options.

TYMS promotes genomic instability and tumor progression in Ink4a/Arf null background.

We previously showed that elevated TYMS exhibits oncogenic properties and promotes tumorigenesis after a long latency, suggesting cooperation with sequential somatic mutations. Here we report the cooperation of ectopic expression of human TYMS with loss of Ink4a/Arf, one of the most commonly mutated somatic events in human cancer. Using an hTS/Ink4a/Arf -/- genetically engineered mouse model we showed that deregulated TYMS expression in Ink4a/Arf null background accelerates tumorigenesis and metastasis. In addition, tumors from TYMS-expressing mice were associated with a phenotype of genomic instability including enhanced double strand DNA damage, aneuploidy and loss of G1/S checkpoint. Downregulation of TYMS in vitro decreased cell proliferation and sensitized tumor cells to antimetabolite chemotherapy. In addition, depletion of TYMS in vivo by TYMS shRNA reduced tumor incidence, delayed tumor progression and prolonged survival in hTS/Ink4a/Arf -/- mice. Our data shows that activation of TYMS in Ink4a/Arf null background enhances uncontrolled cell proliferation and tumor growth, supporting the development of new agents and strategies targeting TYMS to delay tumorigenesis and prolong survival.

First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival.

Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.

Aneurysmal bone cyst: a review.

Aneurysmal bone cyst (ABC) is a benign locally destructive bone neoplasm composed of multi-loculated blood-filled cystic spaces. The most common sites of involvement are the meta-diaphysis of the long bones and posterior elements of the vertebrae. Secondary, ABC-like changes can complicate a variety of other benign and malignant primary bone neoplasms, including giant cell tumor, fibrous dysplasia, and osteosarcoma. About two-third of primary ABCs have a rearrangement of the USP6 gene, which is not present in the ABC-like changes that occur secondary to other primary bone tumors (i.e., secondary ABC). Primary ABC of bone carries a variable but generally high rate of local recurrence. This paper provides an overview of the pathophysiology, clinical presentation, radiographic and pathologic findings, treatment, and prognosis of ABC.

Myofibroma mimicking peripheral nerve sheath tumour with ulnar nerve compression symptoms.

We report a case of myofibroma encasing the ulnar nerve on the medial aspect of the left arm with motor and sensory deficit secondary to compression. Initially, the tumour appeared to be a benign peripheral nerve sheath tumour based on preoperative imaging, with clinical examination positive for left hand clawing and a positive Wartenberg's and Froment's sign. However, intraoperative dissection demonstrated that the mass did not originate from the ulnar nerve proper, lowering suspicion for a peripheral nerve sheath tumour. Histopathological analysis showed spindle cell neoplasm, consistent with myofibroma. The patient underwent hand occupational therapy subsequently, with improvement of grip strength from 5 lb to 12 lb by 4 months postoperatively and resolution of clawing of the hand postoperatively. We discuss differentiating features for this rare occurrence of solitary adult myofibroma, where the final diagnosis was only made after formal histopathological analysis.

Metastatic malignant peripheral nerve sheath tumour in a patient with neurofibromatosis 1 and review of contemporary systemic treatments.

Malignant peripheral nerve sheath tumours are rare soft tissue sarcomas commonly seen in patients with neurofibromatosis type 1. They typically manifest in the fibrous sheaths of major nerve trunks in the extremities or in an axial location. Presenting symptoms are generally non-specific, including pain and weakness, and survival is dependent on size and location of the tumour. Surgical resection is the primary treatment modality followed by radiotherapy or chemotherapy; however, prognosis is poor. Medications such as tyrosine kinase inhibitors and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway inhibitors are increasingly being recognised as potentially effective therapy for these malignancies. We report a case of a patient with neurofibromatosis type 1 presenting with a malignant peripheral nerve sheath tumour along the tibial nerve that was initially diagnosed as a muscle strain. We discuss the utility of diagnostic imaging and pathology in correctly identifying this aggressive tumour as well as review the drugs used in her care.

Arthroscopic treatment for intra-articular fibroma of the tendon sheath in a teenager.

An adolescent female patient presented with atraumatic left knee pain and limited flexion. MRI demonstrated evidence of a soft tissue lesion abutting the posterior cruciate ligament. Differential diagnosis included pigmented villonodular synovitis (PVNS) and fibroma of the tendon sheath (FTS). Following arthroscopic biopsy, histopathological evaluation confirmed FTS. The tumour was then excised via an arthroscopic approach. This case report provides a unique example of FTS abutting the cruciate ligaments in an uncommonly young female patient. It highlights the importance of including benign processes, such as FTS, in the differential with more aggressive-type diagnoses like PVNS. Furthermore, this case exemplifies an appropriate surgical indication for FTS. Finally, it emphasises the importance of communication and collaboration among orthopaedic subspecialists in providing safe and effective arthroscopic treatment of this unique tumour presentation.

Complex Reconstruction for Acetabular Pathologic Fracture in Unusual Chondroblastoma With Aneurysmal Bone Cyst.

Treating bone loss with complex arthroplasty poses a significant challenge for the arthroplasty surgeon. When considering a reconstructive case after pathologic fracture and oncologic excision, a multidisciplinary approach with reliance on arthroplasty principles is critical. An 18-year-old patient presented with a complex acetabular pathologic fracture through a chondroblastoma with a secondary aneurysmal bone cyst. An outside institution performed a biopsy and placed a hip-spanning external fixator. Multidisciplinary planning led to tumor excision, complex acetabular arthroplasty reconstruction including structural bone grafting, and internal fixation. At the third year of follow-up, there was no evidence of mechanical loosening of the hip arthroplasty, reoperation, or tumor recurrence. The structural graft was completely osseointegrated, confirmed by a computed tomography scan obtained at 2 years postoperatively. This report demonstrates an unusual location of chondroblastoma, presenting with acetabular fracture definitively treated with complex multidisciplinary reconstruction leading to an excellent outcome in a young patient.

Leiomyosarcoma of the Nasal Cavity and Paranasal Sinuses: A Case Report and Comprehensive Review of the Literature.

Sinonasal leiomyosarcoma (LMS) is a rare and aggressive mesenchymal tumor with smooth muscle differentiation. The sinonasal tract is an unusual primary site for LMS, as scant smooth muscle exists in this location, with only 75 cases reported in the English literature including the case presented herein. Sinonasal LMS is considered an aggressive head and neck tumor with significant potential for recurrence and metastasis. Since recurrence is high and the potential for late metastasis exists, lifelong follow-up in these patients would be beneficial, especially among those with previous history of RB.

Self-Complementary Adeno-Associated Virus-Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model.

The authors are investigating self-complementary adeno-associated virus (scAAV) as a vector for intra-articular gene-delivery of interleukin-1 receptor antagonist (IL-1Ra), and its therapeutic capacity in the treatment of osteoarthritis (OA). To model gene transfer on a scale proportional to the human knee, a frequent site of OA incidence, studies were focused on the joints of the equine forelimb. Using AAV2.5 capsid and equine IL-1Ra as a homologous transgene, a functional ceiling dose of ∼5 × 1012 viral genomes was previously identified, which elevated the steady state levels of eqIL-1Ra in synovial fluids by >40-fold over endogenous production for at least 6 months. Here, using an osteochondral fragmentation model of early OA, the functional capacity of scAAV.IL-1Ra gene-delivery was examined in equine joints over a period of 12 weeks. In the disease model, transgenic eqIL-1Ra expression was several fold higher than seen previously in healthy joints, and correlated directly with the severity of joint pathology at the time of treatment. Despite wide variation in expression, the steady-state eqIL-1Ra in synovial fluids exceeded that of IL-1 by >400-fold in all animals, and a consistent treatment effect was observed. This included a 30-40% reduction in lameness and ∼25% improvement in total joint pathology by both magnetic resonance imaging and arthroscopic assessments, which included reduced joint effusion and synovitis, and improved repair of the osteochondral lesion. No vector-related increase in eqIL-1Ra levels in blood or urine was noted. Cumulatively, these studies in the equine model indicate scAAV.IL-1Ra administration is reasonably safe and capable of sustained therapeutic IL-1Ra production intra-articularly in joints of human scale. This profile supports consideration for human testing in OA.

Gene Therapy for Osteoarthritis: Pharmacokinetics of Intra-Articular Self-Complementary Adeno-Associated Virus Interleukin-1 Receptor Antagonist Delivery in an Equine Model.

Toward the treatment of osteoarthritis (OA), the authors have been investigating self-complementary adeno-associated virus (scAAV) for intra-articular delivery of therapeutic gene products. As OA frequently affects weight-bearing joints, pharmacokinetic studies of scAAV gene delivery were performed in the joints of the equine forelimb to identify parameters relevant to clinical translation in humans. Using interleukin-1 receptor antagonist (IL-1Ra) as a secreted therapeutic reporter, scAAV vector plasmids containing codon-optimized cDNA for equine IL-1Ra (eqIL-1Ra) were generated, which produced eqIL-1Ra at levels 30- to 50-fold higher than the native sequence. The most efficient cDNA was packaged in AAV2.5 capsid, and following characterization in vitro, the virus was injected into the carpal and metacarpophalangeal joints of horses over a 100-fold dose range. A putative ceiling dose of 5 × 1012 viral genomes was identified that elevated the steady-state eqIL-1Ra in the synovial fluids of injected joints by >40-fold over endogenous levels and was sustained for at least 6 months. No adverse effects were seen, and eqIL-1Ra in serum and urine remained at background levels throughout. Using the 5 × 1012 viral genome dose of scAAV, and green fluorescent protein as a cytologic marker, the local and systemic distribution of vector and transduced cells following intra-articular injection scAAV.GFP were compared in healthy equine joints and in those with late-stage, naturally occurring OA. In both cases, 99.7% of the vector remained within the injected joint. Strikingly, the pathologies characteristic of OA (synovitis, osteophyte formation, and cartilage erosion) were associated with a substantial increase in transgenic expression relative to tissues in healthy joints. This was most notable in regions of articular cartilage with visible damage, where foci of brilliantly fluorescent chondrocytes were observed. Overall, these data suggest that AAV-mediated gene transfer can provide relatively safe, sustained protein drug delivery to joints of human proportions.

Eps8 expression is significantly lower in p16+ head and neck squamous cell carcinomas (HNSCCs) compared with p16- HNSCCs.

In vitro head and neck cancer studies have demonstrated that epidermal growth factor receptor kinase substrate 8 (Eps8) overexpression contributes to squamous carcinogenesis. Oral squamous cell carcinoma studies have correlated Eps8 expression with metastatic disease and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) studies comparing its expression by anatomic site or in in vivo regional metastases have not been performed. In this study, we compared Eps8 expression in HNSCCs arising in the oral cavity (OCSCC) and oropharynx (OPSCC) along with their corresponding regional lymph node (LN) metastases. We then correlated our findings with clinicopathologic data including tumor-node-metastasis stage, p16 status, age, sex, and smoking and alcohol history. Eps8 immunohistochemistry was performed on 69 archived OCSCCs and OPSCCs, and 24 paired and 4 unpaired LNs. Expression was scored from 0 to 3. Eps8 expression was detected in 49% of combined OCSCC and OPSCC cases. We found that expression correlated with advanced tumor stage (P = .022) and p16 status (P = .032) but not with anatomic site. Notably, p16+ HNSCCs had significantly lower Eps8 expression than p16- HNSCCs. No significant difference was observed between primary HNSCCs and their corresponding metastatic LNs. Neither p16 status nor anatomic site influenced Eps8 expression in regional LN metastases. In conclusion, our data offer in vivo support that, in HNSCCs, Eps8 is involved in tumor invasion but not necessarily the development of regional LN metastasis. The association between low Eps8 expression and p16+ HNSCCs suggests that alternative signaling pathways may be used for their tumorigenesis.