A Dog in the Cancer Fight: Comparative Oncology in Osteosarcoma

Since the great Rudolf Virchow advised, “Between animal and human medicine there is no dividing line, nor should there be,” limited attention has been paid to cancer in animals. This is finally changing thanks to a renewed focus on studying pet dogs with cancer. Unlike the laboratory mice who have been the mainstay of animal models of disease, pet dogs share an environment with their human owners, have an intact immune system, and often develop diseases spontaneously in ways that mimic their human counterparts. Osteosarcoma (OSA) – while uncommon in humans - is a common malignancy in dogs. This comparatively high incidence alone renders pet dogs an ideal “model” to conduct translational and clinical research into OSA. Indeed, there are many similarities between the two species with respect to this disease. However, owing to the shorter life span and accelerated disease progression, treatment effects can be assessed much more rapidly in canines than in humans. Overall, dogs represent a unique model to study OSA; this chapter aims to discuss the ways that comparative oncology between dogs and humans are being used from basic science research, to genetics and mechanisms of disease, to tumor biology and finally to developing novel treatments

A Novel Imaging System Permits Real-time in Vivo Tumor Bed Assessment After Resection of Naturally Occurring Sarcomas in Dogs

Background Treatment of soft tissue sarcoma (STS) includes complete tumor excision. However, in some patients, residual sarcoma cells remain in the tumor bed. We previously described a novel hand-held imaging device prototype that uses molecular imaging to detect microscopic residual cancer in mice during surgery. Questions/purposes To test this device in a clinical trial of dogs with naturally occurring sarcomas, we asked: (1) Are any adverse clinical or laboratory effects observed after intravenous administration of the fluorescent probes? (2) Do canine sarcomas exhibit fluorescence after administration of the cathepsin-activated probe? (3) Is the tumor-to-background ratio sufficient to distinguish tumor from tumor bed? And (4) can residual fluorescence be detected in the tumor bed during surgery and does this correlate with a positive margin? Methods We studied nine dogs undergoing treatment for 10 STS or mast cell tumors. Dogs received an intravenous injection of VM249, a fluorescent probe that becomes optically active in the presence of cathepsin proteases. After injection, tumors were removed by wide resection. The tumor bed was imaged using the novel imaging device to search for residual fluorescence. We determined correlations between tissue fluorescence and histopathology, cathepsin protease expression, and development of recurrent disease. Minimum followup was 9 months (mean, 12 months; range, 9–15 months). Results Fluorescence was apparent from all 10 tumors and ranged from 3 × 107 to 1 × 109 counts/millisecond/cm2. During intraoperative imaging, normal skeletal muscle showed no residual fluorescence. Histopathologic assessment of surgical margins correlated with intraoperative imaging in nine of 10 cases; in the other case, there was no residual fluorescence, but tumor was found at the margin on histologic examination. No animals had recurrent disease at 9 to 15 months. Conclusions These initial findings suggest this imaging system might be useful to intraoperatively detect residual tumor after wide resections. Clinical Relevance The ability to assess the tumor bed intraoperatively for residual disease has the potential to improve local control

Can Experienced Observers Differentiate between Lipoma and Well-Differentiated Liposarcoma Using Only MRI?

Well-differentiated liposarcoma represents a radiographic diagnostic dilemma. To determine the accuracy, interrater reliability, and relationship of stranding, nodularity, and size in the MRI differentiation of lipoma and well-differentiated liposarcoma, MRI scans of 60 patients with large (\u3e5 cm), deep, pathologically proven lipomas or well-differentiated liposarcomas were examined by 10 observers with subspecialty training blinded to diagnosis. Observers indicated whether the amount of stranding, nodularity, and size of each tumor suggested a benign or malignant diagnosis and rendered a diagnosis of lipoma or well-differentiated liposarcoma. The accuracy, reliability, and relationship of stranding, nodularity, and size to diagnosis were calculated for all samples. 69% of reader MRI diagnoses agreed with final pathology diagnosis (95% CI 65-73%). Readers tended to err choosing a diagnosis of liposarcoma, correctly identifying lipomas in 63% of cases (95% CI 58-69%) and liposarcomas in 75% of cases (95% CI 69-80%). Assessment of the relationship of stranding, nodularity, and size to correct diagnosis showed that the presence of each was associated with a decreased likelihood of a lipoma pathological diagnosis (P \u3c 0.01). While the radiographic diagnosis of lipoma or well-differentiated liposarcoma cannot be made with 100% certainty, experienced observers have a 69% chance of rendering a correct diagnosis

Inequitable distribution of plastic benefits and burdens on economies and public health

Plastic heterogeneously affects social systems – notably human health and local and global economies. Here we discuss illustrative examples of the benefits and burdens of each stage of the plastic lifecycle (e.g., macroplastic production, consumption, recycling). We find the benefits to communities and stakeholders are principally economic, whereas burdens fall largely on human health. Furthermore, the economic benefits of plastic are rarely applied to alleviate or mitigate the health burdens it creates, amplifying the disconnect between who benefits and who is burdened. In some instances, social enterprises in low-wealth areas collect and recycle waste, creating a market for upcycled goods. While such endeavors generate local socioeconomic benefits, they perpetuate a status quo in which the burden of responsibility for waste management falls on downstream communities, rather than on producers who have generated far greater economic benefits. While the traditional cost-benefit analyses that inform decision-making disproportionately weigh economic benefits over the indirect, and often unquantifiable, costs of health burdens, we stress the need to include the health burdens of plastic to all impacted stakeholders across all plastic life stages in policy design. We therefore urge the Intergovernmental Negotiating Committee to consider all available knowledge on the deleterious effects of plastic across the entire plastic lifecycle while drafting the upcoming international global plastic treaty.publishedVersio

Superficial Soft-Tissue Sarcomas Rarely Require Advanced Soft-Tissue Reconstruction Following Resection

Objective: Soft-tissue sarcomas are most frequently located deep within myofascial compartments. Superficial soft-tissue sarcomas (S-STS) are relatively less common and may be managed differently than deep sarcomas because generous resection margins are often possible without sacrificing critical structures. We sought to investigate the frequency and types of soft-tissue reconstructive procedures that are required following excision of S-STS. Methods: We reviewed 457 consecutively treated patients with S-STS with a minimum 2-year follow-up from our prospectively maintained database between 1989 and 2009. Results: Mean follow-up was 10.5 years (range, 2–23). Four hundred twenty-one tumors (91%) were excised with negative margins, 38 (8.3%) had microscopically positive margins, and three (0.7%) had grossly positive margins. One patient required an amputation. In 271 (58%) patients, the wounds were closed primarily. In comparison, 93 patients (20%) required a rotation flap, 70 (15%) required a split-thickness skin graft, and 23 (5%) underwent a free tissue transfer (ie, advanced reconstructive procedure). The overall complication rate was 12%, although 43% of patients undergoing free tissue transfer developed complications (P = 0.04). An unplanned excision before referral to our center was a risk factor for local recurrence (P = 0.03) when residual tumor was recovered in the reexcision specimen pathologically. Conclusions: Although concern about the morbidity associated with a free tissue transfer (ie, advanced reconstructive procedure) may potentially limit the adequacy of resection in some patients with S-STS, the results of this study showed that the majority of patients had complete excisions with negative margins and primary closure. Obtaining a negative margin when excising a known or suspected S-STS rarely requires an advanced reconstructive procedure and almost never results in loss of limb

Can Experienced Observers Differentiate between Lipoma and Well-Differentiated Liposarcoma Using Only MRI?

Well-differentiated liposarcoma represents a radiographic diagnostic dilemma. To determine the accuracy, interrater reliability, and relationship of stranding, nodularity, and size in the MRI differentiation of lipoma and well-differentiated liposarcoma, MRI scans of 60 patients with large (>5 cm), deep, pathologically proven lipomas or well-differentiated liposarcomas were examined by 10 observers with subspecialty training blinded to diagnosis. Observers indicated whether the amount of stranding, nodularity, and size of each tumor suggested a benign or malignant diagnosis and rendered a diagnosis of lipoma or well-differentiated liposarcoma. The accuracy, reliability, and relationship of stranding, nodularity, and size to diagnosis were calculated for all samples. 69% of reader MRI diagnoses agreed with final pathology diagnosis (95% CI 65–73%). Readers tended to err choosing a diagnosis of liposarcoma, correctly identifying lipomas in 63% of cases (95% CI 58–69%) and liposarcomas in 75% of cases (95% CI 69–80%). Assessment of the relationship of stranding, nodularity, and size to correct diagnosis showed that the presence of each was associated with a decreased likelihood of a lipoma pathological diagnosis (P < 0.01). While the radiographic diagnosis of lipoma or well-differentiated liposarcoma cannot be made with 100% certainty, experienced observers have a 69% chance of rendering a correct diagnosis

The Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) Collaborative Quality Improvement Initiative in Percutaneous Coronary Interventions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72388/1/j.1540-8183.2002.tb01071.x.pd

Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) shows efficacy against Osteosarcoma

Therapeutic advances for osteosarcoma (OS) have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for OS by reformulating and validating niclosamide, an established anthelminthic agent, as a Niclosamide Stearate Prodrug Therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anti-cancer drugs. Nanoparticles were fabricated by rapid-solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell-viability, cell-proliferation, intracellular-signaling by western blot; ex vivo pulmonary metastatic assay model; and in vivo PK and lung mouse metastatic model of OS. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t1/2 ~5 h; reduces cell-viability and cell-proliferation in human and canine OS cells in vitro at 0.2 - 2 µM IC50; inhibits recognized growth pathways, and induces apoptosis at 20µM; eliminates metastatic lesions in the ex-vivo lung metastatic model; and, when injected intravenously (i.v.) at 50mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of OS over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected i.v. at 50mg/kg (1.9mM). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in OS patients