Hypofractionated radiation therapy for the treatment of microscopic canine soft tissue sarcoma.

Soft tissue sarcomas (STSs) are locally invasive and surgery with or without radiation therapy is the current standard of care in dogs. Typical protocols for treating incompletely excised STSs involve curative intent radiation with total dose in excess of 50 Gy. Forty-eight dogs with histologically confirmed incomplete or closely excised STSs were treated with a hypofractionated protocol that is typically reserved for palliative radiation therapy (RT) (6-8 Gy/weekly fractions to a total dose of 24-32 Gy). Ten dogs (21%) developed local recurrence, 11 dogs (23%) developed metastasis, and 3 dogs developed both (included in each group). The median progression free survival was 698 days. The local failure-free probability at 1 and 3 years was 81 and 73%. The 1 and 3 years tumour-specific overall survival was 81 and 61%. Long-term local tumour control was achieved in the majority of dogs. This protocol is reasonable to prescribe in older patients or when financial limitations exist.

Recommended guidelines for submission, trimming, margin evaluation, and reporting of tumor biopsy specimens in veterinary surgical pathology.

Neoplastic diseases are typically diagnosed by biopsy and histopathological evaluation. The pathology report is key in determining prognosis, therapeutic decisions, and overall case management and therefore requires diagnostic accuracy, completeness, and clarity. Successful management relies on collaboration between clinical veterinarians, oncologists, and pathologists. To date there has been no standardized approach or guideline for the submission, trimming, margin evaluation, or reporting of neoplastic biopsy specimens in veterinary medicine. To address this issue, a committee consisting of veterinary pathologists and oncologists was established under the auspices of the American College of Veterinary Pathologists Oncology Committee. These consensus guidelines were subsequently reviewed and endorsed by a large international group of veterinary pathologists. These recommended guidelines are not mandated but rather exist to help clinicians and veterinary pathologists optimally handle neoplastic biopsy samples. Many of these guidelines represent the collective experience of the committee members and consensus group when assessing neoplastic lesions from veterinary patients but have not met the rigors of definitive scientific study and investigation. These questions of technique, analysis, and evaluation should be put through formal scrutiny in rigorous clinical studies in the near future so that more definitive guidelines can be derived.

Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas.

Nineteen dogs with histologically confirmed soft tissue sarcomas of the extremities were treated with a combination of marginal surgery and intra-operative chemotherapy in the form of cisplatin in a biodegradable implant delivery system (Atrigel; Atrix Laboratories, Fort Collins, Co, USA). None of the dogs had evidence of metastasis at time of treatment. The median dose of cisplatin was 52.1 mg/m(2) (mean 55.4 mg/m(2), range 18.5-108.6 mg/m(2)). Wound complications were noted in 16 dogs (84.2%). Median follow-up time was 874 days (mean 777 days, range 125-1463 days). Nine dogs (47.3%) were alive at the time of analysis. Local recurrence occurred in three dogs (16.6%). The time to recurrence was 214, 264 and 874 days.

Multilobular osteochondrosarcoma of the hard palate in a dog.

A 14-year-old castrated male Rhodesian Ridgeback was presented with a history of sneezing and epistaxis. Diagnostic procedures included physical examination, regional and thoracic radiography, computed tomography and histological examination of an incisional biopsy. A multilobular osteochondrosarcoma of the hard palate with pulmonary metastases was diagnosed. Surgical resection of the primary tumour was achieved with clean margins and the defect was repaired using bilateral mucosal transposition flaps from the lips. Wound dehiscence and oesophageal stricture were postoperative complications, but these resolved with treatment. A long-term survival time of 14 months resulted, with good quality of life and function during this time.

Treatment of eight dogs with nasal tumours with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam.

OBJECTIVE: To determine the efficacy and toxicity of chemotherapy in the treatment of canine nasal tumours. DESIGN: Retrospective clinical study PROCEDURE: Eight dogs with histologically confirmed nasal tumours were staged by means of complete blood count, serum biochemical analysis, cytological analysis of fine needle aspirate of the regional lymph nodes, thoracic radiographs and computed tomography scan of the nasal cavity. All dogs were treated with alternating doses of doxorubicin, carboplatin and oral piroxicam. All dogs were monitored for side effects of chemotherapy and evaluated for response to treatment by computed tomography scan of the nasal cavity after the first four treatments. RESULTS: Complete remission was achieved in four dogs, partial remission occurred in two dogs and two had stable disease on the basis of computed tomography evaluation. There was resolution of clinical signs after one to two doses of chemotherapy in all dogs. CONCLUSIONS: This chemotherapy protocol was efficacious and well tolerated in this series of eight cases of canine nasal tumours.

A prospective randomised trial comparing intra-articular Hyalgan injection and arthroscopic washout for knee osteoarthritis.

Thirty-eight patients with symptomatic knee osteoarthritis without mechanical symptoms were randomised after informed consent to receive either a course of intra-articular Hyalgan injections or an arthroscopic washout. The patients were prospectively assessed pre-intervention, 6 weeks, 3 months, 6 months and 1 year using a 10 cm visual analogue pain score, the Knee Society function score and the Lequesne index. There was no significant difference between the two groups at 6 weeks, 3 months, 6 months or 1 year. The use of intra-articular Hyalgan injections in patients with knee osteoarthritis without mechanical symptoms gives results comparable with arthroscopic washout. Hyalgan is an alternative to arthroscopy in this patient group. Further study is needed to confirm these findings and improve patient selection.

Posterior cruciate ligament at total knee replacement. Essential, beneficial or a hindrance?

We report the results of a prospective randomised trial which assessed the role of the posterior cruciate ligament (PCL) following total knee replacement (Genesis I; Smith and Nephew, Memphis, Tennessee). Over a four-year period, 211 patients underwent total knee replacement by the senior author (TJW). They were randomised at surgery to have the PCL either retained, excised or substituted with a posterior stabilised insert. If it was not possible to retain the ligament due to soft-tissue imbalance, it was released from its tibial insertion until suitable tension was obtained. This created a fourth group, those who were intended preoperatively to have the ligament retained, but in whom it was partially released as a result of findings at the time of surgery. All patients were evaluated using the Knee Society rating system (adapted from Insall). A total of 188 patients (212 knees) was available for follow-up at a mean of 3.5 years after surgery. Preoperatively, there was a varus deformity in 191 knees (90%) and a valgus deformity in 21 (10%). There were no statistical differences in the knee or function scores or the range of movement between the excised, retained and substituted groups. There were, however, significantly worse knee and function scores in the group in whom the PCL was released (p = 0.002).

Matrix metalloproteinase-2 and -9 involvement in canine tumors.

Matrix metalloproteinases (MMPs) are a family of enzymes implicated in the degradation and remodeling of extracellular matrix and in vascularization. They are also involved in pathologic processes such as tumor invasion and metastasis in experimental cancer models and in human malignancies. We used gelatin zymography and immunohistochemistry to determine whether MMP-2 and MMP-9 are present in canine tumors and normal tissues and whether MMP production correlates with clinicopathologic parameters of prognostic importance. High levels of pro-MMP-9, pro-MMP-2, and active MMP-2 were detected in most canine tumors. Significantly higher MMP levels were measured in canine tumors than in nontumors, malignancies had higher MMP levels than benign tumors, and sarcomas had higher active MMP-2 than carcinomas. Cartilaginous tumors produced higher MMP levels than did nonsarcomatous malignancies, benign tumors, and normal tissues, and significantly greater MMP-2 than osteosarcomas and fibrosarcomas. Pro-MMP-9 production correlated with the histologic grade of osteosarcomas. The 62-kd form of active MMP-2 was detected only in high-grade, p53-positive, metastatic malignancies. Zymography proved to be a sensitive and quantitative technique for the assessment of MMP presence but has the limitation of requiring fresh tissue; immunohistochemistry is qualitative and comparatively insensitive but could be of value in archival studies. MMP presence was shown in a range of canine tumors, and their link to tumor type and grade was demonstrated for the first time. This study will allow a substantially improved evaluation of veterinary cancer patients and provides baseline information necessary for the design of clinical trials targeting MMPs.

Surgical repair of a chronic rupture of the rectus femoris muscle at the proximal musculotendinous junction in a soccer player.

A rare case is presented of a longstanding rupture of the rectus femoris muscle at the proximal musculotendinous junction in a semiprofessional soccer player. Its different and unique presentation, the surgical repair, and the remarkable functional recovery are discussed.

Transposition of first digital pad for reconstruction of a palmar antebrachial soft tissue defect in a cat.

An 8-year-old female neutered Siamese cat was presented with a recent history of incomplete excision of an apocrine gland adenocarcinoma from the palmar aspect of the right antebrachium, just proximal to the carpal joint. There was no evidence of metastasis. Wide surgical excision of the previous surgery site was performed resulting in a soft tissue defect. Partial reconstruction was achieved using digital pad transposition of the first digit (dewclaw), forming a local axial pattern flap that was transposed into the adjacent defect. The remaining defect was closed by primary apposition. The skin flap healed successfully. Some breakdown of the skin closed by primary apposition necessitated open wound management. The cosmetic and functional result of the first digital pad transposition was considered excellent, rendering it a useful means to reconstruct soft tissue defects in the carpal region.

Scaphoid nonunion: treatment with a pedicled vascularized bone graft based on the 1,2 intercompartmental supraretinacular branch of the radial artery.

Pedicled vascularized bone grafts (Zaidemberg's technique) were used to treat 22 established scaphoid fracture nonunions, 16 of which were found to have avascular proximal poles at surgery. After a follow-up of 1-3 years, only six (27%) of the 22 fracture nonunions had united. Only two of the 16 nonunions with avascular proximal poles united, compared with four of the six nonunions with vascular proximal poles. We conclude that this technique of pedicled vascularized bone grafting may not improve the union rate for scaphoid fracture nonunions with avascular proximal pole fragments.

Use of mandibular symphysiotomy to allow extensive caudal hemimaxillectomy in a dog.

A 5-year-old dog was presented with a large caudal maxillary osteosarcoma, which was causing extreme pain on opening of the mouth. The mass was not resectable through a standard oral approach. This article describes the successful use of mandibular symphysiotomy to allow extensive caudal hemimaxillectomy to remove the mass and provide excellent postoperative quality of life for the dog.

Adduction sign in pediatric hip arthrography.

Various techniques for improving the success of needle placement in hip arthrography have been described. The authors describe a simple consistent sign that occurs in both subluxated and dislocated hips and is present only when the needle is correctly placed within the hip joint. This, in conjunction with other techniques, has improved their quality of hip arthrography.

Comparative genome sequence analysis of the Bpa/Str region in mouse and Man.

The progress of human and mouse genome sequencing programs presages the possibility of systematic cross-species comparison of the two genomes as a powerful tool for gene and regulatory element identification. As the opportunities to perform comparative sequence analysis emerge, it is important to develop parameters for such analyses and to examine the outcomes of cross-species comparison. Our analysis used gene prediction and a database search of 430 kb of genomic sequence covering the Bpa/Str region of the mouse X chromosome, and 745 kb of genomic sequence from the homologous human X chromosome region. We identified 11 genes in mouse and 13 genes and two pseudogenes in human. In addition, we compared the mouse and human sequences using pairwise alignment and searches for evolutionary conserved regions (ECRs) exceeding a defined threshold of sequence identity. This approach aided the identification of at least four further putative conserved genes in the region. Comparative sequencing revealed that this region is a mosaic in evolutionary terms, with considerably more rearrangement between the two species than realized previously from comparative mapping studies. Surprisingly, this region showed an extremely high LINE and low SINE content, low G+C content, and yet a relatively high gene density, in contrast to the low gene density usually associated with such regions.

Outcome following treatment of vertebral tumors in 20 dogs (1986-1995).

Twenty dogs with histopathologically confirmed primary (n=15) or metastatic (n=5) osteosarcoma (n=14) or fibrosarcoma (n=6) of the vertebral column were treated with surgery (n=4), radiation therapy and chemotherapy (n=6), surgery and chemotherapy (n=2), or surgery, radiation, and chemotherapy (n=8). All dogs died due to their disease; 15 died due to local failure, and five died due to nonvertebral metastasis. Overall median survival time was 135 days, with a range of 15 to 600 days. Of the factors evaluated, only postoperative neurological status had a significant influence on outcome by multivariate analysis. This study supports the overall guarded prognosis for dogs with vertebral neoplasia. Better combinations of surgery, chemotherapy, and radiation therapy remain to be defined for this difficult subset of animal cancer.

Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To develop a scheme for early identification of individuals at risk for symptomatic vasospasm after subarachnoid hemorrhage (SAH). DESIGN: Analysis of prospectively collected data from the placebo-treated group in a multicenter clinical trial. SETTINGS: Fifty-four neurosurgical centers in North America. MEASUREMENTS AND MAIN RESULTS: We identified independent predictors of symptomatic vasospasm using stepwise logistic regression analysis from demographic, clinical, laboratory, and neuroimaging characteristics of the participants. We developed a scoring system (symptomatic vasospasm risk index) based on a combination of these predictors. Out of 283 patients in the analysis (all treated with oral nimodipine), 93 (33%) developed symptomatic vasospasm within 14 days after SAH. There were four independent predictors of symptomatic vasospasm: thickness of subarachnoid clot on computed tomographic scan (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.8-10.0); early rise in middle cerebral artery mean flow velocity (MCA-MFV), defined as a value > or =110 cm/sec recorded on or before post-SAH day 5 (OR, 1.9; 95% CI, 1.1-3.3), Glasgow Coma Scale score <14 (OR, 1.8; 95% CI, 1.1-3.1); and rupture of anterior cerebral or internal carotid artery aneurysm (OR, 1.9; 95% CI, 1.0-3.4). The probability of identifying patients who would develop symptomatic vasospasm (percentage of area under receiver operating characteristics curve +/- SEM) was higher with symptomatic vasospasm risk index (68%+/-8%) compared with thickness of clot (62%+/-8%; p = .08) or MCA-MFV (45%+/-7%, p < .05) criteria alone. CONCLUSIONS: Patients at high risk for symptomatic vasospasm can be identified early in the course of SAH using a risk index. A risk index based on a combination of variables may represent a predictive paradigm superior to conventionally used criteria based on clot thickness or MCA-MFV criteria.

Factors associated with aneurysm size in patients with subarachnoid hemorrhage: effect of smoking and aneurysm location.

OBJECTIVE: Intracranial aneurysm size is an important determinant of risk of rupture and outcome after rupture. Risk factors influencing aneurysm formation and growth are not well defined. In this study, we examined the association between known risk factors for cerebrovascular disease and size of intracranial aneurysms in patients with aneurysmal subarachnoid hemorrhage. METHODS: We analyzed prospectively collected data from the placebo-treated group in a multicenter clinical trial conducted at 54 neurosurgical centers in North America. The presence, location, and size of intracranial aneurysms were determined by review of the admission angiograms. Pertinent information regarding the presence of various cerebrovascular risk factors was collected for each patient. Using logistic regression analysis, we identified independent determinants of aneurysm size from demographic, clinical, and angiographic characteristics of the participants. The impact of aneurysm size on 3-month mortality was analyzed after adjusting for potential confounding factors. RESULTS: For 298 patients admitted with subarachnoid hemorrhage, the ruptured aneurysms were graded as small (<13 mm) in 235 patients (79%) and large (> or =13 mm) in 63 patients (21%). In the logistic regression model, both smoking at any time (odds ratio, 2.2; 95% confidence interval, 1.1-4.5) and middle cerebral artery origin (odds ratio, 2.5; 95% confidence interval, 1.3-4.9) were independently associated with large aneurysms. Neither hypertension, diabetes mellitus, nor alcohol and illicit drug use were associated with large-sized aneurysms. After adjusting for initial Glasgow Coma Scale score and age in the logistic regression model, the presence of large-sized aneurysms was independently associated with 3-month mortality (odds ratio, 2.3; 95% confidence interval, 1.1-4.8). CONCLUSION: Cigarette smoking and middle cerebral artery origin seem to increase the risk for developing large aneurysms in patients predisposed to intracranial aneurysm formation. Further studies are required to investigate the mechanism underlying the association between cigarette smoking and intracranial aneurysm formation.

Effects of a controlled-release cisplatin delivery system used after resection of mammary carcinoma in mice.

OBJECTIVE: To evaluate efficacy of a controlled-release cisplatin delivery system, used after marginal resection of mammary carcinoma (ie, resection of grossly evident tumor) in mice, to prevent tumor regrowth and metastasis. ANIMALS: 42 female C3H-HeJ mice. PROCEDURE: Mice were inoculated with mammary carcinoma cells. Between 2 and 6 days later, tumors were marginally resected and mice were assigned to 1 of 3 groups: no treatment (control; n = 14), cisplatin administered intraperitoneally (i.p. cisplatin; 14), and cisplatin delivered by use of an open-cell polylactic acid system placed within the tumor bed (slow-release cisplatin; 14). Tumor regrowth was measured daily. Mice were euthanatized 14 days after surgery, and complete necropsies were performed. RESULTS: Tumor regrowth was not detected in the slow-release cisplatin group; however, tumor regrowth was detected in 7 of 14 mice in the i.p. cisplatin group and 14 of 14 mice in the control group. Median (+/-SD) number of days to tumor regrowth was 13.5+/-0.64 and 7.79+/-0.87 in the i.p. cisplatin and control groups, respectively. Mice in the i.p. cisplatin group had significantly delayed tumor regrowth, compared with control mice. Metastases to lungs were detected in 8 of 14 control mice but were not detected in mice in either cisplatin treatment group. CONCLUSIONS AND CLINICAL RELEVANCE: The open-cell polylactic acid with cisplatin delivery system was successful in delaying local tumor regrowth and metastasis in mice with marginally resected mammary carcinoma. Use of a controlled-release cisplatin delivery system may be an effective adjunct treatment following excision of mammary carcinoma in humans and other animals.

Prognostic value and determinants of ultraearly angiographic vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: A small number of patients with aneurysmal subarachnoid hemorrhage have angiographic evidence of cerebral vasospasm within 48 hours of the onset of hemorrhage. The present study analyzes the prognostic value and determinants of this ultraearly angiographic finding. METHODS: We analyzed prospectively collected data from the placebo-treated group in a multicenter clinical trial conducted at 54 neurosurgical centers in North America. The presence and severity of ultraearly angiographic vasospasm (UEAV) was determined by a blinded review of the admission angiograms. Using logistic regression analysis, we identified independent determinants of UEAV from demographic, clinical, laboratory, and neuroimaging characteristics of the patients. The impact of UEAV on the risk of symptomatic vasospasm and 3-month outcome was analyzed after adjusting for potential confounding factors. RESULTS: Of 296 patients in the analysis, 37 (13%) had angiographic evidence of vasospasm at admission. An initial Glasgow Coma Scale score of less than 14 (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.1-6.0), and serum sodium greater than 138 mmol/L (OR, 3.4; 95% CI, 1.5-8.3) were associated with UEAV. UEAV was associated with increased risk of symptomatic vasospasm (OR, 2.5; 95% CI, 1.2-5.4) and poor outcome at 3 months (OR, 2.8; 95% CI, 1.2-6.3), after adjusting for other variables. This risk of symptomatic vasospasm was not influenced by early surgery (within 48 h of hemorrhage onset). Poor outcome was more likely to occur in patients with UEAV who did not undergo early surgery (P = 0.03). CONCLUSION: Our analysis suggests that patients with angiographic evidence of vasospasm at admission are at high risk for both symptomatic vasospasm and poor outcome. We also found that early surgery did not aggravate this risk.

Apparent interaction of dimethyl sulfoxide with cisplatin released from polymer delivery devices injected subcutaneously in dogs.

Local tissue toxicity, systemic toxicity and platinum pharmacokinetics were evaluated in 6 normal healthy beagle dogs injected subcutaneously with two formulations of a polylactide biodegradable polymer (Atrigel) system containing cisplatin. Dogs were injected 4 times at 30 day intervals at platinum dosages of 70, 105 and 157.5 mg/m2 (dose escalation). Once pharmacokinetics were established, 29 dogs with spontaneous stage IIb appendicular osteosarcoma were treated with 4 injections of the same polymer system containing cisplatin at 70 mg/m2 (20 dogs) and 100 mg/m2 (9 dogs) to establish efficacy against micrometastatic disease. Local tissue toxicity was variable. Systemic toxicity, as judged by clinicopathologic evaluation was not noted at any dose level or injection number. Interim (6 month) survival analysis revealed a median disease-free interval of 180 days. Consistent platinum release characteristics were found, however, the lack of toxicity and decreased disease-free-interval raised concerns over the biologic activity of the cisplatin. Prior to completion of the study, it was discovered that dimethyl sulfoxide, the solvent used in the co-polymer system, may be responsible for biologic inactivation of cisplatin. This was subsequently demonstrated in tissue culture assays. The clinical trial was suspended and dogs were treated with traditional chemotherapy.