Animal models of spinal cord injury: a systematic review.

STUDY DESIGN: PRISMA-guided systematic review. OBJECTIVES: To provide a comprehensive framework of the current animal models for investigating spinal cord injury (SCI) and categorize them based on the aims, patterns and levels of injury, and outcome measurements as well as animal species. SETTING: Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran. METHODS: An electronic search of the Medline database for literature describing animal models of SCI was performed on 1 January 2016 using the following keywords: 'spinal cord injuries' and 'animal models'. The search retrieved 2870 articles. Reviews and non-original articles were excluded. Data extraction was independently performed by two reviewers. RESULTS: Among the 2209 included studies, testing the effects of drug's or growth factor's interventions was the most common aim (36.6%) followed by surveying pathophysiologic changes (30.2%). The most common spinal region involved was thoracic (81%). Contusion was the most common pattern of injury (41%) followed by transection (32.5%) and compression (19.4%). The most common species involved in animal models of SCI was the rat (72.4%). Two or more types of outcome assessments were used in the majority of the studies, and the most common assessment method was biological plus behavioral (50.8%). CONCLUSIONS: Prior to choosing an animal model, the objectives of the proposed study must precisely be defined. Contusion and compression models better simulate the biomechanics and neuropathology of human injury, whereas transection models are valuable to study anatomic regeneration. Rodents are the most common and probably best-suited species for preliminary SCI studies.

Potential variables affecting the quality of animal studies regarding pathophysiology of traumatic spinal cord injuries.

STUDY DESIGN: This is a Delphi study. OBJECTIVES: Defining variables that potentially influence the outcomes of an animal study regarding pathophysiology of traumatic spinal cord injury (TSCI). SETTING: This study was conducted in Iran. METHODS: A modified two-round Delphi study was conducted. As the first round, an initial questionnaire was developed on the basis of literature and a series of focus group discussions. In the second round, the participants were asked to score the items through a 10-point scale. Consensus was achieved through the following criteria: (1) the median of scores has to be at 7.5 or higher, and (2) at least 70% of participants need to rate 7 or higher. Also, the inter-rater reliability analysis was performed to determine consistency among raters using the Kappa coefficient and Cronbach's alpha. RESULTS: Twenty-one experts participated in our study. From the first round of the study, a 47-item checklist was developed. By considering the aforementioned criteria for consensus building on extremely important factors, we reached a 15-item checklist including species, strain, method and level of injury, control group, genetic background, severity of injury, attrition, use of appropriate test, blindness, method of allocation to treatments, regulation and ethics, age/weight, bladder expression, number of animals/group and statistics. The inter-rater reliability for the raters was found to be Kappa=0.82 (P<0.001). A Cronbach's alpha of 0.9 for all the questions indicated high internal consistency. CONCLUSION: This study introduces a checklist of variables that potentially influence the outcomes of animal studies regarding TSCI pathophysiology and describe its validity and reliability.

Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guerin or adriamycin. Results of long-term follow-up.

We evaluated 158 cases of patients with superficial bladder cancers (Stages Ta, T1, and Tis). These cases were treated with either intravesical bacillus Calmette-Guerin (BCG) (Tice strain) or Adriamycin (ADR), in a multicenter, nonrandomized study. One hundred thirty-one of these patients were followed up; the results continue to show a higher percentage of initial complete remissions with BCG (68%) than with ADR (57%). With additional therapy, both BCG and ADR achieved complete remission in 83 percent of the patients. When 7 failures with patients taking ADR were switched to BCG and the disease cleared, the rate of complete remission for BCG rose to 85 percent. The recurrence rate per 100 patient-months was only slightly different for BCG (0.9) and ADR (0.8). The percentage of progressions continued to be higher for BCG (8%) than for ADR (5%). Cystectomies were performed in 2.5 percent of the BCG patients. Using the Cox regression model with covariates, we found drug treatment, tumor grade, and sex to be statistically significant in determining failures throughout the protocol. Although both BCG and ADR were effective over the course of the study, BCG is the drug of choice for residual tumor (Stages T1 and Tis).

Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or adriamycin.

We evaluated 155 patients with superficial bladder cancers (Stages Ta, T1, and TIS) and treated them with either intravesical bacillus Calmette-Guérin (Tice strain) (BCG) or doxorubicin hydrochloride (Adriamycin), in a multicenter nonrandomized study. At present 140 of these patients in treatment Groups I and II are being followed up. With additional follow-up, BCG continued to produce a higher percentage of complete remissions (71%) than doxorubicin (54%). The percentage of incomplete remission with BCG (7%) was half that with doxorubicin (14%). Half of the patients whose initial therapy failed had complete remission after additional therapy. However, for patients with recurrence, additional follow-up shows a recurrence rate per 100 patient-months for BCG (1.0) only slightly lower than that for doxorubicin (1.1). The percentage of progressions continued to be higher with BCG (8.5%) than with doxorubicin (5%), but the difference between these results for the two drugs proved slightly less than we reported previously. Of the patients in this study, 2.5 percent (all treated with BCG) required cystectomy. A comparison of the results of our study with those of 13 other studies using BCG to treat bladder cancer indicates that therapy beyond an initial course of 6 weekly treatments increases the percentage of complete response. All of the studies showed that the greatest improvement in percentage of complete response occurred with the second course of treatment. The value of maintenance therapy cannot yet be determined, since few studies have used that protocol. The percentage of patients requiring cystectomy in studies with fewer than 20 treatments was 2.2 times higher than in studies with more than 20 treatments.

Does bacillus Calmette-Guérin immunotherapy accelerate growth and cause metastatic spread of second primary malignancy?

In our study, 29 of 150 patients with bladder cancer also had other associated primary malignancies, 10 of which were manifested after intravesical treatment with bacillus Calmette-Guérin (BCG). Second primary malignancies developed in 5 of these patients within three months of the start of BCG therapy. All 5 showed acceleration of the second primary tumor, and distant metastatic lesions developed in 4. In the other 5 patients nonbladder primary malignancies developed eight months or more after intravesical BCG therapy started, but did not show acceleration or spread. Twenty patients with other primary malignancies that had developed months to years before intravesical therapy did not show acceleration or spread of those tumors. We have seen enough cases of patients who received intravesical BCG at the time of growth and spread of second primary malignancies to warrant concern. Animal and human studies of BCG use for treatment of malignancy indicate that the temporal relationship between the starting point of tumor development and the starting point of BCG treatment is crucial in determining whether BCG will eradicate or exacerbate the tumor. We have therefore instituted a change in our treatment until the question of whether or not BCG causes the appearance and spread of these second malignancies is answered.

Superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or adriamycin: follow-up report.

We evaluated 139 patients with superficial bladder cancer (Stages Ta, Tl, and TIS) and treated them with either intravesical bacillus Calmette-Guérin, Tice strain (BCG), or doxorubicin hydrochloride (Adriamycin [ADR]) in a nonrandomized, multicenter study. Our follow-up study comprises 135 of these patients. Of these patients, 78 tumors were completely resected, and 61 were incompletely resected. When a proportional-hazards model (Cox) was applied, there was a statistically significant difference between the recurrence rates for the two drugs. On the basis of recurrence rates per 100 patient-months, both BCG (1.2) and ADR (0.9) worked well with completely resected tumors. However, for incomplete resections, the recurrence rate for BCG (0.9) was less than half that for ADR (1.9). The overall recurrence rates were 1.1 and 1.3 for BCG and ADR, respectively. There have been 42 failures of treatment with either BCG or ADR. We defined failure as any recurrence of tumor; progression of the cancer in stage, grade, tumor number or size; or any residual tumor after 18 treatments (14 months of therapy). As to the failures in patients whom we followed up, and whose treatment was either switched from ADR to BCG or continued on further BCG treatment, 53 per cent have achieved complete remission. Complete remission for BCG and ADR were 76 per cent and 52 per cent, respectively. Of the various factors considered in the study, only tumor grade and treatment drug were statistically significant. The cystectomy rate was 1 per cent for BCG-treated patients and 0 for ADR-treated patients.

Superficial bladder cancer treated by intravesical bacillus Calmette-Guerin or adriamycin: multicenter study interim report.

One hundred sixteen patients with superficial bladder cancers (Stages Ta, T1, and TIS) were evaluated and treated with either intravesical bacillus Calmette-Guerin [Tice strain] (BCG) or doxorubicin hydrochloride (Adriamycin [ADR]), in a multicenter study. One hundred nine of these patients currently have follow-up. Of these, 54 were completely resected and 55 incompletely resected. For complete resections, based on recurrence rates per 100 patient months, both BCG (0.22) and ADR (0.91) worked well, although BCG had a slightly lower recurrence rate. However, for incomplete resections, BCG (0.20) had a markedly lower recurrence rate than ADR (2.52). Eighteen patients failed initial treatment, with either BCG or ADR. All have been placed on long-term therapy schedules. Of the 12 failures who currently have follow-up, 11 (92%) have either partially or completely responded with additional intravesical therapy. No patients in this study have yet required cystectomies.