The vestibulocochlear bases for wartime posttraumatic stress disorder manifestations.

Preliminary findings based on earlier retrospective studies of 229 wartime head injuries managed by the Walter Reed Army Medical Center (WRAMC)/National Naval Medical Center (NNMC) Neurosurgery Service during the period 2003-08 detected a threefold rise in Posttraumatic Stress Disorder (PTSD) manifestations (10.45%) among Traumatic Brain Injuries (TBI) having concomitant vestibulocochlear injuries compared to 3% for the TBI group without vestibulo-cochlear damage (VCD), prompting the authors to undertake a more focused study of the vestibulo-auditory pathway in explaining the development of posttraumatic stress disorder manifestations among the mostly Blast-exposed head-injured. The subsequent historical review of PTSD pathophysiology studies, the evidence for an expanded vestibular system and of a dominant vestibular system, the vascular vulnerability of the vestibular nerves in stress states as well as the period of cortical imprinting has led to the formation of a coherent hypotheses utilizing the vestibulocochlear pathway in understanding the development of PTSD manifestations. Neuroimaging and neurophysiologic tests to further validate the vestibulocochlear concept on the development of PTSD manifestations are proposed.

Insulin-like growth factor 1 (IGF-1) receptors, IGF-1, and IGF-2 are expressed in primary human sarcomas.

A variety of bone and soft-tissue sarcoma cell lines have been shown to express receptors for insulin-like growth factor-1 (IGF-1) and to respond mitogenically to IGF-1 in vitro. We have recently demonstrated evidence of IGF dependency in murine MGH-OGS and RIF-1 sarcomas, which express relatively high and intermediate levels of IGF-1 receptors. Overexpression of IGF-1 receptors and/or IGF ligands might, therefore, be a mechanism by which human bone and soft-tissue sarcomas obtain a proliferative advantage over normal adjacent tissues. Therefore, we evaluated 29 human sarcoma specimens for expression of IGF-1 receptor, IGF-1, and IGF-2 by competitive binding and reverse-transcription polymerase chain reaction (RT-PCR) techniques. Twelve of 29 sarcomas examined by RT-PCR and 13 of 25 examined by affinity-binding studies expressed IGF-1 receptor levels equal to or greater than levels determined in the IGF-responsive MCF-7 breast carcinoma cell line. DNA amplification of the IGF-1 receptor gene was not identified in this group of sarcomas that expressed high levels of IGF-1 receptor. Evaluation of IGF ligand expression by RT-PCR revealed that 22 of 28 sarcomas expressed IGF-1 levels comparable to or above those of the RPMI 7666 control line, and 17 of 27 sarcomas expressed significant levels of IGF-2 compared with the NCI H69 control cell line. These results suggest that autocrine/paracrine regulatory mechanisms might be responsible for the growth of some sarcomas.

Timing of chemotherapy and surgery in a murine osteosarcoma model.

The sequential use of chemotherapy and surgery in the treatment of osteosarcoma developed in an empirical fashion without the benefit of investigations in animal models. The MGH-OGS murine osteosarcoma is a transplantable tumor that resembles the human disease with respect to histology, local invasiveness, metastatic characteristics, tumor ploidy, and its response to chemotherapy. We have used this tumor model to investigate the efficacy of preoperative, perioperative, and postoperative chemotherapy on the development of pulmonary metastases in three different experimental protocols. In each experimental design, perioperative chemotherapy demonstrated a significant advantage in preventing systemic relapse.

Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas.

Amplification of genes in the 12q13-15 region occurs frequently in several malignancies including osteosarcoma. The products of these amplified genes are thought to provide cancer cells with a selective growth advantage; however, the specific gene(s) driving this amplicon is unknown. We have previously shown that the SAS gene is amplified in most parosteal osteosarcomas. In this study we analysed additional putative growth regulatory genes in this chromosomal region in 24 primary osteosarcoma specimens. CDK4 and SAS were coamplified in 6/6 parosteal tumors, and MDM2 was also amplified in 4/5 parosteal cases. In comparison, amplification occurred in only 2/16 classical intramedullary osteosarcomas and involved the SAS gene. Each amplified gene had a correspondingly elevated mRNA level. Four high grade intramedullary tumors had elevated mRNA expression of SAS, but did not exhibit gene amplification. Gene amplification/overexpression was not associated with metastatic disease and did not change markedly with tumor progression, as evidenced by analysis of sequential tumor specimens from eight patients. Three other genes in the 12q13-15 region (CDK2, WNT1 and WNT10b) were not amplified in any of the tumors. The different patterns of gene amplification and overexpression of CDK4, SAS and MDM2 in parosteal and intramedullary osteosarcomas may help explain the disparity in the biological behaviour of these two types of osteosarcoma.

Prognostic factors in osteosarcoma: a critical review.

PURPOSE: The purpose of this critical appraisal was to determine the prognostic factors that influence survival in patients with nonmetastatic, high-grade osteosarcoma of the extremities. DESIGN: A computerized literature search of reports published from January 1973 to March 1992 was conducted to determine those eligible for inclusion in the review. Reports were reviewed blindly by two of the authors; inclusion and scoring were determined according to preestablished criteria. RESULTS: Eight reports were included in the appraisal. The prognostic variables evaluated were age, sex, anatomic tumor location, tumor size, and tumor necrosis. Tumor size and necrosis following preoperative chemotherapy were significant prognostic variables in relation to survival in univariate analysis. However, only tumor necrosis maintained its significance in multivariate modeling. CONCLUSION: The most important prognostic variable for patients with osteosarcoma of the extremity was tumor necrosis evident following preoperative chemotherapy. There is no consensus as to any prognostic variable that might be used to stratify patients before the onset of therapy.

MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Increased expression of the multidrug resistance gene (MDR1) has been implicated in osteosarcoma prognosis. This study represents the first prospective assessment of the prognostic value of MDR1 mRNA expression in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: A series of patients with high-grade, nonmetastatic extremity osteosarcoma were enrolled from six tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 30 months). All patients were treated with (neo)adjuvant chemotherapy and surgery. Tumors from 123 patients were analyzed for MDR1 mRNA expression. The association of the level of MDR1 expression with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Using the highest MDR1 value for each patient, a dose-response relationship was not identified between the level of MDR1 expression and systemic relapse (relative risk, 1.15; P =.44). Analyses based on biopsy or resection values alone gave similar results (P =.11 and.41, respectively, log rank test). In multivariate analysis, large tumor size (> 9 cm) was the only significant independent predictor of systemic outcome (relative risk, 2.8; P =.002). CONCLUSION: We did not identify any correlation between MDR1 mRNA expression and disease progression in patients with osteosarcoma. It is likely that alterations in other genes are involved in resistance to chemotherapy in osteosarcoma and that they play a more critical role than MDR1 in this disease.

Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma.

PURPOSE: Morbidity associated with wound complications may translate into disability and quality-of-life disadvantages for patients treated with radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional outcome and health status of extremity STS patients randomized in a phase III trial comparing preoperative versus postoperative RT is described. PATIENTS AND METHODS: One hundred ninety patients with extremity STS were randomized after stratification by tumor size dichotomized at 10 cm. Function and quality of life were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery. RESULTS: One hundred eighty-five patients had function data. Patients treated with postoperative RT had better function with higher MSTS (25.8 v 21.3, P <.01), TESS (69.8 v 60.6, P =.01), and SF-36 bodily pain (67.7 v 58.5, P =.03) scores at 6 weeks after surgery. There were no differences at later time points. Scores on the physical function, role-physical, and general health subscales of the SF-36 were significantly lower than Canadian normative data at all time points. After treatment arm was controlled for, MSTS change scores were predicted by a lower-extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS change scores were predicted by lower-extremity tumor and prior incomplete excision. When wound complication was included in the model, patients with complications had lower MSTS and TESS scores in the first 2 years after treatment. CONCLUSION: The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.

Local control of soft tissue sarcoma of the extremity: the experience of a multidisciplinary sarcoma group with definitive surgery and radiotherapy.

Data gathered on 62 patients with soft tissue sarcoma of an extremity, treated in entirety by an experienced multidisciplinary sarcoma group, were analysed. With a philosophy of emphasising attainment of histologically negative margins at carefully planned limb sparing surgery, combined with either pre-operative or postoperative radiation therapy, a crude local control rate of 95% (59 of 62 patients) at a minimum of 24 months follow-up was obtained. Of 9 patients with microscopically positive margins after definitive surgery, 8 had undergone maximal resection compatible with preservation of function. One of these 9 failed locally, indicating that radiation therapy is effective in eradicating microscopic disease in this tumour. The excellent local control obtained with limb-sparing surgery in this series justifies early referral of patients with these uncommon cancers to an experienced multidisciplinary unit. 26 patients (42%) failed systemically at a minimum of 24 months follow-up, and 19 (30.6%) died of their disease, confirming the need for effective systemic therapy in soft tissue sarcoma. Tumours greater than 10 cm in diameter had a greater risk of systemic relapse.

Preoperative and postoperative irradiation of soft tissue sarcomas: effect of radiation field size.

For the treatment of soft tissue sarcomas it has frequently been staged but not quantitatively demonstrated, that the volume irradiated is smaller when irradiation is given preoperatively as compared to postoperatively. In this study the field size used for preoperative irradiation was compared with that necessary in the same patient had the radiation been given postoperatively. Twenty-six patients with soft tissue sarcomas of the extremity, groin, and shoulder girdle who had received preoperative irradiation were resimulated following surgery to determine the size of the postoperative field. The simulation was performed by a physician not involved in the preoperative treatment planning. Preoperatively a radial margin of 5 cm around the tumor was used for low and intermediate grade and 7 cm for high grade sarcomas. Postoperatively the same margins were used but around the surgical field. Twelve patients underwent a wide resection and 14 patients a resection followed by vascularized tissue transfer to the surgical bed. The median follow-up was 22 months (range 13-46). No local recurrences and two cases of distant metastasis were observed. Independently of surgical procedure and tumor grade, the size of the preoperative radiation field and number of joints included in the field were significantly smaller than that of postoperative radiation (p less than 0.001). In two patients preoperatively and four patients postoperatively, the radiation field involved the whole circumference of the limb. Provided that equivalent radiation time-dose-fraction parameters are used and that the complication rate is proportional to the radiation field size, late complications may be less after preoperative irradiation than after post-operative irradiation.

Efficacy...what's that??

We need to develop techniques for measuring the usefulness of medical services. If resources are limited, and we cannot do all the diagnostic tests we would like to do, we must be able to select those that are most useful. To do this we need to known how to weigh benefits against risks and how to measure the worth of a given outcome. This article discusses efficacy, in diagnosis, management, and outcome. Diagnostic efficacy of a test is measured by its ability to change the probability of disease (pre- versus post-test likelihood). Management efficacy is a measure of how the test changes patient management. Outcome efficacy, which may take years to evaluate, is the ultimate yardstick of usefulness. Even though there are many problems in estimating the likelihood of a disease (subjectivity, varying terminology, etc.), physicians can make reasonably close estimates, as shown by the American College of Radiology's Efficacy Study, which analyzed the diagnostic process in 9000 cases. Efficacy studies may be a mixed blessing, however, as they may result in overly strict criteria and sweeping economic changes. They may be ignored because of the difficulty in following the "perfect" protocol for a given clinical situation, and it remains to be shown that they themselves are efficacious. Nevertheless, we are finally coming to grips with the question of how useful our tests are in patient management.

Ollier's disease with multiple sarcomatous transformations.

A 53-year-old man had the monomelic form of Ollier's disease, which resulted in deformity of the left leg. The patient was otherwise well until pain and increasing size of the left thigh led him to seek treatment. Biopsy revealed chondrosarcomatous transformation in the distal left femur. Hip disarticulation was performed. This case is unusual in that multiple foci of chondrosarcomatous transformation at various stages of development were present throughout the left femur, tibia, and fibula.

Changing rates of cancer. The hazards of using a single definition.

Changing cancer rates, abstracted from tumor registries, are used to make inferences about the effect of carcinogens and cancer treatments on a population-wide basis. We compared the annual age-standardized incidence rates of extremity soft tissue sarcomas from two large tumor registries using different case definitions. We identified all limb soft tissue sarcoma cases diagnosed 1973-1993 in the Ontario Cancer Registry (OCR) and the Surveillance, Epidemiology, and End Results (SEER) databases. Two case definitions for limb soft tissue sarcoma were used based on missing data, incomplete diagnostic methods and ICD-9 codes; an upper limit estimate of the rates which included all possible cases of limb soft tissue sarcoma and a lower limit estimate of the rates which included all definite cases of limb soft tissue sarcoma (with the true rates lying in between). The upper limit OCR rates showed a statistically significant decreasing linear trend (slope = -0.021, P < 0.01). Whereas the slope of the OCR lower limit regression line showed a statistically significant increase in rates (slope = 0.01, P = 0.04). Neither the upper or lower limit SEER rates had a statistically significant linear trend (slope = 0.002, P = 0.60 and slope = 0.001, P = 0.18, respectively). Case definition affects incidence rates and changing rates of cancer. Thus the use of a single case definition along with changing coding practices may alone explain changing cancer rates.

Chemotherapy and surgery in a murine osteosarcoma.

Surgical and chemotherapeutic effects on pulmonary metastatic disease were evaluated in the MGH-OGS murine osteosarcoma. The tumor responded to three sequential injections of doxorubicin with prolonged growth delay but cisplatin administration (although given in doses sufficient to cause weight loss and significant mortality) was not effective in controlling local disease progression. Using a protocol with three injections of doxorubicin (0.006 mg/g of body weight), it was observed that disease-free survival was enhanced when one of the three doses of doxorubicin was given at the time of surgery (perioperatively). By marginally resecting the primary tumor and permitting its regrowth, a model was developed with recurrent primary and metastatic disease present simultaneously. It was observed in this model that amputation or resection of the recurrent primary lesion resulted in pulmonary metastatic growth acceleration. Using this recurrent primary tumor model, doxorubicin's effect on pulmonary metastatic lesions was enhanced when the drug was given at the time of amputation.

Effect of doxorubicin on local recurrence following marginal resection in the MGH-OGS murine model.

Despite the fact that preoperative chemotherapy causes substantial necrosis in the primary osteosarcoma tumor, most authorities recommend resecting these lesions with a wide margin of normal tissue to avoid local recurrence. This study evaluated the effect of systemic chemotherapy (doxorubicin) on tumor growth and histology in the MGH-OGS transplantable murine model and examined whether this drug prevents local recurrence after resection of the tumor with positive microscopic margins. The results indicate that doxorubicin caused prolonged cessation of tumor growth, produced substantial necrosis within the lesion, and decreased the risk of local relapse following marginal surgery. The drug effect was dose-dependent and drug efficacy in preventing local relapse was maximal with administration prior to or at the time of surgery.

Expression of the multidrug resistance gene in osteosarcoma: a pilot study.

Resistance to combination chemotherapy remains a challenge in the treatment of osteosarcoma yet has not been studied extensively in this tumour. One mechanism of multiple drug resistance is increased expression of the multidrug resistance gene (mdr1). The level of mdr1 messenger RNA (mRNA) expression has been found to correlate with the degree of drug resistance in a number of tumour cell lines in vitro, which suggests that it also may be useful as a predictor of similar resistance in vivo. Using a highly sensitive assay based on the polymerase chain reaction to measure the amount of mdr1 mRNA, we detected various levels of mdr1 expression in 18 osteosarcoma specimens from 15 patients with resectable nonmetastatic osteosarcoma. At follow-up at a minimum of 30 months later, a trend toward a worse outcome was observed in patients with tumours exhibiting high levels of mdr1 expression. The results of this pilot study suggest that a larger scale prospective investigation of the effect of mdr1 gene expression on outcome in osteosarcoma is warranted.

Expression of osteocalcin and its transcriptional regulators core-binding factor alpha 1 and MSX2 in osteoid-forming tumours.

Osteosarcoma, fibrous dysplasia, and myositis ossificans contain osteoid-producing cells that are not necessarily morphologically typical osteoblasts. Nevertheless, these pathologic cells may share differentiation steps with osteoblasts at the molecular level. Osteocalcin, a bone-specific extracellular matrix protein, is a marker of mature osteoblasts. Osteocalcin is upregulated by the transcription factor core-binding factor alpha 1, which is responsible for commitment to the osteoblastic lineage, and is downregulated by MSX2, a homeobox-containing transcription factor expressed during the early proliferative phase of osteoblast differentiation. Semiquantitative reverse transcription-polymerase chain reaction was used to compare expression levels of osteocalcin, core-binding factor alpha 1, and MSX2 in 34 osteosarcoma, five fibrous dysplasia, and five myositis ossificans specimens, as well as in seven normal cortical bone samples. Despite normal or elevated levels of core-binding factor alpha-1 expression in most specimens, osteocalcin expression was low or undetectable in most cases of osteosarcoma (25 of 34) and myositis ossificans (4 of 5). Single-strand conformation polymorphism and sequencing did not identify any mutations in the DNA-binding domain of core-binding factor alpha 1. However, a high level of MSX2 expression was demonstrated in these lesions, which may inhibit osteocalcin transcription. The presence of moderate levels of osteocalcin in fibrous dysplasia may contribute to the characteristic disconnected appearance of trabeculae in that entity because osteocalcin is a negative regulator of bone formation.

Growth factor production by sarcoma cells in primary culture.

Cell lines derived from human sarcomas have been previously shown to produce a protein growth factor which, similar to platelet-derived growth factor (PDGF), can induce competence for mitosis in fibroblasts. Whether this factor production is an important feature of sarcomas in vivo or simply an artefact caused by long-term culture conditions is unclear, however. We demonstrated growth factor activity in conditioned medium from six of 11 primary sarcoma cultures, utilizing flow cytometric analysis of DNA to monitor the presence of sarcoma cells in cultures. Cells isolated from control tissues failed to show a similar mitotic effect.

Multidrug resistance-1 gene expression does not increase during tumor progression in the MGH-OGS murine osteosarcoma tumor model.

In addition to its possible role in drug resistance, expression of the multidrug resistance-1 gene may also be associated with a more malignant phenotype and tumor progression. This study evaluated its expression during tumor progression in the MGH-OGS transplantable murine osteosarcoma tumor model. Three variables of tumor progression were analyzed: tumor size, local recurrence, and metastasis. With a highly sensitive reverse transcription-polymerase chain reaction method, mRNA levels of multidrug resistance-1 were compared in primary tumors of different sizes. In addition, the levels were compared in primary, locally recurrent, and metastatic tumors isolated from individual mice. No significant difference was found in the levels of expression with increasing primary tumor size. In addition, the levels in primary, locally recurrent, and metastatic tumors were not significantly different. Our results indicate that--at least in the MGH-OGS tumor model, which is analogous to the majority of spontaneously occurring human osteosarcomas in that it has low levels of multidrug resistance-1/P-glycoprotein and is sensitive to doxorubicin--there is no evidence of upregulation of multidrug resistance-1 expression during tumor progression.

SAS is amplified predominantly in surface osteosarcoma.

The development of several types of human tumors is related to amplification of genes that are involved in cell growth. The protein products of these genes give the cells a selective growth advantage. The q13-15 region of chromosome 12 is frequently altered in human sarcomas, and the SAS gene has been identified in an amplification unit mapping to this region. Gene amplification of SAS was analyzed to determine the frequency of genetic alteration of this gene in osteosarcoma. Using Southern blot analysis as well as quantitative polymerase chain reaction, SAS was found to be amplified in 10 (36%) of 28 osteosarcomas. Gene amplification was evaluated in subtypes of osteosarcoma. All seven surface osteosarcomas displayed amplified SAS. In contrast, SAS was amplified in only two (13%) of 15 intramedullary osteosarcomas. The finding that all surface osteosarcomas demonstrated SAS gene amplification suggests that this gene may play a role in the pathogenesis of osteosarcoma subtypes and that surface osteosarcoma may be genetically different from high-grade intramedullary osteosarcoma.

Kinetic effects of adriamycin and bleomycin on two osteosarcoma models.

Although chemotherapeutic drugs are frequently administered to patients with osteosarcoma, there has been little research into the effect of cytotoxic drugs on osteosarcoma cell biology. The effect of two drugs (Adriamycin and bleomycin) on cell cycle kinetics was investigated in vitro in an established line of human osteosarcoma cells and in vivo using the Dunn osteosarcoma model. The cell cycle changes were consistent with G2 arrest for both drugs in vivo and in vitro. The alteration in cell cycle distribution was correlated with inhibition of 3H-thymidine incorporation in vitro. In vivo, the greater change in cell cycle distribution caused by Adriamycin was reflected in the increased inhibition of tumor growth found with this drug.