The surgical management of sacral chordomas.

STUDY DESIGN: Retrospective case series. OBJECTIVE: The purpose of this study was to evaluate factors that contribute to improved local control and survival. In addition, we sought to define the expected morbidity associated with treatment. SUMMARY OF BACKGROUND DATA: Sacral chordomas are rare tumors presumed to arise from notochordal cells. Local recurrence presents a major problem in the management of these tumors and it has been correlated with survival. Resection of sacral tumors is associated with significant morbidity. METHODS: Forty-two patients underwent resection for sacral chordoma between 1990 and 2005. Twelve patients had their initial surgery elsewhere. There were 12 female and 30 male patients. The proximal extent of the sacrectomy was at least S2 in 32 patients. RESULTS: Median survival was 84 months, and 5-year disease-free (DFS) and disease-specific survival (DSF) were 56% and 77%, respectively. Local recurrence (LR) and metastasis occurred in 17 (40%) and 13 (31%) patients, respectively. Local recurrence (P=0.0001), metastasis (P=0.0001), prior resection (P=0.046), and higher grade (P=0.05) were associated with a worse DSF. Prior resections (P=0.0001) and intralesional resections (P=0.01) were associated with a higher rate of LR. Intralesional resections were associated with a lower DSF (P=0.0001). Wide contaminated margins treated with cryosurgery and/or radiation were not associated with a higher LR rate. Rectus abdominus flaps were associated with decreased wound complications (P=0.01). Thirty-one (74%) patients reported that they self catheterize; and 16 (38%) patients required bowel training, while an additional twelve (29%) patients had a colostomy. Twenty-eight (67%) patients reported sexual dysfunction. Two (5%) patients died due to sepsis. CONCLUSIONS: Intralesional resection should be avoided as it is associated with a higher LR rate and worse survival. Rectus abdominus flaps ought to be considered as they lower the wound complication rate. Sacral resection is associated with significant morbidity.

Tumour interstitial fluid pressure may regulate angiogenic factors in osteosarcoma.

PURPOSE: We have previously shown that osteosarcomas have states of increased interstitial fluid pressure (IFP) which correlate with increased proliferation and chemosensitivity. In this study, we hypothesized that constitutively raised IFP in osteosarcomas regulates angiogenesis. MATERIALS AND METHODS: Sixteen patients with the clinical diagnosis of osteosarcomas underwent blood fl ow and IFP readings by the wick-in-needle method at the time and location of open biopsy. Vascularity was determined by capillary density in the biopsy specimens. We performed digital image analysis of immunohistochemical staining for CD31, VEGF-A, VEGF-C and TPA on paraffin-embedded tissue blocks of the biopsy samples. Clinical results were validated in a pressurised cell culture system. RESULTS: IFPs in the tumours (mean 33.5 +/- SD 17.2 mmHg) were significantly higher (P = 0.00001) than that in normal tissue (2.9 +/- 5.7 mmHg). Pressure readings were significantly higher in low vascularity tumours compared to high vascularity tumours (P <0.001). In the osteosarcoma cell lines, growth in a pressurised environment was associated with VEGF-A downregulation, VEGF-C upregulation and TPA upregulation. The reverse was seen in the OB cell lines. Growth in the HUVEC cell line was not significantly inhibited in a pressurised environment. Immunohistochemical assessment for VEGF-A (P = 0.01), VEGF-C (P = 0.008) and TPA (P = 0.0001) translation were consistent with the findings on PCR. CONCLUSION: Our data suggest that some molecules in angiogenesis are regulated by changes in IFP.

Tumor interstitial fluid pressure may regulate angiogenic factors in osteosarcoma.

We have previously shown that osteosarcomas (OS) have states of increased interstitial fluid pressure (IFP), which correlate with increased proliferation and chemosensitivity. In this study, we hypothesized that constitutively raised IFP in OS regulates angiogenesis. Sixteen patients with the clinical diagnosis of OS underwent blood flow and IFP readings by the wick-in-needle method at the time and location of open biopsy. Vascularity was determined by capillary density in the biopsy specimens. We performed digital image analysis of immunohistochemical staining for CD31, VEGF-A, VEGF-C, and TPA on paraffin-embedded tissue blocks of the biopsy samples. Clinical results were validated in a pressurized cell culture system. Interstitial fluid pressures in the tumors (mean 33.5 +/- SD 17.2 mmHg) were significantly higher (p = 0.00001) than that in normal tissue (2.9 +/- 5.7 mmHg). Pressure readings were significantly higher in low vascularity tumors compared to high vascularity tumors (p < 0.001). In the OS cell lines, growth in a pressurized environment was associated with VEGF-A downregulation, VEGF-C upregulation, and TPA upregulation. The reverse was seen in the OB cell line. Growth in the HUVEC cell line was not significantly inhibited in a pressurized environment. Immunohistochemical assessment for VEGF-A (p = 0.01), VEGF-C (p = 0.008), and TPA (p = 0.0001) translation were consistent with the findings on PCR. Our data suggests that some molecules in angiogenesis are regulated by changes in IFP.

Sacral resection for recurrent rectal cancer: analysis of morbidity and treatment results.

PURPOSE: Composite sacropelvic resection for locally advanced recurrent rectal cancer is a high-risk procedure that benefits select patients. We reviewed our recent institutional experience to evaluate case selection, morbidity, and outcomes. METHODS: Between 1987 and 2004, 29 patients underwent composite resection for recurrent locoregional rectal cancer (17 females; median age, 60 years). Clinicopathologic indicators were evaluated as indicators of survival by log-rank test and Cox proportional hazards model. RESULTS: Of 29 total patients, 27 (93 percent) received radiotherapy with their previous surgery (n = 10; 34 percent) or before sacrectomy (n = 17; 59 percent), and 12 (41 percent) received intraoperative therapy. Sacral resections were performed at S2/S3 (55 percent) or S4/S5 (45 percent) using anterior (41 percent) or combined anterior-posterior approach (59 percent), with adherence to (62 percent) or cortical invasion in (38 percent) the sacrum. A majority of those who had undergone previous abdominoperineal resection had total exenteration (9/13), whereas most patients who had undergone a previous sphincter-preserving procedure had abdominoperineal resection (12/16) and none had exenteration. Pedicle flaps (omental, 11; abdominal rectus, 7) often were used. A median of five (range, 1-33) units of blood was given intraoperatively. Transfusions were associated with previous abdominoperineal resection (P < 0.03), correlating strongly with postoperative morbidity (P < 0.02). There were 33 complications in 17 (59 percent) patients, most commonly perineal wound breakdown (9 (31 percent)) and pelvic abscess (5 (17 percent)). Median hospital stay was 18 (range, 7-56) days, significantly longer in patients with previous abdominoperineal resection (P < 0.02) or postoperative morbidity (P < 0.03). The only postoperative death was from pelvic sepsis. Resection was complete (R0) in 18 patients (62 percent), with microscopically positive margins (R1) in 10 (34 percent) and grossly positive margins (R2) in 1 (3 percent). Two-year and five-year recurrence rates were 47 and 85 percent, respectively; disease-specific survival was 63 and 20 percent, respectively. Less transfusion (P = 0.03), R0 resection (P = 0.005), lack of anterior organ involvement (P = 0.02), and absence of cortical bone invasion (P < 0.001) were associated with better survival on univariate analysis; original colorectal cancer stage was not. CONCLUSIONS: Sacrectomy for rectal cancer is a high-risk procedure that can achieve clear resection margins with low mortality in select patients. This procedure has a low cure rate but may provide local disease control with acceptable morbidity.

Cell proliferation of cultured human cancer cells are affected by the elevated tumor pressures that exist in vivo.

Elevated interstitial fluid pressure (IFP) is observed in most solid tumors. However, the study of the cellular processes of tumors and the development of chemotherapy are routinely studied using in vitro culture systems at atmospheric pressure. Using a new pressurized cell culture system, we investigated the influence of hydrostatic pressure on population dynamics of three primary osteosarcoma (HOS, U2OS, SaOS2) and two metastatic tumor cell lines (MCF7 breast, H1299 lung) that invade bone. Values of IFP in normal human bone and muscle, and in osteosarcoma tumors obtained during their surgical biopsy established the hydrostatic pressure range for the in vitro cell studies. The IFP values were obtained from a retrospective review of patient records. IFP from confirmed osteosarcoma was 35.9+/- 16.2 mmHg. Tumor IFP was significantly higher than muscle IFP (p < 0.001) and bone IFP (p < 0.003). The in vitro study measured the cell-line proliferation using hydrostatic pressures of 0, 20, 50 and 100 mmHg. The findings suggest that hydrostatic pressure either increases or decreases tumor proliferation rates depending on cell type. Furthermore, cell death was not associated with apoptosis.

Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma.

PURPOSE: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity. EXPERIMENTAL DESIGN: We did pressure and blood flow assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for proliferative and therapeutic indices in a replicated high-pressure environment. RESULTS: Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 +/- SD, 18.6 mmHg). This was not associated with significantly impeded blood flow as measured by a Doppler probe at a single site (P < 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher interstitial fluid pressures (P < 0.05). In vitro, cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized system had variable cell line-specific growth proportional to the level of pressure. They were more proliferative as indicated by cell cycle analysis with more cells in S phase after 48 hours of pressurization (P < 0.01). There was a significant elevation in the cell cycle-related transcription factors E2F-1 (P < 0.03) and E2F-4 (P < 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased sensitivity to cisplatin (P < 0.00006) and doxorubicin (P < 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure in the clinical study. CONCLUSIONS: The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.

Differences in the work-up and treatment of conditions associated with low back pain by patient gender and ethnic background.

STUDY DESIGN: Retrospective review comparing physician workup of degenerative lumbosacral pathologies between different genders and ethnic groups. OBJECTIVES: To investigate whether patient ethnicity and gender influence the workup and treatment of degenerative spinal pathologies. SUMMARY OF BACKGROUND DATA: Data from numerous studies suggest that patient gender and ethnicity play a role in medical decision-making, with white males receiving more frequent interventions than women and minorities. METHODS: Patients enrolled for an "initial visit" in the National Spine Network database with lumbosacral level degenerative diagnosis were reviewed. Variables included patient gender, ethnicity, age, duration of symptoms, patient-graded severity of symptoms, radicular symptom pattern, and work status. RESULTS: We identified 5690 patients with degenerative lumbosacral pathologies. Although females were more likely than males to have imaging tests ordered, male (18.5%) patients were significantly more likely to have surgery recommended than female (16.3%) patients (P < 0.031). Nonwhite females were 52% less likely to have surgery offered at initial visit, as compared to white males (P < 0.005). More imaging tests were ordered or reviewed among whites (76.6%) than among any other ethnic group (P = 0.162). White (18.3%) and Asian (22.5%) patients were significantly more likely to have surgery recommended or prescribed than black (11.1%) and Hispanic (14.5) patients (P < 0.0001). CONCLUSIONS: This study suggests that ethnicity and gender affect the workup and surgical management of degenerative spinal disorders. However, it should be noted that there are a number of confounding factors not identified in the database, including managed care and insurance status and cultural differences, which may affect both test ordering and treatment recommendations. Further study of bias in clinical decision-making is indicated to assure equal delivery of quality care.

Elucidation of the molecular mechanisms of malignant bone tumors: refining diagnosis and identifying novel targets for treatment.

Primary bone tumors are rare, accounting for less than 0.2% of all cancers diagnosed yearly in the United States. Study of the molecular mechanisms of these diseases has given insight into their pathobiology. It has also identified molecular alterations that, if present, may be used in conjunction with histologic evaluation to further refine diagnosis, allowing cases to be stratified into prognostic groups more or less likely to show response to current cytotoxic protocols. Recent findings have lead to the identification of molecular pathways that may serve as targets of novel therapies, especially in the case of Ewing sarcoma. Telomere maintenance mechanisms are also emerging as potential targets for anticancer therapy. As the molecular mechanisms underlying malignant bone tumors are better understood, new anticancer agents targeting specific pathways are likely to emerge. This may make it possible to tailor treatment for each individual patient, using a combination of cytotoxic and targeted therapies based on the histologic and molecular profile of the patient's tumor.

Advances that are changing the diagnosis and treatment of malignant bone tumors.

PURPOSE OF REVIEW: Several neoplastic conditions may affect bone. These include primary bone tumors as well as metastatic disease from distant primary sites. Often, these entities produce symptoms that may be difficult to distinguish from those of various rheumatologic entities. The purpose of this review is to discuss recent developments in orthopedic oncology, with special attention given to advances that are changing the diagnosis and treatment of bone sarcomas and carcinomas metastatic to bone. RECENT FINDINGS: Much effort in the field of musculoskeletal oncology has been dedicated to the elucidation of the molecular mechanisms underlying bone sarcomas, especially in the case of osteogenic sarcoma and Ewing family tumor. Telomere maintenance mechanisms are emerging as potential targets for anticancer therapy. The most exciting advances have been in the development of novel treatments for cancers affecting bone. The anticancer effects of bisphosphonates, cyclooxygenase-2 inhibitors, and statins may expand their indications to the treatment of primary bone tumors. Finally, new expandable implants have been developed for the treatment of bone tumors in growing children. These devices may help solve some of the problems encountered with reconstruction of the growing skeleton. SUMMARY: Recent discoveries in the molecular mechanisms of bone sarcomas may help to elucidate the pathogenesis of these rare diseases. This, combined with the recent findings of the anticancer effects of bisphosphonates, cyclooxygenase-2 inhibitors, and statins, may lead to the development of novel treatments for sarcomas of bone and of carcinomas metastatic to bone.

Leiomyosarcoma of somatic soft tissues.

Leiomyosarcoma is a rare, aggressively malignant connective tissue tumor of mature adults, which arises from smooth muscle. It occurs most frequently in the uterus, bowel, vascular tissues, and less commonly in somatic soft tissue or bone. The tumor when it arises in soft tissue has distinctive histologic features which somewhat resemble malignant fibrous histiocytoma (otherwise known as myxofibrosarcoma). The Orthopaedic Oncology Service at our institution has treated 66 patients with these lesions and thus far, 1/2 of the patients have died of disease at a mean of 3 years after discovery. Factors that increase the death rate include size of the tumor, Musculoskeletal Tumor Society Stage of disease, and to a lesser extent particularly in the lower extremities, anatomic site. Radiation and chemotherapy had little direct effect on the outcome but patients treated with surgery and adjunctive agents seemed to live longer than their cohorts treated with surgery alone. The purpose of this study is a general review of the clinical and prognostic features of this cancer.