The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.

Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.

Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.

Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.

Polymorphisms in the prostate-specific antigen gene promoter do not predict serum prostate-specific antigen levels in African-American men.

A major problem with the use of serum prostate-specific antigen (PSA) in predicting prostate cancer risk is the considerable variability of such measurements. Cramer et al. identified a set of single-nucleotide polymorphisms (SNPs) in the upstream regulatory region of the PSA gene that were each associated with increased promoter activity and serum PSA, further suggesting that genotyping these SNPs could be useful in improving the predictive value of PSA screening. In order to replicate this finding, DNA samples from 475 African-American men were genotyped for the same SNPs and no association was observed with either serum PSA level or prostate cancer diagnosis.

A randomized prospective study of posterolateral lumbar fusion. Outcomes with and without pedicle screw instrumentation.

STUDY DESIGN: A prospective evaluation of the clinical and radiographic outcomes of 71 patients who underwent lumbar fusion, with or without transpedicular instrumentation. The patients completed a questionnaire that determined pain relief, medication use, return to work, and overall satisfaction with surgery. OBJECTIVES: To explore the effect, if any, of instrumentation on the outcome of lumbar fusion surgery, according to reports of the patients, and whether there is a correlation between the radiographic determination of a solid fusion and the same patient-reported outcome. SUMMARY OF BACKGROUND DATA: The literature on this topic reports pseudarthrosis rates from 0% to 57% and good to excellent results from 56% to 95%. These studies provide no clear-cut recommendations concerning the effect of added lumbar instrumentation on patient-reported outcome in a prospective manner using concurrent control subjects. METHODS: The patients were randomized to groups with and without instrumentation after deciding to undergo a lumbar fusion and consenting to enter the study. Radiographs were obtained and questionnaires filled out at 6 weeks, 6 months, 1 year, and 2 years after surgery. RESULTS: There was no statistical difference in patient-reported outcome between the two groups. There was a slight nonsignificant trend toward increased radiographic fusion rate in the group with instrumentation that did not correlate with an increased patient-reported improvement rate. CONCLUSIONS: These results do not provide data that indicate a benefit in outcome from added instrumentation in elective lumbar fusions.

Buyouts & ventures. Selling ... or selling out.

Charity begins at home, yet across the country hometown not-for-profit hospitals are forming joint partnerships with investor-owned systems. In some of these cases no foundation is created to continue the hospital's good deeds. In this special report, Hospitals & Health Networks looks at the issues and asks, "Do these joint ventures need more public scrutiny?"

The morbidity of heparin therapy after development of pulmonary embolus in patients undergoing thoracolumbar or lumbar spinal fusion.

STUDY DESIGN: The postoperative course of patients who developed a pulmonary embolus after thoracolumbar or lumbar spinal fusion treated with heparin was studied to quantify the morbidity risk of anticoagulation. OBJECTIVE: To compare the morbidity risk of heparinization with that of an alternative form of therapy--inferior vena cava filter placement. SUMMARY OF BACKGROUND DATA: Therapeutic heparinization was the current treatment of choice for patients who develop thromboembolic disease after surgery. Although heparin usage was reported to be associated with a number of complications after other orthopedic and general surgical procedures, no information was available to identify complications of heparinization after lumbar or thoracolumbar spine surgery or to define the risk of such complications. METHODS: Twenty-two members of the Scoliosis Research Society were polled to determine their experiences with the anticoagulation of this subset of patients. Surgeons polled had a combined experience of 250 man-years and had performed more than 13000 thoracolumbar and lumbar spinal fusions. The MEDLINE database was used to review pertinent English language publications describing inferior vena cava filter complications, effectiveness, safety, and indications for use. RESULTS: Nine patients were located who fit the inclusion criteria of this study. Six (67%) had complications attributable to heparinization. Clinically significant complications of filter placement ranged from 0.12% to 10.1%. CONCLUSIONS: Heparinization after the development of pulmonary embolus in patients recently undergoing spinal fusion is associated with a high complication rate. The morbidity of vena cava filter placement is low and should be considered a treatment alternative in the treatment of patients who experience pulmonary embolus after surgery.

The effect of fibrin sealant on the strength of tendon repair of full thickness tendon lacerations in the rabbit Achilles tendon.

The influence of fibrin sealant on healing was investigated in the suture of Achilles tendons of 24 rabbits. The Achilles tendon cut through was anastomosed with a 4-0 prolene suture alone in one group and fibrin sealant was applied to the cut surfaces of the tendon prior to suture repair in the second group. After 17 and 27 days, five animals in each group were sacrificed. The repaired Achilles tendons were retrieved and the tensile strength of the repaired tendons measured using an Instron. One rabbit in each group was sacrificed at 3 weeks and 6 weeks and the repaired tendons were harvested and fixed for histologic study. At 17 and 27 days there was no significant difference between the tensile strength of the control and fibrin sealant groups. Histologically there was no distinct difference of the repair process of the tendons between the two groups.

The influence of anulotomy selection on disc competence. A radiographic, biomechanical, and histologic analysis.

STUDY DESIGN: This study analyzed the radiographic, biomechanical, and histologic attributes of three commonly used anulotomy techniques. OBJECTIVES: This study defined the propensity of the anulus fibrosus to heal after discectomy and correlated biomechanical differences between subgroups of the motion segments studied. SUMMARY OF BACKGROUND DATA: No previous report that compares the influence of anulotomy selection on disc competence exists. METHODS: Anulotomies were performed on the anterolateral aspects of the lumbar discs of 54 adult goats. The goats were randomly assigned to one of three subgroups containing 18 animals. In subgroup A, a full-thickness anular window was excised. In subgroup B, a full-thickness cruciate anulotomy was accomplished. In subgroup C, a full-thickness anulotomy was developed by inserting a trocar, 2.5 mm in diameter, into the disc. RESULTS: Histologic analysis revealed that primary anular healing did not occur in any specimen. The anulotomy tracts in subgroup C (trocar) were consistently narrower than those of subgroups A and B. Discography demonstrated the presence of severe and early disc degeneration with subgroup A (anular window), a finding not observed within the trocar anulotomy group. Biomechanical testing demonstrated increased resistance to pull out by the trocar anulotomy group at 4 weeks, as well as increased torsional stiffness of the motion segment when compared to both window and cruciate anulotomy. CONCLUSIONS: The authors conclude that attempts should be made to minimize injury to the anulus fibrosus during the performance of discectomy.

Muscle flap closure for salvage of complex back wounds.

STUDY DESIGN: The use of muscle flaps for closing complex thoracolumbar and lumbar spine wounds was studied retrospectively. Five patients in whom traditional, conservative treatment modalities did not work underwent a variety of muscle flap closures with successful healing. OBJECTIVES: Patients with complicated back wounds ranging from exposed hardware to post-traumatic defects were treated initially with conservative treatments. The authors evaluated the efficacy of applying techniques and knowledge gained from complex lower extremity wound coverage of back wounds. SUMMARY OF BACKGROUND DATA: Six muscle transfer procedures were performed on five patients. All patients were closed with local muscle flaps using the trapezius and latissimus dorsi muscles. METHODS: Success was defined as a closed stable wound that needed no future surgery nor allowed the primary defect to heal before hardware removal. There was no evidence of chronic infection. Surgical hardware was salvaged in one of three patients. RESULTS: All were successfully closed and have been followed up to 30 months without evidence of recurrence. CONCLUSIONS: The cases presented illustrate the usefulness of rotation flaps when there is an extensive soft tissue defect that has exposed neural, osseous, and foreign structures. The use of local transposition muscle flaps as an adjunct in closing complex back wounds has been very successful in our experience. Although recurrent infection may occur, this technique has facilitated the establishment of a soft tissue envelope to achieve short- and long-term wound healing.

Management of retroperitoneal chylous leakage.

Lymphatic complications are uncommon after spinal surgery. Postsurgical collections of lymph may result in chyloma, chylothorax, chylous ascites, or chyloretroperitoneum. Recommended treatment of chylothorax or chylous ascites includes drainage, and a low-fat diet using medium-chain triglyceride or total parenteral nutrition. The only reported case of chyloretroperitoneum concluded with a recommendation for retroperitoneal drainage. The authors present a series of three patients who underwent anterior spinal procedures complicated by retroperitoneal lymphatic injury. All three were treated without retroperitoneal drains, and at follow-up, none has shown any adverse sequelae from this method of treatment. The authors disagree with past recommendations for drainage of the retroperitoneal space because this may prolong drainage and deplete nutrition.

Vertebrodiatasis experimental lengthening of the juvenile goat spine.

The purpose of this study is to describe the biology of spinal lengthening (vertebrodiatasis) in a juvenile goat model. A small Orthofix dynamic fixator was affixed to 5.5 mm pedicular halfpins placed bilaterally at T12, L1, L5 and L6 in six juvenile goats. Distraction was performed across vertebral endplates between L1 and L5. Uninstrumented twins served as controls. Two pairs of animals were deleted due to anesthetic complications. Lumbar lengthening was successful in 3 animals resulting in an increase in length of up to 696% from L1 to L5 compared to the growth rate of the controls (mean 4.3 cm vs. mean .56 cm, respectively). Lengthening of the spinal cord was not associated with brain stem migration or spinal cord injury.

Pathomechanical analysis of thoracolumbar burst fracture reduction. A calf spine model.

Burst fractures were created in the spines of twelve dairy calves and the mechanism of indirect canal clearance studied. The spines were reduced posturally and divided in to four subsets--control, and subsets in which either the posterior longitudinal ligament (PLL), the PLL and annulus, or posterior osteoligmentous structures were sectioned. The specimens were then instrumented and further reduction obtained through application of extension and distraction forces. Statistically significant reduction of the intracanal burst fragment occurred even if the PLL or PLL and annulus were incompetent but did not occur in that group in which the posterolateral complex had been sectioned.

Spine injuries in combat troops--Panama, 1989.

Operation Just Cause was until recently the largest American combat operation since Vietnam, and remains the largest nighttime parachute operation since World War II. All 252 casualties were airlifted to San Antonio, Texas, for medical treatment. Greater than 80% sustained orthopedic injuries. Sixteen patients were admitted for injuries to the back or neck. Three of the four patients with significant fractures or fracture-dislocations were paraplegic. Two of the three patients with gunshot wounds to the back required extensive reconstruction for wound management. In addition to the 252 casualties, there were 23 fatalities, among whom 7 suffered major injuries to the spine. Spine injuries represented the most significant source of long-term morbidity among those soldiers wounded in combat in Panama, and were common among the fatalities. Noteworthy in these cases was the high percentage of severe neurologic injuries in patients with significant fractures (75%), particularly fractures associated with gunshot wounds. Also of interest were the cases of major soft tissue injury associated with high-velocity gunshot wounds (66%) and the extensive soft tissue surgery needed to treat these injuries.

Posterior sacroiliac fixation using a sacral pedicle targeting device: an anatomical study.

This study compares the accuracy of posterior sacroiliac (SI) screw placement using a "free-hand" method, without the use of fluoroscopy, versus a specially developed targeting device. Posterior SI screws were inserted after exposing the iliac wing in five cadavers on one side, and inserted percutaneously with a unique targeting device on the opposite side. Fluoroscopy was not used for screw or pedicle placement on either side. Computed tomography and dissection results were then used to grade screw placement for both sides. A statistically significant difference between the sides was found. More importantly, three screws on the free-hand side violated major neurovascular structures. The regional anatomy was defined: structures most at risk are the iliac vein ventrally and the sacral canal dorsally. A highly variable "safe zone" (mean arc 43 degrees at the S1 level and 30 degrees at the S2 level) was established. Inclination of the SI joint was also defined (mean 29 degrees at the S1 level and 17 degrees at the S2 level). SI screw placement using the specially developed targeting device is technically less demanding, requires less soft tissue dissection, allows variable placement, and poses minimal risk to major neurovascular structures. Our limited clinical experience with the device is encouraging. The potential application of this technique to unstable vertical shear fractures is appealing.

Age-related disk degeneration: preliminary report of a naturally occurring baboon model.

Anteroposterior and lateral radiographs of 126 adult baboons were reviewed. The mean age was 15.7 years (range 6-30 years). Evidence of disk degeneration, to include disk-space narrowing, osteophyte formation, endplate changes, and facet joint arthropathy, was noted, and a grading scale, grades 0-3, was used to assign each animal an overall grade for degree of disk degeneration. Lateral radiographs were measured in the area of maximal sagittal plane curvatures. Radiographic review demonstrated a strongly positive correlation between the age of the baboons and the degree of degenerative change (p less than 0.0001), between the degree of kyphosis and the degree of degenerative change (p less than 0.0001), and between the age of the animal and the degree of kyphosis (p less than 0.001). This pilot study demonstrates plain radiographic confirmation of a naturally occurring primate model of disk degeneration, the first such model described, and is the basis for further investigation into magnetic resonance imaging and histopathologic confirmation of this model.

The histomorphologic sequence of dural repair. Observations in the canine model.

This study was undertaken to investigate the histopathologic events of the dural reparative process. Uniform 2-mm dural defects were created in adult beagles, repaired, and then examined in a 6-week period. Primary fibroblastic bridging of the durotomy was not seen until Postoperative Day 6, and it was not until Postoperative Day 10 that ablation of this defect was uniformly seen. Cerebrospinal fluid egress through the dural defects was prevented in the vast majority of cases by the formation of an internal patch composed of proliferative elements of pia and arachnoid mater.

Quantification of leakage pressures after durotomy repairs in the canine.

This study was undertaken to investigate the relative strengths of dural repair using standard suture techniques, suture supplemented with tissue adhesive, and tissue adhesive alone. Uniform 2 mm dural defects were created in adult beagles, repaired, and then subjected to pressurization testing. Defects repaired with suture alone initially leaked within the range of physiologic pressurization, while those supplemented with tissue adhesive or repaired with tissue adhesive alone failed at higher pressurization levels. Histologic sections obtained from the dura treated with fibrin adhesive sealant demonstrated minimal inflammatory response not significantly different than those sections examined at sites repaired by suture alone. A new substance, fibrin adhesive sealant, appears to be useful in effecting dural repair due to its ability to withstand pressures greater than those obtained with suture alone.

The neuroradiographic diagnosis of lumbar herniated nucleus pulposus: II. A comparison of computed tomography (CT), myelography, CT-myelography, and magnetic resonance imaging.

The accuracy of computed tomography (CT), myelography, CT-myelography (myelo-CT) and magnetic resonance imaging (MRI) for the diagnosis of lumbar herniated nucleus pulposus (HNP) is compared prospectively in 59 patients, all of whom underwent surgical exploration. All tests were read independently of each other and the level of confidence in each diagnosis was recorded. The results are based on the negative (61) as well as positive (59) findings at the 120 disc sites (level and side) explored. Magnetic resonance imaging was the most accurate test (76.5%) compared with myelo-CT (76.0%), CT (73.6%), and myelography (71.4%). The false positive rate was lowest for MRI (13.5%) followed by myelography (13.7%), CT (13.8%), and myelo-CT (21.1%). The false negative rate was lowest for myelo-CT (27.2%) followed by MRI (35.7%), CT (40.2%), and myelography (44.1%). In that subset of 19 patients who had prior surgery, myelography was the most accurate means of diagnosing lumbar HNP (88.8%), followed by MRI (83.3%), myelo-CT (78.4%), and CT (72.6%). The false positive rates in these patients were 11.6% for myelography, 13.2% for MRI, 14.5% for CT, and 16.4% for myelo-CT; the false negative rates were 22.7% for MRI, 24.4% for myelography, 29.5% for myelo-CT, and 47.7% for CT. Magnetic resonance imaging compares very favorably with other currently available imaging modalities for diagnosing lumbar HNP. Magnetic resonance imaging is painless, has no known side effects or morbidity, no radiation exposure, and is noninvasive. The authors recommend it as the procedure of choice for the diagnosis of most lumbar disc herniations.

Evaluation of dural closure techniques. Suture methods, fibrin adhesive sealant, and cyanoacrylate polymer.

A study was undertaken to investigate the relative strengths of dural repair using standard suture techniques, suture supplemented with tissue adhesive, and tissue adhesive alone. The efficacy of two tissues adhesives, fibrin adhesive sealant and cyanoacrylate polymer, as adjunctive or the sole means of effecting dural closure, was studied. In vitro analysis of repair techniques was accomplished using fresh human cadaveric dura. Uniform 4 mm defects were created, repaired using various techniques, and then subjected to pressurization testing. Defects repaired with suture alone leaked at pressurization levels within the physiologic range, while those supplemented with tissue adhesives failed at higher pressurization levels. In vitro testing, accomplished in white New Zealand rabbits, supported this conclusion. Histologic sections obtained from dura treated with fibrin adhesive sealant demonstrated minimal inflammatory response, while those sections obtained at the site of dural repair augmented with cyanoacrylate polymer featured significant inflammatory responses, including dural thinning, gliosis, and cortical necrosis. Results indicate that a new substance, fibrin adhesive sealant, appears to have application as an adjunctive means of effecting dural closure.

Hamatometacarpal fracture-dislocation: classification and treatment.

Seventeen male patients with a fourth metacarpal fracture and fifth carpometacarpal joint injury were treated. Distinct patterns of injury were recognized and in each case fell into one of three categories. Type IA lesions were characterized by subluxation or dislocation of the fifth carpometacarpal joint without hamate avulsion fracture. Type IB lesions were identical to type IA lesions except for the appearance of a small dorsal rim hamate avulsion fracture. Type II lesions were distinguished by subluxation or dislocation of the fifth carpometacarpal joint and comminution of the dorsal hamate rim. Finally, type III lesions exhibited coronal splitting of the hamate.