John A. Handal

Atorvastatin activates heme oxygenase‐1 at the stress response elements

Statins are known to inhibit growth of a number of cancer cells, but their mechanism of action is not well established. In this study, human prostate adenocarcinoma PC‐3 and breast adenocarcinoma MCF‐7 cell lines were used as models to investigate the mechanism of action of atorvastatin, one of the statins. Atorvastatin was found to induce apoptosis in PC‐3 cells at a concentration of 1 μM, and in MCF‐7 cells at 50 μM. Initial survey of possible pathway using various pathway‐specific luciferase reporter assays showed that atorvastatin‐activated antioxidant response element (ARE), suggesting oxidative stress pathway may play a role in atorvastatin‐induced apoptosis in both cell lines. Among the antioxidant response genes, heme oxygenase‐1 (HO‐1) was significantly up‐regulated by atorvastatin. Pre‐incubation of the cells with geranylgeranyl pyrophosphate blocked atorvastatin‐induced apoptosis, but not up‐regulation of HO‐1, suggesting that atorvastatin‐induced apoptosis is dependent on GTPase activity and up‐regulation of HO‐1 gene is not. Six ARE‐like elements (designated StRE1 [stress response element] through StRE6) are present in the HO‐1 promoter. Atorvastatin was able to activate all of the elements. Because these StRE sites are present in clusters in HO‐1 promoter, up‐regulation of HO‐1 by atorvastatin may involve multiple StRE sites. The role of HO‐1 in atorvastatin‐induced apoptosis in PC‐3 and MCF‐7 remains to be studied.

Effect of atorvastatin on the cortical bones of corticosteroid treated rabbits

Osteoporosis (“secondary” osteoporosis) and avascular necrosis (AVN) of the femoral head are well‐known adverse effects of corticosteroid therapy. Statins have been reputed to increase bone strength and bone density. In this study, we evaluated the effect of atorvastatin calcium on the flexural properties (3‐point bending strength and modulus) of corticosteroid (methylprednisolone acetate) treated rabbit femurs and tibias. Our study hypothesis was that the use of statins would counteract the loss of bone strength caused by corticosteroid treatment. The 40 rabbits were divided into 5 groups: control, corticosteroid alone and corticosteroid combined with oral doses of atorvastatin calcium (2, 10, or 20 mg/day). A daily oral dose of atorvastatin calcium treatment for 70 days weakened the long bones of methylprednisolone acetate treated rabbits irrespective of the dosage (2, 10, or 20 mg). Cortical bone strength was assessed using the 3‐point bending test at the end of the study period. A daily oral dose of atorvastatin calcium did not attenuate the loss of cortical bone strength caused by corticosteroid treatment in rabbits. It appeared to decrease that bone strength. If these results hold true in humans, they would have wide applicability given the frequent combined use of corticosteroids and statins in many patients.

Fatal fat embolism in isolated vertebral compression fracture

Fat embolism after long bone and pelvic fractures as well as orthopedic interventions is a well-documented phenomenon, but it is highly unusual after isolated vertebral fractures. We report a case of fatal fat embolism in a 78-year-old man after an isolated vertebral compression fracture with no related orthopedic intervention. A high index of suspicion is necessary for early diagnosis and successfully treating this unusual complication.

The irreducible floating hip: a unique presentation of a rare injury

A floating hip injury occurs in the setting of poly-trauma and is a rare and difficult problem to manage. Floating hip injuries require vigilant attention not only to the osseous injuries but also the surrounding compartments and soft tissue envelope. We report the case of a 35-year-old male with a lower extremity posterior wall acetabular fracture, ipsilateral femoral shaft fracture and a postero-superior hip dislocation. Closed reduction failed, necessitating an open reduction internal fixation of his hip dislocation and acetabular fracture. The patient then developed a thigh compartment syndrome requiring a fasciotomy. Despite the obvious bony injuries, orthopedic surgeons must be vigilant of the neurovascular structures and soft tissues that have absorbed a great amount of force. A treatment plan should be formulated based on the status of the overlying soft tissue, fracture pattern and the patients physiologic stability.

Polyethylene glycol improves elution properties of polymethyl methacrylate bone cements

BACKGROUND Bone cements are used as adjuncts to fracture fixation methods and can also function as a local drug delivery system. The ability to elute drugs makes bone cement a promising and powerful chemotherapy treatment modality for osseous tumors. However, because of poor elution rates, the clinical application of this drug delivery mode remains challenging. Soluble fillers, such as sugars, salts, or biocompatible polymers, offer a solution to improve elution rates. This study quantified the effect of polyethylene glycol (PEG) on the elution properties of three commercially available bone cements. METHODS Two grams of Vertebroplastic, Palacos, and Confidence bone cement powder containing three concentrations (0%, 20%, or 50%) of PEG filler were hand mixed with 10 mg of methotrexate. This powder mixture was then polymerized with 1.0 mL of the cement specific liquid monomer. The cylindrical elution samples were placed in saline solution and methotrexate elution was recorded for 720 h. RESULTS The cumulative and daily elution rate increased as the concentration of PEG increased for each bone cement. However, the percent of increase depended on the bone cement used. Cumulative methotrexate elution increased by 40%-54% in case of the highest PEG filler concentration when compared with controls. CONCLUSIONS PEG soluble filler offers a promising method for improving methotrexate drug elution in bone cement. Future studies need to optimize the PEG and bone cement ratio that produces the greatest drug elution profile without sacrificing the biomechanical properties of bone cement.

Successful treatment of a T4 lung tumor with vertebral body invasion using fiducial markers in the thoracic spine for image-guided radiation therapy: A case report

IntroductionParavertebral and paraspinal tumors pose a significant challenge in radiation therapy because of the radiation sensitivity of the spinal cord and the need for maximum treatment accuracy. Implantation of fiducial markers into vertebral bodies has been described as a method of increasing the accuracy of radiation treatment for single-dose stereotactic radiosurgery for spinal and paraspinal primary tumors and metastases. However, utilization of this technique has not been described for conventionally fractionated radiation therapy. This report is the first of its kind in the literature and describes successful treatment of a T4 primary lung tumor with vertebral body invasion with conventionally fractionated, image-guided radiotherapy using fiducial markers implanted in the thoracic spine.Case presentationOur patient was a 47-year-old African-American man who presented to our hospital with a history of several months of increasing left arm pain, chest pain, dyspnea on exertion, occasional dry cough, and weight loss. He was found to have stage IIIA T4, N0, M0 lung cancer with vertebral body invasion. He had fiducial markers placed in the thoracic spine for image-guided radiation treatment set-up. The patient received 74 Gy radiation therapy with concurrent chemotherapy, and daily matching of the fiducial markers on the treatment machine allowed for treatment of the tumor while sparing the dose to the adjacent spinal cord. With one year of clinical follow-up, the patient has had regression of the tumor with only asymmetric soft-tissue thickening seen on a computed tomographic scan and grade 1 dyspnea on exertion as the only side effects of the treatment.ConclusionFiducial marker placement is a safe and effective technique for maximizing the accuracy and reproducibility for radiation treatment of lesions near the spinal cord. This technique may be used in conventionally fractionated radiation treatment regimens, such as those employed to treat a lung tumor with vertebral body invasion, to potentially improve clinical outcomes for patients.