Paclitaxel enhanced radiation sensitization for the suppression of human prostate cancer tumor growth via a p53 independent pathway

BACKGROUND: This study investigated the influence of p53 status on treatment using combined paclitaxel and irradiation for human prostate cancer (PC) in vitro and in vivo. METHODS: Enhancement of the radiation response by paclitaxel was determined by MTT and clonogenic assays in four sublines of the human PC cell line, LNCaP, stably transfected to express different p53 mutations found in PC patients. Suppression of xenograft growth by combined paclitaxel and radiation was assessed in NOD.SCID mice in vivo. Expression of p53 and downstream functional proteins, p21 and Bax, was assessed by Western blotting. RESULTS: Paclitaxel (8-10 nM) suppressed cell proliferation by 50% by inducing G2M mitotic arrest in LNCaP cell lines transfected to overexpress wild-type or mutant p53. Exposure to 20 nM paclitaxel before radiation therapy enhanced cytotoxicity in clonogenic assays. The dose and duration of paclitaxel exposure were important in inducing both G2M arrest and cell growth suppression and were critical factors in paclitaxel/irradiation combination therapy. Western blotting indicated that combination therapy increased p21 protein expression to varying degrees in all cell lines. In vivo studies indicated that paclitaxel pre-treatment followed by irradiation significantly suppressed tumor growth compared with either treatment alone. CONCLUSIONS: Pre-treatment with paclitaxel enhances radiation efficacy on cell killing and suppression of growth of human PC cell lines in vitro and in vivo via p53 independent pathways. Paclitaxel has potential for use as a radiosensitizer in the treatment of patients with PC with either wild-type or mutant p53 genetic status.     

Completion thyroidectomy versus total thyroidectomy: is there a difference in complication rates? An analysis of 350 patients

BACKGROUND: This study compared our experience with completion thyroidectomy (CT) and total thyroidectomy (TT) in the management of well-differentiated thyroid cancer (WDTC). We compared complication rates and analyzed the implications of the intraoperative management of the parathyroid glands. STUDY DESIGN: We performed a retrospective cohort study comparing outcomes between patients undergoing CT and TT between January 1994 and December 2004. All patients had surgery for either suspected or confirmed WDTC on fine-needle aspiration. RESULTS: There were 201 CTs and 149 TTs. Mean hospital stays were 4.5 and 3.5 days for the CT and TT groups, respectively (p=0.001). Temporary recurrent laryngeal nerve paresis occurred in 2.0% (4 of 201) and 3.3% (5 of 149) of patients in the CT and TT groups, respectively. There was one (0.5%) case of permanent recurrent laryngeal nerve paralysis in the CT group. Permanent hypoparathyroidism rates were 2.5% and 3.3% in the CT and TT groups, respectively. There was no difference between the two groups in terms of total numbers of parathyroid glands autotransplanted (p=0.63) or present in the specimen (p=0.26). CONCLUSIONS: Completion thyroidectomy is a safe and appropriate option in the management of select cases of WDTC in which a definitive preoperative or intraoperative diagnosis is not available. But it requires a longer hospitalization, so it has implications for both hospital resources and the patients involved.     

The use of chest computed tomography versus chest X-ray in patients with major blunt trauma

INTRODUCTION: Computed tomography (CT) scans are often used in the evaluation of patients with blunt trauma. This study identifies the clinical features associated with further diagnostic information obtained on a CT chest scan compared with a standard chest X-ray in patients sustaining blunt trauma to the chest. METHODS: A 2-year retrospective survey of 141 patients who attended a Level 1 trauma centre for blunt trauma and had a chest CT scan and a chest X-ray as part of an initial assessment was undertaken. Data extracted from the medical record included vital signs, laboratory findings, interventions and the type and severity of injury. RESULTS: The CT chest scan is significantly more likely to provide further diagnostic information for the management of blunt trauma compared to a chest X-ray in patients with chest wall tenderness (OR=6.73, 95% CI=2.56, 17.70, p<0.001), reduced air-entry (OR=4.48, 95% CI=1.33, 15.02, p=0.015) and/or abnormal respiratory effort (OR=4.05, 95% CI=1.28, 12.66, p=0.017). CT scan was significantly more effective than routine chest X-ray in detecting lung contusions, pneumothoraces, mediastinal haematomas, as well as fractured ribs, scapulas, sternums and vertebrae. CONCLUSION: In alert patients without evidence of chest wall tenderness, reduced air-entry or abnormal respiratory effort, selective use of CT chest scanning as a screening tool could be adopted. This is supported by the fact that most chest injuries can be treated with simple observation. Intubated patients, in most instances, should receive a routine CT chest scan in their first assessment.     

Structural determinants of vertebral fracture risk.

Vertebral fractures are more strongly associated with specific bone density, structure, and strength parameters than with areal BMD, but all of these variables are correlated. INTRODUCTION: It is unclear whether the association of areal BMD (aBMD) with vertebral fracture risk depends on bone density per se, bone macro- or microstructure, overall bone strength, or spine load/bone strength ratios. MATERIALS AND METHODS: From an age-stratified sample of Rochester, MN, women, we identified 40 with a clinically diagnosed vertebral fracture (confirmed semiquantitatively) caused by moderate trauma (cases; mean age, 78.6 +/- 9.0 yr) and compared them with 40 controls with no osteoporotic fracture (mean age, 70.9 +/- 6.8 yr). Lumbar spine volumetric BMD (vBMD) and geometry were assessed by central QCT, whereas microstructure was evaluated by high-resolution pQCT at the ultradistal radius. Vertebral failure load ( approximately strength) was estimated from voxel-based finite element models, and the factor-of-risk (phi) was determined as the ratio of applied spine loads to failure load. RESULTS: Spine loading (axial compressive force on L3) was similar in vertebral fracture cases and controls (e.g., for 90 degrees forward flexion, 2639 versus 2706 N; age-adjusted p = 0.173). However, fracture cases had inferior values for most bone density and structure variables. Bone strength measures were also reduced, and the factor-of-risk (phi) was 35-37% greater (worse) among women with a vertebral fracture. By age-adjusted logistic regression, relative risks for the strongest fracture predictor in each of the five main variable categories were bone density (total lumbar spine vBMD: OR per SD change, 2.2; 95% CI, 1.1-4.3), bone geometry (vertebral apparent cortical thickness: OR, 2.1; 95% CI, 1.1-4.1), bone microstructure (none significant); bone strength ("cortical" [outer 2 mm] compressive strength: OR, 2.5; 95% CI, 1.3-4.8), and factor-of-risk (phi for 90 degrees forward flexion/overall vertebral compressive strength: OR, 3.2; 95% CI, 1.4-7.5). These variables were correlated with spine aBMD (partial r, -0.32 to 0.75), but each was a stronger predictor of fracture in the logistic regression analyses. CONCLUSIONS: The association of aBMD with vertebral fracture risk is explained by its correlation with more specific bone density, structure, and strength parameters. These may allow deeper insights into fracture pathogenesis.     

Evaluation of 18 F-fluorodeoxyglucose positron emission tomography and computed tomography with histopathologic correlation in the initial staging of head and neck cancer

OBJECTIVE: To prospectively evaluate the use of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) in the initial staging of squamous cell head and neck carcinoma. SUMMARY BACKGROUND DATA: The status of cervical lymph nodes is an important prognostic factor and determinant of management approach in squamous cell head and neck cancer. METHODS: FDG-PET findings were compared with those of computed tomography (CT) before removal of the primary tumor and/or neck dissection. Histopathologic analysis was used as the gold standard for assessment of the sensitivity and specificity of these modalities. RESULTS: FDG-PET correctly identified the primary tumor in 35 of 40 patients in whom the site of the primary was known clinically and still present (sensitivity 88%). None of four unknown primaries were detected. Tumors not detected by FDG-PET were generally superficial, with depths of less than 4 mm. CT correctly identified 18 of the 35 primary tumors (sensitivity 51%). Eleven of 17 CT false-negative tumors were detected by FDG-PET. The sensitivity and specificity for the presence of metastatic neck disease on FDG-PET were 82% and 100%, respectively; those for CT were 81% and 81%, respectively. FDG-PET was true positive for metastatic neck disease in two of the three CT false-negative patients. CONCLUSIONS: FDG-PET shows promise in the initial staging of head and neck cancer and provides additional accuracy to a conventional staging process using CT.     

Sulfonylurea-sensitive K(+) transport is involved in Cl(-) secretion and cyst trowth by cultured ADPKD cells

Transepithelial chloride and fluid secretion by many types of epithelia involves activation of a conductive K(+) pathway that serves to support the electrochemical driving force for Cl(-) secretion. This study sought to determine if such a pathway is involved in Cl(-) and fluid secretion by the cystic epithelia in autosomal dominant polycystic kidney disease (ADPKD). Primary cultures of cells derived from the cysts of patients with ADPKD were used. Confluent monolayers of these cells, mounted in Ussing chambers, were stimulated to secrete Cl(-) by application of the adenylyl cyclase agonist, forskolin. The effects of various K(+) channel blockers on the increase in short-circuit current (I(sc)) generated by active Cl(-) secretion were determined. Charybdotoxin, an inhibitor of Ca(2+)-sensitive K(+) channels exerted no effect. Similarly, the chromanole 293B, an inhibitor of cAMP-induced K(+) conductance, exerted no effect on cAMP-dependent anion secretion. Glibenclamide, an inhibitor of ATP-sensitive K(+) channels and the cystic fibrosis transmembrane conductance regulator (CFTR), modestly inhibited the forskolin-stimulated current when applied to the apical surface of the monolayers, suggesting a relatively weak effect on CFTR. Basolateral application of glibenclamide inhibited I(sc) to a greater extent. This latter effect may be due to inhibition of a K(+)-conductive transport step. Glibenclamide exerted little effect on the I(sc) of nonstimulated monolayers. Cyst growth in ADPKD is driven by cell proliferation and Cl(-) and fluid secretion. The effect of glibenclamide on the growth of cysts formed within a collagen gel by cultured ADPKD cells was tested. Addition of glibenclamide to the media bathing the cysts inhibited their growth. Glibenclamide also blocked the formation of cysts when it was added to the media at the time the cells were seeded within the collagen gel. Glibenclamide was also found to inhibit the proliferation of ADPKD cells. RT-PCR analysis demonstrated that the ATP-sensitive K(+) channel, K(ir) 6.2, is expressed in cultured ADPKD cells and in normal human kidney. These results suggest that ATP-sensitive K(+) channel blockers should be investigated as possible therapeutic agents to inhibit cyst growth in ADPKD.     

The association between isoinertial trunk muscle performance and low back pain in male adolescents

The literature reports inconsistent findings regarding the association between low back pain (LBP) and trunk muscle function, in both adults and children. The strength of the relationship appears to be influenced by how LBP is qualified and the means by which muscle function is measured. The aim of this study was to examine the association between isoinertial trunk muscle performance and consequential (non-trivial) low back pain (LBP) in male adolescents. Healthy male adolescents underwent anthropometric measurements, clinical evaluation, and tests of trunk range of motion (ROM), maximum isometric strength (STRENGTH) and peak movement velocity (VEL), using an isoinertial device. They provided information about their regular sporting activities, history and family history of LBP. Predictors of “relevant/consequential LBP” were examined using multivariable logistic regression. LBP status was reassessed after 2 years and the change from baseline was categorised. At baseline, 33/95 (35%) subjects reported having experienced consequential LBP. BMI, a family history of LBP, and regularly playing sport were each significantly associated with a history of consequential LBP (p < 0.05). 85/95 (89%) boys participated in the follow-up: 51 (60%) reported no LBP at either baseline or follow-up (never LBP); 5 (6%) no LBP at baseline, but LBP at follow-up (new LBP); 19 (22%) LBP at baseline, but none at follow-up; and 10 (12%) LBP at both time-points (recurrent/persistent LBP). The only distinguishing features of group membership in these small groups were: fewer sport-active in the “never LBP” group); worse trunk mobility, in the “persistent LBP” group, lower baseline sagittal ROM in the “never LBP” and “new LBP” (p < 0.05). Regular involvement in sport was a consistent predictor of LBP. Isoinertial trunk performance was not associated with LBP in adolescents.     

Protection From the Second Warm Ischemic Injury in Kidney Transplantation Using an Ex Vivo Porcine Model and Thermally Insulating Jackets

BackgroundKidney transplantation is the optimum treatment for kidney failure in carefully selected patients. Technical surgical complications and second warm ischemic time (SWIT) increase the risk of delayed graft function (DGF) and subsequent short- and long-term graft outcomes including the need for post-transplant dialysis and graft failure. Intraoperative organ thermal regulation could reduce SWIT, minimizing surgical complications due to time pressure, and limiting graft ischemia-reperfusion injury.MethodsA novel ischemic-injury thermal protection jacket (iiPJ) was designed and fabricated in silicone composite and polyurethane (PU) elastomer prototypes. Both were compared with no thermal insulation as controls. Time to reach ischemic threshold (15°C) and thermal energy transfer were compared. A water bath model was used to examine the thermal protective properties of porcine kidneys, as a feasibility study prior to in vivo translation.ResultsIn both iterations of the iiPJ, the time taken to reach the warm ischemia threshold was 35.2 ± 1.4 minutes (silicone) and 38.4 ± 3.1 minutes (PU), compared with 17.2 ± 1.5 minutes for controls (n = 5, P < .001 for both comparisons). Thermal energy transfer was also found to be significantly less for both iiPJ variants compared with controls. There was no significant difference between the thermal performance of the 2 iiPJ variants.ConclusionProtection from SWIT by using a protective insulation jacket is feasible. With clinical translation, this novel strategy could facilitate more optimal surgical performance and reduce transplanted organ ischemia-reperfusion injury, in particular the SWIT, potentially affecting delayed graft function and long-term outcomes.     

Favorable results of acetabular reconstruction with impacted morsellized bone grafts in patients younger than 50 years: A 10- to 18-year follow-up study of 34 cemented total hip arthroplasties

We report a long-term review of 41 acetabular reconstructions using impacted morsellized bone grafts and a cemented total hip arthroplasty (THA) in patients younger than 50 (22-49; average 38) years. Reconstruction was performed in 23 primary THA (19 patients) and 18 revision THA (17 patients). 3 patients were lost to follow-up and 3 (4 hips) died within 10 years of surgery; none had a revision. Thus, 34 hips (30 patients) were reviewed with an average follow-up of 13 (10-18) years. In 2 hips, a revision was performed for aseptic loosening of the acetabular component 7 and 11 years after surgery. One additional cup was revised after 12 years during a femoral stem revision due to wear and matching problems, but was well fixed. The survival rate of the acetabular reconstruction technique was 94% (95% CI: 90-98%).     

Evaluation of polyurethane stent implantation for the treatment of complete obstruction of the nasolacrimal system: 8-month follow-up and complications

Dacryocystorhinostomy is still the standard procedure complete stenosis of the nasolacrimal duct. New methods try to preserve the natural lacrimal pathway. Song implanted in 1995 a nasolacrimal polyurethane stent through the nasolacrimal duct. The results and complications of this new method are described in this prospective study. METHODS: Thirty consecutive patients with complete obstruction of the nasolacrimal duct or lacrimal sac were included in the study. The stenosis was localized by dacryocystography. The ages ranged from 22 to 87 years (mean, 58.9 +/- 16 years). Dacryocystography was performed immediately, 4 weeks and 8 months after the procedure to verify the position and patency of the stent. RESULTS: Twenty-five short (35 mm) and 5 long (45 mm) stents were implanted. Twenty-four of 30 patients after 4 weeks and 9 of 10 patients after 8 months had reduced or no complaints. In 1 patient the stent was obstructed. Forceful irrigation with saline solution permitted recanalization. In 1 patient the stent had moved into the upper canaliculus. Because of irritation of the canaliculus it had to be pulled out after 2 months. CONCLUSION: The follow-up is still too short to recommend stent implantation as a real alternative to dacryocystorhinostomy. The main advantages are that the procedure is faster, no incision is necessary, and the local anesthesia is easier. The disadvantage is the need for X-ray examination.