Muscle cell-mediated gene delivery to the rotator cuff

Rotator cuff lesions are one of the most common causes of upper extremity disability. Surgical therapy addresses mostly the extrinsic etiology, but not intrinsic factors such as aging, structural changes, low vascularity, and inflammatory processes. In this study, genetically engineered, highly purified muscle-derived cells (MDCs) were characterized and injected into the supraspinatus tendons of nude rats. The injected cells were monitored for 3 weeks. In vitro, the engineered, highly purified MDCs do not express vimentin; 98% of them are positive for the beta-galactosidase marker gene, and 99% hybridize with the specific pancentromeric mouse probe. beta-Galactosidase marker gene expression of the injected cells was detected up to 21 days. From day 7 after injection, the cell nuclei became spindle shaped, cells were integrated into the tendon collagen bundles, and the cells showed differentiation into vimentin-expressing fibroblastic cells. The results indicate that the rotator cuff tendon matrix and its original cellular components modulated the injected MDCs toward a fibroblastic phenotype. The compatibility and ability of MDCs to differentiate into other cell lineages, such as fibroblasts, might have high potential utility in tissue-engineering applications for tendon healing. This approach facilitates the application of muscle-derived progenitor cells and ex vivo gene therapy for the treatment of rotator cuff lesions.     

Laparoscopic pancreatic resections

The feasibility of laparoscopic pancreatic resection has been demonstrated. However, the real clinical benefit for the patients remains questioned. The best indication for a laparoscopic approach appears to be the resection of benign or neuro-endocrine tumors without a need for pancreato-enteric reconstruction (i.e enucleation or distal pancreatectomy). The use of the laparoscopic approach for malignant tumors still remains controversial. The benefits of minimally invasive surgery are clearly correlated with the successful management of the pancreatic stump. Pancreatic related complication rate (fistula and collection) is 15% when using pancreatic transection with a laparoscopic endostappler.     

Positron emission tomography in clinical oncology

A NEW FORM OF MEDICAL IMAGING: Positron emission tomography (PET) is used for the non-invasive in vivo visualisation of biochemical cell processes. It reveals the metabolic characteristics of neoplastic lesions and hence their identification by compensating the lack of lesion specificity of radiological techniques. VARIOUS INDICATIONS: Using the current oncology marker, 18F-fluorodeoxyglucose (FDG), excellent results with PET have been established at all stages of neoplasia, notably for the diagnosis of initial malignancy and the identification of residual lesions and early detection of relapses. Moreover, the fact that the whole of the body can be explored makes PET the tool of choice in the control of the extension and operability of cancers. With the close correlation between imaging and the metabolism of the lesions, PET is the earliest and most precise for assessing the effects of treatment. LIMITS AND PERSPECTIVES: The existence of benign inflammatory FDG binding should lead to the development of markers of other metabolisms directly linked to cell proliferation. The lack of anatomical reference points characteristic of PET does not permit the precise localisation of the lesions detected and could be corrected by combining, in a single apparatus, the PET camera and an X scan, the anatomical resolution of which is irreplaceable. This type of equipment represents the development of a new branch of medical imaging, oncological imaging.     

Strontium ranelate: a new paradigm in the treatment of osteoporosis

Not one of the currently available medications has, so far, unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once osteoporosis is established. Therefore, several new therapies are currently under development to optimize the risk/benefit ratio of osteoporosis treatment. Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable nonradioactive strontium. In vitro, strontium ranelate increases collagen and noncollagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cell replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cell and collagen, as well as noncollagenic protein synthesis in osteoblasts, provides substantial evidence to categorize strontium ranelate as a bone-forming agent. In the isolated rat osteoclast assay, a pre-incubation of bone slices with strontium ranelate induced a dose- dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both carbonic anhydrase II and the alpha-subunit of the vitronectin receptor. These effects showing that strontium ranelate significantly affects bone resorption due to a direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation, are compatible with the profile of an anti-resorptive drug. In normal rats, administration of strontium ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. Strontium ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg and 1 g of strontium ranelate were compared with a placebo. At the conclusion of the study, the percent variation of lumbar-adjusted bone mineral density from baseline was significantly different in the group receiving 1 g/day of strontium ranelate compared with placebo (+1.41% vs. -0.98%, respectively). Increase in total hip and neck bone mineral density averages, respectively, 3.2% and 2.5%. Strontium ranelate does not induce any significant adverse reaction compared with those observed in women receiving a placebo for the same duration. In a phase II study, the effect of strontium ranelate in postmenopausal women with vertebral osteoporotic fractures was assessed during a double-blind, placebo-controlled trial. Doses of 500 mg, 1 g and 2 g daily of strontium ranelate or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar-adjusted bone mineral density of the group receiving 2 g of strontium ranelate was + 2.97%. This result was significantly different compared with placebo. A significant increase in bone alkaline phosphatase and, over a 6-month period, a significant decrease in urinary-pyridium crosslinks (NTX) were evidenced. During the second year of treatment, the dose of 2 g was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralization defects. The same percentage of withdrawals following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. The compound was further investigated in a large phase III program that included two extensive trials for the treatment of severe osteoporosis, one assessing the effects of strontium ranelate on the risk of vertebral fractures (SOTI) and one evaluating its effects on peripheral (nonspinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates, revealed a 41% reduction in the relative risk of expein the relative risk of experiencing a first new vertebral fracture with strontium ranelate, throughout the 3-year study, compared with placebo. The TROPOS study, showed a significant (p = 0.05) reduction in the relative risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study compared with placebo in the intention-to-treat population. A 41% reduction in the relative risk of experiencing a hip fracture was demonstrated in the per protocol population. All these results imply that strontium ranelate is a new, effective and safe treatment for vertebral and nonvertebral osteoporosis, with a unique mode of action.     

Gallstones--an increasing problem: a study of hospital admissions in England between 1989/1990 and 1999/2000

BACKGROUND: The number of operations for cholelithiasis increased from the 1950s to the 1990s. AIMS: To determine the time trends in cholelithiasis for hospital admissions, operations and in-hospital case fatalities in England between 1989/1990 and 1999/2000, and population mortality rates between 1979 and 1999. METHODS: Hospital Episode Statistics for admissions were obtained from the Department of Health and mortality data were obtained from the Office for National Statistics. RESULTS: Between 1989/1990 and 1999/2000, age-standardized hospital admission rates for cholelithiasis increased by 30% for males and 64% for females. The proportions of admissions undergoing an operation declined progressively over the study period. In 1999/2000, the frequency of operation was approximately 50-60% for most age groups, but decreased progressively with advancing age at > or = 65 years. The proportions of admissions undergoing therapeutic endoscopy increased several-fold, especially amongst older individuals. Case fatality rates declined. Mortality rates declined from 1979 to 1988, but showed no further change from 1989 to 1999. CONCLUSIONS: There has been a steady increase in admission rates for cholelithiasis over the study period. Whilst the frequency of operation has declined, the proportion of patients undergoing therapeutic endoscopy has increased.     

Clinical significance of proliferative potential of occult metastatic cells in bone marrow of patients with breast cancer

There is increasing statistical evidence that the presence of tumour cells in bone marrow detected by immunocytochemistry represents an important prognostic indicator in breast cancer, but their individual capacity to become clinical metastases is unknown. The aim of this study was to assess the proliferative capacity of these occult metastatic cells in the bone marrow of patients with various stages of breast cancer. We obtained bone marrow aspirates from 60 patients with breast cancer before treatment with chemotherapy: 17 stage II, 12 stage III and 31 stage IV. After bone marrow culture for 6-34 days (median: 17 days) under specific cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 40 patients (66%). Expansion of tumour cells was poorly correlated with tumour cell detection on primary screening (P=0.06). There was a nonsignificant correlation between the number and the presence of expanded tumour cells and the UICC stage of the patients. On primary screening, tumour cell detection was positive in 56% of patients and was correlated with clinical UICC stage (P=0.01). However, with a median follow-up of 23 months, expansion of tumour cells from bone marrow was associated with decreased patient survival (P=0.04), whereas the survival difference according to detection of CK-positive cells on primary screening was not statistically significant. In conclusion, viable tumour cells can be detected in the bone marrow of breast cancer patients. Their proliferative potential could be predictive of outcome and deserves further investigation.     

Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients

Prediction of survival for patients with metastatic breast cancer is often inaccurate and may be helped by new biological parameters. Tumour growth being angiogenesis-dependent, it has been hypothesised that the assessment of angiogenic factor production might reflect the clinical behaviour of cancer progression. This study was designed to investigate the clinical significance of vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in hormone-refractory metastatic breast cancer. Serum and plasma concentrations of VEGF and serum concentration of IL-6 were measured in 87 patients with a fully documented history of metastatic breast cancer using an enzyme-linked immunoassay. All patients had detectable levels of VEGF, whereas 39% patients had detectable serum levels of IL-6. There was a positive correlation between IL-6 levels and the theoretical VEGF load of platelets (P<0.001). The presence of high levels of serum IL-6, but not VEGF, was significantly correlated to a shorter survival. In a multivariate analysis along with clinical prognostic parameters, serum IL-6 was identified as an independent adverse prognostic variable for overall survival (P&<0.001). These results indicate that serum IL-6 levels correlate to poor survival in patients with hormone-refractory metastatic breast cancer. Vascular endothelial growth factor serum and plasma levels are not useful indicators of prognosis for these patients.     

Evaluation of core needle biopsy as a substitute to open biopsy in the diagnosis of soft-tissue masses

Open biopsy is recommended for a soft-tissue sarcoma (s-t-S) diagnosis. Core needle biopsy (CNB) was recently associated with minimal morbidity, cost and time-consumption, but also potential inaccuracy. Its diagnostic utility was investigated retrospectively in 110 patients with soft-tissue masses (s-t-M) undergoing CNB between September 1994 and September 2000. Sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values were determined for malignancy (benign/malign), soft-tissue tumour (yes/no), and sarcoma diagnosis (yes/no), comparing CNB and the best standard test available; concordance was evaluated. 103/110 CNB were suitable for analysis. Final diagnosis was 23 benign tumours (19%), 65 s-t-S (59%), 9 lymphomas (8%), 6 fibromatoses (desmoid) (5%) and 7 carcinomas (6%). CNB Sp and PPV were 100%, Se was 95, 99 and 92%, and NPV 85, 95 and 88% for diagnosing malignancy, soft-tissue tumour and sarcoma. CNB Se and NPV were 100% for malignancy, connective tumour and sarcoma in lymphomas, high-grade sarcomas and desmoid tumours. In low grade sarcomas, Se was 94 and 85%, and NPV 84 and 77% for malignancy and sarcoma. Histological grade on CNB seems uneasy, except for grade-III tumours. CNB is accurate, not misleading for s-t-M diagnosis, avoids open biopsy complications, and allows one-surgery or neo-adjuvant chemotherapy planning when combined with appropriate imaging.     

Relief in mild-to-moderate pain is not a confounder in joint space narrowing assessment of full extension knee radiographs in recent osteoarthritis structure-modifying drug trials

OBJECTIVE: To assess whether improvement in knee pain biased the determination of the structure-modifying effect reported for glucosamine sulfate in two recent 3-year, randomised, placebo-controlled clinical trials, in which conventional standing antero-posterior full extension knee radiographs were used for the measurement of joint space narrowing, and in which pain relief might have improved knee full extension. DESIGN: Patients completing the 3-year treatment course were selected based on a WOMAC pain decrease at least equal to the mean improvement in the glucosamine sulfate arms in either of the original studies, irrespective of treatment with glucosamine sulfate or placebo (drug responders or placebo responders). In a second approach, 3-year completers were selected if their baseline standing knee pain (item #5 of the WOMAC pain scale) was 'severe' or 'extreme' and improved by any degree at the end of the trials. In both cases, changes in minimum joint space width were compared between treatment groups. RESULTS: Global knee pain was mild-to-moderate in the two study populations and in all patient subsets identified. There were obviously more pain improvers in the glucosamine sulfate subsets (N=76 in the two studies combined) than in the placebo subsets (N=57), but WOMAC pain scores improved to the same extent, which was as large as over 50% relative to baseline. Nevertheless, the placebo subsets in both studies underwent an evident mean (SD) joint space narrowing, which in the pooled analysis of both studies was -0.22 (0.80) mm, and was not observed with glucosamine sulfate: +0.15 (0.60) mm (P=0.003 vs placebo). Similar results were found in the smaller subsets with > or = severe baseline standing knee pain that improved after 3 years, with a joint space narrowing nevertheless of -0.28 (0.76) mm with placebo (N=26), not observed with glucosamine sulfate: +0.21 (0.68) mm (N=31; P=0.014 vs placebo). CONCLUSIONS: Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials using conventional standing antero-posterior radiographs, possibly due to the mild-to-moderate patient characteristics.