Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones.

We hypothesized that pro-inflammatory cytokines can act locally in the growth plate to impair longitudinal growth. In a model of cultured fetal rat metatarsal bones, we found that IL-1beta and TNF-alpha act in synergy to inhibit longitudinal growth, an effect linked to decreased proliferation and increased apoptosis of growth plate chondrocytes. IGF-I could partially reverse all these effects. INTRODUCTION: Children with chronic inflammatory conditions, such as Crohn's disease or rheumatoid arthritis, experience impaired longitudinal growth. The inflammatory process itself, which includes upregulation of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha, is believed to be at least partly responsible for the poor growth in these patients. This study aimed to clarify whether these cytokines can act locally in the growth plate to suppress longitudinal growth and whether any negative effects can be reversed by insulin-like growth factor-I (IGF-I). MATERIALS AND METHODS: The effects of cytokines on longitudinal bone growth were studied in fetal (day E20) rat metatarsal bones kept in culture. After a 7-day culture, the bones were sectioned, and chondrocyte proliferation was assessed by bromodeoxyuridine (BrdU) incorporation and apoptosis by TUNEL. RESULTS: When added separately, IL-1beta and TNF-alpha impaired longitudinal bone growth only at a high concentration (100 ng/ml each; p < 0.05 versus control). In contrast, when added in combination, IL-1beta and TNF-alpha potently inhibited growth at far lower concentrations (from 3 ng/ml each; p < 0.001 versus control) and also decreased chondrocyte proliferation and increased apoptosis. Growth failure induced by the combination of IL-1beta and TNF-alpha (10 ng/ml each) could be counteracted by anti-IL-1beta (100 ng/ml; p < 0.001), anti-TNF-alpha (100 ng/ml; p < 0.001), or IGF-I (100 ng/ml; p < 0.01). IL-6 did not affect longitudinal growth even when added in combination with IL-1beta or TNF-alpha (10 ng/ml each). CONCLUSIONS: We show that IL-1beta and TNF-alpha act in synergy to locally suppress longitudinal growth, an effect that can be partially reversed by IGF-I. Although growth hormone (GH)/IGF-I may improve longitudinal growth in children with chronic inflammatory diseases, our results suggest that the inflammatory process itself must be targeted to achieve normal growth.     

Multiparametric prognostic evaluation of biological factors in primary breast cancer.

BACKGROUND: An array of biological features related to tumor cell differentiation status, growth rate, and invasive potential have been identified as potential prognostic factors in breast cancer. We were interested in determining their relative importance in predicting patient survival. PURPOSE: We evaluated the relative weight of the following four biological factors in predicting survival of patients with breast cancer: tumor cell DNA content (determined by flow cytometry), tumor cell proliferation rate (determined by thymidine kinase activity), expression levels of cathepsin D and urokinase plasminogen activator, and several "classical" clinical and histological factors. METHODS: Selected from a prospectively updated database, the study population consisted of 319 primary breast cancer patients who received treatment and follow-up care (median, 6 years) in the Centre René Huguenin. To determine the profile of biological factors for each patient, we used frozen tumor specimens and (except for the flow cytometric DNA content assay) commercially available assay kits. We determined by Cox multivariate analysis the relationships of the biological factors to each other, to classical prognostic factors, and to disease-free and metastasis-free survival. RESULTS: In the overall population, disease-free survival was best predicted by node status (P = .004), clinical tumor size (P = .02), and cathepsin D expression (P = .01), whereas metastasis-free survival was best predicted by node status (P = .0004), clinical tumor size (P = .009), and urokinase plasminogen activator expression (P = .04). In node-negative patients, thymidine kinase activity was the only factor selected for disease-free (P = .04) and metastasis-free (P = .05) survival. In node-positive patients, the number of positive axillary lymph nodes was the only factor selected for disease-free (P = .0008) and metastasis-free (P = .00017) survival. CONCLUSIONS: Our retrospective analysis has identified protease expression and tumor cell proliferation rate as important biological prognostic factors in breast cancer. Prospective clinical trials should be undertaken to confirm these results.     

Prognostic value of urokinase plasminogen activator in primary breast carcinoma: comparison of two immunoassay methods.

Urokinase-type plasminogen activator (uPA) is a potentially important prognostic factor in breast cancer for identifying patients at high risk of recurrence. This retrospective study assessed two enzyme-linked immunosorbent assay (ELISA) methods measuring uPA antigen levels in 499 primary breast cancer cytosols. Both uPA methods were applied to cytosols used routinely for oestrogen (ER) and progesterone (PgR) receptor assays. uPA was determined using a classical ELISA method (Imubind; American Diagnostica) and a novel automatic immunoluminometric assay (Lia; Sangtec Medical). The uPA Imubind method revealed about twice as much uPA antigen (median 0.75 ng mg(-1) protein) as the uPA Lia method (median 0.38 ng mg(-1) protein). The correlation coefficient between the two methods was acceptable (r = 0.81), but the two techniques are not interchangeable. Univariate analyses confirmed the poor outcome of patients whose tumours contained large amounts of uPA, regardless of the technique used. Multivariate analyses showed that uPA Imubind and uPA Lia values were both strong independent prognostic factors.     

Concurrent pleural infiltration by chronic lymphocytic leukemia and adenocarcinoma of unknown primary site diagnosed by effusion cytology

Synchronous malignancies in a pleural effusion are rare. A case of concurrent pleural infiltration by adenocarcinoma of unknown primary site and chronic lymphocytic leukemia (CLL) is presented in this case study, which was diagnosed by effusion cytology. Pleural effusion is not an uncommon complication in patients with B‐CLL. Even in a pleural effusion rich in monoclonal lymphocytes, the presence of a second cancer must be excluded because this can be the main cause of mortality. The role of cytology in such cases is of paramount importance. Diagn. Cytopathol. 2014;42:151–155. © 2012 Wiley Periodicals, Inc.     

Developing and validating a center-specific preoperative prediction calculator for risk of outcomes following major hepatectomy procedures

Background

The American College of Surgeons NSQIP^® Surgical Risk Calculator (SRC) was developed to estimate postoperative outcomes. Our goal was to develop and validate an institution-specific risk calculator for patients undergoing major hepatectomy at Carolinas Medical Center (CMC).

Long-Term and Oncologic Outcomes of Robotic Versus Laparoscopic Liver Resection for Metastatic Colorectal Cancer: A Multicenter,Propensity Score Matching Analysis

World Journal of Surgery - To assess long-term oncologic outcomes of robotic-assisted liver resection (RLR) for colorectal cancer (CRC) metastases as compared to a propensity-matched cohort of...     

Total versus selective hepatic vascular exclusion in major liver resections

BACKGROUND: Total hepatic vascular exclusion (THVE) and selective hepatic vascular exclusion (SHVE) are two effective techniques for bleeding control in major hepatic resections. Outcomes of the two procedures were compared. METHODS: Patients undergoing major liver resection were randomly allocated to the THVE and SHVE groups. Intraoperative hemodynamic changes and the postoperative course of the two groups were compared. RESULTS: During vascular clamping, the THVE group showed a significant elevation in pulmonary vascular resistance, systemic vascular resistance, intrapulmonary shunts, and a significant reduction in cardiac index, compared with the SHVE group (P <0.05). Patients undergoing THVE received more crystalloids and blood, showed more severe liver, renal and pancreatic dysfunction, and had a longer hospital stay than the SHVE group (P <0.05). CONCLUSIONS: Both techniques are equally effective in bleeding control in major liver resections. THVE is associated with cardiorespiratory and hemodynamic alterations and may be not tolerated by some patients. SHVE is well tolerated with fewer postoperative complications and shorter hospitalization time.     

Urinary transforming growth factor-beta1 excretion in renal allograft recipients during the early post-transplantation period

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1), the major fibrogenic growth factor, is implicated in the pathogenesis of renal scarring in experimental and clinical nephropathies as well as in chronic allograft nephropathy. In this study we examined the pattern of changes of TGF-beta1 excretion in the urine and the sites of TGF-beta1 expression in the kidney of transplanted patients during the early post-transplantation period. METHODS: Eighteen renal allograft recipients were included in the study. In all patients urinary TGF-beta1 levels were determined by ELISA in sequential measurements during the first two postoperative months and compared to that of 14 healthy subjects. The renal expression of TGF-beta1 protein was studied in 4 patients that underwent a biopsy of the transplanted kidney at the same period. All patients were treated with prednisolone, cyclosporin, and mycophenolate mofetil. RESULTS: Urinary TGF-beta1 levels were increased during the first postoperative days. Although they were gradually reduced during the first two post-operative months, they remained significantly higher compared to those of normal subjects (580 +/- 148 ng/24 h vs. 310 +/- 140 ng/ 24 h p < 0.01). The decline of urinary TGF-beta1 excretion followed that of serum creatinine. TGF-beta1 protein expression was identified within the cytoplasm of tubular epithelial cells of transplanted patients. CONCLUSIONS: Elevated urinary TGF-beta1 levels are observed during the early post-transplantation period in renal allograft recipients and are maintained high even after restoration of renal function to normal.     

Sequential cytopunctures during preoperative chemotherapy for primary breast carcinoma. II. DNA flow cytometry changes during chemotherapy, tumor regression, and short-term follow-up.

Between May 1986 and May 1987, 35 primary noninflammatory breast carcinomas (T3N0-N1M0) were studied by means of DNA flow cytometry (FCM-DNA) before and after each of three courses of preoperative chemotherapy (doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil) to assess initial nuclear DNA content, initial S-phase fraction (SPF), and the impact of chemotherapy on these parameters. Correlations were sought with objective regression and short-term follow-up. Four sequential cytopunctures were performed for cytologic examination and FCM-DNA analyses. Ten tumors were diploid and 25 aneuploid. No significant changes in FCM-DNA parameters during chemotherapy were observed in diploid tumors, and no regression was seen in nine of the ten cases. Among the 25 aneuploid tumors, 10 showed changes in DNA content and/or kinetic parameters. A significant correlation was observed between objective regression and initial FCM-DNA content (P = 0.008), initial SPF (P = 0.004), and changes in FCM-DNA patterns observed during chemotherapy (P = 0.00005). During the follow-up period (range, 27 to 41 months), 13 patients had relapses. Patients with aneuploid tumors were more likely to have relapses (n = 11) than patients with diploid tumors (n = 2), and patients with high SPF were more likely to have relapses than patients with low SPF, but the differences were not significant. Similarly, changes in FCM-DNA parameters were observed more often in patients who had relapses, but, again, the difference was not significant. In 5 of the 13 patients who had relapses, FCM-DNA analyses were performed on cytopunctures of the recurrences: patterns were identical to those observed before treatment even when the primary tumor regressed or showed changes in FCM-DNA parameters during chemotherapy.