Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib -- analysis of prognostic factors (EORTC-STBSG collaborative study).

BACKGROUND: Long-term complete remissions remain a rare exception in patients with metastatic gastrointestinal stromal tumors (GIST) treated with IM (imatinib). To date the therapeutic relevance of surgical resection of metastatic disease remains unknown except for the use in palliative intent. PATIENTS AND METHODS: We analyzed overall survival (OS) and progression-free survival (PFS) in consecutive patients with metastatic GIST who underwent metastasectomy and received IM therapy (n = 239). RESULTS: Complete resection (R0+R1) was achieved in 177 patients. Median OS was 8.7 y for R0/R1 and 5.3 y in pts with R2 resection (p = 0.0001). In the group who were in remission at time of resection median OS was not reached in the R0/R1 surgery and 5.1 y in the R2-surgery (p = 0.0001). Median time to relapse/progression after resection of residual disease was not reached in the R0/R1 and 1.9 years in the R2 group of patients, who were resected in response. No difference in mPFS was seen in patients progressing at time of surgery. CONCLUSIONS: Our analysis implicates possible long-term survival in patients in whom surgical complete remission can be achieved. Incomplete resection, including debulking surgery does not seem to prolong survival. Despite the retrospective character and likely selection bias, this analysis may help in decision making for surgical approaches in metastatic GIST.

Ligation of integrin alpha 3beta 1 by laminin 5 at the wound edge activates Rho-dependent adhesion of leading keratinocytes on collagen.

Wounding of the epidermis signals the transition of keratinocytes from quiescent anchorage on endogenous basement membrane laminin 5 to migration on exposed dermal collagen. In this study, we attempt to characterize activation signals that transform quiescent keratinocytes into migratory leading cells at the wound edge. Previously, we reported that adhesion and spreading on collagen via integrin alpha(2)beta(1) by cultured human foreskin keratinocytes (HFKs) requires RhoGTP, a regulator of actin stress fibers. In contrast, adhesion and spreading on laminin 5 requires integrins alpha(3)beta(1) and alpha(6)beta(4) and is dependent on phosphoinositide 3-hydroxykinase (Nguyen, B. P., Gil, S. G., and Carter, W. G. (2000) J. Biol. Chem. 275, 31896-31907). Here, we report that quiescent HFKs do not adhere to collagen but adhere and spread on laminin 5. By using collagen adhesion as one criterion for conversion to a "leading wound cell," we found that activation of collagen adhesion requires elevation of RhoGTP. Adhesion of quiescent HFKs to laminin 5 via integrin alpha(3)beta(1) and alpha(6)beta(4) is sufficient to increase levels of RhoGTP required for adhesion and spreading on collagen. Consistently, adhesion of quiescent HFKs to laminin 5, but not collagen, also promotes expression of the precursor form of laminin 5, a characteristic of leading keratinocytes in the epidermal outgrowth. We suggest that wounding of quiescent epidermis initiates adhesion and spreading of keratinocytes at the wound edge on endogenous basement membrane laminin 5 via alpha(3)beta(1) and alpha(6)beta(4) in a Rho-independent mechanism. Spreading on endogenous laminin 5 via alpha(3)beta(1) is necessary but not sufficient to elevate expression of precursor laminin 5 and RhoGTP, allowing for subsequent collagen adhesion via alpha(2)beta(1), all characteristics of leading keratinocytes in the epidermal outgrowth.

Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion.

Adhesion of keratinocytes in a wound outgrowth to laminin 5 in the basement membrane via integrins alpha6beta4 and alpha3beta1 is distinct from adhesion to dermal collagen via alpha2beta1 or to fibronectin via alpha5beta1. Leading cells in the outgrowth are distinguished from following keratinocytes by deposition of laminin 5, failure to communicate via gap junctions and sensitivity to toxin B, an inhibitor of RhoGTPase. Laminin 5 deposited by leading keratinocytes onto dermal collagen dominates over dermal ligands and changes the cell signals required for adhesion from collagen-dependent to laminin-5-dependent. Thus, deposition of laminin 5 can instruct keratinocytes to switch from an activated phenotype to a quiescent and integrated epithelial phenotype.

Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling.

Deposition of laminin 5 over exposed dermal collagen in epidermal wounds is an early event in repair of the basement membrane. We report that deposition of laminin 5 onto collagen switches adhesion and signaling from collagen-dependent to laminin 5-dependent. Ligation of laminin 5 by integrin alpha(6)beta(4) activates phosphoinositide 3-OH-kinase (PI3K) signaling. This activation allows for adhesion and spreading via integrin alpha(3)beta(1) on laminin 5 independent of RhoGTPase, a regulator of actin stress fibers. In contrast, adhesion and spreading on collagen via alpha(2)beta(1) is Rho-dependent and is inhibited by toxin B, a Rho inhibitor. Deposition of laminin 5 and ligation of alpha(6)beta(4) increases PI3K-dependent production of phosphoinositide di- and triphosphates, PI3K activity, and phosphorylation of downstream target protein c-Jun NH(2)-terminal kinase. Conversely, blocking laminin 5-deposition with brefeldin A, an inhibitor of vesicle transport, or with anti-laminin 5 monoclonal antibodies abolishes the PI3K-dependent spreading mediated by alpha(3)beta(1) and phosphorylation of c-Jun NH(2)-terminal kinase. Studies with keratinocytes lacking alpha(6)beta(4) or laminin 5 confirm that deposition of laminin 5 and ligation by alpha(6)beta(4) are required for PI3K-dependent spreading via alpha(3)beta(1). We suggest that deposition of laminin 5 onto the collagen substratum, as in wound repair, enables human foreskin keratinocytes to interact via alpha(6)beta(4) and to switch from a RhoGTPase-dependent adhesion on collagen to a PI3K-dependent adhesion and spreading mediated by integrin alpha(3)beta(1) on laminin 5.

Cellular interaction of integrin alpha3beta1 with laminin 5 promotes gap junctional communication.

Wounding of skin activates epidermal cell migration over exposed dermal collagen and fibronectin and over laminin 5 secreted into the provisional basement membrane. Gap junctional intercellular communication (GJIC) has been proposed to integrate the individual motile cells into a synchronized colony. We found that outgrowths of human keratinocytes in wounds or epibole cultures display parallel changes in the expression of laminin 5, integrin alpha3beta1, E-cadherin, and the gap junctional protein connexin 43. Adhesion of keratinocytes on laminin 5, collagen, and fibronectin was found to differentially regulate GJIC. When keratinocytes were adhered on laminin 5, both structural (assembly of connexin 43 in gap junctions) and functional (dye transfer) assays showed a two- to threefold increase compared with collagen and five- to eightfold over fibronectin. Based on studies with immobilized integrin antibody and integrin-transfected Chinese hamster ovary cells, the interaction of integrin alpha3beta1 with laminin 5 was sufficient to promote GJIC. Mapping of intermediate steps in the pathway linking alpha3beta1-laminin 5 interactions to GJIC indicated that protein trafficking and Rho signaling were both required. We suggest that adhesion of epithelial cells to laminin 5 in the basement membrane via alpha3beta1 promotes GJIC that integrates individual cells into synchronized epiboles.

Patients' perceptions compared with objective ratings of asthma severity.

BACKGROUND: Optimal asthma management requires accurate assessment of asthma severity. OBJECTIVE: To compare patients' perceptions of their asthma severity with that obtained by using the guidelines published by the National Asthma Education and Prevention Program's Expert Panel and with functional impairment measured by spirometry and numeric criteria of the American Thoracic Society. METHODS: We enrolled 323 patients age 18 to 50 years who were members of the Kaiser Foundation Health Plan for > or = 1 year in a randomized control trial of an asthma education program. Each had a confirmed diagnosis of bronchial asthma and had been receiving antiasthma medication for > or = 1 year. Patients rated the severity of their asthma. Office spirometry was performed, and, using the Mini-Wright peak flow meter, patients kept 2-week diaries of at-home recordings of morning and evening peak expiratory flow rates. RESULTS: A statistically significant association was noted between patients' perceptions of asthma severity and both medication severity rating (P < .001) and diurnal variation rating (P = .003) and evening peak expiratory flow rate percentage (P = .019). In comparison with a severity composite based on criteria of the National Asthma Education Program, 54% of patients accurately estimated asthma severity, 27% overestimated, and 20% underestimated severity. CONCLUSION: A clinically significant proportion of asthmatic patients substantially underestimate disease severity and thereby may be at risk of increased mortality or morbidity.

Intravenous fenoldopam versus sodium nitroprusside in patients with severe hypertension.

In an open-label study, we compared the efficacy and safety of intravenous infusion of fenoldopam mesylate with that of sodium nitroprusside in patients with severe hypertension or in hypertensive crisis. Both antihypertensive medications were infused at a maximal dose increment of 0.2 microgram/kg/min (fenoldopam) and 1 microgram/kg/min (nitroprusside), with a maximal infusion rate of 1.5 micrograms/kg/min fenoldopam mesylate or 8 micrograms/kg/min sodium nitroprusside. Once the desired reduction in diastolic blood pressure was achieved (less than 110 mm Hg if initial diastolic blood pressure was 120-149 mm Hg, or by at least 40 mm Hg if initial diastolic blood pressure was 150-190 mm Hg), the maximal infusion rate used was maintained for at least 1 hour, and then, the infusion was slowed gradually over 2 hours. After the infusion treatment, patients remained in the hospital for 2 days of follow-up. Both antihypertensive agents successfully controlled the blood pressure in all the patients by the end of the maintenance periods. Between the baseline and the end of the maintenance period, analysis of variance showed that the changes in the variables induced by fenoldopam mesylate did not differ significantly from those induced by sodium nitroprusside. The incidence of side effects listed were similar in both groups of patients. The detection of toxic levels of thiocyanate in two patients treated with nitroprusside, however, shows that fenoldopam might be preferable for the control of a hypertensive crisis or severe hypertension in patients with decreased renal function.

Macronodular lesions associated with Staphylococcus aureus bacteremia. A condition that resembles a 'lymphocutaneous' syndrome.

A 54-year-old man, diagnosed as having Wegener's granulomatosis and treated with a regimen of cyclophosphamide and prednisone and hemodialysis, was found to have Staphylococcus aureus in blood, urine, and pus that were removed from the infected area. He had unusual macronodular lesions of the skin that resembled the lymphocutaneous syndrome. These lesions resolved with antibiotic therapy. To our knowledge, this condition has not been described previously.