Multidisciplinary treatment approach to locally advanced non-inflammatory breast cancer using chemotherapy and radiotherapy with or without surgery

Between April 1982 and December 1987, 82 locally advanced non-metastatic and non-inflammatory breast cancers were treated (42 stage IIIA, 40 stage IIIB). The median follow-up is 70 months from the beginning of the treatment. The initial treatment consisted of 4 courses of chemotherapy (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by irradiation (45 Gy to the breast and nodal area). A fifth course of chemotherapy was given after radiation therapy. Three different locoregional approaches were proposed depending on the tumoral response. In 32 patients (39%) with residual tumor larger than 3 cm in diameter or located behind the nipple or with multifocal tumors, mastectomy and axillary dissection were performed. Fifty other patients (61%) benefited from conservative treatment: 32 patients (39%) achieved complete remission and received a boost to the initial tumor bed; 18 patients (22%) who had a residual mass less than or equal to 3 cm in diameter were treated by tumorectomy and axillary dissection followed by a boost to the tumorectomy site. After completion of local therapy, all patients received a sixth course of chemotherapy. A maintenance adjuvant chemotherapy regimen without anthracycline was prescribed (12 monthly cycles). Three- and 5-year disease-free survival rates were 81.7% and 72% respectively. Five-year locoregional relapse rate (with or without other sites of failure) was 8.8%. In a multivariate analysis, disease-free survival was significantly influenced by the N-stage (p < 0.0001), initial tumor size (p = 0.01), and tumor response after initial chemotherapy (p = 0.02). Five-year breast conservation probability was 58.4%.(ABSTRACT TRUNCATED AT 250 WORDS

Local and cellular Ca2+ transients in smooth muscle of pressurized rat resistance arteries during myogenic and agonist stimulation

Confocal laser scanning microscopy was used to visualize Ca2+ transients in the vascular smooth muscle cells (VSMC) of intact, pressurized rat mesenteric resistance arteries loaded with fluorescent calcium indicators. Vasoconstriction was assessed by measuring inner arterial diameter. All arteries were studied at 70 mmHg intralumenal pressure and 37 °C.In the control condition of myogenic tone the arteries were constricted to 62 % (n = 10) of their passive diameter (p.d.). The [Ca2+]i in most VSMC of these arteries was constant over time. In a small percentage (< 10 %) of cells in each artery, [Ca2+]i oscillated regularly. Local calcium transients (Ca2+ sparks) were observed in five arteries studied with confocal linescan imaging.Activation of α-adrenoceptors by phenylephrine (PE, 1.0 μM) induced further vasoconstriction of pressurized arteries (to 27 % of p.d.). In this condition, [Ca2+]i oscillations were prominent in a large percentage (83 %) of the VSMC. The Ca2+ oscillations ranged in frequency from 4 to 22 min−1, and were usually asynchronous between cells.High [KCl]o (65 mM) induced nearly comparable vasoconstriction to PE (37 % of p.d.) but [Ca2+]i oscillated in only about 13 % of cells in each artery.Block of L-type Ca2+ channels (with nifedipine) in arteries activated by PE caused nearly full vasodilatation, but did not abolish the Ca2+ oscillations. Subsequent block of the sarcoplasmic reticulum Ca2+ pump (with cyclopiazonic acid) abolished Ca2+ oscillations in all cells.We conclude that Ca2+ entering VSMC via L-type Ca2+ channels has an obligatory role in force development, both in myogenic tone and during α1-adrenoceptor activation. The oscillatory pattern of [Ca2+]i that persists in the absence of Ca2+ entry via L-type Ca2+ channels is ineffective in activating contraction

Preoperative radiation therapy and surgery in the treatment of "bulky" squamous cell carcinoma of the uterine cervix (stage Ib, IIa, and IIb operable tumors)

Forty-two women with "bulky" squamous cell carcinoma of the uterine cervix, larger than 5 cm, were treated between 1982 and 1988. The median follow-up was 5 years (from 37 to 106 months). The age range was from 25 to 77 years (mean: 49). There were 14 stage Ib, 5 stage IIa, and 23 stage IIb operable patients. Forty grays were delivered at mid-plane of the pelvis (23 fractions in 31 days) using the four-field technique (6-18 MV). External beam radiation therapy was followed by 20 Gy of intracavitary radiation therapy. Forty-eight days later total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) and bilateral pelvic lymphadenectomy were performed. The 3- and 5-year disease-free survival was 83 and 81%, respectively. The 5-year locoregional control rate was 83%. Thirteen patients suffered from mild to severe complications (31%) but there were only two long-term (5%) complications

Comparison of U46619-, endothelin-1- or phenylephrine-induced changes in cellular Ca2+ profiles and Ca2+ sensitisation of constriction of pressurised rat resistance arteries

1. In pressurised rat mesenteric small arteries (50 mmHg), we examined the effects of stimulation with U46619, endothelin-1 (ET-1) or phenylephrine (PE) on changes in vessel diameter, global [Ca(2+)](i), individual smooth muscle cell [Ca(2+)](i) and Ca(2+)-sensitisation of contraction. 2. U46619 or ET-1 gave tonic diameter reductions, whereas PE-stimulated vessels gave tonic contractions or initial vasoconstrictions followed by diameter oscillations. Global [Ca(2+)](i) changes were transient for each agonist, with tonic constrictions being accompanied by maintained submaximal global [Ca(2+)](i) levels. 3. U46619, ET-1 or PE tonic constrictions were accompanied by apparently asynchronous [Ca(2+)](i) waves in individual smooth muscle cells of the vessel wall, as examined by confocal fluorescent microscopy. In vessels exhibiting vasomotion to PE, some apparent synchrony of activation of individual cells was evident; however, this was incomplete with many cells responding out of phase with their neighbours. 4. In α-toxin-permeabilised preparations, agonist-induced Ca(2+)-sensitisation of constriction at submaximal Ca(2+) (pCa6.7) in the presence of GTP was greater with U46619 or ET than PE. 5. We conclude that, in pressurised mesenteric arteries, (i) a general feature of receptor-coupled constriction is the generation of periodic smooth muscle [Ca(2+)](i) waves; (ii) complete synchrony of Ca(2+) oscillations between smooth muscle cells is not a prerequisite for receptor-coupled vasomotion; (iii) varied Ca(2+)-sensitising actions of agonists may partly determine tonic or phasic vessel responses to different stimuli

Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy

Protein kinase A (PKA) is a ubiquitous phosphoryl transferase that mediates hundreds of cell signaling events. During turnover, its catalytic subunit (PKA-C) interconverts between three major conformational states (open, intermediate, and closed) that are dynamically and allosterically activated by nucleotide binding. We show that the structural transitions between these conformational states are minimal and allosteric dynamics encode the motions from one state to the next. NMR and molecular dynamics simulations define the energy landscape of PKA-C, with the substrate allowing the enzyme to adopt a broad distribution of conformations (dynamically committed state) and the inhibitors (high magnesium and pseudosubstrate) locking it into discrete minima (dynamically quenched state), thereby reducing the motions that allow turnover. These results unveil the role of internal dynamics in both kinase function and regulation

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy

The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAPLbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment