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Background: The Glasgow prognostic score (GPS) is an inflammation-based score based on albuminemia and C-reactive protein concentration proved to be associated with cancer-specific survival in several neoplasms. The present study explored the immediate postoperative value of the GPS for patients undergoing pneumonectomy for lung cancer., Methods: The value of the GPS preoperatively was studied in 250 patients undergoing pneumonectomy for non-small cell lung cancer (NSCLC). We analyzed overall postoperative complications, pulmonary and cardiac complications, 30-day postoperative death, reoperation for early complications, intensive care unit (ICU) length of stay and total length of hospital stay., Results: Patients with a GPS of 0 and 1 had a mean ICU length of stay of 0.8 days, whereas patients with a GPS of 2 had a mean ICU stay of 5.0 days (p = 0.004). The postoperative mortality rate in patients with a GPS of 2 was much higher than in patients with a GPS of 1 and 2, although it was not statistically significant (p = 0.083)., Conclusions: A preoperative GPS of 2 effectively predicts a prolonged ICU stay in patients who undergo pneumonectomy for cancer. The score may be proposed as an easy-to-determine, economical, and fast preoperative tool to plan and optimize ICU admissions after elective pneumonectomy., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: We performed a prospective, randomized clinical study to assess whether prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, reduces the incidence of postoperative atrial fibrillation., Background: Postoperative atrial fibrillation is a well recognized complication after lung cancer surgery, with an incidence as high as 30%. Perioperative increase of NT-proBNP has been demonstrated to be a strong independent predictor of postoperative atrial fibrillation in this setting., Methods: NT-proBNP concentration was measured 24 hours before surgery and soon after surgery in 1116 patients. Three hundred twenty (29%) patients showed a high NT-proBNP value and were enrolled: 108 were assigned to the metoprolol group, 102 to the losartan group, and 110 to the control group., Results: Overall, the incidence of postoperative atrial fibrillation was 20% (n = 64); it was significantly lower in the metoprolol and losartan groups compared with the control group [6%, 12%, and 40%, respectively; relative risk 0.19, 95% confidence intervals (CIs), 0.09-0.37; P < 0.001 in the metoprolol group; and 0.29, 95% CI, 0.16-0.52; P < 0.001 in the losartan group). No significant difference was found when the metoprolol and losartan groups were directly compared (P = 0.21)., Conclusions: A prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with high NT-proBNP levels, significantly reduced the occurrence of postoperative atrial fibrillation.

The present study determines the oncologic outcome of the combined resection and ablation strategy for colorectal liver metastases (CRLM). Between January 1994 and December 2014, 360 patients underwent surgery for CRLM. There were 280 patients who underwent hepatic resection only (group 1) and 80 hepatic resection plus ablation (group 2). group 2 patients had a higher incidence of multiple metastases than group 1 cases (100% in group 2 vs. 28.2% in group 1; P<0.001) and bilobar involvement (76.5% in group 2 vs. 12.9% in group 1; P<0.001). Perioperative mortality was nil in either group with a higher postoperative complication rate amongst group 1 vs. group 2 cases (18 vs. 0, respectively). The median follow-up was 90 months (range, 1-180) with a 5-year overall survival for group 1 and group 2 of 49 and 80%, respectively (P=0.193). The median disease-free survival for patients with R0 resection was 50, 43 and 34% at 1, 2 and 3 years, respectively, and remained steadily higher (at 50%) in those patients treated with resection combined with ablation up to 5 years (P=0.069). The only intraoperative ablation failure was for a large lesion (≥5 cm). Our data support the use of intraoperative ablation when complete hepatic resection cannot be achieved.

No international guidelines are available for the treatment of oral tongue cancer during pregnancy. Six patients with tongue cancer during pregnancy were identified by a retrospective chart review. In three of the cases we did not follow the standard treatment, the women had disease progression, and two of them died after a short time. A multidisciplinary discussion and literature review suggest that following the standard surgical procedure could be the optimal treatment to ensure mother and baby health in tongue cancer. Nonetheless choosing between maternal advantage and potential fetal damage should not be an individual medical decision. Treatment "customization" is a possibility. Patients and their families should be provided with comprehensive information and appropriate support in order to fully participate in the decision-making process. The patient's care may be improved if carried out in a specialized maternity center where the surgical oncologic treatment is managed together with the obstetric aspects., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The therapeutic value of pulmonary middle lobectomy (PML) has been questioned. PML is currently regarded as a standard form of lobectomy, even so it shares some surgical features with segmentectomies (SEG) more than with lobectomies. The present study's aim was to assess the therapeutic value of PML with respect to other lobectomies (LOBs) and SEGs., Methods: A total of 902 consecutive patients who underwent lobectomy or SEG with mediastinal lymph node dissection for Stage I-IIIa non-small-cell lung cancer were analysed. Patients with pT4 tumours and/or pathologically incomplete resection were excluded., Results: PML was performed in 50 patients, SEG in 44 and LOBs were performed in 808. The three study groups were homogeneous, except for gender, pT and grade: females, pT1 and G1 tumours were more frequent in the PML and SEG groups. The lymph node dissection yield was poorer in PML (P < 0.007) and SEG (P < 0.001) groups when compared with LOB group. Five-year overall survival (OS) was 45.3% for PML, 54.0% for SEG and 60.2% for LOB (P = 0.793). When limiting the analysis to G2-3 right-sided tumours, 5-year survival was lower in the PML group than in the LOB group: 41.3 vs 59.0% (P = 0.057). Similar results were found when analysing pT2-3 right-sided tumours: 27.3 vs 57.3% (P = 0.049). Multivariable analysis showed four independent prognostic factors: age (P = 0.001), pathological stage (P < 0.001), gender (P = 0.005) and the type of surgical resection (P = 0.029). PML (hazard ratio, HR = 1.63) and SEG (HR = 1.64) were detrimental in comparison with LOB. After adjusting for baseline differences between groups (propensity score), a trend towards a worse OS in PML group when compared with LOB group was observed (HR = 1.38, P = 0.150)., Conclusions: Both the lymphadenectomy yield and prognosis make PML more similar to SEG than lobectomy, especially for pT2-3 or G2-3 tumours., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Psychosocial stressors faced by patients with fragile X-associated tremor/ataxia syndrome (FXTAS) and their caregivers have not been systematically explored. FXTAS is a neurodegenerative disease occurring in approximately 45% of elderly male carriers and 8-16% of female carriers of the fragile X mental retardation one premutation. This study investigated the subjective needs of patients with FXTAS and their family caregivers, by utilizing Q-sort methodology., Method: Patients with FXTAS and their caregivers seen during January 2005 to June 2007 participated. The Q-sort was composed of 17 (eight formal and nine informal) items, designed to explore emotional, informational, and instrumental needs of patients with FXTAS and their caregivers. Item scores were generated from 1 = least important to 7 = most important. Analysis included descriptive statistics for all the demographic and outcome variables. Generalized estimating equations were used to identify which of the need domains were perceived as most important by the participants., Results: A total of 24 patients (79% men, mean age 65.6 ± 6.4 years) with FXTAS and 18 caregivers (11% men, mean age 63.6 ± 6.2 years) completed the Q-sort. Both patients and caregivers rated informational needs as most important, followed by emotional and, finally, by instrumental needs. Participants lacked many important resources, in particular those addressing instrumental needs., Conclusion: Providers should be educated and able to provide timely information and referrals to formal services, as well as to informal resources, including the National Fragile X Foundation online support network (www.fragilex.org).

The principal cause of perioperative morbidity and mortality following hepatic resection is excessive intraoperative hemorrhage. This study evaluates the operative use of the LigaSure device in sealing ductal structures during major and minor hepatic resections. Patients were analyzed between June 1994 and December 2005, comparing 89 randomly selected cases undergoing hepatic resections using the clamp-crushing technique with LigaSure electrocautery and hepatic inflow occlusion where appropriate with 70 patients undergoing various hepatic resections using the clamp-crushing technique alone with hepatic inflow occlusion where appropriate. Intraoperative blood loss and perioperative blood transfusion requirements were significantly less for patients in the LigaSure group. LigaSure-assisted hepatic resection was generally performed more quickly than the conventional clamp-crushing technique. The overall maximum postoperative AST, ALT, and bilirubin serum levels were similar in the two groups, as was the incidence of major postoperative complications. The LigaSure device in this randomized study is safe and simple to use, resulting in less perioperative blood loss and transfusion requirement during hepatic parenchymal transection.

Background/aims: The major complication for liver resection is hemorrhage. Energy sources other than electrosurgery have become popular with the promise of quick and effective vascular control. This study evaluates alternative energy sources in sealing ductal structures for use in liver resection with minimal blood loss., Methodology: Between June 1994 and December 2003, a consecutive 116 patients (59 male; 57 female; mean age: 60 +/- 11 years; range: 27-79 years) underwent surgery for primary (n = 30), metastatic liver cancer (n = 79), or benign lesions (n = 7). The extent of hepatic parenchymal division is marked on the surface with a diathermy-scored line. The arteries, veins, and bile ducts crossing the line of division are grasped, singly or in groups, by the Ligasure (Autosuture, United States Surgical Corp., Norwalk, CT) electrocautery device., Results: Fifty-eight formal hepatic resections, and 58 non-anatomical wedge resection were performed. The blood loss ranged from 100 mL to 3000 mL (median: 430 mL). Only 32 patients received preoperative blood transfusions. Perioperative mortality was nil (within 30 days following surgery), and postoperative major complications were seen in 14 patients (12%)., Conclusions: The Ligasure device uses bipolar electrothermal energy to coagulate the opposing walls of the target vessels. A feedback-control mechanism ensures that tissues are not charred by overcoagulation. This results in a high-burst strength vessel seal. Sealing is effective in vessels up to 7mm in diameter. Larger vessels require formal suture or stapling. This described technique is simple, rapid, safe for parenchymal division during hepatectomy, resulting in minimal blood loss.

Background: This study evaluates the surgical morbidity and long-term outcome of colorectal cancer surgery in an unselected group of patients treated over the period 1994-2003., Methods: A consecutive series of 902 primary colorectal cancer patients (489 M, 413 F; mean age: 63 years +/- 11 years, range: 24-88 years) was evaluated and prospectively followed in a university hospital (mean follow-up 36 +/- 24 months; range: 3-108 months). Perioperative mortality, morbidity, overall survival, curative resection rates, recurrence rates were analysed., Results: Of the total, 476 colorectal cancers were localized to the colon (CC, 53%), 406 to the rectum (RC, 45%), 12 (1%) were multicentric, and 8 were identified as part of HNPCC (1%). Combining all tumours, there were 186 cancers (20.6%) defined as UICC stage I, 235 (26.1%) stage II, 270 (29.9%) stage III and 187 (20.6%) stage IV cases. Twenty-four (2.7%) cases were of undetermined stage. Postoperative complications occurred in 38% of the total group (37.8% of CC cases, 37.2% of the RC group, 66.7% of the synchronous cancer patients and 50% of those with HNPCC, p = 0.19) Mortality rate was 0.8%, (1.3% for colon cancer, 0% for rectal cancer; p = 0.023). Multivisceral resection was performed in 14.3% of cases. Disease-free survival in cases resected for cure was 73% at 5-years and 72% at 8 years. The 5- and 8-year overall survival rates were 71% and 61% respectively (total cases). At 5-year analysis, overall survival rates are 97% for stage I disease, 87% for stage II, 73% for stage III and 22% for stage IV respectively (p < 0.0001). The 5-year overall survival rates showed a marked difference in R0, R1+R2 and non resected patients (82%, 35% and 0% respectively, p < 0.0001). On multivariate analysis, resection for cure and stage at presentation but not tumour site (colon vs. rectum) were independent variables for overall survival (p < 0.0001)., Conclusion: A prospective, uniform follow-up policy used in a single institution over the last decade provides evidence of quality assurance in colorectal cancer surgery with high rates of resection for cure where only stage at presentation functions as an independent variable for cancer-related outcome.

Background/aims: This study analyzed the results of treatment of rectal cancer (tumor within 12 cm of the anal verge) with different techniques., Methodology: Two hundred and sixty-four patients who had undergone elective curative surgical resection of rectal cancer within 12cm of the anal verge were evaluated. The operative data and follow-up data were collected prospectively. Comparisons were made between patients who had different surgical procedures., Results: The overall peroperative mortality rate was nil, and the morbidity 39.4%. Local recurrence occurred in 21 of the patients with a median follow-up of 34 months (range: 5-105 months). The 3-year actuarial local recurrence rates for double-stapled anastomosis, low straight anastomosis and APR were 25%, 6%, and 5%, respectively. The local recurrence rate was significantly higher for double-stapled low anterior resection than for the other types of operation (p = 0.013). On multivariate analysis reconstruction with Knight-Griffen anastomosis (p = 0.013) and tumor distance from the anal verge <6 cm (p = 0.001), were associated with local recurrence but only stage was a significant prognosticator of overall survival (p = 0.012)., Conclusions: Following total mesorectal excision, the local recurrence rate was higher in patients treated with double-stapled low anterior resection than in those with termino-terminal low anterior resection or APR; survival rates were similar in these groups.

Background: Most patients with growth hormone deficiency (GHD) show high body mass index. Overweight subjects, but GHD patients, were demonstrated to have high left ventricular mass index (LVMi) and abnormal LV geometric remodeling. We sought to study these characteristics in a group of GHD patients, in an attempt to establish the BMI-independent role of GHD., Methods: Fifty-four patients, 28 F and 26 M, aged 45.9 +/- 13.1, with adult-onset GHD (pituitary adenomas 48.2%, empty sella 27.8%, pituitary inflammation 5.5%, cranio-pharyngioma 3.7%, not identified pathogenesis 14.8%) were enrolled. To minimize any possible interferences of BMI on the aim of this study, the control group included 20 age- and weight-matched healthy subjects. The LV geometry was identified by the relationship between LVMi (cut-off 125 g/m2) and relative wall thickness (cut-off 0.45) at echocardiography., Results: There was no significant between-group difference in resting cardiac morphology and function, nor when considering age-related discrepancy. The majority of patients had normal-low LVM/LVMi, but about one fourth of them showed higher values. These findings correlated to relatively high circulating IGF-1 and systolic blood pressure at rest. The main LV geometric pattern was eccentric hypertrophy in 22% of GHD population (26% of with severe GHD) and in 15% of controls (p = NS)., Conclusion: Though the lack of significant differences in resting LV morphology and function, about 25% of GHD patients showed high LVMi (consisting of eccentric hypertrophy), not dissimilarly to overweight controls. This finding, which prognostic role is well known in obese and hypertensive patients, is worthy to be investigated in GHD patients through wider controlled trials.

Hypothesis: Although postoperative fractionated radiotherapy (PFR) remains the standard method for conservative treatment of breast carcinomas, widespread experience in the use of full-dose intraoperative radiotherapy with electrons (ELIOT) merits its application in novel clinical situations, although long-term results of ongoing clinical trials have not been fully reported., Design: Retrospective case series., Setting: Division of breast surgery in a comprehensive cancer center., Patients: From June 1999 to September 2003 ELIOT was used as the sole radiotherapy in 355 patients with unifocal invasive carcinoma who were candidates for breast-conserving surgery and most of whom were participating in an ongoing institutional trial. In a group of patients in whom PFR was not considered safe or feasible (because of previous mantle field irradiation for Hodgkin disease, cosmetic breast augmentation, severe cardiopathy, large hypertrophic scarring from skin burns, vitiligo, and geographic or social obstacles), ELIOT was performed outside of the ongoing trial., Results: No particular adverse effects, unusual acute reactions, late sequelae, and local or systemic events were noted in these patients after a mean follow-up of 27.3 months., Conclusions: In appropriated selected patients, when it is critical to perform PFR after breast-conserving therapy, a single dose of ELIOT may be considered to avoid mastectomy, reduce potential treatment toxicity, improve quality of life, and resolve logistic problems. The long-term results of ongoing clinical trials will further delineate patients in whom ELIOT may replace PFR.

Background and Aims: This study reviewed the results of surgery for distal rectal cancer (where the tumour was within 6 cm of the anal verge) following the introduction of total mesorectal excision for rectal cancer in one institution., Patients and Methods: One hundred and fifty-three patients who had undergone elective curative surgical resection of rectal cancer within 6 cm of the anal verge were included. The demographic, operative and follow-up data were collected retrospectively. Comparisons were made between patients who had different surgical procedures., Results: The overall operative mortality rate was nil, and the morbidity 41%. With a mean follow-up of 37 months (range 5-100 months), local recurrence occurred in 18 of the patients. The 5-year actuarial local recurrence rates for double-stapled anastomosis, low-strength anastomosis and abdominoperineal resection (APR) were 39, 17 and 11% respectively. The local recurrence rate was significantly higher for double-stapled low anterior resection than for the other types of operation (P=0.007). On multivariate analysis type of surgery (P=0.025) and tumour stage (P=0.043), were associated with local recurrence, but only stage was a significant prognosticator of overall survival (P=0.0006)., Conclusion: With the practice of total mesorectal excision, APR was still necessary in 40% of patients with rectal cancer within 6 cm of the anal verge. The local recurrence rate was lower in patients treated with APR than in those with double-stapled low anterior resection; however, survival rates were similar in these two groups.

Background: Immediate or delayed breast reconstruction is usually performed using expansion techniques or pedicled or free flaps. The suspension technique hereby described can reduce the number of surgical stages, as well as donor-site sequelae., Technique: The authors describe a new technique of breast reconstruction with implants using a nonabsorbable mesh to create a superior abdominal cutaneous flap, which contributes to the skin envelope of the reconstructed breast. The advantage of this technique is the opportunity to use immediately a definitive prosthesis also in cases requiring a mastectomy with the resection of a large amount of skin, consequently reducing the indications of tissue expanders or myocutaneous flaps., Results: We performed the "suspension technique" in 67 cases of immediate reconstruction and in 6 cases of delayed reconstruction. No further surgery under general anesthesia was necessary in 56 patients (76.7%). In 14 cases (19.2%), a second operation under general anesthesia was necessary for implant replacement, capsula revision, and nipple and areola (NAC) reconstruction. In 3 cases (4.1%), implant removal was necessary due to implant exposition or infection. In 33 patients, only NAC reconstruction was performed under local anesthesia. In our series, capsula contracture was graded as Baker I in 24 cases, grade II in 16 cases, grade III in 9 cases, and grade IV in 1 case. Breast symmetry, patient's satisfaction, and surgeon cosmetic evaluation were respectively scored 7.56, 7.75, and 7.60 (range from 1 to 10)., Conclusion: In conclusion, this technique can be applied in cases requiring a large skin resection at the time of mastectomy and refusing a reconstruction with myocutaneous flaps or a second surgery, necessary if a reconstruction with tissue expanders is planned.

Integrin-mediated cell adhesion cooperates with growth factor receptors in the control of cell proliferation, cell survival, and cell migration. One mechanism to explain these synergistic effects is the ability of integrins to induce phosphorylation of growth factor receptors, for instance the epidermal growth factor (EGF) receptor. Here we define some aspects of the molecular mechanisms regulating integrin-dependent EGF receptor phosphorylation. We show that in the early phases of cell adhesion integrins associate with EGF receptors on the cell membrane in a macromolecular complex including the adaptor protein p130Cas and the c-Src kinase, the latter being required for adhesion-dependent assembly of the macromolecular complex. We also show that the integrin cytoplasmic tail, c-Src kinase, and the p130Cas adaptor protein are required for phosphorylation of EGF receptor in response to integrin-mediated adhesion. We show that integrins induce phosphorylation of EGF receptor on tyrosine residues 845, 1068, 1086, and 1173, but not on residue 1148, a major site of phosphorylation in response to EGF. In addition we find that integrin-mediated adhesion increases the amount of EGF receptor expressed on the cell surface. Therefore these data indicate that integrin-mediated adhesion induces assembly of a macromolecular complex containing c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosine residues.

Introduction: Intrathoracic pressure variation during mechanical ventilation has different effects on cardiac preload and stroke volume in both ventricles. Changes in left ventricle stroke volume are reflected by fluctuations of the arterial pressure waveform or Systolic Pressure Variation (SPV). SPV has been proposed as a way to evaluate vascular volume status in mechanically ventilated patients as well as responsiveness of the left ventricle stroke volume to volume loading., Objective: In this paper an automated system is presented which is designed in order to provide physicians with information on SPV in mechanically ventilated patients. Methods. The developed system acquires the pressure transducer signal and analyses the pressure waveform in order to detect and identify the hemodynamic changes. Five patients underwent the clinical protocol in order to evaluate the software reliability. Each patient underwent measurements with positive end-expiratory pressure (PEEP) equal to 0 cm H2O, at an increase of 30% tidal volume, and at 15 cm H2O of PEEP, before and after infusion of 7 ml/kg of colloid solution., Results: The reliability of the automated procedure has been verified by comparing the obtained results with data collected manually in order to test on whether the new method data are correlated with the conventional procedure. Our results show that in the worst case when the widest range for the limits of agreement is considered, the error is within 15%., Conclusions: The automated SPV measurement requires less time as well as human errors compared to the manual method; this makes SPV calculation a competitive alternative to methods for the measurements of stroke volume variations as arterial thermodilution technique and transesophageal echocardiography, which require sophisticated equipment and specific experience.

Both overweight and insulin resistance predispose to atherosclerosis and cardiovascular diseases, independently of other risk factors. We studied the relationship between insulin resistance and heart function and dimension in 39 patients with different degrees of obesity. Twenty-six women and 13 men with body mass index (BMI) ranging 26.1-41 kg/m2 (mean +/- SD = 33.9 +/- 3.8), without diabetes, hypertension and heart, liver or kidney diseases were studied. Patients were subdivided into 2 groups, 25 with overweight or grade I obesity (group A) and 14 with severe (grade II or III) obesity (group B). Insulin sensitivity was evaluated by the Insulin Tolerance Test (ITT), performed after an overnight fast and K(ITT) was calculated. Echocardiographic measurements were also assessed. Between the two groups no significant difference was observed for either K(ITT) (group A, K(ITT) = 5.47 +/- 1.30; group B, K(ITT) = 4.57 +/- 1.53) or the ejection fraction (EF%) (group A, 71.40 +/- 6.63; group B, 69.86 +/- 7.43). No correlation was observed between BMI and both the EF% and other echocardiographic measurements. In patients with mild obesity (group A) a significant negative correlation between EF% and KITT (r = -0.62,p < 0.001) was observed. In mild obesity, therefore, cardiac function changes occur in relation to the level of insulin resistance but these changes are not related to mass and/or volume changes. The cause(s) of this relationship is not clear, but most likely involves metabolic or endocrine factors. The increased EF% in moderately obese patients that are insulin-resistant may provide an initial compensatory mechanism but may also contribute to a late cardiac damage.

Objectives: Translaryngeal tracheotomy (TLT) is a widely accepted procedure in intensive-care units for its simplicity of execution, low morbidity, rapid wound closure after cannula removal, good esthetic results, and lack of long-term sequelae. The aim of this study was to evaluate the feasibility and use of adopting TLT in patients with cancer undergoing major head and neck surgery., Study Design: Prospective analysis of learning curve and incidence of complications in 41 patients with cancer who underwent TLT at the Division of Head and Neck Surgery of the European Institute of Oncology from November 1997 to June 1999., Methods: Patient characteristics, pathology, anatomic characteristics of the neck, and surgical short-term and long-term complications were noted. The patients were divided into consecutive groups of six or seven patients, and time trends in occurrence of complications and time to execute the procedure were assessed., Results: TLT performance time decreased from 50 minutes in the first seven patients to 24 minutes in the last group. The technique was easy to perform and safe, with only two minor complications during surgery. However, minor complications occurred in three and major complications in 17 patients in the days immediately following surgery, almost entirely attributable to lack of counter-cannula and stylet., Conclusions: In view of the high proportion of major complications, TLT using the presently available kit is unsuitable for major head and neck surgery. However, the considerable advantages of the technique would recommend it as a valid alternative to surgical tracheotomy if the kit included a counter-cannula and stylet.

Cell matrix adhesion regulates actin cytoskeleton organization through distinct steps, from formation of filopodia and lamellipodia in the early phases of cell adhesion to organization of focal adhesions and stress fibers in fully adherent cells. In this review, we follow the events induced by integrin-mediated adhesion, such as activation of GTPases Cdc42 and Rac and their effectors and their role in actin polymerization leading to formation of lamellipodia and filopodia and cell spreading. We also show that actin stress fiber and focal adhesion formation following adhesion requires cooperation between integrin-mediated signaling and additional stimuli, including activation of PKC, Rho GTPases, and PTKs such as p125Fak and Src., (Copyright 1999 Wiley-Liss, Inc.)

Integrin-mediated adhesion induces several signaling pathways leading to regulation of gene transcription, control of cell cycle entry and survival from apoptosis. Here we investigate the involvement of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in integrin-mediated signaling. Plating primary human endothelial cells from umbilical cord and the human endothelial cell line ECV304 on matrix proteins or on antibody to beta1- or alphav-integrin subunits induces transient tyrosine phosphorylation of JAK2 and STAT5A. Consistent with a role for the JAK/STAT pathway in regulation of gene transcription, adhesion to matrix proteins leads to the formation of STAT5A-containing complexes with the serum-inducible element of c-fos promoter. Stable expression of a dominant negative form of STAT5A in NIH3T3 cells reduces fibronectin-induced c-fos mRNA expression, indicating the involvement of STAT5A in integrin-mediated c-fos transcription. Thus these data present a new integrin-dependent signaling mechanism involving the JAK/STAT pathway in response to cell-matrix interaction.

Adhesion of human primary skin fibroblasts and ECV304 endothelial cells to immobilized matrix proteins, beta1 or alphav integrin antibodies stimulates tyrosine phosphorylation of the epidermal growth factor (EGF) receptor. This tyrosine phosphorylation is transiently induced, reaching maximal levels 30 min after adhesion, and it occurs in the absence of receptor ligands. Similar results were observed with EGF receptor-transfected NIH-3T3 cells. Use of a kinase-negative EGF receptor mutant demonstrates that the integrin-stimulated tyrosine phosphorylation is due to activation of the receptor's intrinsic kinase activity. Integrin-mediated EGF receptor activation leads to Erk-1/MAP kinase induction, as shown by treatment with the specific inhibitor tyrphostin AG1478 and by expression of a dominant-negative EGF receptor mutant. EGF receptor and Erk-1/MAP kinase activation by integrins does not lead per se to cell proliferation, but is important for entry into S phase in response to EGF or serum. EGF receptor activation is also required for extracellular matrix-mediated cell survival. Adhesion-dependent MAP kinase activation and survival are regulated through EGF receptor activation in cells expressing this molecule above a threshold level (5x10(3) receptors per cell). These results demonstrate that integrin-dependent EGF receptor activation is a novel signaling mechanism involved in cell survival and proliferation in response to extracellular matrix.

Background and Objective: The main objective of this pilot study was to assess the possibility of achieving engraftment of HLA-matched sibling donor mobilized hematopoietic stem cells after immunosuppressive non-myeloablative therapy. The second objective was to verify whether high-dose therapy with autologous stem cells rescue followed by allografting conditioned by only an immunosuppressive regimen, can be combined in order to achieve the reduction of tumor burden after autografting and the control of residual disease with immune-mediated effects after allografting., Design and Methods: To enter the pilot study the patients had to fulfil the following criteria: advanced resistant disease, presence of an HLA matched sibling donor, no general contraindications to stem cell transplantation. Our data refers to 9 patients: Hodgkin's disease (n = 4), non-Hodgkin's lymphoma (n = 2), advanced chronic myelogenous leukemia (n = 2) (one patient with accelerated phase Ph-negative but p190 BCR-ABL gene positive by RT-PCR and one with Ph-positive blastic phase), refractory anemia with excess of blasts t(1;3) (p36;q21) (n = 1). All patients but one received the combined approach. At a median of 40 days (range 30-96), after high-dose therapy and autologous stem cell engraftment, the patients were treated with immunosuppressive therapy consisting of fludarabine and cyclophosphamide (Flu-Cy protocol) and then HLA matched donor mobilized stem cells were infused into the patients. GvHD prophylaxis consisted of cyclosporin and methotrexate., Results: To date, with a median observation period of 4 months (range, 2-10), complete chimerism (100% donor cells) has been achieved in 6 patients. Three patients did not achieve complete chimerism: one patient died of progressive Hodgkin's disease when he reached 55% of donor cells, another patient is now in increasing phase of donor cell engraftment and the last patient (blastic phase-CML) was the only case who appears to have had autologous recovery. Two of the Hodgkin's disease patients, who were in partial remission after autografting, achieved complete remission after allografting and both are disease free 2 and 6 months after. Another Hodgkin's disease patient is alive at 10 months but she has progressive disease. One of the two patients with non-Hodgkin's lymphoma, who achieved partial remission after autografting, obtained complete remission and he is disease free 2 months after allografting. The other patient maintains partial remission obtained after autografting. The accelerated phase-CML patient obtained hematologic and molecular remission; the RAEB patient achieved hematologic and cytogenetic remission. In two patients severe aGVHD (grade II-III) was the single major complication but neither patient died of it. Mild aGVHD was seen in another patient. In only one patient did the ANC decrease to below 1 x 10(9)/L and in no case did platelets decrease below 20 x 10(9)/L. No patients required a sterile room or any red cell or platelet transfusions., Interpretation and Conclusions: Immunosuppressive therapy with a Flu-Cy protocol allowed engraftment of HLA-matched sibling donor stem cells without procedure-related deaths; moreover, we have demonstrated that this combined procedure can be pursued in safety in a serious ill population and some of these patients achieved a complete remission. This procedure is not likely to be curative, but a fascinating step along the path to curing these diseases. Of course, the follow-up is too short to document the incidence of cGvHD.

The effectiveness of different pain-distraction tasks was compared as a function of level of hypnotizability, using the cold-pressor pain-testing procedure. Selected high, medium, or low hypnotizable participants first underwent a 1-minute baseline immersion of a hand in ice water, with periodic pain ratings. Independent groups were then given 4-minute test immersions under one of five conditions. Analgesia suggestion and guided imagery were conceived to be internal distractors, whereas word memory and pursuit-rotor tasks were external distractors. Placebo-control groups were given permission to let their minds wander. All four experimental treatments reduced pain significantly for highly hypnotizable participants, compared to the control group, whereas none of the experimental treatments were effective for low hypnotizables. The different treatment instructions did not produce different preimmersion anxiety state ratings, so the treatment effects on pain ratings could not be explained in terms of their effects on anxiety. It appears that high hypnotizables are more effective than low hypnotizables at diverting attention to control pain, regardless of whether internal or external distractor tasks are used. Treatment effects on pain ratings did not change between 1 and 4 minutes of test immersion.

Background: The purpose of this study was to investigate whether the combined positive inotropic and vasodilating properties of enoximone have a short-term benefit when used in patients who underwent open heart surgery., Methods: From 7/1994 to 1/1995 twenty-six patients with severe myocardial dysfunction (ejection fraction < 35%) were enrolled into a prospective trial before undergoing coronary artery bypass graft. They were randomly selected into two study groups: the first treated with enoximone (group E) and the other one with dopamine (group D). Anaesthesia was the same for both groups using high-dose fentanyl. Buckberg cardioplegia was used. All patients were followed by: conventional monitoring, Swan-Ganz catheter and transesophageal echocardiography. measurements (hemodynamic parameters, end-systolic and diastolic area and left ventricular wall motion) were recorded: after induction of anesthesia, after loading-dose and an intensive care unit. Enoximone- and dopamine infusions were started during weaning from cardiopulmonary bypass and tailored to hemodynamic parameters (cardiac index > 2.8 l/min, wedge pressure < 16 mmHg, mixed venous blood saturation > 65%). Major events were defined as: endotracheal intubation > 36 h, using intraortic balloon pump or centrifugal pump, intensive care timer > 48 h, in hospital cardiac death. Prices, were established by DRG-tables (diagnosis related groups). Statistical analysis were performed by X and "t" Student tests., Results: Cardiac index increased more significantly in group E (CI 1.9-->3.9 vs 2.3-->3.3; p 0.05) thanks to a higher reduction of vascular systemic (SVRI 2889-->1447 vs 2536 -->1565; p 0.005) and pulmonary resistances (PVRI 271-->193 vs 288-->218; p 0.05). Fewer major cumulative events and intensive care costs were observed in group E rather than group D., Conclusions: Enoximone administer immediately after open heart surgery had more beneficial hemodynamic and clinical effects than dopamine in patients with severe left ventricular dysfunction.

The analysis of our case histories aims at verifying if the immunological phenotype of the leukaemic lymphocyte B, essential diagnostic element, can have prognostic meaning and integrate the known methods of staging. We tested peripheral blood and samples of bone marrow at the cytofluorimeter with techniques of immunofluorescence. We considered the density of the sIg, lymphocytic doubling time (LDT), clusters of designation 23 (CD23), as immunological marker of activation, we also documented a relationship between these indicators and the classic clinical stage. We observed that the chronic lymphocytic leukaemia (CLL) in the stage B and C have generally sIg at high density, correlated to a short time of lymphocytic doubling, and that in the group with a low risk (stage A) the low density of sIg is correlated with a long time of doubling, index of the growth of tumoral bulk. The activation marker (CD23) shows a positive prognostic meaning, as it is more expressed in CLL at a low density of sIg and present in larger quantity in the initial clinical stage. We defined a classic immunophenotypic pattern for the CLL-B with positivity of CD5, sIg at a low density, Ag of activation highly positive related to a history of favourable disease; while an immunologic structure with CD5 negativity, less activated and more differentiated phenotype (CD23 low expression, high density sIg) seems to define a more severe prognosis.

p125FAK is a major tyrosine kinase phosphorylated in response to integrin-dependent adhesion. In this study we use vanadate and phenylarsine oxide (PAO), known inhibitors of phosphotyrosine phosphatases (PTPases), as a tool to artificially modulate p125FAK phosphorylation in human endothelial and in Chinese hamster ovary cells. Vanadate treatment strongly upregulates in a dose-dependent manner the level of tyrosine phosphorylation of several proteins in adherent cells. PAO induces a more restricted profile of tyrosine-phosphorylated proteins, increasing primarily a broad band of 120-140 kDa. Maximal stimulation of p125FAK tyrosine phosphorylation is reached at 10 microM PAO. In contrast, in vanadate-treated cells the p125FAK tyrosine phosphorylation shows a biphasic curve, being increased at high doses of vanadate (100 microM) and downregulated at low doses (25 microM). Immunofluorescence analysis of cells treated with PTPase inhibitors showed a direct correlation between the level of p125FAK tyrosine phosphorylation and the assembly of focal adhesions and actin stress fibers. Downregulation of p125FAK tyrosine phosphorylation is observed by treating cells with cytochalasin D (CD), a drug known to rapidly disrupt the actin cytoskeleton. When PTPase inhibitors are added in combination to CD, the level of tyrosine phosphorylation of p125FAK remains high and focal adhesions and actin stress fibers are preserved from the CD-mediated disruption. Based on these data we suggest that assembly of actin cytoskeleton plays an important role in inhibiting PTPases involved in p125FAK tyrosine phosphorylation.

The use of endocervical brushes has led to a generous sampling of both endocervical and "lower uterine segment" (LUS) cells. To an unfamiliar eye, the large fragments of endometrial tissue from the LUS may lead to misinterpretation as endometriosis or glandular malignancy, as happened in our institution when the use of endocervical brush and recognition of LUS cells in cervical smears were limited. Eight cases, cytologically interpreted as such, were proven to be benign following cervical biopsy or endometrial curettage. The nature of LUS cells was recognized only on retrospective review of this cytologic material. However, in recent years, routine use of the endocervical brush resulted in an influx of similar cases referred by the cytotechnologists to the pathologist as glandular atypia. Thus, to get familiarized with the cytomorphology of LUS cells and its diagnostic pitfalls, a prospective study was undertaken. This entailed a review of 62,187 consecutive cervicovaginal smears (women of post-hysterectomy status were excluded) received within a 12-mo period (July 1, 1992-June 30, 1993). A total of 344 smears (0.55%) showed large tissue fragments of branching tubular endometrial glands with and without surrounding stroma. Patients ranged from 14-82 yr of age. History of cervical cone biopsy was noted in nine patients (2.6%). Repeat cervical smear or concurrent endometrial or endocervical biopsy available in 84 patients (24.4%) were negative. LUS cells may be mistaken for endometriosis, epithelial glandular atypia, as well as carcinoma of both endocervical and endometrial origin. In addition to glandular abnormality, LUS cells may also be misinterpreted as that of squamous intraepithelial lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

Miniaturized sensors, based upon the principles of optical fluorescence, can measure in vivo the pH, pCO2 value and pO2 value of blood. In this report we studied continuous intra-arterial blood gas monitoring in 27 patients undergoing cardiac surgery (no. 16 coronary artery by-pass grafting, no. 2 valvular surgery) and major vascular surgery (no. 9 abdominal aortic aneurysms). Total duration of continuous intra-arterial blood gas monitoring was 677 hours, with a ratio of 25.0 +/- 14.8 hours/patient (range 4-96 hours). The in vitro values of pH, pCO2 and pO2 were compared to simultaneous records from the fiberoptic sensor for each of the 283 arterial blood gas samples obtained, by means of linear regression and Bland-Altman method, in order to test the correlation and the agreement between the two methods of measuring. For pH average bias was -0.023 and intersensor precision was 0.028, with a strong correlation (R = 0.92; p < 0.001) and agreement. For pCO2 the average bias was 0.91 and the inter-sensor precision was 2.65, with a slight decrease in correlation (R = 0.89; p < 0.001) and agreement. For pO2 average bias was -2.69 and the intersensor precision was 12.16, with a strong correlation (R = 0.97; p < 0.001) and agreement. In addition, we tested the reliability of the system for values of pO2 above 100 mmHg and we found a strong correlation (R = 0.96; p20.001) and agreement even for these clinical conditions, largely out of physiologic parameters. This study demonstrates the feasibility and reliability of continuous intra-arterial three-component PB 3300 (Puritan Bennett) blood gas monitoring.

Adhesion of human umbilical endothelial cells to fibronectin resulted in increased tyrosine phosphorylation of a group of proteins with molecular mass ranging from 100 to 130 kDa and of a 70 kDa protein. This pattern of tyrosine phosphorylation was also observed when endothelial cells adhered to vitronectin, collagen IV, collagen I and laminin or to culture dishes coated with antibodies directed to either beta 1, alpha 3, alpha 5, alpha 6 or beta 3 integrin subunits. Increased phosphorylation of the 100-130 kDa proteins was detectable as early as 30 sec after adhesion, reached maximal level after 15 min, and remained high as long as the cells adhere to culture dishes. The 70 kDa protein was phosphorylated with a slower kinetics and its phosphorylation increased over a period of 3 h. Using specific monoclonal antibodies, the major component of the 100-130 kDa complex was identified as the focal adhesion tyrosine kinase p125FAK. The phosphorylation of the p125FAK was also observed by inducing beta 1 integrin clustering in non adherent HEC, indicating that this is a primary signalling event induced by integrins. Using tyrosine kinase inhibitors, we show a direct correlation between integrin-stimulated tyrosine kinases and assembly of focal adhesions and actin fibres.

An information tradeoff is an increased processing or utilization of information from one stimulus source at the expense of processing or utilization of information from a different source. An experiment was conducted to determine whether information tradeoffs occurred when subjects attended selectively to one of two different structural levels of naturalistic scenes. The subjects' attentional focus was directed to either the global or local structure of a scene (i.e., the scene or an object in the scene, respectively) either before or after presentation of a scene. They then had to use the information obtained from a 100-msec exposure of the scene to choose between two forced-choice alternatives that described one of the levels. The nature of the alternatives was such that both alternatives adequately characterized one of the structural levels on the basis of physical and semantic relations within the scene. Results showed that the subjects were significantly slower and less accurate when their attentional focus and the forced-choice alternatives were at different levels of stimulus structure than when they were at the same level, providing evidence of an information tradeoff when different types of information from a scene were used. When processing information from a particular structural level, information from the other level either was less available or was not used efficiently. Furthermore, the information tradeoffs were more severe in the precue than in the postcue condition, indicating differences in the efficiency of the selectivity process. The results are interpreted with respect to the role of selective attention in processing complex stimuli such as naturalistic scenes.

Two experiments examined the effects of automatic processing and code dissimilarity on the performance of successive memory searches through a single memory set having the same or different kinds of information (i.e., verbal and spatial). The results of both experiments showed that the total time to complete the successive searches was less when automatic processing was involved compared with when both searches required controlled processing. Performance of the successive searches improved substantially with practice. Both experiments also showed an asymmetrical temporal interference between the two searches. Aspects of the to-be-performed second search did not affect first-search reaction times (RTs), but performing the first search did affect the second-search RTs. The interfering effect of the first search was greatest when controlled processes that used the same code were required for both searches, whether the code was verbal or spatial. Several interpretations are offered for the interference generated by the first search. The joint effects of automatic processing and code dissimilarity are also discussed.

Basal insulin secretion stimulated by allogeneic lymphocyte injection was inhibited by SRIF, diazoxide and verapamil but was not affected by theophylline or imidazole. Glucose stimulated insulin secretion induced by alloantigens was inhibited by imidazole. Maximum insulin secretion was achieved with 2.1 mg/ml theophylline in allogeneized mouse pancreata and with 4.2 mg/ml in control pancreata. Propranolol also blocked allogen-induced glucose-stimulated insulin secretion. Phentolamine enhanced insulin secretion from both experimental groups, but phentolamine plus epinephrine only stimulated insulin secretion in control pancreata. Verapamil, diazoxide and SRIF diminished insulin secretion in both experimental groups. These results suggest that: a) basal insulin secretion induced by alloantigens may be mediated by an increase in calcium translocation, and b) glucose-stimulated insulin secretion induced by alloantigen may be mediated by a rise in B-cell cAMP.

Procoagulant activity (PCA) of peripheral blood mononuclear cells was studied in vitro in 14 consecutive patients with essential mixed cryoglobulinemia (EMC). Mononuclear cells tested immediately after isolation expressed significantly higher PCA than cells from a matched control group (P less than 0.01). PCA generated by patients' cells after incubation at 37 degrees C for four hours without any stimulant was significantly higher than that produced by control cells (P less than 0.001). Lower mononuclear cell PCA was observed in the subgroup of patients treated with low doses of prednisone than in untreated patients. In two patients given high-dosage prednisone, cell PCA was markedly reduced. These findings suggest that mononuclear cells may be activated for PCA production in vivo by cryoglobulins or other unknown stimuli. Mononuclear phagocytes, by producing PCA in vivo, might be directly implicated in the local fibrin deposition in tissue lesions of EMC.

Insulin and somatostatin (SRIF) secretion induced by alloantigen were studied in genetically diabetic mice from the C57BL/KsJ mdb-mdb strain. Diabetic (db) mice injected with allogeneic lymphocytes (A.L.) did not show any increase in their second phase of 27.5 mM glucose stimulated secretion and slightly increased their first phase. Normal A.L. injected mice showed a significant increase in both phases of 27.5 mM glucose stimulated secretion. SRIF secretion of A.L. injected normal and diabetic mice did not significantly differ from that obtained when injected with syngeneic lymphocytes. Lymphocytes from db mice injected into allogeneic mice caused an insulin secretion similar to that produced by allogeneic lymphocytes from non-diabetic mice. Lymphocytes from db mice injected into normal syngeneic mice caused an insulin secretion which was not significantly different from the one caused by syngeneic lymphocytes from non-diabetic mice, and is smaller than the secretion caused by A.L. injection. In summary, db mice showed an impaired hormone response to alloantigenic stimulus, while their lymphocytes maintained their alloantigenic action.