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Cartilage repair and replacement is a major challenge in plastic reconstructive surgery. The development of a process capable of creating a patient-specific cartilage framework would be a major breakthrough. Here, we described methods for creating human cartilage in vivo and quantitatively assessing the proliferative capacity and cartilage-formation ability in mono- and co-cultures of human chondrocytes and human mesenchymal stem cells in a three-dimensional (3D)-bioprinted hydrogel scaffold. The 3D-bioprinted constructs (5 × 5 × 1.2 mm) were produced using nanofibrillated cellulose and alginate in combination with human chondrocytes and human mesenchymal stem cells using a 3D-extrusion bioprinter. Immediately following bioprinting, the constructs were implanted subcutaneously on the back of 48 nude mice and explanted after 30 and 60 days, respectively, for morphological and immunohistochemical examination. During explantation, the constructs were easy to handle, and the majority had retained their macroscopic grid appearance. Constructs consisting of human nasal chondrocytes showed good proliferation ability, with 17.2% of the surface areas covered with proliferating chondrocytes after 60 days. In constructs comprising a mixture of chondrocytes and stem cells, an additional proliferative effect was observed involving chondrocyte production of glycosaminoglycans and type 2 collagen. This clinically highly relevant study revealed 3D bioprinting as a promising technology for the creation of human cartilage.

Background: The three-dimensional (3D) bioprinting technology allows creation of 3D constructs in a layer-by-layer fashion utilizing biologically relevant materials such as biopolymers and cells. The aim of this study is to investigate the use of 3D bioprinting in a clinically relevant setting to evaluate the potential of this technique for in vivo chondrogenesis., Methods: Thirty-six nude mice (Balb-C, female) received a 5- × 5- × 1-mm piece of bioprinted cell-laden nanofibrillated cellulose/alginate construct in a subcutaneous pocket. Four groups of printed constructs were used: (1) human (male) nasal chondrocytes (hNCs), (2) human (female) bone marrow-derived mesenchymal stem cells (hBMSCs), (3) coculture of hNCs and hBMSCs in a 20/80 ratio, and (4) Cell-free scaffolds (blank). After 14, 30, and 60 days, the scaffolds were harvested for histological, immunohistochemical, and mechanical analysis., Results: The constructs had good mechanical properties and keep their structural integrity after 60 days of implantation. For both the hNC constructs and the cocultured constructs, a gradual increase of glycosaminoglycan production and hNC proliferation was observed. However, the cocultured group showed a more pronounced cell proliferation and enhanced deposition of human collagen II demonstrated by immunohistochemical analysis., Conclusions: In vivo chondrogenesis in a 3D bioprinted human cell-laden hydrogel construct has been demonstrated. The trophic role of the hBMSCs in stimulating hNC proliferation and matrix deposition in the coculture group suggests the potential of 3D bioprinting of human cartilage for future application in reconstructive surgery.

In this report, we describe a case of difficult esophageal reconstruction using temporary banking of a jejunal free flap. This flap was temporarily placed on the patient's chest wall using the internal mammary vessels (IMVs) as recipient vessels. After 15 days, the jejunal flap was transferred to the neck region, and permanent coverage was provided using a pedicled latissimus dorsi musculocutaneous flap., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

3 Screen, a new ELISA for the combined measurement of autoantibodies to GAD 65 , to IA-2 and to ZnT8, has been developed and evaluated. In the assay serum samples were incubated (overnight; 2-8°C) in ELISA plate wells coated with GAD 65 , IA-2 and ZnT8 followed by a wash step and incubation with biotinylated GAD 65 , IA-2 and ZnT8 (1h; 2-8°C,). The assay was completed by addition of streptavidin-peroxidase and tetramethylbenzidine. Samples tested in the 3 Screen were also analysed in ELISAs and radiobinding assays for the three individual autoantibodies. 129/132 (98%) samples from newly diagnosed T1DM children and 1/100 non-diabetic children controls were positive in 3 Screen. There was good agreement between 3 Screen and the individual autoantibody assays. Dilution of positive samples showed good linearity characteristics. In the 2015 Islet Autoantibody Standardization Program 3 Screen achieved 94% sensitivity, 95.6% specificity and 0.948 area under curve by ROC analysis. 3 Screen provides a simple and sensitive method for combined measurement of three major diabetes associated autoantibodies in a single sample. The assay should be a useful tool for large scale population screening for individuals at risk of developing T1DM., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Testing for beta cell autoantibodies is used for wide-scale identification of early stages of type 1 diabetes. This requires suitable screening assays. We aimed to establish screening that utilized a first step assay (3 Screen) able to detect autoantibodies to the target antigens glutamic acid decarboxylase-65 (GAD), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) to identify children positive for multiple beta cell autoantibodies., Methods: An ELISA format was used where plates were coated with a mixture of recombinant GAD, IA-2, and ZnT8 325 W/R-dimer molecules. The performance was determined in venous blood from 686 first-degree relatives of patients with type 1 diabetes, and 200 patients at onset of type 1 diabetes, and applied as a screening assay in capillary blood from 33,639 general population children., Results: The 3 Screen assay sensitivity for detecting autoantibody-positive patients at onset of type 1 diabetes was similar to that achieved by separate radiobinding assays (RBAs) for antibodies to GAD, IA-2, and ZnT8. Results in venous and capillary serum were correlated (R = 0.987). At a threshold corresponding to the 98th centile (29.1 U/mL) of all 33,639 capillary samples, the 3 Screen was positive in 123 samples with two or more RBA-positive antibodies to insulin, GAD, IA-2, or ZnT8, 146 with one antibody, and 479 that were RBA negative for beta cell autoantibodies., Conclusion: A 3 Screen ELISA was developed that was suitable for first step screening of multiple beta cell autoantibodies in capillary blood.

Background: Several studies have attempted to identify an objective description of the aesthetically ideal breast, but they have all suffered in their reliability because of having several intrinsic limitations. It is therefore essential to design a template of ideal breast features in order to predict and evaluate aesthetic outcomes in both reconstructive and cosmetic breast surgery. The aim of this study was to determine the aesthetically preferred position of the nipple-areola complex on the breast., Methods: A questionnaire was sent by regular mail to 1000 men and 1000 women aged between 16 and 74 years. They were asked to rank the attractiveness of a series of breasts of women in images with different NAC positions. The images showed breasts from two different angles: 12 frontal-view images with both breasts shown, and five side-view images with only one breast shown. All of the breasts had equal dimensions and proportions, with the same areola size but different NAC positions. Statistical analysis of data was carried out., Results: Eight hundred and thirteen of 2000 participants completed the questionnaire. The NAC placement preferred by both genders had a ratio of 40:60 x and 50:50 y, which means that it was best situated in the middle of the breast gland vertically and slightly lateral to the midpoint horizontally. Significant differences were found between the age and gender subgroup preferences., Conclusions: This study identified the preferred position of the nipple-areola complex on the female breast in the general population. This is an important information when planning breast reconstructive and cosmetic surgery., Level of Evidence Ii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background: Several studies showed the detrimental effect of pedicle torsion on flap survival; however, the impact of hemodilution in this peculiar condition has never been investigated. This study evaluated the effect of acute normovolemic and hypervolemic hemodilution on flap survival in a perforator flap with twisted pedicle model., Methods: Sixty-three female Wistar rats were divided into three groups of 21 rats each: group 1, superficial inferior epigastric artery flap, which was elevated bilaterally and transposed back to the abdominal wall with different angles of rotation (i.e., 90, 180, 270, and 360 degrees); group 2, surgery with previous acute normovolemic hemodilution; and group 3, surgery with previous acute hypovolemic hemodilution. Normovolemic hemodilution was obtained, simultaneously removing 2 cc of blood and replacing it with an equal volume of isotonic sodium chloride 0.9% (two-thirds) plus hydroxyethyl starch 6% (one-third). Hypervolemic hemodilution was obtained by hemodilution and a 20 percent blood volume expansion. Microangiography of the flap and histopathologic analyses were performed., Results: Mean hematocrit values after hemodilution were 27.80 ± 0.04 percent for the acute normovolemic hemodilution group and 27.01 ± 0.03 percent for the acute hypovolemic hemodilution group. Twisting the pedicle at 90, 180, and 270 degrees had no effect on flap survival in all groups. However, 360-degree pedicle torsion showed flap edema, congestion, and necrosis., Conclusions: The authors' hemodilution protocol is an effective and reliable method that could be used to further investigate the impact of the hemodynamic changes that occur during hemodilution on flap microcirculation. The results obtained sustain the existence of a strong correlation between necrosis rate and hemodilution.

Background: Nowadays, postoperative flap perfusion impairment still occurs in free flap surgery; despite several studies on microcirculatory physiology, the effect of hemodilution is still extremely controversial. The aim of this study was to investigate the impact of acute normovolemic and hypervolemic hemodilution on the incidence of flap survival rate in a microsurgical rat model., Methods: Forty female Wistar rats were divided into four groups of 10 rats each: in group 1, a superficial inferior epigastric artery flap was elevated until femoral vessels were isolated, sectioned, and anastomosed without hemodilution; in group 2, surgery with previous acute normovolemic hemodilution was performed; in group 3, surgery with previous hypervolemic hemodilution was performed; and group 4, was used as a negative control to validate the microsurgical model. Normovolemic hemodilution was obtained, with simultaneous removal of an average of 2.25 cc of blood and replacement with an equal volume of isotonic sodium chloride 0.9 percent and hydroxyethyl starch 6 percent. Hypervolemic hemodilution was obtained by hemodilution and a 20 percent blood volume expansion. Microangiography of the flap and histopathologic analyses were performed., Results: Mean hematocrit values after the hemodilution were 26.80 ± 0.05 percent for group 2 and 28.11 ± 0.04 percent for group 3. Skin flap survival and vascularization after 7 days were significantly higher in both hemodiluted groups compared with the control group (p < 0.05)., Conclusion: Hemodilution was an effective way of providing better microcirculatory blood perfusion, increasing significantly the flap survival rate in the authors' microsurgical model.

Aims: A bridging-type ELISA for measuring autoantibodies to zinc transporter 8 (ZnT8A) was assessed using samples from different forms of diabetes mellitus., Methods: ZnT8A were measured using an ELISA in patients with type 1 diabetes mellitus (T1DM; n=94), latent autoimmune diabetes of adulthood (LADA; n=51), type 2 diabetes mellitus (T2DM; n=59) and healthy blood donors (HBD; n=200). ZnT8A in ELISA and immunoprecipitation assays (IPA) using ZnT8 dimer (W325/R325) and monomers (W325, R325 and Q325) were compared., Results: Inter- and intra-assay coefficients of variation (CV) were 7.1% and 1.7%, respectively (medium ZnT8A) and 8.5% and 2.7%, respectively (high ZnT8A). In the ELISA 51/94 (54.3%) T1DM, 16/51 (31.4%) LADA and 1/59 (1.7%) T2DM sera were ZnT8A positive. ROC analysis of T1DM and HBD for the ELISA showed 54% sensitivity and 99% specificity (cutoff 15u/mL) and AUC 0.80 (95% CI, 0.74-0.86). ELISA and IPA measurements were in very good agreement (r=0.856, k=0.889, n=204). Measurement of ZnT8A in addition to autoantibodies for GAD, IA-2 and insulin increased antibody positivity in T1DM by 4.3%, from 80.9% to 85.1%., Conclusions: The bridging-type ELISA is a convenient and reproducible method for determination of ZnT8A in serum. Measurement of ZnT8A increased autoantibody positivity in adult T1DM., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Arm morbidity following unilateral Latissimus Dorsi (LD) flap harvest is controversial and bilateral harvest is considered potentially disabling. Arm and shoulder disability was investigated in patients undergoing bilateral mastectomy and immediate LD flap reconstruction. Thirty consecutive bilateral immediate reconstructions with denervated LD flaps, performed between 2005-2009, were retrospectively analyzed. Patients were assessed for arm function by conducting the Disability of Arm, Shoulder and Hand (DASH) test, between 12-51 months after surgery (mean 23 months). Disability scores ranged from 1-100%, with 1-25% being regarded as mild dysfunction, 26-50% as moderate dysfunction, 51-75% as severe dysfunction, and 76-100% as total dysfunction. A statistical analysis was performed using the Fisher exact test and the multivariate linear regression model for variables. The Global Mean Dash score was 14.8%. Twenty-four patients presented a mild functional deficit (< 25%), while six presented a moderate one (< 50%). Five of them presented a score < 40%, while only one patient presented a score of 49.1%. Higher scores were significantly associated (p < 0.001) with major postoperative complications and lower ones with re-innervated LD flaps (p < 0.01). An insignificant functional impairment was noted in most patients, while a moderate-to-severe one was noted only in the group with complications. Greater impairment is observed in the heavy activities. The DASH test is a useful tool in terms of informing patients and helping the surgeon to choose the best surgical option.

Background: The Coleman technique is universally recognized as the gold standard for fat transfer, but although effective, it is tedious, time consuming, and costly. This report proposes a new and more efficient method of fat grafting (simplified lipostructure)., Methods: This report introduces a modification of the standard Coleman transfer and injection technique, performed by connecting a 10-ml syringe to a 1-ml syringe and to a blunt infiltrating cannula through a "three-way stopcock valve." The study retrospectively evaluated two groups of patients who had undergone either Coleman or simplified lipostructure, comparing surgical staff, operative time, volume of infiltrated fat, cosmetic outcome, and complications. Statistical analyses were conducted using the Wilcoxon rank sum test and Spearman's rank-order correlation., Results: The simplified lipostructure group compared with Coleman lipostructure showed a reduced operative staff (1 vs. 2 members), a reduced operative time (66 vs. 74.2 min) (α = 0.0035), and an increased volume of infiltrated fat (167.2 vs. 138.7 ml) (p < 0.0001) while retaining comparable cosmetic results (7.45 vs. 7.25; visual analog scale 0-10), and only minor complications., Conclusion: The three-way stopcock valve system appears to be a smart technical solution that eases syringe refilling, improves fat transplantation times, and reduces costs. The findings show this technical modification to be easy and effective. The authors therefore recommend it to all surgeons performing fat transfer., Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background: A retrospective analysis of our series of denervated latissimus dorsi (LD) breast reconstructions showed a high incidence of postoperative LD contraction. Anatomical studies with a prospective clinical trial are set up to outline a successful denervation procedure., Methods: Fifteen fresh cadavers were dissected to study thoracodorsal nerve course. Subsequently, 40 consecutive LD breast reconstructions were divided randomly in equal groups and underwent either distal (group A) or proximal (group B) nerve resection and clipping. The presence of postoperative contraction was evaluated clinically and instrumentally at 2-year follow-up. Statistical analysis of data was performed by Fisher exact test., Results: Cadaver dissections showed distal branching of thoracodorsal nerve in 20% of cases. Incidence of postoperative LD contraction was 35% (7/20) in group A and 0% in group B. A significantly lower rate of contraction in group B was demonstrated (P = 0.004)., Conclusions: Type B proximal nerve resection allows for effective denervation reducing incidence of postoperative contraction (P = 0.004).

Cavernous malformations (CMs) are vascular anomalies of the nervous system mostly located in the brain. Cerebral cavernous malformations can present sporadically or familial, as a consequence of an autosomal dominant condition, with incomplete penetrance and variable clinical expression. Occasionally, extraneural manifestations of CMs involving the skin have been described. We report the case of two siblings presenting in adulthood diffuse cutaneous vascular lesions associated with cerebral CMs that, after surgical excision and histopathologic analysis, resulted to cavernous haemangiomas. Genomic DNA was extracted from peripheral blood, and molecular evaluation of KRIT1 gene was performed. Although no signs of neurological impairment were reported, cerebral MRI revealed multiple images in both patients, suggestive of cavernous haemangiomas. The genetic study demonstrated a nonsense mutation (c.535C>T) in the KRIT1 (Krev-1/rap1 interaction trapped 1) gene. Few reports describe extraneural manifestations of Cavernous malformation syndrome (CMs) related to a KRIT1 mutation; these involve the skin and are associated with hyperkeratotic cutaneous capillary-venous malformation. CMs should be suspected in patients developing multiple nodular cutaneous venous lesions in adulthood.

Influenza virus (InfV) infection during pregnancy is a known risk factor for neurodevelopment abnormalities in the offspring, including the risk of schizophrenia, and has been shown to result in an abnormal behavioral phenotype in mice. However, previous reports have concentrated on neuroadapted influenza strains, whereas increased schizophrenia risk is associated with common respiratory InfV. In addition, no specific mechanism has been proposed for the actions of maternal infection on the developing brain that could account for schizophrenia risk. We identified two common isolates from the community with antigenic configurations H3N2 and H1N1 and compared their effects on developing brain with a mouse modified-strain A/WSN/33 specifically on the developing of dopaminergic neurons. We found that H1N1 InfV have high affinity for dopaminergic neurons in vitro, leading to nuclear factor kappa B activation and apoptosis. Furthermore, prenatal infection of mothers with the same strains results in loss of dopaminergic neurons in the offspring, and in an abnormal behavioral phenotype. We propose that the well-known contribution of InfV to risk of schizophrenia during development may involve a similar specific mechanism and discuss evidence from the literature in relation to this hypothesis.

Background: Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but the clinical impact of lymphadenectomy has not been addressed in randomized studies. We conducted a randomized clinical trial to determine whether the addition of pelvic systematic lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy improves overall and disease-free survival., Methods: From October 1, 1996, through March 31, 2006, 514 eligible patients with preoperative International Federation of Gynecology and Obstetrics stage I endometrial carcinoma were randomly assigned to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Patients' clinical data, pathological tumor characteristics, and operative and early postoperative data were recorded at discharge from hospital. Late postoperative complications, adjuvant therapy, and follow-up data were collected 6 months after surgery. Survival was analyzed by use of the log-rank test and a Cox multivariable regression analysis. All statistical tests were two-sided., Results: The median number of lymph nodes removed was 30 (interquartile range = 22-42) in the pelvic systematic lymphadenectomy arm and 0 (interquartile range = 0-0) in the no-lymphadenectomy arm (P < .001). Both early and late postoperative complications occurred statistically significantly more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm, P = .001). Pelvic systematic lymphadenectomy improved surgical staging as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs 3.2%, difference = 10.1%, 95% confidence interval [CI] = 5.3% to 14.9%, P < .001). At a median follow-up of 49 months, 78 events (ie, recurrence or death) had been observed and 53 patients had died. The unadjusted risks for first event and death were similar between the two arms (hazard ratio [HR] for first event = 1.10, 95% CI = 0.70 to 1.71, P = .68, and HR for death = 1.20, 95% CI = 0.70 to 2.07, P = .50). The 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively)., Conclusion: Although systematic pelvic lymphadenectomy statistically significantly improved surgical staging, it did not improve disease-free or overall survival.

Stocks of the WHO islet cell antibody, GAD(65) antibody, and IA-2 antibody standard (NIBSC 97/550) are now very limited. We have therefore made and tested a series of control preparations in which human monoclonal autoantibodies to IA-2 and to GAD(65) were diluted in antibody-negative human serum to different concentrations. Three different diabetes autoantibody controls (DAC 1-3) were made as was a negative control preparation. Aliquots containing 1 mL of autoantibodies in serum were freeze-dried. After reconstitution (with 1 mL of water) the controls were tested by (125)I-IA-2 immunoprecipitation assay (IPA), (125)I-GAD(65) IPA, GAD(65) Ab ELISA and IA-2 Ab ELISA (kits from RSR Ltd.) and for ICA by immunofluorescence test (IFT). DAC1 is particularly suitable as a control for the (125)I IA-2 IPA; DAC2 is suitable for the (125)I-GAD(65) IPA, GAD(65) Ab ELISA, and IA-2 Ab ELISA; and DAC3 is suitable for the ICA IFT. Freeze-dried preparations showed good stability at 37 degrees C. Reconstituted liquid preparations were stable when stored at 4 degrees C and at 37 degrees C. Availability of an essentially unlimited supply of these reagents should be useful in establishing reproducible and comparable measurements of diabetes autoantibodies in different laboratories using different assays.

The Brazilian Institute for the History of Medicine was founded on 1945 by the physician Ivolino de Vasconcellos. Because the movement intended to be of national scope, the Federação Nacional de História da Medicina e Ciências Afins was also created (National Federation for the History of Medicine and Related Sciences). The latter group had a humanistic understanding of medicine, wherein the history of medicine played a central role; since this subject honored great names and achievements in medicine, members of the federation felt it was a prime tool in the ethical and humanistic training of healthcare professionals. Thus was born the Revista Brasileira de História da Medicina, which fostered scientific and academic production and events in the field of history of medicine and also registered the Federation's activities and scientific output.

Aims: The prevalence of islet cell, thyroid, adrenal and celiac disease related autoantibodies in patients with Type 1 diabetes mellitus (Type 1 DM) from Sri Lanka is described., Design and Methods: Autoantibodies to glutamic acid decarboxylase 65 (GAD65Ab), protein tyrosine phosphatase IA-2 (IA-2Ab), insulin (IAAb), thyroglobulin (TgAb), thyroid peroxidase (TPOAb), TSH receptor (TRAb), 21-hydroxylase (21-OHAb) and tissue transglutaminase (tTGAb) were measured in 122 Type 1 DM patients who had low C-peptide activity or were >20 yr old at the time of diagnosis and in 100 non-diabetic blood donors., Results: GAD65Ab and/or IA-2Ab were present in 74/122 (60.7%) Type 1 DM subjects with a significantly higher prevalence compared to non-diabetic controls (no. 100) (GAD65Ab-59 vs 4%; IA-2Ab-14 vs 0%; respectively) (p<0.001). The median (inter-quartile range) Type 1 DM duration in antibody positive subjects was 3.3 (0.99-6.9) vs 4.9 (1.7-7.5) yr in antibody negative subjects (p=0.23). IA-2Ab prevalence decreased with disease duration > or =5 yr (19 vs 4%) (p<0.001). There was no difference in the prevalence of TgAb (25 vs 33%)(p=0.21) and TPOAb (22 vs 18%) (p=0.48) in Type 1 DM and non-diabetic subjects. Also, there was no difference in TgAb and TPOAb prevalence in antibody positive Type 1 DM (34.7%) compared to antibody negative Type 1 DM (24.4%) subjects (p=0.24). tTGAb (3/119) and TRAb (1/119) were found in low prevalence and 21-OHAb were not detected., Conclusions: Diabetes associated autoantibodies were detected in the majority of Type 1 DM subjects, suggesting a major role for autoimmunity in the pathogenesis of Type 1 DM in Sri Lankans. The prevalence of TgAb and TPOAb in Type 1 DM subjects and non-diabetic controls was relatively high and similar in both groups.

A sensitive and specific method for the quantification of sufentanil in human plasma by liquid chromatography coupled with tandem mass spectrometry has been developed. Fentanyl was used as the internal standard. Rapid sample preparation involved purification on a C(18) solid-phase extraction column. Chromatographic separation of the analytes was obtained using an RP-C(18) mu-HPLC column. LC-MS-MS detection was performed by atmospheric pressure ionisation (API) source equipped with an ionspray (IS) interface operating in the positive ion mode. For unambiguous substance confirmation, three analyte precursor-product ion combinations were monitored during multiple reaction monitoring (MRM) LC-MS-MS analysis. The method's performance characteristics were evaluated in blank and spiked control plasma samples. Overall accuracy (relative error, R.E., %), repeatability (relative standard deviations, R.S.D., %) and within-laboratory reproducibility (R.S.D., %) ranged from -9.28 to -2.71%, from 6.42 to 2.82% and from 13.52 to 6.06%, respectively, for sufentanil. The limit of quantification for sufentanil in human plasma samples was 0.3 ng ml(-1). Due to its high sensitivity and specificity, the method was successfully employed for sufentanil determination in maternal plasma samples collected immediately before epidural administration of a single sufentanil dose to women in labour, 20 min after drug administration, and at birth in arterial and venous umbilical cord plasma samples from the newborn babies. Research is in progress to adopt the method for performance of complete pharmacokinetic studies of sufentanil in human plasma.

Background: A new ELISA for 65 kDa isoform of glutamic acid decarboxylase autoantibodies (GAD(65) Abs), which depends on GAD(65) Ab acting divalently and forming a bridge between immobilized GAD(65) and liquid-phase GAD(65)-biotin, is described., Methods: Sera (25 microl) were incubated in GAD(65)-coated ELISA plate wells followed by washing and incubation with GAD(65)-biotin. After a further wash step, GAD(65)-biotin bound was quantitated by addition of streptavidin peroxidase followed by tetramethylbenzidine. Assay calibration was with WHO reference preparation 97/550., Results: Using a cut-off for positivity of 5 units/ml, sera from 0.7% (2/300) healthy blood donors (HBDs), 100% (39/39) selected type 1 diabetes mellitus (DM) patients, 1.6% (1/62) type 2 diabetes mellitus patients and 3% (4/119) autoimmune disease controls were GAD(65) Ab positive in the ELISA. Levels of positivity in an immunoprecipitation assay (IPA) based on 125I-labelled GAD(65) (cut-off 25 units/ml) were 1%, 82%, 0% and 3%, respectively. ELISA inter-assay coefficients of variation (n=12) were 7.3%, 3.8%, 7.2% and 6.3% at 5.4, 40.8, 137 and 382 units/ml, respectively., Conclusions: The ELISA we have described has sensitivity and specificity at least as high as current radioactive assays. It has good precision and handling making it suitable for routine use.

Purpose: The main goal of our study was to assess estrogen contents of breast tumor tissues, having different estrogen receptor status, in relation to long-term follow-up of patients., Experimental Design: Twenty-one breast cancer cases, all collected from January 1986 to January 1988 at the M. Ascoli Cancer Hospital Centre in Palermo, were included in the study and compared with 6 healthy women as a control group. Average follow-up time of patients was 144 +/- 10 months. The estrogen receptor status of tissues was determined by both ligand binding and immunohistochemical assays. A high performance liquid chromatography-based approach, jointly with gas chromatography/mass spectrometry, was used to identify and measure main estrogens, various hydroxyestrogens, and their methoxy derivatives in both normal and tumor tissues., Results: Although variable concentrations of hydroxylated estrogens were detected, they consistently accounted for >80% of all of the estrogens. Significantly greater amounts of both 2- and 4-hydroxyestradiol, along with a marked increase of 16 alpha-hydroxyestrone (OHE(1)), were observed in cancer with respect to normal breast tissues. A significant positive association was observed with elevated 16 alpha OHE(1) (P = 0.015) in patients alive, leading to significantly lower (P = 0.043) 2OHE(1):16 alpha OHE(1) ratio values. Conversely, ratio values of 4:2 hydroxy+methoxy estrogens was significantly lower (P = 0.006) in deceased patients. Using cutoff values of 1.2 for 4:2 hydroxy+methoxy ratio and 150 fmol/mg tissue for 16 alpha OHE(1) we achieved a clear-cut separation of patients, with over-cutoff patients having 147 months and under cutoff patients showing only 47 months median survival time (P = 0.00008)., Conclusions: Our data imply that individual hydroxyestrogens may have a distinct role in the onset and the clinical progression of breast cancer, with greater 16 alpha OHE(1) levels being in turn associated to cancer with respect to normal tissues and to a prolonged survival of breast cancer patients.

Expression of gap-junction proteins connexins (Cx), specifically Cx43, Cx32, and Cx26, in both nontumorigenic (RWPE-1) and tumorigenic (RWPE-2) human prostate epithelial cells as well as in two cell clones (WPEI-7 and WPEI-10) originating from the RWPE-1 cell line was investigated. The aim was to determine whether individual connexins are differentially expressed in cultured cells. Western blot analysis revealed striking differences in the expression of individual connexins in the cell lines studied. In particular, Cx43 is largely expressed in RWPE-1 and WPEI-10 cells, whereas Cx32 is expressed predominantly in RWPE-2 and WPEI-7 cells. In addition, both forskolin and estrone increase Cx43 expression levels in WPEI-10 cells, with no apparent effect on WPEI-7 cells. Conversely, forskolin and especially estrone induce a marked increase of Cx32 in WPEI-7 cells, whereas Cx32 expression is limitedly affected by both agents in WPEI-10 cells. Overall, expression levels of Cx43 and Cx32 appear to be inversely related, with RWPE-1 and WPEI-10 cells having a significantly higher Cx43 to Cx32 ratio than that observed in RWPE-2 and WPEI-7 cells. We recently reported that junctional communication could be rescued in RWPE-1 cells by either forskolin or estrone and that restoration of GJIC is associated with an increase of Cx43 or a decrease of Cx32, or both, eventually leading to a marked rise of the Cx43 to Cx32 ratio. Studies are currently ongoing in our laboratories to assess the potential effect of agents increasing the Cx43 to Cx32 ratio on GJIC activity in these systems.

Background: Gap-junction-mediated intercellular communication (GJIC) is required for normal development and tissue homeostasis. However, the role of GJIC in human prostate carcinogenesis and progression remains ill-defined., Methods: The ability of hormones, anti-hormones, and the anti-hypertensive drug, forskolin, to restore GJIC in non-tumorigenic (RWPE-1 and PWR-1E) and malignant (RWPE-2, LNCaP, DU-145) human prostate epithelial cell lines, was examined by Scrape-Loading/Dye Transfer (SL/DT) and Fluorescence Recovery After Photobleaching (FRAP) methods using an Ultima laser cytometer., Results: Results from both assays show that PWR-1E, RWPE-2, LNCaP, and DU-145 cells have weak or absent GJIC activity. However, the non-tumorigenic RWPE-1 cells showed restoration of some GJIC (nearly 10%) after 1 hr in the FRAP assay. Forskolin and estrone, which increase intracellular cAMP levels, induced a significant and consistent increase (2.8- and 4.4-fold, respectively) in cell-to-cell communication only in the non-tumorigenic RWPE-1 cells. Furthermore, estrone induced a two-fold increase in connexin 43 (Cx43) and a 30% decrease in Cx32 expression, while forskolin caused a 50% reduction in Cx32 with no effect on Cx43 expression in RWPE-1 cells., Conclusions: These data suggest that agents that increase Cx43:Cx32 ratio may be used to restore GJIC in junctionally-deficient, non-tumorigenic immortalized cells, thus providing insights into potential mechanisms responsible for the multistep carcinogenesis in the human prostate., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity., Patients and Methods: Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B)., Results: Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS., Conclusion: Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.

The treatment of recurrent or progressive ovarian cancer has limited therapeutic potential. The clinical outcome of second-line therapy largely depends on the potential chemo-sensitivity of the tumor expressed during up-front chemotherapy, as well as on the treatment-free interval from the last course of cytotoxic therapy. However, the identification of agents such as tamoxifen (TAM) at nontoxic doses, able to act synergistically with standard chemotherapy, may be useful to overcome resistance. Fifty patients with recurrent or progressive ovarian cancer following platinum (P)-based chemotherapy (28 platinum-resistant and 22 platinum-sensitive) entered a Phase II trial to evaluate the efficacy and toxicity of P re-challenge with the addition of TAM as a chemotherapy response modulator. The choice of the P compound (100 mg/m2 cisplatin or 400 mg/m2 carboplatin, q3 weeks) was made on the basis of the prior total cisplatin dose and the presence of neurotoxicity. TAM was administered at the doses of 80 mg/day for 30 days followed by 40 mg/day for the remaining period of treatment. Toxicity consisted mainly of mild to moderate nausea and vomiting (76%), peripheral neuropathy (43%), nephrotoxicity (4%), anemia (16%), leukopenia (58%) and thrombocytopenia (16%). The overall response to the P-TAM combination was 50% (complete response 30%; partial response 20%) with a median duration of 8.5 months (3-42). Sixty-four percent of the P-sensitive and 39% of the P-resistant patients responded (59% and 33%, respectively, for those bearing measurable disease). The overall median survival was 23 (3-48) and 19 months for the patients with measurable disease (20 months for the P-resistant group). This phase II trial confirmed the activity for a re-challenge employing a P compound and TAM in clinically defined P-resistant ovarian cancer patients. The mild toxicity profile and the relatively low cost of the treatment render further investigations on the P-TAM regimen worthwhile.

Bothrops ammodytoides, the smallest representative of this genus, is found only in Argentina. Venom was extracted from thirty adult specimens (35-70 cm in length, 90-300 g in weight) captured in the Province of Buenos Aires and kept in captivity. Venom yield was 3-30 mg. SDS-PAGE showed strong bands at 14.0; 23-25; 45; 54 and 63 kDa and weak bands at 17.0; 30.0; 40.0 and 85.0 kDa. Toxic activities were: LD50 (intravenous, mice) 0.5+/-0.2 microg/g; minimal procoagulant dose on human plasma (MPD-P) 35+/-2 mg/l; and minimal defibrinogenating dose (MDD, mice) 6-12 microg. Hemorrhagic and/or necrotic activities appear to play a major role in lethality; minimal hemorrhagic dose (MHD, mice) is 10+/-2 microg/g and minimal necrotizing dose (MND, mice) is 38+/-5 microg. The LD50, MPD-P and MND are among the lowest in venoms from Bothrops species found in Argentina. B. ammodytoides venom exhibited high proteolytic and phospholipase A2 activities. Most of the B. ammodytoides venom components cross-react with Bivalent Bothropic antivenom (Instituto Nacional de Producción de Biológicos ANLIS Dr. G. Malbrin, against B. alternatus and B. neuwiedii venoms). One ml of antivenom neutralizes 1.2 mg of B. ammodytoides venom.

Background: Parastomal hernias are the most common cause of in patients surgically with stomy reoperation treated., Methods: Treatment of parastomal hernias has been faced through two kind of technics: the first one consisted in the translocation of colostomy, the second one was placing around the colostomic hole a marlex mesh which was inserted at muscular structure level. From January 1993 to May 1997 we treated 8 patients affected by paracolostomic hernia associated to laparocele. The laparocele was treated according Rives' technique with the prosthesis positioned in the properitoneal site. The parastomal hernia was treated with translocation of the colostomy in 3 cases; in the other patients a plastic surgery of the colostomic orifice was made using polypropylene little bandages in properitoneal site., Results: In the postoperative period the complications concerned a single case of skin parcellar necrosis, that healed spontaneously with medications and a case of prolonged serous secretion the mean follow-up was 2 years from the wound., Conclusions: In our experience the use of marlex mesh may be effective in treatment of parastomal hernia only a patient treated with translocation of the stoma showed a recurrence of parastomal hernia. The positioning of the prosthesis at properitoneal level is subject to a lower incidence of recurrent parastomal hernia.

In order to determine patterns of peritoneal spread in locally advanced cervical cancer, 59 patients with previously untreated stages IB and IIA tumor size > 4 cm, IIB, III and IVA cervical cancer were considered for laparoscopic abdominal staging. Fifty-six patients (95%) were considered suitable and underwent laparoscopy. Peritoneal spread was found in 15 (27%) patients. The location was pelvic in nine (17%), extra-pelvic in one (2%), both pelvic and extra-pelvic in four (8%). Peritoneal washing was positive in five (9%) patients, being the unique site of peritoneal spread in one. Overall, 16 (29%) patients had evidence of abdominal disease. The median number of positive sites was one (range 1-4); uterine serosa was positive in nine (17%) patients, pre-vesical peritoneum in seven (13%), Douglas peritoneum in five (10%), paracolic gutter in three (6%), adnexa and omentum in two (4%), and sigmoid serosa in one (2%) patient. One operative complication occurred and all patients were discharged the day after the procedure. To date, with a median follow-up of 27 months (range 7-38), no metastasis has been detected at the trocar insertion sites. To summarize, laparoscopic staging in locally advanced cervical cancer is a safe, feasible and simple technique which is able to accurately detect abdominal disease.

We conducted a randomized clinical trial to compare the efficacy and safety of paclitaxel and a combination including paclitaxel and epidoxorubicin as second-line treatment in platinum-refractory or -resistant ovarian cancer. Patients who had progressive or stable disease during first-line therapy with regimens containing cisplatin or carboplatin (platinum-refractory patients) or who responded and subsequently relapsed within 6 months after discontinuation of first-line platinum-based regimen (platinum-resistant patients) were eligible for the study. They were randomly allocated to paclitaxel 175 mg/m2 every 28 days (41 women) for five cycles or epidoxorubicin 120 mg/m2 iv plus paclitaxel 150 mg/m2 iv every 28 days (40 women). The overall response rates (complete plus partial response) were, respectively, 17.1% in the paclitaxel and 34.2% in the epidoxorubicin plus paclitaxel group (P = 0.10). The 2-year percentage survival was 18 in the paclitaxel group and 10 in the epidoxorubicin plus paclitaxel group. A higher frequency of leukopenia and thrombocytopenia was reported in women allocated to epidoxorubicin plus paclitaxel than in the paclitaxel alone group, but the frequency of neurotoxicity was higher in the paclitaxel alone group. An important limitation of the study is the small sample size. With this sample size we can exclude that multiagent therapy in comparison with single-agent therapy improves response in platinum-refractory and -resistant ovarian cancer of more than 25%., (Copyright 1999 Academic Press.)

The aim of this study was to analyse the long-term survival and the relationships between prognostic factors at presentation, chemoresponsiveness and disease outcome in patients with locally advanced cervical cancer treated by neoadjuvant chemotherapy and radical surgery (RS). Two consecutive studies of neoadjuvant chemotherapy containing cisplatin, bleomycin plus/minus methotrexate followed by radical hysterectomy and systematic aortic and pelvic lymphadenectomy were carried out between January 1986 and September 1990 on 130 patients with > or = 4 cm stage IB2-III cervical cancer. Survival analysis was performed using the Kaplan and Meier test and Cox's multivariate regression analysis. 128 (98%) of the patients enrolled were evaluable for clinical response and survival, 83% (106) of the patients responded to chemotherapy, with a 15% complete response rate. Logistic regression analysis demonstrated that International Federation of Gynecology and Obstetrics (FIGO) stage, cervical tumour size, parametrial involvement and histotype are highly predictive of response. Responding patients underwent laparotomy, but 8% were not amenable for radical surgery. The 10-year survival estimates were 91%, 80% and 34.5% for stage IB2-IIA bulky, IIB and III, respectively (P < 0.001). After Cox's regression analysis, the parameters significantly associated with survival were the same factors predicting response to neoadjuvant chemotherapy. No stage IB2-IIA bulky patient has so far relapsed, while 12% stage IIB and 56% stage III patients recurred. The 10-year disease-free survival estimates are 91% and 44% for stage IB2-IIB and III, respectively (P < 0.001). Metastatic nodes and persistent tumour in the parametria were the only two independent factors for disease-free survival after multiple regression analysis. After a long-term follow-up (median follow-up 98 months (20-129+)), our results give new evidence of the prognostic value of response to neoadjuvant chemotherapy and of a possible therapeutic benefit of the sequential treatment adopted which, however, must be verified in a randomised setting.

Background: Due to the high prevalence of perioperative major morbidity and the difficulties in achieving surgical disease free margins, surgery has had no role in the treatment of patients with Stage III cervical carcinoma., Methods: Forty-two women with International Federation of Gynecology and Obstetrics (FIGO) Stage III cervical carcinoma responding to platinum-based neoadjuvant chemotherapy underwent the maximum surgical effort, comprised of a modified type IV-V radical hysterectomy (37 patients) or anterior pelvectomy (5 patients) with systematic pelvic and aortic lymphadenectomy. Feasibility, modifications of surgical technique, and pathologic and clinical data were analyzed., Results: Surgery was feasible in all 42 patients intraoperatively selected. Disease free margins were achieved in all but one patient. The median operating time was 390 minutes, and the median estimated blood loss was 800 mL. In the last series of patients, these figures declined to 320 minutes and 600 mL, respectively. Major morbidity consisted of severe intraoperative hemorrhage in two patients, pulmonary embolism in four, ureteral fistula in three, and laparocele in three. The number of lymph nodes removed ranged from 30 to 117 with a median of 56. The mean lengths of vagina and lateral parametrium resected were 55 and 48 mm, respectively. Despite perioperative chemotherapy, lymph node metastasis was present in 36% of patients, parametrial disease in 38%, and vaginal disease in 45%. After a median follow-up of 53 months, the 5-year overall and disease-free survival rates of radically operated patients were 70% and 58%, respectively., Conclusions: Thanks to improved surgical technique and perioperative care, extended radical surgery appears to be feasible with acceptable morbidity in chemosensitive women with Stage III cervical carcinoma and may constitute a valid alternative to radiotherapy in these patients.

The increased frequency and poor prognosis of cervical adenocarcinoma call for new therapeutic strategies, especially in locally advanced disease. Combined neoadjuvant chemotherapy (NACT)-radical surgery (RS) has been investigated to assess its feasibility and the possible impact on disease outcome. Data were pooled from three consecutive trials on a total of 42 patients with FIGO Stage IB-IIA >4 cm (9), IIB (19), and IIIB (14) cervical adenocarcinomas. NACT regimens consisted of cisplatin (P), bleomycin (B) and methotrexate, high-dose PB, and P and doxorubicin combinations for one to three cycles. Responding patients underwent RS while those still ineligible for RS underwent radiotherapy. Fisher and chi squared tests were used to detect significant factors affecting response to NACT. Cox multivariate regression analysis was used to evaluate parameters affecting response and survival. Medians and life tables were computed by the method of Kaplan and Meier. Median follow-up times were 56 (17-95) and 54 months (15-92) from enrollment and RS, respectively. NACT-induced toxicity was generally mild and did not compromise RS when indicated. The 33 (79%) responders underwent laparotomy, while the 9 nonresponders received radiotherapy. RS was feasible in 29 (69%) patients. Macroscopic intraperitoneal tumor (IPT) excluded abandoning RS in 4 cases. Mild to moderate RS-related complications were seen in 41% of cases with the same pattern as in the absence of any prior treatment. In patients undergoing RS, node metastasis and microscopic IPT were detected in 2 (7%) and 3 (10%) patients, respectively. The 5-year overall and disease-free survivals were 71% (100% IB-IIA and 84% IIB vs 36% IIIB; P = 0.001) and 88%, respectively. None of the nonresponders survived (median 10 months, 6-25), compared with an 84% 5-year survival of responders (P < 0.001). FIGO stage and parametrial involvement significantly predicted response to NACT which was the only independent variable affecting survival (P = 0.006). This retrospective study provided evidence of the chemosensitivity of locally advanced cervical adenocarcinoma and that chemoresponsiveness is the most potent predictor of cure, as demonstrated in squamous cell cervical cancer. Combined NACT and RS is a feasible treatment which seems to be able to improve the outcome of Stage IB-IIB cervical adenocarcinoma. Randomized trials comparing this new strategy with conventional treatments seem to be warranted.

Purpose: The aim of the study was to investigate the role of squamous cell carcinoma antigen (SCC) in the management of patients with locally advanced cervical cancer treated by neoadjuvant chemotherapy and radical surgery., Patients and Methods: SCC assay was performed with a radioimmunoassay kit in a series of 102 patients with locally advanced cervical cancer. The values of 2.5, 5, and 7 ng/mL were used to define SCC antigen positivity. The chi 2 and Fisher's exact test and the stepwise logistic regression were used to evaluate the distribution of marker values. Analysis of survival was performed using the Kaplan and Meier test and Cox multivariate regression analysis., Results: SCC levels were elevated in 65%, 45%, and 32% of patients with primary tumors for cutoff values of 2.5, 5, and 7 ng/mL, respectively. SCC pretreatment levels correlated with stage, tumor volume and lymph node status. In the multivariate analysis, SCC expression proved to be an independent predictor of response to neoadjuvant chemotherapy. SCC posttreatment levels were strongly related to chemotherapy response. Moreover, the overall correlation between the clinical course of the disease and the variation of SCC levels was 83%. In patients with squamous cell tumors, survival was significantly longer in SCC-negative cases compared with SCC-positive cases (P = .04). Moreover, in patients undergoing surgery after response to neoadjuvant chemotherapy, low SCC values were associated with better prognosis (P = .02). In the multivariate analysis, parametrial involvement and SCC status proved to retain an independent prognostic value., Conclusion: Our data show that SCC assay may provide useful information to improve the prognostic characterization and disease monitoring of patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy.

Serum levels of CA 125 and CA 15-3 were measured in 148 patients with primary endometrial carcinoma. CA 125-positive levels were found in 33 and 22% of the cases using a cutoff of 35 and 65 U/ml, respectively. Thirty-five (24%) and 12 (8%) patients had CA 15-3 levels higher than 30 and 50 U/ml, respectively. Among 144 patients with clinical stage I-II, 17 (12%) had extrauterine disease. CA 125 (> 65 U/ml) and CA 15-3 titers (> 30 U/ml) were found in 59 and 47% of occult stage III with respect to 16 and 18% in stage I-II of disease, respectively (P = 0.0001 and P = 0.01). The combined use of CA 125 and CA 15-3 resulted in a reduction of false-positive results of CA 125 with an acceptable sensitivity of 41%. Low-risk patients (G1 and M0-M1 tumors) showed a CA 125 positivity (> 35 U/ml) of 10% with respect to 37% of high-risk patients (G2-G3 and M2 tumors) (P = 0.0026). CA 125 positivity (> 65 U/ml) was 22% in patients without metastatic lymph node involvement, compared to 58% of cases with histologically positive lymph nodes (P = 0.022). A similar trend, although not statistically significant, was found for CA 15-3. A good correlation was found between CA 125 and CA 15-3 serum levels and clinical course of disease during chemotherapy. A statistically significant relationship was demonstrated between CA 125 (> 65 U/ml) (P = 0.0027) and CA 15-3 positivity (CA 15-3 > 30 and 50 U/ml) (P = 0.0004 and P = 0.00025) and a shorter survival. Our data show that CA 125 and CA 15-3 may be used as predictors of extrauterine spread and in monitoring of chemotherapy response in endometrial cancer. Moreover, the presence of elevated levels of these antigens may identify a subset of patients with a particularly poor prognosis.

Immunosuppressive acidic protein (IAP) and squamous cell carcinoma (SCC) serum levels were assayed in a group of 63 primary cervical cancer patients. IAP serum levels were significantly higher in cancer patients (median, 630 micrograms/ml; range, 290-1150) than in controls (median, 290 micrograms/ml; range, 135-775) (P < 0.01). The percentage of IAP-positive (> 613 micrograms/ml) cases was 50.7%. SCC serum levels were found to be above 2.5 ng/ml in 73% of cervical cancer patients, and in 6% of controls. A statistically significant correlation was observed between IAP and SCC levels in cancer patients (r = 0.35, P < 0.004). When IAP and SCC were considered together the overall sensitivity was 87.3% and an improvement of both predictive value of negative test and accuracy without any significant reduction of predictive value of positive test was found. IAP status correlated with metastatic lymph node involvement. A statistically significant association between a shorter survival and high serum LAP levels was observed. The 24-month overall survival (OS) was 92% for IAP- cases with respect to 65% for IAP+ cases (P = 0.036). In the univariate analysis, advanced stage of disease, clinical parametrial involvement, and lymph node involvement were also associated with poor survival. In the multivariate analysis IAP status showed a statistically significant association with poor survival (P = 0.049), together with lymph node involvement (P = 0.007) and advanced stage of disease (P = 0.008).

Serum levels of IL-6 were evaluated in a large group of patients with benign or malignant gynecological tumors. The results obtained were correlated with the patients' clinicopathological features and follow-up data. Using a highly sensitive immunoenzymatic method for the evaluation of serum IL-6 levels, we observed that > 95% of normal healthy women exhibited values within the range of 1.9-6 pg/ml. Using a cut-off of 6 pg/ml, elevated levels of serum IL-6 were found in 53% of 45 patients with primary epithelial ovarian cancer and less frequently in patients with endometrial and cervical cancer (37% and 10% respectively). Elevated levels of IL-6 were occasionally seen in patients with benign disease. IL-6 serum levels appeared to be less sensitive than CA 125 in ovarian cancer diagnosis. In cancer patients, increased IL-6 serum levels were related to the presence of the tumor since all post-operative patients exhibited a marked decrease. In patients with advanced ovarian cancer post-operative levels of IL-6 correlated with residual disease. Very high levels of IL-6 were observed in the ascitic fluid of 9 ovarian cancer patients, but IL-6 mRNA was not detected in tumor cells. This suggests that the increased production of IL-6 observed in ovarian cancer is reactive. Higher levels of IL-6 were found in patients unresponsive to chemotherapy, as compared with responsive ones. Univariate analysis of survival data suggests that increased IL-6 serum levels correlate with negative prognosis.

The pattern of lymphatic spread was evaluated in 81 previously untreated ovarian cancer patients (Stage I, 35; Stage II, 2; Stage III, 44) undergoing systematic aortic and pelvic lymphadenectomy. Positive nodes were found in 14% Stage I and 68% Stage III patients. Either pre- and paraaortic, or pre- and paracaval nodes were the only aortic node metastasis in 14% of patients. Common iliac nodes were the sole metastasis in pelvic area in 11%, external iliac in 14%, and obturator in 6% of patients. Therefore, the above node groups, which overall were the most frequently involved, may be considered those primarily invaded by the tumor. When data were analyzed according to stage, aortic nodes were the site of metastasis in 6% Stage I and 14% Stage III patients and pelvic nodes in 8% Stage I and 11% Stage III patients. Both aortic and pelvic areas were positive in 43% Stage III patients. The median number of positive nodes/patient was 2 (range, 1-3) and 4 (range 2-46) in Stages I and III, respectively. Lymphatic spread was ipsilateral to the tumor in all Stage I and in 40% Stage III patients. In Stage III metastases were also observed in intercavoaortic, retrocaval, retroaortic, internal iliac, and presacral nodes. In apparent Stage I, lymphatic metastasis seemed to be limited to one ipsilateral group, and the removal of the primary nodes ipsilateral to the tumor may be considered an adequate procedure. In Stage III, the presence of metastasis beyond the primary nodes and the frequent bilateral involvement suggest that all lymphatic tissue surround the aorta, the cava, and the pelvic vessels should be removed if a cytoreductive intent is pursued.

Objective: We postulated that the CT finding of periportal low density after acute blunt trauma of the abdomen or pelvis results from elevated central venous pressure caused by rapid expansion of intravascular volume during IV resuscitation or by other trauma-related pathologic changes., Materials and Methods: CT scans and medical records of 58 patients, including 42 with CT evidence of hepatic injury and 16 with periportal low density without CT evidence of hepatic injury, were reviewed retrospectively to determine the extent of liver injury, the extent of periportal low density, and the ratio of the transverse diameter of the inferior vena cava to the transverse diameter of the aorta at the level of the right adrenal gland. The ratio, which served as an indirect measure of central venous pressure, was also measured in 20 randomly selected nontrauma patients with normal findings on abdominal CT scans., Results: The ratios in 29 patients with CT evidence of liver injury without periportal low density were 0.6-2.0 (mean, 1.22), the ratios in 13 patients with diffuse (six) or focal (seven) periportal low density were 0.8-1.6 (mean, 1.31), and the ratios in 16 patients with periportal low density but no evidence of liver injury were 1.1-2.5 (mean, 1.36). The ratios were not statistically different among these three groups of patients. The ratios were 0.5-1.3 (mean, 0.86) for the 20 nontrauma control patients and were significantly lower than those in the trauma patients (p < or = .05). In all patients with periportal low density, the inferior vena cava remained distended at multiple levels through the abdomen without the variation in size expected from respiration, whereas a change in diameter was always observed on sequential CT sections in the nontrauma group. Among the 16 patients with periportal low density but no hepatic injury, a likely cause for elevated central venous pressure, excluding IV volume expansion, was observed in three., Conclusion: The CT finding of periportal low density after blunt abdominal trauma indicates acute elevation of central venous pressure and does not by itself signify hepatic parenchymal injury, as has been previously reported.

Serum levels of squamous cell carcinoma antigen were measured in 688 samples from 119 patients with cervical cancer. Ninety-seven patients had primary tumors and 22 had recurrent disease. Serum samples were obtained before each cycle of chemotherapy, before surgery, at least 4 weeks after surgery, and at 2- to 3-month intervals during follow-up from 78 of the patients with locally advanced cervical cancer who were receiving neoadjuvant chemotherapy. Squamous cell carcinoma antigen serum levels were elevated (greater than 2.5 ng/ml) in 71% of the patients with primary tumors and in 77% of the patients with recurrent carcinomas. The percentage of positivity increased significantly with stage (p = 0.03) and was higher in squamous cell tumors than in adenocarcinomas (p less than 0.001). Pretreatment squamous cell carcinoma antigen levels were not predictive of neoadjuvant chemotherapy response; however, the serial measurement during chemotherapy showed a good correlation with clinical response. In the patients who had surgery, squamous cell carcinoma antigen positivity did not correlate to pathologic findings (lymph node status, cervical and parametrial infiltration). Disease-free survival was significantly longer in patients with squamous cell carcinoma antigen pretreatment values that were lower than 5 ng/ml, compared with patients with marker higher than 5 ng/ml (p less than 0.01). Abnormal squamous cell carcinoma antigen serum levels preceded the clinical detection of recurrence in eight of 11 patients with a median lead time of 5 months.