Retinol-binding protein, acute phase reactants and Helicobacter pylori infection in patients with gastric adenocarcinoma

AIM: To determine the serum levels of c-reactive protein (CRP), transferrin (TRF), a2-macroglobulin (A2M), ceruloplasmin (CER), a1-acid glycoprotein (AAG), pre-albumin (P-ALB) and retinol-binding protein (RBP) in gastric carcinoma patients and to explore their possible correlation with underlying Helicobacter pylori (H pylori) infection. METHODS: We measured the serum levels of CRP, TRF, A2M, CER, AAG, P-ALB, and RBP in 153 preoperative patients (93 males; mean age: 63.1±11.3 years) with non-cardia gastric adenocarcinoma and 19 healthy subjects. RESULTS: The levels of CRP, CER, RBP, and AAG in cancer patients were significantly higher than those in healthy controls (P<0.0001), while no difference was found regarding the TRF, P-ALB, and A2M levels. Cancer patients with H pylori infection had significantly lower RBP values compared to non-infected ones (P<0.0001) and also higher values of CRP and AAG (P=0.09 and P=0.08, respectively). CONCLUSION: High serum levels of CRP, CER and AAG in cancer patients do not seem to be related to H pylori infection. Retinol-binding protein seems to discriminate between infected and non-infected patients with gastric carcinoma. Further studies are needed to explore if it is directly involved in the pathogenesis of the disease or is merely an epiphenomenon.     

Expiratory flow limitation in morbidly obese postoperative mechanically ventilated patients

Although obesity promotes tidal expiratory flow limitation (EFL), with concurrent dynamic hyperinflation (DH), intrinsic PEEP (PEEPi) and risk of low lung volume injury, the prevalence and magnitude of EFL, DH and PEEPi have not yet been studied in mechanically ventilated morbidly obese subjects. In 15 postoperative mechanically ventilated morbidly obese subjects, we assessed the prevalence of EFL [using the negative expiratory pressure (NEP) technique], PEEPi, DH, respiratory mechanics, arterial oxygenation and PEEPi inequality index as well as the levels of PEEP required to abolish EFL. In supine position at zero PEEP, 10 patients exhibited EFL with a significantly higher PEEPi and DH and a significantly lower PEEPi inequality index than found in the five non-EFL (NEFL) subjects. Impaired gas exchange was found in all cases without significant differences between the EFL and NEFL subjects. Application of 7.5 +/- 2.5 cm H2O of PEEP (range: 4-16) abolished EFL with a reduction of PEEPi and DH and an increase in FRC and the PEEPi inequality index but no significant effect on gas exchange. The present study indicates that: (a) on zero PEEP, EFL is present in most postoperative mechanically ventilated morbidly obese subjects; (b) EFL (and concurrent risk of low lung volume injury) is abolished with appropriate levels of PEEP; and (c) impaired gas exchange is common in these patients, probably mainly due to atelectasis.     

Distributed diffusion-clearance model for transient drug distribution within the skin

Quantitative predictions of molecular transport rates through the skin are key to the development of topically applied and transdermally delivered drugs, as well as risk assessment associated with dermal exposure. Most research to date has focused on correlations for the permeability of the stratum corneum, and transient diffusion models that oversimplify vascular clearance processes in terms of a perfect-removal boundary condition at an artificially introduced lower boundary. Considerations of the spatially distributed nature and action of blood vessels have usually been limited to the steady-state case. This article describes a more comprehensive transient model of percutaneous absorption formulated in terms of volumetric dispersion and clearance coefficients reflecting the spatial distribution of vascular processes. The model was implemented through an analysis of published experimental results on in vivo permeation of salicylic acid (SA) in de-epidermized rat skin. With regard to the characterization of SA in rat dermis ("de") in vivo, it was found that: (i) SA is likely to have a dermal effective partition coefficient (relative to pH 7.4 aqueous buffer "pH7.4") around unity (K(de/pH7.4) = 0.9 +/- 0.3); (ii) vascular processes seem not to increase drug dispersion significantly beyond molecular diffusion [D(de) approximately (D(de))(mol) = (8 +/- 3) . 10(-7) cm(2) s(-1)]; and (iii) vascular clearance is characterized by a rate coefficient k(de) = (7 +/- 2) . 10(-4) s(-1). Application of a whole-skin variant of the model (including the stratum corneum and viable epidermis) allowed realistic predictions to be made of transient subsurface concentration levels after application from a finite dose.     

The effect of Edrecolomab (Mo17-1A) or fluorouracil-based chemotherapy on specific immune parameters in patients with colorectal cancer. A comparative study

OBJECTIVES: We investigated the immune profile of patients with resected Dukes' stage C colorectal cancer (CRC), receiving adjuvant therapy with edrecolomab (Mo17-1A) or first-line 5-fluorouracil (5-FU)-based chemotherapy. PATIENTS AND METHODS: Patients received either 5 doses of Mo17-1A over 13 weeks, or 5-FU/leucovorin, or 5-FU/levamisole over 6 and 12 months, respectively. Peripheral blood was collected postoperatively and 4 months after therapy initiation. Peripheral blood mononuclear cells were tested in the autologous mixed lymphocyte reaction (AMLR), for natural killer (NK) and lymphokine-activated killer (LAK) cell activity. Serum cytokines were quantified by ELISA. RESULTS: Fifty-two patients entered the study. Postoperatively, they exhibited decreased levels of interleukin (IL)-2, interferon-gamma, IL-12, granulocyte-macrophage colony-stimulating factor and IL-15, low cellular immune responses (AMLR, NK- and LAK-cytotoxicity) and increased levels of IL-1beta, tumor necrosis factor-alpha, IL-6, IL-10 and prostaglandin E(2). After four months of therapy, patients receiving edrecolomab demonstrated enhanced AMLR, NK, LAK activity, increased serum levels of cytokines regulating such responses and reduced levels of acute-phase cytokines and immune suppressors, compared to patients treated with conventional chemotherapy. CONCLUSIONS: Postoperative adjuvant therapy with edrecolomab restores the in vivo deficient immune responses of patients with resected Dukes' C CRC despite its clinical ineffectiveness in recent randomized adjuvant trials. These results suggest that further immunological studies with the combination of edrecolomab and chemotherapy are required.     

Breast cancer after curative chemotherapy in non-Hodgkin's lymphoma: examination of the role of drug resistance and retrospective comparison to the outcome of de novo breast cancer

We examined the outcome of patients who developed breast cancer after curative chemotherapy (CHOP) for aggressive non-Hodgkin's lymphoma (NHL) in comparison to the outcome of a retrospectively selected matched-pair group of patients with de novo breast cancer, and evaluated the role of drug resistance-related protein (MDR, MRP, LRP) expression in breast cancer tissue. Twenty-two patients presented with breast cancer (BC) in complete remission after CHOP for NHL. The median age was 62 (49-70) years, each had high/intermediate grade B-cell NHL treated with 6 courses of CHOP, and were in complete remission. These patients were compared to a matched-pair group of de novo BC patients selected from our database over the same time period. Breast cancer tissue was stained by immunohistochemistry for drug resistance proteins LRP, MRP, and MDR. Breast cancer developed after a median of 26 (9-49) months of NHL diagnosis; breast tumor grades 1-2 were seen in 12, and grade 3 in 10 patients; 15 were negative and 7 weakly positive for estrogen and progesterone receptors. Twelve patients were stage IIIA/B, and 10 stage IV and were treated with conventional chemotherapy regimens. All progressed early in liver (n=13), brain (n=9), lung (n=6), bone (n=8), lymph nodes (n=7) and soft tissue (n=5), and received second-line chemotherapy with mitomycin-C + vinblastine or taxanes. The overall survival was 11.8 (6-26) months (p<0.01). Time from NHL to breast cancer development was 19 (14-27) months in patients with positive drug resistance proteins (group A), and 37 (26-56) months in patients with 1 or 2 positive resistance proteins (group B) (p<0.001). In patients with stage IIIA/B disease, there was no difference between the examined and control matched-pair group in median TTP, but there was in overall survival (OS) (23 vs 36 months, p=0.029). In advanced disease, there were more responders in the control vs the examined group (p=0.07). Patients in the control matched-pair group had more prolonged OS when compared to group A patients who developed BC in <24 months from NHL to BC (p=0.017). We conclude that breast cancer developing shortly after a complete response in NHL, is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of drug resistance mechanisms concerning MDR, MRP and LRP indicates that most of these patients have BC that overexpress these proteins leading to the suggestion that these mechanisms might be a part of the aggressive disease phenotype and partially explain the poor outcome.     

Phase I-II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I-II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel-ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70-100 mg x m(-2) over 1 h on day 1 followed by ifosfamide 5-6 g x m(-2) divided over days 1 and 2 (2.5-3.0 g x m(-2) day(-1) over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32-72) years and performance status (WHO) of 1 (range, 0-2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3-68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3-24 months), median time to progression 6.5 month (0.1-26 month), and median overall survival 13 months (0.1-33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients-with 63% developing grade 4 neutropenia (相似文献   

A Reappraisal of Drug Release Laws Using Monte Carlo Simulations: The Prevalence of the Weibull Function

Purpose. To verify the Higuchi law and study the drug release from cylindrical and spherical matrices by means of Monte Carlo computer simulation. Methods. A one-dimensional matrix, based on the theoretical assumptions of the derivation of the Higuchi law, was simulated and its time evolution was monitored. Cylindrical and spherical three-dimensional lattices were simulated with sites at the boundary of the lattice having been denoted as leak sites. Particles were allowed to move inside it using the random walk model. Excluded volume interactions between the particles was assumed. We have monitored the system time evolution for different lattice sizes and different initial particle concentrations. Results. The Higuchi law was verified using the Monte Carlo technique in a one-dimensional lattice. It was found that Fickian drug release from cylindrical matrices can be approximated nicely with the Weibull function. A simple linear relation between the Weibull function parameters and the specific surface of the system was found. Conclusions. Drug release from a matrix, as a result of a diffusion process assuming excluded volume interactions between the drug molecules, can be described using a Weibull function. This model, although approximate and semiempirical, has the benefit of providing a simple physical connection between the model parameters and the system geometry, which was something missing from other semiempirical models.     

Hypersensitivity reactions to carboplatin administration are common but not always severe: a 10-year experience

We have retrospectively evaluated and characterized the hypersensitivity reactions associated with carboplatin administration in ovarian cancer patients treated mainly on an outpatient basis at the Laikon Hospital from 1988 to 1998. A total of 240 patients, who had never been exposed to platinum compounds previously, received carboplatin plus cyclophosphamide (n = 58) or paclitaxel (n = 136) intravenously, and intraperitoneal carboplatin plus intravenous cyclophosphamide (n = 46). The median number of carboplatin courses was 6 (range 3-12) and 5 (range 4-6) for the intravenous and intraperitoneal treatment regimens, respectively. Thirty-two of 194 patients (16%) who were on intravenous carboplatin treatment developed symptoms compatible with a hypersensitivity reaction to carboplatin, that was always verified by manifestation of at least similar symptoms on rechallenging. In contrast, in the group of 46 patients on intraperitoneal carboplatin treatment, no hypersensitivity reaction was ever noticed. Hypersensitivity reactions always occurred after administration of the first 4 intravenous courses of carboplatin; 4, 19, 4, and 5 reactions occurred at the 5th, 6th, 7th, and 8th courses, respectively. These reactions could be distinguished in: (a) mild hypersensitivity reactions in 20 of 194 patients, which manifested as itching (20 patients) and small area erythema plus erythema of the palms and soles (12 patients), occurring either during intravenous injection when most of the drug scheduled had been administered, or within 3 days, and (b) in severe reactions in 12 of 194 patients, which manifested acutely as itching, diffuse erythroderma, rigor, facial swelling, throat and chest tightness, tachycardia (12 patients) and bronchospasm (2 patients), and hypertension or hypotension in 8 and 4 patients, respectively. With appropriate symptomatic management, discontinuation of carboplatin treatment was not required in patients with mild hypersensitivity reactions, but none of the 12 patients with severe reactions was able to receive a full subsequent dose of carboplatin on rechallenging. However, in 4 of these 12 patients carboplatin was replaced by cisplatin, which was given for 4-6 courses without side effects. These findings indicate that although hypersensitivity reactions are common in general, occurring in almost 1 of every 6 patients treated intravenously with carboplatin, their clinical picture is variable, leading to discontinuation of treatment in only 6% of patients. This is not the case when the intraperitoneal route of carboplatin administration is used when indicated.