Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer.

PURPOSE: In a phase II trial with paclitaxel and simultaneous radiotherapy in non-small-cell lung cancer (NSCLC) patients, an unexpected high incidence of interstitial pneumonias was observed. The type of immunodeficiency associated with this treatment approach is characterized. PATIENTS AND METHODS: Fifteen patients with inoperable stage IIIA/B NSCLC were treated with paclitaxel as a 3-hour infusion on day 1 in weeks 1 to 3 and 6 to 8 at dose levels between 50 mg/m2 and 86 mg/m2 and with simultaneous radiotherapy in daily doses of 2 Gy, 5 days per week, in weeks 1 to 3 and 6 to 8 up to a total dose of 56 Gy. Hematologic parameters and lymphocyte subsets were monitored. RESULTS: Fourteen patients are assessable for response. The overall response rate was 78%, with four major responses, six partial remissions, and four minor responses. The major toxic effect observed was a moderate to severe protracted lymphocytopenia (380 +/- 310/microL) in all patients. Seven patients developed moderate to severe interstitial pneumonia; one had an additional herpes zoster infection, while an eighth patient had a cytomegalovirus infection. During treatment, all lymphocyte subsets were reduced, as follows (n = 9, mean +/- SD): CD4+ T cells (100 +/- 90/microL), CD8+ T cells (130 +/- 160/microL), natural killer (NK) cells (70 +/- 80/microL), and B cells (20 +/- 10/microL). Thus, the most pronounced toxicity was seen in CD4+ T and B cells. There was no recovery of lymphocyte subsets during a 3-month follow-up period. CONCLUSION: Paclitaxel with simultaneous radiation induces lymphocytopenia and promotes opportunistic infections. Long-term antibiotic and antimycotic prophylaxis is recommended. Whether the lymphocytopenia is an additive effect of paclitaxel and radiation or whether it can be induced by low-dose weekly paclitaxel alone remains to be determined.

Differential pattern of integrin receptor expression in differentiated and anaplastic thyroid cancer cell lines.

Adhesion of tumor cells to the extracellular matrix (ECM) is a crucial step for the development of metastatic disease and is mediated by specific integrin receptor molecules (IRM). The pattern of metastatic spread differs substantially among the various histotypes of thyroid cancer (TC). However, IRM have only occasionally been characterized in TC until now. IRM expression was investigated in 10 differentiated (FTC133, 236, 238, HTC, HTC TSHr, XTC, PTC4.0/4.2, TPC1, Kat5) and two anaplastic TC cell lines (ATC, C643, Hth74), primary cultures of normal thyroid tissue (Thy1,3), and thyroid cancer specimens (TCS). Expression of 16 IRM (beta1-4, beta7, alpha1-6, alphaV, alphaIIb, alphaL, alphaM, alphaX) and of four IRM heterodimers (alpha2beta1, alpha5beta1, alphaVbeta3, alphaVbeta5), was analyzed by fluorescent-activated cell sorter (FACS) and immunohistochemical staining. Thyroid tumor cell adhesion to ECM proteins and their IRM expression in response to thyrotropin (TSH) was assessed. Follicular TC cell lines presented high levels of integrins alpha2, alpha3, alpha5, beta1, beta3 and low levels of alpha1, whereas papillary lines expressed a heterogenous pattern of IRM, dominated by alpha5 and beta1. ATC mainly displayed integrins alpha2, alpha3, alpha5, alpha6, beta1 and low levels of alpha1, alpha4 and alphaV. Integrin heterodimers correlated with monomer expression. Evaluation of TCS largely confirmed these results with few exceptions, namely alpha4, alpha6, and beta3. The ability of TC cell lines to adhere to purified ECM proteins correlated with IRM expression. TSH induced TC cell adhesion in a dose-dependent fashion, despite an unchanged array of IRM expression or level of a particular IRM. Thyroid carcinoma cell lines of different histogenetic background display profoundly different patterns of IRM expression that appear to correlate with tumor aggressiveness. In vitro adhesion to ECM proteins and IRM expression concur. Finally, TSH-stimulated adhesion of thyroid tumor cell lines to ECM may not be associated with altered IRM expression.

Phenotypic analysis of receptor-ligand pairs on B-cells in B-chronic lymphocytic leukemia.

Whole-blood three-color immunofluorescence analysis was used to investigate the role of CD5/CD72 and CD21/CD23 receptor-ligand pair formation on B-chronic lymphocytic leukemia (B-CLL) cells as well as sCD23 and bcl-2 oncoprotein expression in disease progression and activity and total tumor mass in B-cell chronic leukemia (B-CLL) patients. Thirty-four patients with B-CLL and 19 controls were included in the study. The majority of B-cells in B-CLL patients coexpressed CD5 and CD72 as well as the CD23 antigen. Unlike B-cells in B-CLL patients, B-cells in all healthy controls tested had high expression of CD21 antigen. We identified two groups of B-CLL patients according to high (n = 20) or low levels (n = 14) of CD21 expression on CD19+CD23+ B-cells. Only in the patients with high CD21 expression, were sCD23 levels positively correlated with factors known to have prognostic significance in B-CLL (Rai stage and TTM) and could, therefore, be used as a prognostic parameter for these B-CLL patients. Bcl-2 oncoprotein expression did not differ between these patient groups. We presumed that in patients with a lower expression of CD21 antigen, the contribution of the CD21 molecule to homotypic adhesion was lacking. Further studies are necessary to determine the possible association of higher expression of the CD21 antigen with disease progression and the aggressive character of the B-CLL.

Granulocyte colony-stimulating factor but not peritoneal lavage increases survival rate after experimental abdominal contamination and infection.

BACKGROUND: The value of peritoneal lavage for intra-abdominal contamination and infection has never been proven scientifically. In contrast, the stimulation of host defence mechanisms with cytokines such as granulocyte colony-stimulating factor (G-CSF) has appeared promising in recent clinical trials. METHODS: Clinic modelling randomized trials (CMRTs), which model the complexity of the clinical reality, were used in rats in which peritoneal contamination and infection (PCI) was produced with human stool bacteria. The following groups were compared: trial 1, intraoperative peritoneal lavage with saline versus taurolin (18 rats per group); trial 2, no lavage versus saline lavage versus saline lavage plus subcutaneous administration of G-CSF (18 rats per group); trial 3, lavage with saline versus no lavage (30 rats per group). The primary endpoint was mortality at 120 h. Secondary endpoints were the phagocytic activity of granulocytes, and systemic and peritoneal cytokine levels. RESULTS: In trial 1 lavage with taurolin was not superior to that with saline (five of 18 versus eight of 18 animals survived; P = 0.32). In trial 2, six of 18 animals having no lavage and three of 18 receiving saline lavage survived. The combination of lavage and G-CSF increased the number of animals surviving to 11 of 18 (P < 0.05). Lavage combined with G-CSF stimulated granulocyte phagocytic activity (P < 0.01) and reduced the levels of interleukin (IL) 6 (P < 0.01) and tumour necrosis factor alpha (P < 0.05) in peritoneal fluid, as well as plasma levels of IL-6 (P < 0.05) and IL-10 (P < 0.01). In trial 3, survival was not significantly different in animals having lavage (14 of 30) and no lavage (19 of 30) (P = 0.14). CONCLUSION: In these CMRTs of intra-abdominal contamination and infection, peritoneal lavage was not beneficial, but when lavage was combined with subcutaneous administration of G-CSF mortality was reduced and the local and systemic cytokine response was downgraded. Results from these CMRTs were used directly to define the trial conditions of a randomized clinical trial with G-CSF. Peritoneal lavage is not recommended.