Impairment of in vitro natural antibacterial activity in HIV-infected patients

Circulating PBMC of healthy subjects possess an in vitro natural antibacterial (NA) against enteropathogenic bacteria, including Salmonella species. The effector cell of NA activity is a CD: 4+, 8-, Leu-8/TQ-1+ T lymphocyte acting against bacteria via cytophylic IgA in a mechanism similar to antibody-dependent cellular activity. Because AIDS is a profound immunodeficiency caused by HIV involving primarily CD4 lymphocytes and in particular the Leu-8/TQ-1 subset, it was of interest to assess NA activity of HIV+ subjects at various stages of the disease. Results indicate that NA activity against Salmonella typhi and Salmonella paratyphi C is significantly decreased in AIDS as well as in lymphadenopathy syndrome patients. Furthermore, sera containing IgA against salmonellae were not able to arm PBMC from HIV+ patients. The humoral response against S. typhi-LPS was also greatly decreased after HIV infection, in contrast to the known hypergammaglobulinemia seen in these subjects. Defective NA activity might contribute to the increased incidence of salmonellosis observed in AIDS.     

Testicular creatine and urinary creatine-creatinine profiles in mice after the administration of the reproductive toxicant methoxyacetic acid

It was previously observed that the acute or subchronic administration of some testicular toxicants, caused a significant raise in urinary creatine in rats. The aim of this study was to verify whether creatinuria could be detected in mice (a species with a different excretion profile of creatine) and whether it could be correlated to the levels of creatine in testis and to other parameters of testicular toxicity. The well known testicular toxicant methoxyacetic acid (MAA) was orally administered as a single dose (400 or 600 mg kg^-) to male adult mice B6C3F1. Twenty-four hours after dosing, urinary creatine and creatinine showed a significant reduction with respect to the pre-treatment values. At the following times post-dosing (48 and 72 h) the creatine exceeded the control and pre-treatment values, while creatinine had not yet recovered. The ratio creatine/creatinine was significantly higher than control and pre-treatment values, at 24 and 48 h after the treatments. In testis a significant, dose-dependent, decrease of creatine was observed 24 h after dosing, with a pattern related to the histopathologic alterations observed at different times after the treatments. Creatine determination was the earlier quantitative parameter of testicular toxicity, since at this time testis weights, sperm head number and enzyme activities (LDH-C4, SDH) were less affected, their maximum decrease being reached at 14 days after the treatments. These data suggest that in mice, 2-MAA could interfere with the metabolism of creatine, both in testis and other biosynthetically active tissues.     

Assessing the presence of abnormal regulation of cortisol secretion by membrane hormone receptors: in vivo and in vitro studies in patients with functioning and non-functioning adrenal adenoma.

Regulation of cortisol secretion by aberrant hormone receptors may play a role in the pathogenesis of ACTH-independent Cushing's syndrome. In this study, the topic was evaluated by combining in vivo and in vitro approaches. Cortisol responses to various stimuli (standard meal, GnRH + TRH, cisapride, vasopressin, glucagon) were assessed in 6 patients with clinical or subclinical adrenal Cushing's syndrome, and non-functioning adrenal adenoma in two cases. Abnormal responses were observed in three patients with Cushing's syndrome; one patient showed a gastric inhibitory polypeptide (GIP)-dependent cortisol rise after meal, together with responses after GnRH and cisapride; the second patient showed an LH-dependent cortisol response to GnRH, and in the third cortisol rose after cisapride. The pattern of receptor expression performed by RT-PCR showed that while GIP-R was only expressed in tumor from the responsive patient, 5-hydroxytryptamine type 4 receptor and LH-R were also present in normal adrenal tissues and tissues from non-responsive patients. Interestingly, an activating mutation of Gsalpha gene was identified in one of these tumors. Therefore, cortisol responses to agents operating via Gs protein coupled receptors (in one case associated with Gsalpha mutation) were found in Cushing's patients, while these responses were absent in the others. The finding of receptor expression in normal and non-responsive tumors suggests that different mechanisms are probably involved in inducing in vivo cortisol responses.     

Neo-adjuvant chemo-(immuno-)therapy of advanced squamous-cell head and neck carcinoma: a multicenter, phase III, randomized study comparing cisplatin + 5-fluorouracil (5-FU) with cisplatin + 5-FU + recombinant interleukin 2

We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III–IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m² cisplatin i.v. on day 1 plus 1000 mg m⁻² day⁻¹ 5-FU on days 1–5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8–12 and 15–19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and 1 from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved. Received: 9 April 1998 / Accepted: 30 June 1998     

Molecular mechanisms of perineural invasion,a forgotten pathway of dissemination and metastasis

Invasion and metastasis are key components of cancer progression. Inflammatory mediators, including cytokines and chemokines, can facilitate tumor dissemination. A distinct and largely forgotten path is perineural invasion (PNI), defined as the presence of cancer cells in the perinerium space. PNI is frequently used by many human carcinomas, in particular by pancreas and prostate cancer, and is associated with tumor recurrence and pain in advanced patients. Neurotrophic factors have been identified as molecular determinants of PNI. A role for chemokines in this process has been proposed; the chemokine CX3CL1/Fractalkine attracts receptor positive pancreatic tumor cells to disseminate along peripheral nerves. Better understanding of the neurotropism of malignant cells and of the clinical significance of PNI would help the design of innovative strategies for the control of tumor dissemination and pain in cancer patients.