Modulatory effect of prolactin on the resting and mitogen-induced activity of T, B, and NK lymphocytes

Prolactin (PRL) has been shown to contribute to the development of lymphoid tissues and maintenance of physiological immune function. Here we show that the role of the hormone extends to the control of the effector phase of the immune response. In addition to triggering resting lymphocytes to cell division, the hormone can also control the magnitude of their response to polyclonal stimuli. Concentrations of PRL in the physiological range increased the [3H]thymidine, [3H]uridine, and [3H]leucine incorporation of unstimulated NK cells cultured in serum-free conditions. The same concentrations of the hormone increased the response of NK, T, and B cells to the mitogenic stimuli interleukin 2 (IL2), phytohemagglutinin (PHA), and staphylococcus aureus cowan, respectively, the effect being maximally evident in the presence of suboptimal concentrations of the mitogens. By contrast concentrations of PRL five- to tenfold the physiological levels inhibited the mitogenic response to IL2 and PHA. These data indicate a double-faceted regulatory role of this hormone in vivo.     

Clinical and haematological improvement induced by etidronate in a patient with idiopathic myelofibrosis and osteosclerosis

Summary We report a patient with agnogenic myeloid metaplasia associated with debilitating bone pain due to increased bone turnover and osteosclerosis. Treatment with etidronate at a dose of 6 mg/kg per day on alternate months resulted in a complete recovery of bone symptoms and normalization of metabolic parameters of bone turnover; unexpectedly, a sustained haematological improvement was also observed after several months of therapy, suggesting that bone marrow microenvironment improvement was able to restore a nearly normal haemopoiesis. We suggest that diphosphonate therapy may be of value in patients with AMM and increased bone turnover.     

Effects of interleukin-11 on the proliferation and cell cycle status of myeloid leukemic cells

Interleukin-11 (IL-11) is a pleiotropic cytokine with effects on many different targets. Within the hematopoietic system, the effects of IL- 11 are largely manifest only through combination with other cytokines, including IL-3 and Steel factor (SF). In the present study, we addressed the question of IL-11 responsiveness within the different types of human leukemic cells, as well as the mechanism of action of IL- 11 at the cellular level. Analysis of a panel of samples from different patients with acute myeloblastic leukemia (AML) and myeloid leukemic cell lines indicated that IL-11 alone was ineffective in supporting myeloid leukemic cell growth but frequently enhanced growth supported by IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or SF. In contrast, three acute pre-B lymphocytic leukemia (pre-B-ALL) and two acute T lymphocytic leukemia (T-ALL) lines failed to respond to IL- 11 alone or when combined with other cytokines. The growth enhancement of IL-11 among the AML patient samples was dose dependent and remarkably constant with half-efficient concentrations in the range of 0.3 to 0.4 ng/mL. The thymidine suicide studies with the patient samples revealed that 40% to 50% of the blast cells were in S-phase when exposed for 16 hours to IL-3 and this level was increased to 70% to 90% in response to either IL-11 or IL-6. Our data suggest that the latter two interleukins act synergistically with the direct mitogenic factor, IL-3, in triggering AML blast-cell proliferation. Detailed analysis with several patient samples further revealed that SF and IL- 11 both enhance IL-3-supported clonogenic growth of AML blasts and the combination of all three growth factors yields optimal growth. In contrast, IL-6 does not further enhance the effect of IL-11. These results indicate that SF and IL-11 enhance IL-3-dependent clonogenic growth through two distinct pathways, whereas IL-6 and IL-11 may trigger the same pathway.     

Stabilization of disease as an indicator of clinical benefit associated with chemotherapy in non-small cell lung cancer patients

In Phase II oncology studies, response rate has traditionally been used to assess activity. However stabilization of disease (SD) may also provide patient benefit. To assess the value of SD (stabilization of measurable disease for at least 8 weeks) as a predictor of survival following chemotherapy in patients with non-small cell lung cancer (NSCLC), we have analyzed data from 198 NSCLC patients receiving topotecan i.v. or orally as first-line therapy either as single agent or in combination. Proportional hazards (Cox) regression models showed that responders [complete response (CR) + partial response (PR), 1.5% and 11.6% respectively] had an estimated risk of death that was 9.8% (95% CI: 4.2% to 22.7%) of that for progressive disease (PD) (60.1% of the patient population). Similarly, patients with SD (26.8% of the patient population) showed a potential benefit with a risk of death that was 27.7% of the one of patients with PD (95% CI: 17.8% to 43.1%). In conclusion SD may be a useful indicator of patient benefit from chemotherapy for NSCLC.     

Antitumor activity of a human cytotoxic T-cell line (TALL-104) in brain tumor xenografts

Malignant glioma in adults and primitive neuroectodermal tumors/medulloblastomas in children are the most common malignant primary brain tumors that either respond poorly to current treatment or tend to recur. Adoptive therapy with TALL-104 cells-an IL-2-dependent, major histocompatibility complex nonrestricted, cytotoxic T-cell line-has demonstrated significant antitumor activity against a broad range of implanted or spontaneously arising tumors. This study investigates distribution of systemically and locally administered TALL-104 cells and their efficacy in effecting survival of a rat model of human brain tumor. In vitro, TALL-104 cells showed significant cytotoxic activity when added to human glioblastoma cell lines U-87 MG, U-251 MG, and A1690; the medulloblastoma cell lines DAOY, D283 Med, and D341 Med; and the epidermoid cancer cell line A431. In brain tumor-bearing rats, the amount of fluorescent dye-labeled TALL-104 cells in brain increased after they were given by intracarotid injection as compared with i.v. cell administration. However, TALL-104 cells rapidly decreased to low levels within 1 h after intracarotid injection. This finding suggests that TALL-104 cells given systemically may not invade brain or tumor tissues, but rather may remain in the vascular system, making this approach less efficient for brain tumor treatment. In a model of athymic rats engrafted with human A431 carcinoma brain tumor, repetitive local administration of TALL-104 cells directly into the tumor bed resulted in a significant increase in survival time compared with control animals. Therefore, local therapy with TALL-104 cells may be a novel and highly effective treatment approach for malignant brain tumors.     

Salicylate inhibition of rat mammary carcinogenesis and angiogenesis in female rat compatible with misoprostol administration

Epidemiological data suggest that non-steroidal anti-inflammatory drugs prevent colon cancer. The evidence for other types of tumour is less conclusive, though animal and in vitro studies indicate that they may be effective against mammary cancer cells. We assessed the effect of dietary acetylsalicylic and salicylic acid against dimethylbenzanthracene-induced rat tumours. Tumour angiogenesis was also investigated to explore the mechanism responsible for salicylate effect. Mammary tumours were induced in female Sprague-Dawley rats fed with different amounts of acetylsalicylic and salicylic acid. Serum vascular endothelial growth factor concentrations were measured and vascularization of basement membrane proteins injected in vivo (Matrigel) was determined by evaluation of haemoglobin content to assess the extent to which angiogenesis was inhibited. Dimethylbenzanthracene-induced carcinogenesis was inhibited by both acids and there was a log-dose/response correlation between the tumour diameter and salicylate concentration. Salicylic acid seems more effective than acetylsalicylic acid. Vascular endothelial growth factor was less concentrated in treated animals than in the controls and so was Matrigel haemoglobin. The mechanism involved, however, is still uncertain, though concomitant inhibition of tumour angiogenesis may be an important component. The documented salicylate serum VEGF modulation is interesting also for presence of the flk-1 receptor in mammary tumour cells of our model. Although misoprostol is a prostaglandin analogous its concomitant administration did not compromise the salicylate anti-tumour effect.     

CD22-directed monoclonal antibody therapy for lymphoma

Immunotherapy directed against the CD20 antigen has had a profound impact on the management of patients with B-cell non-Hodgkin's lymphoma (NHL). Antibody-based treatments offer a favorable side effect profile, as well as alternate mechanisms of action that may complement those of cytotoxic modalities. Targeting other antigens, such as CD22, may also result in antilymphoma effects. This B-cell-specific molecule is widely expressed in NHL and mediates important functions in B-cell biology. Preclinical and early clinical data suggest that epratuzumab, a humanized anti-CD22 monoclonal antibody, demonstrates antilymphoma effects in both unlabeled and radiolabeled forms, as well as a favorable safety profile. Ongoing and future studies will further determine the role of epratuzumab among the array of antilymphoma therapies, both as a single agent and in combination with other agents.     

Dialock(R)subcutaneous port for hemodialysis: A twelve-month experience in a single center

Background.The arteriovenous fistula (AVF) is still considered the golden standard form of vascular access for hemodialysis. However, the increasing use of central venous catheters mirrors the growing difficulty in planning an AVF. A totally implantable new device, the Dialock(R)system (Biolink Corporation, Norwell, MA), allowed us to conduct the first Italian experience. Methods.From February 1st 2000 to January 31st 2001, we implanted 21 devices in 12 males and 9 females, median age 66+/-12 years, with a dialysis duration ranging from 0 to 22 years. In 6 cases the Dialock (R)was first choice access, in 5 it replaced a malfunctioning tunneled central venous catheter, and in 10 cases it was the rescue access after previous AVF failures. Results.On average, the device was accessed 3.5 days after implantation. Median duration of use was 142 days (range 29-365), for a global observation period of 118.2 pt-months. Nineteen devices are currently working with-out any problem. One port was removed after 60 days due to thrombosis, and another after 9 months of use due to sepsis. Another patient had a systemic infection with cardiac and vertebral involvement with complete remission after 4 months of antibiotic therapy and salvage of the device. The infection rate was 1.3 per 1000 catheter-days. Prescribed blood flow was achieved in 95.7% of the sessions. Conclusion.Our short-term results confirm the efficacy and reliability of the new device. In order to assess the true indication for implanting Dialock(R), a more prolonged observation period is needed.     

Altered excitability of cultured chromaffin cells following exposure to multi-walled carbon nanotubes

We studied the effects of multi-walled carbon nanotubes (MWCNTs) on the electrophysiological properties of cultured mouse chromaffin cells, a model of spontaneously firing cells. The exposure of chromaffin cells to MWCNTs at increasing concentrations (30-263 μg/ml) for 24 h reduced, in a dose-dependent way, both the cell membrane input resistance and the number of spontaneously active cells (from 80-52%). Active cells that survived from the toxic effects of MWCNTs exhibited more positive resting potentials, higher firing frequencies and unaltered voltage-gated Ca(2+), Na(+) and K+ current amplitudes. MWCNTs slowed down the inactivation kinetics of Ca(2+)-dependent BK channels. These electrophysiological effects were accompanied by MWCNTs internalization, as confirmed by transmission electron microscopy, indicating that most of the toxic effects derive from a dose-dependent MWCNTs-cell interaction that damages the spontaneous cell activity.     

Pharmacokinetics of palifermin administered as the standard dose and as a collapsed dose in patients with hematologic malignancies

STUDY OBJECTIVE: To assess the pharmacokinetic profile of palifermin after intravenous dosing with either a collapsed dose of 180 microg/kg/day for 1 day or a standard dose of 60 microg/kg/day for 3 days, before and after myeloablative chemoradiotherapy and peripheral blood progenitor cell (PBPC) transplantation. DESIGN: Prospective, open-label pharmacokinetic study. SETTING: University-affiliated hematology and oncology center. PATIENTS: Twenty-five adult patients with hematologic malignancies receiving myeloablative therapy; 13 were in the standard-dose group, and 12 were in the collapsed-dose group. INTERVENTION: Patients received total-body irradiation (study days -8 to -5), etoposide (day -4), cyclophosphamide (day -2), and PBPC transplantation (day 0). Standard-dose palifermin was administered on days -11, -10, -9, 0, 1, and 2; collapsed-dose palifermin was administered on days -11 and 0. MEASUREMENTS AND MAIN RESULTS: Baseline demographic and clinical characteristics were recorded. Blood samples were obtained for pharmacokinetic assessment, presence of palifermin antibodies, and routine chemistry and hematology panels. Adverse events were documented daily. For both dosing groups, palifermin concentrations declined rapidly (>or= 98%) in the first 30 minutes and increased slightly between 1 and 4 hours after dosing, with a terminal decay phase. For standard-dose palifermin, mean values for area under the serum concentration-time curve (AUC) were within 15% between doses 1 and 3 and within 1% between doses 1 and 4. For collapsed-dose palifermin, mean AUC values and other pharmacokinetic parameters were within 2% between doses 1 and 2. Mean AUC on days -11 and 0 were approximately 4-fold higher for collapseddose palifermin than for standard-dose palifermin. Both dosing regimens were well tolerated. CONCLUSIONS: Our results were consistent with approximately dose-linear pharmacokinetics for the two dosing regimens, with no observed accumulation. A randomized, controlled study is warranted to assess the safety and efficacy of collapsed-dose palifermin, which may provide a more convenient administration schedule.