ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer.

The European Society of Thoracic Surgeons (ESTS) organized a workshop dealing with lymph node staging in non-small cell lung cancer. The objective of this workshop was to develop guidelines for definitions and the surgical procedures of intraoperative lymph node staging, and the pathologic evaluation of resected lymph nodes in patients with non-small cell lung cancer (NSCLC). Relevant peer-reviewed publications on the subjects, the experience of the participants, and the opinion of the ESTS members contributing on line, were used to reach a consensus. Systematic nodal dissection is recommended in all cases to ensure complete resection. Lobe-specific systematic nodal dissection is acceptable for peripheral squamous T1 tumors, if hilar and interlobar nodes are negative on frozen section studies; it implies removal of, at least, three hilar and interlobar nodes and three mediastinal nodes from three stations in which the subcarinal is always included. Selected lymph node biopsies and sampling are justified to prove nodal involvement when resection is not possible. Pathologic evaluation includes all lymph nodes resected separately and those remaining in the lung specimen. Sections are done at the site of gross abnormalities. If macroscopic inspection does not detect any abnormal site, 2-mm slices of the nodes in the longitudinal plane are recommended. Routine search for micrometastases or isolated tumor cells in hematoxylin-eosin negative nodes would be desirable. Randomized controlled trials to evaluate adjuvant therapies for patients with these conditions are recommended. The adherence to these guidelines will standardize the intraoperative lymph node staging and pathologic evaluation, and improve pathologic staging, which will help decide on the best adjuvant therapy.     

CSF cytology of a patient with conversion of an acute lymphatic leukemia to an acute eosinophilic leukemia

The course of leukemic disease in a male adolescent with meningeal leukemia is described. The bone marrow aspirates showed a conversion from an acute lymphatic leukemia to an eosinophilic leukemia. Four weeks after the peripheral shift of phenotype two different cell clones were detected in one CSF smear. While under ultrahigh dose araC therapy the patient died 3 months after conversion. Possible explanation for the shift of phenotype and the peculiar leptomeningeal infiltration are discussed.     

Intravenous substitution with immunoglobulins

A survey of clinical data shows that substitution with intravenous immunoglobulins constitutes an essential further step in the therapy of patients with immunodeficiencies: patients with primary and some secondary immunodeficiencies clearly benefit from intravenous immunoglobulin substitution. Some other diseases including idiopathic thrombocytopenic purpura and the Kawasaki syndrome also constitute indications for this kind of treatment. In other cases (infections in newborn preterm infants, children with AIDS, chronic inflammatory demyelinizing polyneuropathies and the Guillain-Barré syndrome and children with refractory seizures) there are reasons to believe that intravenous immunoglobulin therapy can be of benefit, although bigger controlled studies are still necessary to allow definitive conclusions to be reached. Further attempts will have to be made to improve understanding of the mode of action of intravenously administered immunoglobulin.     

Effects of social stress and intrauterine position on sexual phenotype in wild-type house mice (Mus musculus)

Wild-type house mice were used to test the effect of intrauterine position on anogenital distance (AGD) and to verify whether crowding stress would masculinize female pups, developing at all intrauterine positions, as has been demonstrated in CF-1 mice stressed by restraint, heat, and light. Stress of crowding was documented by comparing aggressive behavior, litter birth weights, and plasma corticosterone levels among females in different densities. AGDs were recorded from pups born to females housed from day 12 to 19 of gestation either individually with their mate (nonstressed) or in one of two group-housed densities. Female pups from nonstressed dams positioned between two males in utero (2M females) had longer AGDs than females positioned between two females (0M females). AGDs of males from nonstressed dams did not differ on the basis of intrauterine position. Group-housed pregnant females in the higher of two densities had female pups with longer AGDs than female pups of other dams. However, variance in female pup AGD was no different among dams in different densities. These results extend to the wild house mouse previous findings in albino mice that intrauterine position influences sexual phenotype. In addition, social stress can induce masculinization of female pups in wild mice as physical stress has been shown to do in albinos. This suggests that intrauterine position effects and their modification by crowding stress can potentially influence the dynamics of wild house mouse populations.     

Effects of leflunomide on immune responses and models of inflammation

Conclusions Leflunomide is an antiphlogistic and immunomodulating agent that has been shown to be effective in preventing and healing autoimmune disorders and reactions leading to organ graft rejection. From our preliminary clinical data [4], we now have hopes that these effects, observed in experimental animals, can truly be transferred to humans.Although we are far from understanding the mode of action of leflunomide, we are slowly gathering some insight. A good many of the immunosuppressive effects of leflunomide can be attributed to the antagonistic effects it has on responses to many cytokines, most likely through receptor expression and signal transduction (tyrosine kinase inhibition). The inhibition of transplant rejection could be explained by interference with the activity of IL-2 and IL-4, i.e. the interference of cytotoxic T cell formation. Considering, further, that increased IL-3-like activity has been reported in autoimmune MRL/lpr mice [23], and that it is felt that this amplified activity may contribute to the pathology of their illness [23], then the interference of leflunomide with IL-3 may, together with the antagonistic activity of TRF and specifically IL-4, explain some of the disease modifying properties of this drug in animals with SLE-like and other autoimmune diseases. Also, interference with responses to IL-6 (Germann, personal communication) could be responsible for the suppression of acute-phase proteins observed in adjuvant-diseased rats [24].Our data concerning tyrosine kinase inhibition as a hypothetical mechanism for the non-cytotoxic and reversible antiproliferative activity of A77 1726 are in many ways, intriguing. First of all, many known receptors for growth factors are associated with tyrosine kinase, i.e. EGF [35], IL-2 (the high binding, 75 kDa chain) [21], IL-3 [26], G-CSF, GM-CSF and TNF- [9]. Leflunomide antagonizes all of these mediators. On the other hand, IL-1, which is not antagonized by leflunomide, is not associated with tyrosine kinase, but with threonine and serine kinase [11]. Much more work must be conducted before we can be sure that tyrosine kinase inhibition is important for the mode of action of leflunomide.Another important aspect of this drug is its inhibitory effect on the release of histamine from basophils and mast cells, because of its role in inflammatory reactions. Relating to our findings on the activity of leflunomide on murine SLE-like disorders, it has been reported recently that SLE patients often exhibit abnormal production of antibodies to IgE, and that these autoantibodies may, by activating mast cells and basophils, play a consequential part in the release of vasoactive amines, thus leading to generalized tissue injury [15].We are confident that leflunomide will prove to be an effective drug in combating human autoimmune disorders. Indeed, we already have preliminary evidence for this, from studies of its effects on humans suffering from autoimmune diseases. Moreover, this drug provides a tool for gaining new insights into both the mechanisms leading to such ailments and their therapeutic control, and as such may facilitate the discovery of even more proficient drugs or other means to modulate these malfunctioning immune reactions.     

Natural killer cell activity and antibody-dependent cellular cytotoxicity in patients under various immunosuppressive regimens

The influence of various modes of immunosuppression using cyclosporin A (CyA), corticosteroids (Cort), azathioprine (AZA), and antithymocyte globulin (ATG) alone or in combination with each other upon natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) was assessed. CyA given alone did not influence either NK or ADCC activity; in contrast, the administration of Cort resulted in a significant decline (P less than 0.01) of ADCC but not of NK activity (P greater than 0.1). The combination of the two drugs led to a significant impairment of NK activity (P less than 0.01). The combination of AZA and Cort was found to produce an even more pronounced reduction in NK activity compared to both healthy controls (P less than 0.001) as well as patients from the CyA + Cort group (P less than 0.001). A similar decrease was found also after the addition of ATG to CyA + Cort (P less than 0.001, compared both with patients on CyA + Cort and with controls). In these instances, ADCC showed an overall similar pattern. We conclude that the administration of either CyA or Cort does not influence NK activity, while the combination of CyA with Cort and of AZA with Cort leads to a decrease in both NK and ADCC activities. The monotherapy with Cort only leads to a reduction of ADCC. These findings may explain the higher incidence of malignancies in patients undergoing combined immunosuppressive treatment.     

Decline in perinatal HIV transmission in New York State (1997-2000)

BACKGROUND: Perinatal HIV transmission has declined significantly in New York State (NYS) since implementation of a 3-part regimen of zidovudine prophylaxis in the antenatal, intrapartum, and newborn periods. This study describes the factors associated with perinatal transmission in NYS from 1997 to 2000, the first 4 years of NYS's comprehensive program in which all HIV-exposed newborns were identified through universal HIV testing of newborns. METHODS: This population-based observational study included all HIV-exposed newborns whose infection status was known and their mothers identified in NYS through the universal Newborn HIV Screening Program (NSP) from February 1997 to December 2000. Antepartum, intrapartum, newborn, and pediatric medical records of HIV-positive mothers/infants were reviewed for history of prenatal care, antiretroviral therapy (ART), and infant infection status. Risks associated with perinatal HIV transmission were examined. RESULTS: Perinatal HIV transmission declined significantly from 11.0% in 1997 to 3.7% in 2000 (P < 0.05). Prenatal ART was associated with a decline in perinatal HIV transmission both for monotherapy (5.8%, relative risk [RR] = 0.3, 95% confidence interval: 0.2%-0.5%) and combination therapy [2.4%, RR = 0.1, 95% confidence interval: 0.1%-0.2%) compared with no prenatal antiretroviral prophylaxis (P < 0.05). CONCLUSIONS: Public health policies to improve access to care for pregnant women and advances in clinical care, including receipt of appropriate preventive therapies, have contributed to declines in perinatal HIV transmission in NYS.     

Radioisotopic pulmonary lobectomy: feasibility study in dogs

In search for an alternate treatment for inoperable cancer of the lung in humans, we investigated the possibility that introduction of radioactive material into a selected lobe of the canine lung would effectively destroy that lobe without systemic effects or radiation injury to adjacent organs. Ten million ion exchange microspheres labeled with 740 MBq of phosphorus-32 (32P) were injected through a catheter placed in a selected lobar branch of a pulmonary artery in 12 anesthetized dogs. Six additional dogs served as controls and received 10 million microspheres not labeled with 32P. Organs were harvested from 1 wk to 12 mo after injection and examined grossly and histologically. There was progressive organization and contraction of each necrosed 32P treated lobe which was reduced to a scarred remnant by 12 mo, whereas only minimal inflammatory changes occurred in controls. Of the 32P injected dose, 94% remained in injected lobe, 4%-5% in nontargeted lobes and less than 0.08% in blood. Radioactivity in liver, kidneys, spleen, heart, and bone marrow was less than 0.1% for each organ. Thus, large doses of radiation in the order of 1,500 Gy can be effectively delivered to a selected lobe to produce a "radioisotopic pulmonary lobectomy."