The liver-cytokine-brain circuit in interferon-based treatment of patients with chronic viral hepatitis.

Psychiatric symptoms are commonly identified in patients with viral hepatitis. They may have been present prior to the onset of disease and may include symptoms related to addiction issues. Furthermore, the virus and antiviral therapy, in particular interferon, may induce or modify psychiatric symptoms. Recent data support chronic hepatitis C replication in the brain and subsequent changes of cerebral metabolite spectra and magnetic resonance alterations. In chronic viral hepatitis and in other chronic inflammatory diseases, an alteration of the neuro-endocrine-immune system response has been observed. Catecholamines and glucocorticoids modulate this immune/inflammatory reaction. Psychiatric assessment and monitoring before, during and after antiviral therapy can identify patients whose psychiatric symptoms preclude therapy, and those who may benefit from psychopharmacological therapy and counselling, thereby improving therapeutic results. This review will discuss current insights into the complex interplay between cytokines, liver and brain in chronic viral hepatitis closely associated with psychiatric issues, especially in the case of antiviral therapy, with the aim of indicating future research and possible treatments.

Assessment of psychological distress in cancer patients: a pivotal role for clinical interview.

OBJECTIVE: The evaluation of psychological distress in cancer patients recently entered oncologic clinical practice. The objective of this study was to evaluate the role of clinical interview within psycho-oncologic assessment. METHODS: Questionnaires assessing distress (PDI), psychopathology (MHQ, HADS) and needs (NEQ) and a subsequent clinical interview were proposed to 320 consecutive inpatients from the Oncology Department of Careggi Hospital in Florence. RESULTS: The clinical interview made it possible to evaluate a significant percentage of patients (30%) who did not fill in questionnaires and to detect the presence of distress in 39 (13.7%) patients who would not have received a diagnosis in a protocol for the assessment of distress based only on questionnaires. It also provided the possibility to ask for help or to receive clinical support to a high percentage of patients (44.1%) who had not requested to speak to a psychologist through the questionnaires (NEQ). Moreover, 25% of patients who received prolonged clinical support had a low score in tests detecting distress, indicating that the opportunity for therapeutic support can emerge during a clinical interview, also in the absence of relevant symptoms detected by questionnaires. CONCLUSIONS: The use of more than one questionnaire in the assessment of distress and psychopathology is associated with reduced compliance and redundant information. On the other hand, clinical interview has a pivotal role in clinical evaluation and access to psychological support. We conclude that optimal efficacy of programs assessing distress in cancer patients is reached when a single questionnaire evaluating distress is associated with a clinical interview.

Effect of age, ethnicity, sex, cognitive status and APOE genotype on amyloid load and the threshold for amyloid positivity.

The threshold for amyloid positivity by visual assessment on PET has been validated by comparison to amyloid load measured histopathologically and biochemically at post mortem. As such, it is now feasible to use qualitative visual assessment of amyloid positivity as an in-vivo gold standard to determine those factors which can modify the quantitative threshold for amyloid positivity. We calculated quantitative amyloid load, measured as Standardized Uptake Value Ratios (SUVRs) using [18-F]florbetaben PET scans, for 159 Hispanic and non-Hispanic participants, who had been classified clinically as Cognitively Normal (CN), Mild Cognitive Impairment (MCI) or Dementia (DEM). PET scans were visually rated as amyloid positive (A+) or negative (A-), and these judgments were used as the gold standard with which to determine (using ROC analyses) the SUVR threshold for amyloid positivity considering factors such as age, ethnicity (Hispanic versus non-Hispanic), gender, cognitive status, and apolipoprotein E ε4 carrier status. Visually rated scans were A+ for 11% of CN, 39.0% of MCI and 70% of DEM participants. The optimal SUVR threshold for A+ among all participants was 1.42 (sensitivity = 94%; specificity = 92.5%), but this quantitative threshold was higher among E4 carriers (SUVR = 1.52) than non-carriers (SUVR = 1.31). While mean SUVRs did not differ between Hispanic and non-Hispanic participants;, a statistically significant interaction term indicated that the effect of E4 carrier status on amyloid load was greater among non-Hispanics than Hispanics. Visual assessment, as the gold standard for A+, facilitates determination of the effects of various factors on quantitative thresholds for amyloid positivity. A continuous relationship was found between amyloid load and global cognitive scores, suggesting that any calculated threshold for the whole group, or a subgroup, is artefactual and that the lowest calculated threshold may be optimal for the purposes of early diagnosis and intervention.

[Neuropsychological predictors of reading ability in Spanish]. / Predictores neuropsicológicos de la lectura en español.

INTRODUCTION: Learning how to read has been associated with different types of linguistic and non-linguistic skills. However, few studies have looked at the association between neuropsychological test performance and reading skills at different ages during childhood. AIM: To analyze the association between neuropsychological test scores and reading performance, and to investigate the influence of age, gender and type of school (public or private) over reading test performance. SUBJECTS AND METHODS: The sample included 625 6 -to-15 year old children (207 Colombians, 418 Mexicans; 277 boys, 348 girls). The following cognitive abilities were assessed: reading speed and reading comprehension and attention, memory (coding and recall), perception, visuospatial and conceptual abilities and executive functions. RESULTS: The best neuropsychological test predictor for reading speed was Letter Cancellation, and for reading comprehension was Memory for a Story. Children from private schools performed better in most reading tests than children from public schools. Differences between boys and girls were observed in only two reading tests. CONCLUSION: Reading speed correlates mainly with attentional skills and reading comprehension with verbal memory. Reading abilities in school age children are influenced mainly by age and type of school and little by gender.

Phase 1B study of subcutaneously administered interleukin 2 in combination with 13-cis retinoic acid as maintenance therapy in advanced cancer.

At present, no therapeutic strategy is available to maintain responses achieved in patients treated with chemotherapy. This Phase IB study was aimed at identifying the optimal biological dose of chronic maintenance therapy using s.c. interleukin (IL) 2 and oral 13-cis retinoic acid (RA) in patients with either tumor stabilization or response to chemotherapy. IL-2 has no cross-resistance with chemotherapy and improves cancer-related lymphocytopenia, a factor that determines poor prognosis, whereas RA has immunomodulatory properties, potentially synergistic with IL-2. Eighteen patients with advanced solid tumor who achieved a response or stable disease as a result of standard chemotherapy, received RA (0.5 mg/kg) and IL-2 5 days/week for two cycles of 3 weeks/month for up to 1 year. Three doses of IL-2 were used: 9.0, 4.5, and 1.8 x 10(6) IU/day. Monitoring consisted in a weekly blood differential count and a bimonthly assessment of tumor markers, CD4+, CD8+, and natural killer cells. Patients were evaluated for toxicity, response maintenance, time to progression, and survival. Patients chronically treated with 9 and 4.5 x 10(6) IU of IL-2 developed dose-limiting toxicity grade III or IV, consisting of fever, fatigue, thrombocytopenia, mucositis, and local cutaneous reaction. No grade III or IV toxicity was observed with the 1.8 x 10(6) IU dose, considered as the optimal biological dose. Fifty courses of IL-2 were administered (median, 3 per patient). An increase in total lymphocyte number, CD4:CD8 ratio and natural killer cell count was observed at all of the three dose levels with respect to baseline values. Two patients with a partial response to chemotherapy achieved a complete response after 6 and 7 months, respectively, of IL-2 + RA maintenance therapy. Median time to progression and overall survival were, respectively, 8.1 and 13.7 months (range, 2-48.8+ months). Low-dose IL-2 + RA as maintenance therapy after chemotherapy is, therefore, feasible and well tolerated and improves immunological parameters known to have a prognostic value in cancer.

Actions of the testicular paracrine factor (P-Mod-S) on Sertoli cell transferrin secretion throughout pubertal development.

Peritubular cells that surround the seminiferous tubules have been shown to produce a paracrine factor, termed P-Mod-S, that has dramatic effects on Sertoli cell function in vitro and is postulated to be important in the control of testicular function. The current study was designed to determine whether P-Mod-S has the ability to regulate Sertoli cell function during pubertal development. Sertoli cells were isolated from 10-, 20-, and 35-day-old rats which correspond to the prepubertal, mid-pubertal, and late pubertal stages of development. Histochemical analysis of cultured cells isolated from each age group was performed to establish the purity of the cell populations used. Testicular transferrin production by Sertoli cells was used as a marker of cellular differentiation. Basal production of transferrin by the cultured cells was found to increase during the pubertal period. P-Mod-S stimulated transferrin production by Sertoli cells isolated from 10-, 20-, and 35-day-old rats. FSH appears to enhance the ability of Sertoli cells to respond to P-Mod-S with cells obtained from 10-day-old rats. Sertoli cells from 35-day-old rats were nonresponsive to regulatory agents such as FSH. P-Mod-S alone, however, significantly stimulated transferrin production by Sertoli cells from this more adult stage of development. P-Mod-S was the only individual regulatory agent tested that could stimulate transferrin production by Sertoli cells from 35-day-old rats. Results indicate that P-Mod-S has the ability to regulate Sertoli cell function throughout pubertal development. Observations suggest that P-Mod-S and FSH may act together in the prepubertal testis to promote Sertoli cell differentiation and that P-Mod-S may act in the adult testis to maintain optimal Sertoli cell function and differentiation.

Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate.

Increased incidence of cardiovascular disease in postmenopausal women (PMW) is accompanied by ovarian dysfunction; hormone replacement therapy (HRT) can have cardioprotective effects. Because hypertension and atherosclerosis are associated with impaired release of endothelium-derived nitric oxide (NO) and increased levels of low-density lipoproteins (LDL), we investigated whether HRT augments NO release, and whether these increases are accompanied by a decrease in LDL levels in PMW. We determined serum nitrite/ nitrate (NO2-/NO3-) and LDL levels at baseline (before initiation of HRT) and during the 6th and 12th months of the study. The PMW (n = 26) received continuous oral administration of estradiol valerate (Progynova, 2 mg daily) for 21 days supplemented with either oral cyproterone acetate (CPA; 1 mg; n = 11) or medroxyprogesterone acetate (MPA; 5 mg; n = 15) on days 12-21 of each treatment cycle. Blood samples in the PMW receiving HRT were collected at times while the subjects were taking estradiol valerate alone and estradiol valerate plus CPA or MPA. Compared with the samples collected at baseline, serum NO2-/NO3- levels increased significantly from 20.1 +/- 1.58 mumol/L at baseline to 30 +/- 3.7 mumol/L (P < 0.01) in samples collected after 12 months of HRT while the PMW were not taking progestins (CPA or MPA), and to 25.4 +/- 2 mumol/L (P < 0.05) when all the samples, regardless of the treatment with CPA or MPA, were included in the analysis. Moreover, > 30% increase in serum NO2-/NO3- levels were observed only in 13 (responders) out of 26 PMW substituted with estradiol valerate, suggesting that estradiol may improve endogenous NO synthesis in a differential fashion. Compared with baseline, no significant increases in serum NO2-/NO3- were observed in samples collected while the estradiol-treated responders were taking either CPA or MPA. In contrast to NO2-/NO3- serum LDL levels were significantly reduced in samples collected after 12 months of HRT (P < 0.05 vs. baseline). Furthermore, levels of NO2-/NO3 showed a significant negative correlation with the levels of LDL (r2 = 0.17; P < 0.05) in the responders but not in nonresponders. These results indicate that oral administration of estradiol valerate in PMW for HRT increases circulating NO levels, an effect that may contribute to the cardioprotective effects of HRT in PMW. In addition, our data suggests but does not prove that concomitant administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release. Finally, our data provides evidence for the existence of responders and nonresponders to postmenopausal estrogen treatment with respect to improvement of endogenous NO levels, suggesting that a significant number, but not all, of the hormonally substituted PMW profit fully from the beneficial properties of a HRT.

Estradiol inhibits smooth muscle cell growth in part by activating the cAMP-adenosine pathway.

Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved remain unclear. Because estradiol stimulates cAMP synthesis and adenosine inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of estradiol on vascular smooth muscle cell growth. To test this hypothesis, we examined the effects of estradiol (0.001 to 1 micromol/L) on serum-induced DNA, collagen, and total protein synthesis and cell number in the absence and presence of 1, 3-dipropyl-8-p-sulfophenylxanthine (10 nmol/L; A(1)/A(2) adenosine receptor antagonist), KF17837 (10 nmol/L; selective A(2) adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A(1) adenosine receptor antagonist), and 2', 5'-dideoxyadenosine (10 micromol/L; adenylyl cyclase inhibitor). Estradiol inhibited all measures of cell growth, and the concentration-dependent inhibitory curves for estradiol were shifted to the right (P<0.05) by 1,3-dipropyl-8-p-sulfophenylxanthine, KF17837, and 2',5'-dideoxyadenosine but not by 8-cyclopentyl-1, 3-dipropylxanthine. Moreover, the inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase with forskolin and by inhibition of adenosine metabolism with erythro-9-(2-hydroxy-3-nonyl)adenine plus iodotubericidin (adenosine deaminase and kinase inhibitors, respectively). Estradiol also increased levels of cAMP and adenosine, and these effects were blocked by 2',5'-dideoxyadenosine (P<0.05). Our results support the hypothesis that estradiol stimulates cAMP synthesis and cAMP-derived adenosine regulates smooth muscle cell growth via A(2) adenosine receptors. Thus, the cAMP-adenosine pathway may contribute importantly to the antivasooclusive effects of estradiol.

Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol and norethisterone acetate. A two-year follow-up study.

Postmenopausal women (PMW) have an increased risk of cardiovascular disease that is attenuated by hormone replacement therapy (HRT). Inasmuch as hypertension and atherosclerosis are associated with diminished endothelium-derived nitric oxide (NO), we investigated whether HRT augments NO release in PMW. We determined serum levels of nitrite/nitrate (NO2 + NO3) at baseline and during the 6th, 12th, and 24th months of the study in two groups of PMW. One group (HRT-PMW, n = 13) received continuous transdermal administration of 17 beta-estradiol (Estraderm-TTS-50) supplemented with oral norethisterone acetate (NETA) on days 1 through 12 of each month, and the other group (control PMW, n = 13) did not receive HRT. Blood samples in the HRT-PMW group were collected without regard to whether subjects were taking NETA at the time of blood sampling. Serum NO2 + NO3 levels increased in HRT-PMW for the duration of the study, whereas serum NO2 + NO3 levels remained unchanged in control PMW. When all samples regardless of timing of collection with respect to NETA treatment were included in the statistical analysis, the change in NO2 + NO3 levels in HRT-PMW was significantly greater compared with the change in control PMW (P = .037). Likewise, when only those samples collected when estradiol-treated subjects were not taking oral NETA were included in the statistical analysis, the change in NO2 + NO3 levels in the HRT-PMW group remained significant (P = .047) compared with control PMW.(ABSTRACT TRUNCATED AT 250 WORDS)

Phytoestrogens inhibit growth and MAP kinase activity in human aortic smooth muscle cells.

-Estrogens are known to induce cardioprotective effects by inhibiting smooth muscle cell (SMC) growth and neointima formation. However, the use of estrogens as cardioprotective agents is limited by carcinogenic effects in women and feminizing effects in men. If noncarcinogenic and nonfeminizing estrogenlike compounds, such as natural phytoestrogens, afford cardioprotection, this would provide a safe method for prevention of cardiovascular disease in both men and women. Therefore, we evaluated and compared in human aortic SMCs the effects of phytoestrogens (formononetin, genistein, biochanin A, daidzein, and equol) on 2.5% fetal calf serum-induced proliferation (3H-thymidine incorporation and cell number), collagen synthesis (3H-proline incorporation), and total protein synthesis (3H-leucine incorporation) and on PDGF-BB (25 ng/mL)-induced migration (modified Boydens chambers). Moreover, the effects of phytoestrogens on PDGF-BB (25 ng/mL)-induced mitogen-activated protein kinase (MAP kinase) activity in SMCs was also studied. Phytoestrogens inhibited proliferation, collagen and total protein synthesis, migration, and MAP kinase activity in a concentration-dependent manner and in the following order of potency: biochanin A>genistein>equol>daidzein>formononetin. In conclusion, our studies provide the first evidence that in human aortic SMCs phytoestrogens inhibit mitogen-induced proliferation, migration and extracellular matrix synthesis and inhibit/downregulate MAP kinase activity. Thus, phytoestrogens may confer protective effects on the cardiovascular system by inhibiting vascular remodeling and neointima formation and may be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.

Randomized trial of sequential administration of G-CSF and GM-CSF vs. G-CSF alone following peripheral blood progenitor cell autograft in solid tumors.

A trial was conducted to investigate whether the sequential administration of recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) could accelerate reconstitution of hematopoiesis, compared with G-CSF alone following high-dose chemotherapy (HDCT). A group of 34 consecutive patients with solid tumors undergoing HDCT and autologous peripheral blood progenitor cell (PBPC) transplantation was studied. Conditioning regimen included carboplatin, etoposide, mitoxantrone, and melphalan for breast cancer and cyclophosphamide or ifosfamide, carboplatin, and etoposide for the other tumors. HDCT was delivered from day -3 to day -1. PBPC were infused on day 0, and on the same day growth factors were administered subcutaneously (s.c.) 5 microg/kg each. Seventeen patients were randomized to receive G-CSF from day 0 to day 13 after HDCT (arm A), and 17 patients received G-CSF from day 0 to day 6 and GM-CSF from day 7 to day 13 (arm B). Patients were stratified, and their characteristics were homogeneous in both arms for age, performance status, and number of previous chemotherapy courses and CD34+ infused. The median time to absolute neutrophil count (ANC) >500/microl was 10 days in arm A and 9 days in arm B (p = 0.96). Days to platelet (PLT) count >20,000 were not different in the two treatment arms (p = 0.1), but patients randomized to arm A had a lower platelet count compared with patients in arm B. One month after PBPC transplantation, a statistically significant difference in PLT count was observed (arm A median 150x10(3)/microl (90-310), arm B median 254x10(3)/microl (117-387),p = 0.0013). The days patients had fever >38 degrees C were 39 in arm A and 26 in arm B (p = 0.18). The difference in the length of hospital stay was not statistically significant between the groups (Mann-Whitney sum rank test). After a median follow-up of 30 months, 21 patients were alive and 20 were disease free. These data show that the two growth factors are associated with different patterns of hematopoietic recovery, and larger randomized trials in groups of more homogeneous patients will be needed to define the effects and benefits of combination growth factor therapies.

Ifosfamide, vinorelbine and gemcitabine in advanced non-small cell lung cancer. A phase I study.

The objective of this phase I study was to identify the maximum tolerated dose (MTD) and toxicity of a three drug, platinum-free regimen, including gemcitabine, ifosfamide and vinorelbine, in the treatment of patients with advanced non-small cell lung cancer (NSCLC). 33 chemotherapy-naïve patients with histologically confirmed, unresectable NSCLC, received fixed doses of ifosfamide (1500 mg/m2 days 1-3 with mesna) and vinorelbine (25 mg/m2 days 3 and 8). The gemcitabine dose was escalated from 500 to 1200 mg/m2 on days 3 and 8 every third week. The escalation was stopped at dose level 4 (gemcitabine 1200 mg/m2) since all 3 patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia at treatment cycle 1. The dose recommended for phase II trials is: gemcitabine 1000 mg/m2 and vinorelbine 25 mg/m2 given on days 3 and 8 plus ifosfamide 1500 mg/m2 on days 1-3. An encouraging response rate of 50% (95% confidence interval (CI): 32-68%) was observed in 32 patients evaluated. Our results show that ifosfamide, vinorelbine and gemcitabine can be safely administered as outpatient chemotherapy for NSCLC. Myelosuppression is the dose-limiting toxicity (DLT) of this regimen with no major subjective side-effects observed.

Calculation deficits in patients with right and left hemisphere damage.

Calculation abilities were studied in 41 left and 21 right hemisphere damaged patients. Their results were compared with a normal group matched by age, sex and educational level. Left hemisphere patients were grouped according to the type of accompanying aphasia. All patient groups presented at least a certain degree of acalculia. However, maximum difficulties were found in retrorolandic left hemisphere patients. Right hemisphere patients, especially retrorolandic patients, also presented impairments in calculation abilities, resulting mainly from spatial defects. Different types of errors were analyzed. Observed errors may be similar, but due to highly different neuropsychological dysfunctioning. Primary and secondary observed defects may be attributed to a diverse array of underlying deficits.

Effects of cultural background and education on handedness.

A 5-item handedness questionnaire was given to 317 subjects in four different groups: (1) 51 Tucano (Amazonian jungle) adolescents (36 male, 15 female); (2) 66 Spanish-speaking adolescents (43 male, 23 female) with similar age and educational background to the Tucano group; (3) 100 urban subjects (50 male, 50 female) with a low educational level; and (4) 100 urban subjects (50 male, 50 female) with a high level of education. Hand preference scores were not affected by sex or educational level. The incidence of left-handedness was lower in the Tucano group than in the other groups, despite the fact that the Tucano culture is a highly permissive one. The two rural groups showed less extreme hand preferences than the urban groups, and the Tucano in particular were less likely to indicate extreme hand preferences on any of the items. These results indicate significant effects of culture and environment on declared hand preference, and may be pertinent to recent discussions of cerebral organization in illiterates.

Developmental regulation of Sertoli cell lactate production by hormones and the testicular paracrine factor, PModS.

Testicular peritubular cells produce a paracrine factor termed PModS that mediates mesenchymal-epithelial interactions and modulates Sertoli cell functions essential for the process of spermatogenesis. Sertoli cells produce lactate as a preferred energy metabolite for developing spermatogenic cells. The current study was designed to examine the actions of PModS and hormones on Sertoli cell lactate production at various stages of pubertal development. Sertoli cells were isolated from pre-pubertal (10 day), mid-pubertal (20 day) and late pubertal (35 day) rat testes. Lactate accumulation in the conditioned-medium of cultured Sertoli cells was measured. Basal lactate production increased approximately fivefold during pubertal Sertoli cell development. Therefore, lactate production increases as the Sertoli cell differentiates during pubertal development. The ability of regulatory agents such as FSH or a combination of FSH, insulin, retinol and testosterone (FIRT) to stimulate lactate production decreased during pubertal development as Sertoli cell differentiation increased. Purified PModS stimulated lactate production in Sertoli cell preparations throughout pubertal development. PModS had a greater effect than FSH in stimulating late pubertal Sertoli cell lactate production. PModS in combination with FIRT resulted in an additive stimulation of lactate production suggesting a distinct mechanism of action for PModS. Observations support the proposal that the locally produced paracrine factor PModS mediates mesenchymal-epithelial cell interactions during pubertal development and that these interactions promote Sertoli cell differentiated functions (i.e. lactate production) required for the developing spermatogenic cells.

Cell-cell interactions and the regulation of testis function.

Regulatory interactions have been shown to occur between all the testicular cell types considered. The paracrine factors mediating these interactions generally influence either cellular growth or differentiation. The regulation of cellular growth is essential in the developing testis and is required for the maintenance of spermatogenesis in the adult testis. The rapid rate of germinal cell proliferation and the continuous but slowed growth of the peritubular cells and Leydig cells requires the presence of specific growth factors in the adult. Therefore, cell-cell interactions have evolved that involve growth factors such as IGF, TGF-alpha, TGF-beta and NGF. Other growth factors such as FGF or less characterized components like the seminiferous growth factor (SGF) also may be involved in the paracrine regulation of testis cell growth. An alternate cellular parameter to cell growth to consider is the regulation of cellular function and differentiation. A number of endocrine agents and locally produced paracrine factors have been shown to control and maintain testis cell function and differentiation. Cell-cell interactions mediated by factors such as androgens, POMC peptides, and PModS are all primarily directed at the regulation of cellular differentiation. Therefore, the agents which mediate cell-cell interactions in the testis can generally be categorized into factors that regulate cell growth or those which influence cellular differentiation. The specific cell-cell interactions identified will likely be the first of a large number of cellular interactions yet to be investigated. Although a number of potentially important cell-cell interactions have been identified, future research will require the elucidation of the in vivo physiological significance of these interactions. The existence of different cell types and potential cell-cell interactions in a tissue implies that the actions of an endocrine agent on a tissue will not simply involve a single hormone and single cell. The endocrine regulation of testis function will have effects on cell-cell interactions and be affected by local cell-cell interactions. The ability of LH to influence Leydig cell androgen production promotes a cascade of interactions mediated through several cell types to maintain the process of spermatogenesis. FSH actions on Sertoli cells also promote cell-cell interactions that influence germinal cell development, peritubular myoid cell differentiation and Leydig cell function. Therefore, elucidation of the endocrine regulation of testis function requires an understanding of the local cell-cell interactions in the testis.

Impairment of the developmental potential of frozen-thawed human zygotes obtained after intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the effects of cryopreservation on the survival, cleavage, and morphology of embryos and on the implantation and embryonic loss rates of human zygotes obtained after ICSI compared with frozen-thawed zygotes obtained after traditional IVF. A further objective was to evaluate the same parameters in nonfrozen sibling ICSI and IVF zygotes and to compare them with corresponding frozen-thawed zygotes. DESIGN: Open, retrospective, comparative study. SETTING: University-associated assisted reproductive program. PATIENT(S): Couples with severe male factor infertility and couples undergoing IVF during the same period. INTERVENTION(S): A cohort of 408 ICSI zygotes and 299 IVF zygotes was frozen in 1,2 propanediol and sucrose using a slow-freezing protocol. Both groups of zygotes were frozen at approximately the same time after microassisted or conventional insemination. One hundred and eighty-seven ICSI and 110 IVF frozen zygotes were rapidly thawed during 44 ICSI cycles and 24 IVF cycles. Zygotes that appeared to have survived were cultured for 24 hours, and most of these embryos that were morphologically normal were transferred into patients. MAIN OUTCOME MEASURE(S): Survival rate (morphologically intact after thawing), cleavage rate and morphology of embryos, implantation rate, and the incidence of embryonic losses. RESULT(S): Except for survival rates, for which both ICSI and IVF frozen-thawed zygotes showed similar and relatively high values (87.7% and 89.1%), the outcomes of other parameters evaluated were significantly different. Thus, from a total of 128 ICSI and 68 IVF embryos transferred, 14 (10.9%) and 17 (25.0%) implanted in 44 ICSI and 24 IVF frozen-thawed cycles, respectively. This difference in implantation corresponded with the rate of cleavage and morphology of the replaced embryos; the embryos that developed from frozen-thawed IVF zygotes cleaved faster and were more regular compared to the frozen-thawed ICSI zygotes. The embryonic loss rate was 57.1% for cryopreserved ICSI zygotes and 11.8% for IVF zygotes. On the other hand, no difference in cleavage pattern, embryo morphology, implantation, and embryonic loss rates was found between nonfrozen sibling ICSI and IVF zygotes. CONCLUSION(S): The zygotes arising from ICSI cycles survived cryopreservation at a rate similar to IVF zygotes, but their ability to implant and develop further was probably affected by the cryopreservation procedure. The timing of zygote freezing was considered to be the principal reason for the lower developmental potential of frozen-thawed ICSI zygotes in the present study.

Chemo-immunotherapy in advanced head and neck cancer.

BACKGROUND: Patients with advanced squamous cell carcinoma of the head and neck (SCC) have a depressed immune system whose function is worsened by chemotherapy. In a pilot phase II study, in order to improve the immune function during chemotherapy, we combined to cisplatin (CDDP) and 5-fluorouracil (5-FU) two biological response modifiers, retinyl palmitate (R) and Thymopentin (TP-5) for the treatment of SCC. PATIENTS AND METHODS: Fifty patients with recurrent or metastatic SCC of the head and neck were treated with Cisplatin 24 mg/m2 from day 1 to 5 and 5-FU 1,000 mg/m2 by a 120 hour continuous infusion. Retinyl palmitate was administered orally 50,000 i.u. b.i.d and Thymopentin 50 mg subcutaneously 3 times a week. RESULTS: Chemotherapy treatment was well tolerated with G3 hematological toxicity in 30% of patients and G2 gastrointestinal toxicity in 20% of patients. 16 patients (32%) had a complete response (CR), 13 patients had partial response (PR) (26%), (response rate 58%, 95% c.i. 43%-72%); stable disease (SD) was observed in 7 patients (14%), while 14 patients progressed (PD) (28%). Median time to progression was 12 months (range 2.8-94.5). Median overall survival was 13.5 months (range 2-104). CONCLUSIONS: The association of CDDP and 5-FU with Retinyl Palmitate and TP5 has a major activity in the treatment of advanced head and neck cancer and a relatively well tolerated toxicity.

Cisplatin, vindesine, mitomycin-C and 13-cis retinoic acid in the treatment of advanced non small cell lung cancer. A phase II pilot study.

BACKGROUND: Thirteen-cis retinoic acid (RA) has been shown to have growth-inhibitory and differentiative activity on non-small cell lung cancer (NSCLC) cells in vitro. This promoted the rationale for combining RA with three active drugs, cisplatin (CDDP) vindesine (VDS) and mitomycin-c (MMC) in the treatment of advanced NSCLC. PATIENTS AND METHODS: Patients with a histologically confirmed non-resectable NSCLC, measurable lesion, performance status < or = 3, and informed consent were enrolled. The chemotherapy schedule included cisplatin 60 mg/m2 and mitomycin-c 10 mg/m2 day 1 and vindesine 3 mg/m2 on days 1 and 5, every 4 weeks. RA was administered orally, at a dose of 0.5 mg/kg, 5 days per week, during chemotherapeutic intervals and to responding patients until disease progression was observed. RESULTS: Thirty patients, receiving a total of 163 chemotherapy courses, were evaluated for response and toxicity. Objective responses included complete response in 2 patients (7%), partial response in 10 patients (33%), stable disease in 9 patients (30%) and progressive disease in 9 patients (30%), (response rate 40%: Confidence interval 95% 22.7% to 59.4%). Median time to progression was 8.6 months (range 3.9-45+). Median overall survival was 11.3 months (range 1-45+). The 1-year survival rate was 47%. Toxicity (WHO) included nausea and vomiting grade 2 in 6 patients, transient ileus in 3 patients and grade 3-4 leukopenia in 5 patients. Two patients underwent surgical resection of residual disease and remain in CR. CONCLUSIONS: The addition of RA to cisplatin, vindesine and mitomycin-c is feasible and shows some activity in the treatment of NSCLC, with manageable toxicity.

Advanced colorectal cancer in elderly patients: tolerance and efficacy of leucovorin and fluorouracil bolus plus continuous infusion.

BACKGROUND: Colorectal cancer (CRC) incidence increases sharply with age. In this study we assessed activity, toxicity and both the activity of daily living (ADL) and instrumental activity of daily living (IADL) of the De Gramont schedule in a series of advanced CRC patients aged > or = 70 years. PATIENTS AND METHODS: Sixty-two previously untreated advanced CRC patients entered the study. Median age was 75 (range 70-88). RESULTS: 447 courses were delivered. All of the 62 patients were evaluable for toxicity, 55 for response and ADL-IADL indexes. We recorded 2 complete and 9 partial responses, for an overall response rate of 20%. ADL and IADL indexes improved in 33%, remained stable in 49% and worsened in 18% of evaluable patients. Treatment was very well-tolerated with no serious hematological or non-hematological toxicities. CONCLUSIONS: The De Gramont schedule was very well tolerated in advanced CRC elderly patients, although our work could not confirm the original reported activity. ADL and IADL indexes improved or remained stable in 82% of evaluable patients.