Prevalence of Malnutrition in Older Hospitalized Cancer Patients: A Multicenter and Multiregional Study.

BACKGROUND: Malnutrition is frequent in older cancer patients, with a prevalence that ranges from 25% to 85%. The aging process is associated with several physiological changes, which may have implications for nutritional status. Screening tools can be useful for identifying malnutrition status among older patients with cancer. METHODS: A hospital-based multicenter cohort study that included 44 institutions in Brazil. The Mini Nutritional Assessment-Short Form (MNA-SF) was administered to 3061 older hospitalized cancer patients within 48 hoursof admission. The Kolmogorov-Smirnov test was used to test the sample distribution, considering sex, age range, calf circumference, body mass index, and MNA-SF score and classification. The categorical data were expressed by frequencies (n) and percentages (%)and compared using the chi-square test or Tukey test. RESULTS: According to the results of the MNA-SF, 33.4% of the patients were malnourished, 39.3% were at risk of malnutrition, and 27.3% were classified as having normal nutritional status. Length of hospital stay (in days) was found to be longer for those patients with a poorer nutritional status (malnourished: 7.07±7.58; at risk of malnutrition: 5.45±10.73; normal status: 3.9±5,84; p <0.001). CONCLUSIONS: The prevalence of malnutrition and nutritional risk is high in older hospitalized cancer patients in all the regions of Brazil and a worse nutritional status is associated with a longer hospital stay. Using a low-cost, effective nutritional screening tool for older cancer patients will enable specialized nutritional interventions and avoid inequities in the quality of cancer care worldwide.

Malnutrition associated with nutrition impact symptoms and localization of the disease: Results of a multicentric research on oncological nutrition.

BACKGROUND & AIMS: Malnutrition in cancer is an independent factor associated with negative clinical outcomes. The aim was to evaluate the prevalence and independent risk factors for malnutrition in hospitalized cancer patients using the Patient-Generated Subjective Global Assessment (PG-SGA). METHODS: We evaluated 4783 cancer patients, aged ≥20 years, in a hospital-based, multicenter, cross-sectional study. Patients were classified as well-nourished (PG-SGA Stage A), moderate/suspected malnutrition (PG-SGA Stage B), or severely malnourished (PG-SGA Stage C), and provided a score to define required nutritional interventions. Multivariate analysis was composed of the odds ratio (OR) estimated by ordinal polytomous logistic regression. RESULTS: 45.3% were classified as Stage B and 11.8% as Stage C. Moreover, 45.3% of the patients presented a need for nutritional intervention. The variables that presented the highest ORs for Stage B or Stage C were: problems with swallowing (OR 2.8, 95% confidence interval (CI) 2.2-3.4, p < 0.001), loss of appetite (OR 1.9, 95% CI 1.6-2.3, p < 0.001), vomiting (OR 1.8, 95% CI 1.5-2.3, p < 0.001), presence of more than 3 nutrition impact symptoms (OR 8.3, 95% CI 5.8-12, p < 0.001), and cancer site: lung (OR 4.6, 95% CI 3.2-6.6, p < 0.001), upper digestive cancer (OR 3.7, 95% CI 2.7-5.2, p < 0.001), and head and neck cancer (OR 3.7, 95% CI 2.7-5.2, p < 0.001). The score for Worksheet 4 on the PG-SGA had a higher association with malnutrition (OR 7.3, 95% CI 6.6-8.2, p < 0.001). CONCLUSIONS: Malnutrition is highly prevalent in cancer patients in Brazil, and is associated with nutritional impact symptoms, cancer site and age ≥65 years.

HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker?

BACKGROUND: Human papillomavirus 16 infection has been proven to be associated with oropharyngeal squamous cell carcinomas (SCCs) and is probably the main reason of the reported increase in the incidence. The role of high-risk (HR) HPV for carcinogenesis of other sites in the head and neck awaits confirmation. With the aim to evaluate the prevalence of HPV infection and the reliability of different diagnostic tools in SCCs of different sites, 109 consecutive untreated head and neck SCCs were enrolled, and fresh tumour samples collected. METHODS: Human papillomavirus DNA was detected by Digene Hybrid Capture 2 (HC2). Human papillomavirus E6 and E7 mRNA were detected by NucliSENS EasyQ HPVv1. P16 expression was evaluated by immunohistochemistry. RESULTS: In all, 12.84% of cases were infected by HR genotypes and 1.84% by low-risk genotypes. Human papillomavirus 16 accounted for 87% of HR infections. The overall agreement between DNA and RNA detection is 99.1%. Although p16 expression clearly correlates with HPV infection (P=0.0051), the inter-rater agreement is poor (k=0.27). The oropharynx showed the highest HR HPV infection rate (47.6%) and was also the only site in which p16 immunohistochemistry revealed to be a fair, but not excellent, diagnostic assay (κ=0.61). CONCLUSION: The prognostic role of HR HPV infection in oropharyngeal oncology, with its potential clinical applications, underscores the need for a consensus on the most appropriate detection methods. The present results suggest that viral mRNA detection could be the standard for fresh samples, whereas DNA detection could be routinely used in formalin-fixed, paraffin-embedded samples.

Mice heterozygous for the oxytocin receptor gene (Oxtr(+/-)) show impaired social behaviour but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect.

We characterised the behavioural phenotype of mice heterozygous (Oxtr(+/-)) for the oxytocin receptor gene (Oxtr) and compared it with that of Oxtr null mice (Oxtr(-/-)), which display autistic-like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to Oxtr(-/-) mice, the Oxtr(+/-) showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, Oxtr(+/-) mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in Oxtr gene expression is sufficient to compromise social behaviour, the Oxtr acts as a haploinsufficient gene. Furthermore, the inactivation of the Oxtr gene affects specific behaviours in a dose-dependent manner: social behaviour is sensitive to even a partial reduction in Oxtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the Oxtr gene to emerge. We then investigated the rescue of the Oxtr(+/-) social deficits by oxytocin (OT) and Thr(4)Gly(7)OT (TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr(+/-) were lower than those required in Oxtr(-/-), thus suggesting that the rescue effect is mediated by OXTR in Oxtr(+/-) and by other receptors (presumably vasopressin V1a receptors) in Oxtr(-/-). In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr(+/-) genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the Oxtr(+/-) mouse is a unique animal model for investigating how partial loss of the Oxtr gene impair social interactions, and for designing pharmacological rescue strategies.

IL-6, M-CSF and IAP cytokines in ovarian cancer: simultaneous assessment of serum levels.

The aim of this study was to simultaneously determine IL-6, M-CSF and IAP levels in 61 serum samples of previously untreated ovarian cancer patients. A direct correlation between IL-6 and M-CSF has been found in our patient population (r = +0.41, p = 0.013), while IAP serum levels failed to correlate with M-CSF (r = +0.15, p = 0. 24) and IL-6 (r = +0.17, p = 0.18) levels. Since IL-6 and M-CSF have been demonstrated to be both induced in response to the same agents, it is conceivable that a mechanism of coregulation in the production of these cytokines by tumor cells and macrophages might occur. The direct correlation between IL-6 and M-CSF also suggests that tumor-derived cytokines can potentially lead to a self-maintaining cytokine network by recruiting cytokine-producing host cells and by perpetuating cytokine production.

Inhibition of lymphocyte blastogenic response in healthy donors treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF): possible role of lactoferrin and interleukin-1 receptor antagonist.

The effects of rhG-CSF on lymphocyte blastogenesis were evaluated in six healthy donors, submitted to progenitor cell mobilization for allogeneic transplantation. Neutrophil, monocyte and lymphocyte count increased 6.7-fold, 5.3-fold and 2.0-fold on day +4 of rhG-CSF as compared with baseline. The DNA stimulation index (DNA SI) of 72 h phytohemagglutinin (PHA)-treated cultures decreased from 20% (15-35.5) prior to rhG-CSF to 6.7% (1.5-11.9; P = 0.0026), 8% (4-12; P = 0.0091) and 15% (9-22; P = 0.0091) on days +2, +4 and +6; similarly, reactivity to concanavalin A decreased from 18% (12-20) to 1.8% (0.5-7; P < 0.01), 3% (2-8; P < 0.01) and 5% (2-11; P = 0.009). No changes of lymphocyte response to pokeweed mitogen were observed. DNA SI of PHA-treated cultures inversely correlated with neutrophil and monocyte count. IL-1 receptor antagonist (IL-1ra) and lactoferrin (Lf) plasma levels sharply increased and correlated with neutrophil and monocyte count. IL-10 increased five-fold on day +2, returned to pretreatment values thereafter and did not show any correlation with DNA SI, suggesting that it was not responsible for the observed phenomena. Interestingly, DNA SI of PHA-treated cultures inversely correlated with IL-1ra and Lf levels. CD3+ and CD19+ lymphocyte activation status, ie CD23, CD25, CD30 and HLA-DR coexpression, was not affected by rhG-CSF administration. Pharmacological doses of rhG-CSF in healthy donors inhibit lymphocyte blastogenesis via an increased production and/or release of immunoregulatory soluble mediators, ie IL-1ra and Lf, by primed neutrophils and monocytes.

Interleukins 6 and 8 as mediators of acute phase response in acute myocardial infarction.

The present study provides evidence that interleukin (IL)-6 and IL-8 are the main endogenous mediators of acute phase response in patients with myocardial infarction. This conclusion was supported by the observation of a strict relation between IL-6 elevation and the extent of myocardial tissue damage and rise in body temperature.

Autologous stem cell transplantation: evaluation of erythropoietic reconstitution by highly fluorescent reticulocyte counts, erythropoietin, soluble transferrin receptors, ferritin, TIBC and iron dosages.

The plasma concentrations of erythropoietin (Ep), soluble transferrin receptors (sTfRs), iron, total iron binding capacity (TIBC) and ferritin were monitored in five leukaemia patients undergoing autologous bone marrow stem cell transplantation (BMSCT) and in 10 lymphoma and 21 ovarian cancer patients undergoing autologous peripheral blood SCT (PBSCT); 9/21 ovarian cancer patients received recombinant human G-CSF and Ep and six recombinant human GM-CSF and Ep following SCT. All parameters were evaluated in relation to the kinetics of erythroid reconstitution as evaluated by haemoglobin (Hb) and reticulocyte levels [including the fraction of immature reticulocytes, also called highly fluorescent reticulocytes (HFR)]. Leukaemia patients undergoing BMSCT showed only a delayed (occurring at days 35-50 after SCT) and partial RBC, neutrophil and platelet recovery, whereas all patients undergoing PBSCT exhibited a rapid (occurring at days 10-15 after SCT) and sustained haemopoietic recovery. The various levels of erythroid rescue observed among these patients markedly influenced the kinetics of the different parameters investigated: (i) in leukaemia BMSCT patients sTfRs declined following SCT and remained at low levels thereafter, whereas Ep, iron. TIBC and ferritin showed a progressive and significant increase; (ii) in the different groups of patients undergoing PBSCT: (a) sTfR levels first declined following SCT and then returned to pre-therapy values at days 12-16, this response preceded erythropoietic recovery; (b) Ep, total iron, TIBC and ferritin showed an initial increase in the first days following SCT and then returned to pre-therapy values. Altogether, these observations indicate that: (i) both sTfR levels and reticulocyte counts are predictive parameters of erythropoietic recovery; (ii) coordinated changes of biochemical parameters underlying iron metabolism (iron, TIBC and ferritin) accompany erythroid rescue following SCT.

Hypereosinophilia during 2-chlorodeoxyadenosine treatment for hairy cell leukaemia.

A 43-year-old male with newly diagnosed hairy cell leukaemia underwent a single course of 2-chlorodeoxyadenosine (2-CdA). Skin rash, facial swelling and marked eosinophilia developed 20 d after treatment and were resolved by 7 d of steroid therapy. Eosinophil peak in peripheral of the eosinophil population showed a high expression of the IL-2 receptor alpha-chain (CD25), representing up to 94% of gated cells. HLA-DR and CD4 antigens were constantly negative; eosinophils strongly reacted with the secretory form of the eosinophil cationic protein (ECP), recognized by EG2 monoclonal antibody. IL-5 serum levels were markedly elevated at the onset of eosinophilia, returned to normal levels after its disappearance and positively correlated with eosinophil count (r = 0.94, P = 0.016). Eosinophilia is an uncommon finding after treatment with 2-CdA. It is unclear whether these phenomena represented a true allergic reaction to the drug or the effect of massive tumour cell lysis and haemopoietic pancytopenia with immunosuppression, which induced the release of IL-5 and possibly other cytokines.

Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer.

High levels of IL-6 were found in 50% of 114 patients with primary ovarian cancer. IL-6 sensitivity was lower than that of CA 125, and the combination of both assays did not increase the sensitivity of CA 125 alone. However, elevated IL-6 serum levels were correlated with a poor prognosis since patients with low IL-6 levels had a better survival than patients with high IL-6 levels (P = 0.0009). Multivariate analysis revealed that IL-6 positivity has an independent value.

Nicotine- or epinephrine-induced uteroplacental vasoconstriction and fetal growth in the rat.

We examined the relationship between nicotine-induced vasoconstriction in pregnant rat dams and fetal growth during the third trimester of pregnancy. Pregnant rats were continuously treated between days 13 and 19 of gestation with either nicotine (9.6, 4.8 or 2.4 mg/kg/day), epinephrine (0.72 microgram/kg/day), or saline via continuous infusion from a subcutaneously implanted osmotic minipump. Placental weights in rats treated with high dose nicotine and dams' body weights were severely reduced. However, fetal weights were not affected. Blood flows in uterus and placenta were quantified by measurement of tissue content of 85Sr-labelled microspheres injected via a carotid artery catheter. Both nicotine and epinephrine caused a significant reduction (> 40%) in uterine and placental blood flow. We conclude that vasoconstriction alone as a result of nicotine or epinephrine administration during the last trimester of gestation does not necessarily reduce nutrient supply to the fetus and does not affect fetal growth in rats.

Autologous stem cell transplantation: release of early and late acting growth factors relates with hematopoietic ablation and recovery.

We have monitored the serum concentrations of hematopoietic growth factors (HGFs; ie, stem cell factor [SCF], leukemia inhibitory factor [LIF], interleukin-3 [IL-3], IL-6, IL-8, and granulocyte colony-stimulating factor [G-CSF]) in 15 lymphoma/leukemia and 6 ovarian cancer patients undergoing autologous bone marrow (BM) or peripheral blood (PB) stem cell transplantation (SCT). Thus, the analysis was performed during and after high-dose chemotherapy (from day -6 to day -1), at the time of SCT (day 0), and thereafter (through day +17). Despite the heterogeneity of these patients and their conditioning regimens, a consistent kinetic pattern was observed for all analyzed cytokines. Particularly, (1) SCF serum concentration did not significantly fluctuate. (2) High levels of LIF (approximately 250 to 450 pg/mL) before chemotherapy rapidly declined to markedly lower concentrations (approximately 10 ng/mL) starting from day -1 through day +17; (3) conversely, IL-3 level was low before treatment, sharply increased during chemotherapy, and rapidly returned to base-line level after SCT. Hypothetically, the sharp LIF decrease and IL-3 increase during chemotherapy may underlie the induction of stem cell cycling and differentiation caused by hematopoietic ablation. Furthermore, (4) IL-6 concentration was low before and immediately after chemotherapy, but increased starting from day +5, peaked at day +6 through 9 and then declined to baseline level from day +10 onward; (5) a strictly similar pattern was consistently observed for both G-CSF and IL-8 levels, in agreement with our previous studies. It is relevant that peak IL-6, G-CSF, and IL-8 concentrations were directly correlated to peak neutrophil numbers in the recovery phase, thus suggesting an important role for these cytokines in granulocyte rescue; in line with this interpretation, hematologic patients undergoing PBSCT (10 of 15) exhibited higher peaks of IL-6, G-CSF, and IL-8 and a more pronounced increase of neutrophil/platelet number than did hematologic cases undergoing BMSCT (5 of 15). Altogether, these studies indicate a coordinate pattern of cytokine release during hematopoietic ablation/recovery after chemotherapy and autologous SCT, the fluctuations of LIF and IL-3 levels during chemotherapy are seemingly related to stem cell recruitment, whereas the post-SCT increase of IL-6, G-CSF, and IL-8 may underlie the neutrophil recovery.

Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles.

Plasma levels of erythropoietin (mU/ml) were measured in patients with congestive heart failure (CHF) (n = 108) and in a control group of normal subjects (n = 45). In normal subjects, plasma levels of erythropoietin were 1.9 +/- 0.2. In patients with CHF, plasma levels of erythropoietin increased progressively according to New York Heart Association (NYHA) class (I: 1.4 +/- 0.2, n = 28; II: 5.4 +/- 0.8, n = 27; III: 9.6 +/- 2, n = 32; IV: 34 +/- 8, n = 21; F = 57.7, p < 0.001) and were significantly higher in NYHA classes II, III, and IV than in normal subjects. Plasma erythropoietin significantly decreased (from 43 +/- 14 to 12 +/- 3 mU/ml, p < 0.01) in patients with severe CHF (n = 9) when enalapril (20 mg/day administered orally) was added to long-term treatment for 3 weeks. Finally, in a subgroup of patients with NYHA class IV CHF (n = 9) and high plasma erythropoietin levels (37 +/- 9 mU/ml), packed red blood cell volume, assessed by the iodine-125-albumin dilution method, was higher than that in normal subjects (n = 11) (2,616 +/- 235 vs 2,028 +/- 119 ml, p < 0.05). The present study demonstrates that plasma erythropoietin levels are elevated in a large cohort of patients with CHF of varying etiology, and that this increase is related to the progression of the disease. The increase in circulating erythropoietin is associated with augmented packed red blood cell volume in patients with severe CHF. These results suggest a participation of erythropoietin in the complex neurohormonal response that occurs in CHF.

Interleukin-6 serum levels in patients with gynecological tumors.

Serum levels of IL-6 were evaluated in a large group of patients with benign or malignant gynecological tumors. The results obtained were correlated with the patients' clinicopathological features and follow-up data. Using a highly sensitive immunoenzymatic method for the evaluation of serum IL-6 levels, we observed that > 95% of normal healthy women exhibited values within the range of 1.9-6 pg/ml. Using a cut-off of 6 pg/ml, elevated levels of serum IL-6 were found in 53% of 45 patients with primary epithelial ovarian cancer and less frequently in patients with endometrial and cervical cancer (37% and 10% respectively). Elevated levels of IL-6 were occasionally seen in patients with benign disease. IL-6 serum levels appeared to be less sensitive than CA 125 in ovarian cancer diagnosis. In cancer patients, increased IL-6 serum levels were related to the presence of the tumor since all post-operative patients exhibited a marked decrease. In patients with advanced ovarian cancer post-operative levels of IL-6 correlated with residual disease. Very high levels of IL-6 were observed in the ascitic fluid of 9 ovarian cancer patients, but IL-6 mRNA was not detected in tumor cells. This suggests that the increased production of IL-6 observed in ovarian cancer is reactive. Higher levels of IL-6 were found in patients unresponsive to chemotherapy, as compared with responsive ones. Univariate analysis of survival data suggests that increased IL-6 serum levels correlate with negative prognosis.

Enhanced production of LPS-induced cytokines during differentiation of human monocytes to macrophages. Role of LPS receptors.

In vitro cultivated human monocytes isolated from normal peripheral blood show a time-dependent differentiation into macrophages characterized by an increased expression of transferrin receptors, CD11/CD18, and CD14 Ag. We measured the secretion of TNF-alpha and IL-6 in freshly isolated monocytes and in differentiated macrophages after LPS treatment. Differentiated macrophages produced significantly higher amounts of TNF-alpha and IL-6 than freshly isolated monocytes. This increased secretion was not a result of an enhanced accumulation of TNF-alpha and IL-6 mRNA, as comparative levels of these transcripts were found in both cell types after LPS treatment. Furthermore, LPS did not induce an antiviral state to VSV3 in monocytes, but it reduced by 3 to 5 log10 the virus yield in differentiated macrophages. The addition of antibodies to IFN-beta completely inhibited the LPS-induced antiviral state to VSV, but antibodies to IFN-alpha, TNF-alpha, or IL-6 were ineffective. A marked accumulation of IFN-beta mRNA was found in both cell types after LPS treatment. Binding experiments with FITC-LPS revealed a slightly higher overall binding affinity for LPS in freshly explanted monocytes as compared with differentiated macrophages, even though the maximal binding was higher in macrophages. In both cell types, the LPS binding was partially inhibited by antibodies to CD14. These results demonstrate that: 1) in vitro differentiation of human monocytes to macrophages leads to an enhanced LPS response in terms of (a) progressive increase of IL-6/TNF-alpha production and (b) acquisition of an IFN-beta mediated antiviral state; 2) this enhanced response to LPS, largely CD14-independent, is not linked to any increased accumulation of cytokine mRNA, but is probably a result of an increased synthesis and/or secretion of these cytokines.

Transforming growth factor-beta potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines.

We have investigated the effects of 1,25-dihydroxyvitamin D3 (D3) and/or transforming growth factor (TGF)-beta on one monocytic (U-937) and two human promyelocytic (HL-60 and AML-193) leukemic cell lines. D3 addition induces a partial monocytic maturation of the cell lines, whereas TGF-beta treatment is largely ineffective. Combined treatment with TGF-beta and D3 causes terminal monocytic maturation, as evaluated both by assessment of a large spectrum of membrane Ag and by functional assays. Furthermore, sequential addition of the two inducers showed that pretreatment with TGF-beta 1 followed by incubation with D3, but not vice versa, induces monocytic maturation as effectively as simultaneous treatment with both agents. In liquid culture the proliferative activity of these cell lines is slightly decreased by D3 and virtually unaffected by TGF-beta, whereas combined treatment with D3 and TGF-beta induces a markedly potentiated inhibitory effect. Furthermore, TGF-beta/D3 treatment (but not D3 alone) elicits the expression of membrane CD14, FcRI, FcRII, CD11a, CD11b, CD11c, ICAM-1, and PECAM-1 Ag at a level comparable to that observed on normal human monocytes. It is noteworthy that several of these Ag play an important role in monocyte physiology (e.g., CD14 Ag mediates the binding of bacterial LPS to monocytes). Treatment with both TGF-beta and D3 (but not D3 alone) induces superoxide anions and H2O2 production similar to that of circulating monocytes. In semisolid culture, D3 and TGF-beta alone cause, respectively, a marked and slight loss of cloning efficiency of the cell lines, whereas their combined addition synergistically results in a complete loss of the cloning capacity. These findings suggest a physiologic role for TGF-beta in monocyte maturation. Furthermore, they may pave the way to the design of clinical protocols combining D3 and TGF-beta in the differentiation therapy of acute promyelocytic/myelomonocytic leukemia.

Autologous stem cell transplantation: sequential production of hematopoietic cytokines underlying granulocyte recovery.

We investigated the serum concentrations of a variety of cytokines [granulocyte-macrophage-colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin (IL) 1 alpha, IL-3, IL-6, IL-8, erythropoietin, tumor necrosis factor alpha, gamma-interferon in 10 patients with advanced ovarian cancer undergoing autologous peripheral blood stem cell (PBSC) harvesting followed by treatment with high-dose cisplatin, etoposide, and carboplatin and PBSC transplantation (chemotherapy was administered on days 1 through 3, PBSCT on day 6). Preliminary observations on cytokine serum levels were performed for 4 patients; on this basis, the kinetics of cytokines was then investigated in greater detail at closely sequential times in 6 further patients. We observed a consistent pattern of sequential GM-CSF, G-CSF, and IL-8 release after chemotherapy/PBSCT in all 10 cases, including the 6 patients monitored in detail: (a) at days 5-10 a GM-CSF peak; (b) at days 12-14 a pronounced release of both G-CSF and IL-8, which always preceded granulocyte recovery by approximately 7 days. At days 17-23, a second GM-CSF peak was monitored in 5 of the 6 patients analyzed in detail, as well as in the other 4 cases. Particularly relevant are the observations that: (a) the peak of G-CSF serum concentration and neutrophil number in the recovery phase are strikingly and directly correlated, thus indicating a key role for G-CSF in granulocyte rescue; (b) the time courses of G-CSF and IL-8 levels are strictly parallel, thereby suggesting a coordinate stimulus for production of granulocytes, mediated by G-CSF, and their activation/migration capacity, mediated by IL-8. Results were essentially negative for IL-3, tumor necrosis factor alpha, and gamma-interferon concentrations (except in one case for each cytokine). An early peak of IL-1 alpha was observed in all 3 analyzed patients, while an IL-6 peak was monitored at days 13-15 in all 4 patients analyzed in detail. The present results indicate a sequential coordinate pattern of cytokine release after ablative therapy and PBSCT and shed light on the mechanisms mediating the recovery of granulocytes, and more generally of hematopoiesis, after stem cell transplantation. Furthermore, these studies may contribute to the design of improved protocols for cytokine administration following myelosuppressive anticancer therapy, as well as to the prediction of granulocytic response.

Evaluation of greyhound susceptibility to malignant hyperthermia using halothane-succinylcholine anesthesia and caffeine-halothane muscle contractures.

We investigated Greyhounds because of prior reports of malignant hyperthermia (MH) episodes and because Greyhounds may express high genetic relatedness due to inbreeding for generations. Seven Greyhound and six mongrel dogs were given halothane and succinylcholine anesthesia as a challenge to trigger MH. They also underwent semitendinosus muscle biopsy for contracture study with halothane and caffeine. Measurements in vivo of mixed venous and arterial blood gases, cardiac output by thermodilution, temperature, blood pressure, and pulse rate provided sequential data regarding whole body O2 consumption (product of cardiac output and arterial-mixed venous O2 content difference), acid-base status, and arterial CO2 tension. Greyhounds and mongrels had uniformly similar in vivo and in vitro responses, without evidence for MH. Contracture thresholds were higher than those reported for normal swine and humans (8 mM vs. 4 mM). Information on MH susceptibility in this breed is important for laboratory investigation in Greyhounds as well as to veterinary medicine in general. Neither mongrels nor this group of Greyhounds were obviously susceptible to MH. If all Greyhounds are genetically homologous, then Greyhounds may not be specifically MH susceptible. These findings overall may provide a protocol and baseline normal comparative data for determining MH susceptibility in dogs and other species.