Serum lactate dehydrogenase level as a prognostic factor in Hodgkin's disease.

The efficacy of currently available treatments for Hodgkin''s disease (HD) has led to a substantial modification in the prognosis of this disease; nevertheless there is still a group of patients that cannot be cured with conventional treatments and who will be candidates for alternative therapy. In the present work we analysed the prognostic influence of the most relevant clinico-biological characteristics of HD in a consecutive series of 137 patients diagnosed and treated in a single institution. Univariate analyses identified six variables with significant prognostic influence, both on achieving complete remission (CR) and overall survival (OS); LDH > 320 U ml-1, age > 45 years, stages IIB, III and IV, extranodal involvement, alkaline phosphatase > 190 UI dl and ESR > 40 mm h. In addition, Hb < 12.5 gr dl-1 and abdominal disease were statistically relevant for CR while a poor performance score (ECOG > or = 2) affected a lower survival. In the multivariate analysis only LDH, age and the clinical stage retained a significant prognostic influence for achieving CR, while the two first factors above, together with performance status were the variables with independent prognostic value with respect to OS. Moreover, only LDH > 320 U ml-1 had prognostic influence in the probability of relapse and disease free survival (DFS), both in the univariate and multivariate analyses. According to the three independent factors obtained in the multivariate analysis for CR (LDH, age and stage) a predictive model was established that allows the stratification of patients into two prognostic groups: one with poor prognosis that includes patients with the three adverse prognostic factors, or two if one of them was elevated LDH, and the other with good prognosis that includes the remaining patients. This model was also able to separate two independent groups of patients with respect to OS and to DFS. In conclusion, the present study shows that LDH is one of the most important prognostic factors in HD.     

Comparative acute effects of l-carnitine and dl-carnitine on hepatic catabolism of l-alanine and l-glutamine in rats

AIM: To compare the acute effects of l-carnitine (LCT) and dl-carnitine (DLC) on hepatic catabolism of l-alanine and l-glutamine in rats. METHODS: Livers from 24 h fasted and fed rats were perfused in situ. The substrates l-alanine (5 mmol/L) and l-glutamine (5 mmol/L) were employed. The gluconeogenic and ureogenic activity was measured as the difference between the rates of glucose and urea released during and before the infusion of l-glutamine or l-alanine. RESULTS: LCT (60 μmol/L) but not DLC (60 μmol/L and 120 μmol/L) increased the production of glucose and urea from l-glutamine. However, neither LCT (60 μmol/L and 120 μmol/L) nor DLC (60μmol/L and 240 μmol/L) showed any significant effect on hepatic glucose and urea production from l-alanine. CONCLUSION: The results showed a different acute effect of LCT and DLC on the activation of hepatic gluconeogenesis and ureagenesis promoted by l-glutamine, reinforcing the idea that DLC could not replace LCT.     

Comparative effect of physiological levels of leptin and insulin on cyclic AMP-induced stimulation of hepatic glycogen breakdown

Physiological level of insulin showed more prominent inhibiting effect on the activation of hepatic glucose production and glycogenolysis promoted by cAMP than physiological levels of leptin.     

In Vitro Growth in Acute Myeloblastic Leukemia: Clinico-Biological Correlations

In the present review we analyse the current knowledge about the growth properties of AML progenitor cells and their relationship with other clinico-bilogical characteristics of the disease. Leukaemic colony forming unit L-CFU is considered to be the clonogenic cell in AML and more immature than the blast cell population. Our studies have shown that in leukaemic hematopoiesis colony forming cells can exist among both cell fractions CD34+ and CD34-. Optimal “in vitro” proliferation of L-CFU is dependent upon the addition of exogenous growth factors. However, it has been observed that leukaemic progenitor cells frequently display a certain degree of autonomous proliferation. In order to quantify the “in vitro” behaviour of L-CFU, we have explored 3 parameters: 1) plating efficiency (PE); 2) autonomous growth (AG); and 3) autonomous proliferative index (API) which was calculated as AG divided by PE and we have correlated them with other clinico-biological data. According to the FAB classification we could observe that patients with M3 subtype showed an higher PE than other AML subgroups and a significantly lower API. Regarding CD34 expression we observed that AG was enhanced in CD34+ cases and also in those showing a higher rh123 elimination. In order to determine whether PE could condition clinical evolution, we analysed this parameter in a large series of patients but failed to demonstrate any relationship. By contrast, we observed that patients who displayed a higher API showed a shorter survival than patients with lower API (18% vs 48% surviving at 3 years).We have also shown that abnormalities in the CFU-GM growth pattern could be associated with risk the of relapse in AML patients; a switch from normal to abnormal “in vitro” growth should alert us. But for the assessment of the real value of these analyses sequential follow-up studies are mandatory. In summary, cell culture studies contribute not only to a better understanding of leukaemic hematopoiesis but may also contribute to better disease monitoring.     

Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells

The present study explored the impact of two novel criteria; having >95% abnormal plasma cells by flow cytometry at diagnosis and the evolving subtype of the disease, as predictors of progression in 61 smouldering multiple myeloma (SMM) and 311 monoclonal gammopathy of unknown significance (MGUS) patients. Although both criteria were of prognostic value, the risk of progression was better identified by immunophenotyping [Hazard Ratio (HR) 6·2 and 17·2 for SMM and MGUS, respectively] than evolving subtype, which had independent prognostic value only in MGUS (HR 3·6). Immunophenotyping discriminated the different risk of progression within the evolving and non-evolving subgroups of SMM ( P  = 0·01) and MGUS ( P  < 0·001).     

Distribution of novel immune-checkpoint targets in ovarian cancer tumor microenvironment: A dynamic landscape.

BackgroundThe disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome.MethodWe identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%.ResultsIn our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival.ConclusionTIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.     

Etxadi–Gangoiti scale: a proposal to evaluate the family contexts of two-year-old children†

This paper makes a proposal for the comprehensive assessment of the family context of children aged two years. It offers an updated resource based on recent research into the assessment of family contexts and their influence on children's psychological development. The proposal explores the following areas: Presence of learning materials; Potential for play; Stimulation of cognitive development; Stimulation of language development; Emotional expressiveness; Setting of limits and optimal frustration; Enhancement of self-esteem and autonomy; Observation of mother–child interactions; Father's involvement; Quality of non-parental care; Relations with the extended family and social support network; Stability of the child's social relationships; Relations with the school; Diversity of experiences; Absence of exposure to conflict; Absence of parental stress; and Quality of the physical context. The areas explored are grouped into three blocks: Stimulation of cognitive and linguistic development; Stimulation of socio-emotional development; and Organisation of the social context and physical environment.