The prognostic and predictive value of sstr2-immunohistochemistry and sstr2-targeted imaging in neuroendocrine tumors.

PURPOSE: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr2) in neuroendocrine tumors (NETs). METHODS: We established a tissue microarray and imaging database from NET patients that received sstr2-targeted radiopeptide therapy with yttrium-90-DOTATOC, lutetium-177-DOTATOC or alternative treatment. We used univariate and multivariate analyses to identify prognostic and predictive markers for overall survival, including sstr2-imaging and sstr2-immunohistochemistry. RESULTS: We included a total of 279 patients. In these patients, sstr2-immunohistochemistry was an independent prognostic marker for overall survival (HR: 0.82, 95 % CI: 0.67 - 0.99, n = 279, p = 0.037). In DOTATOC patients, sstr2-expression on immunohistochemistry correlated with tumor uptake on sstr2-imaging (n = 170, p < 0.001); however, sstr2-imaging showed a higher prognostic accuracy (positive predictive value: +27 %, 95 % CI: 3 - 56 %, p = 0.025). Sstr2-expression did not predict a benefit of DOTATOC over alternative treatment (p = 0.93). CONCLUSIONS: Our results suggest sstr2 as an independent prognostic marker in NETs. Sstr2-immunohistochemistry correlates with sstr2-imaging; however, sstr2-imaging is more accurate for determining the individual prognosis.

Resampling-Based Inference Methods for Comparing Two Coefficients Alpha.

The two-sample problem for Cronbach's coefficient [Formula: see text], as an estimate of test or composite score reliability, has attracted little attention compared to the extensive treatment of the one-sample case. It is necessary to compare the reliability of a test for different subgroups, for different tests or the short and long forms of a test. In this paper, we study statistical procedures of comparing two coefficients [Formula: see text] and [Formula: see text]. The null hypothesis of interest is [Formula: see text], which we test against one-or two-sided alternatives. For this purpose, resampling-based permutation and bootstrap tests are proposed for two-group multivariate non-normal models under the general asymptotically distribution-free (ADF) setting. These statistical tests ensure a better control of the type-I error, in finite or very small sample sizes, when the state-of-affairs ADF large-sample test may fail to properly attain the nominal significance level. By proper choice of a studentized test statistic, the resampling tests are modified in order to be valid asymptotically even in non-exchangeable data frameworks. Moreover, extensions of this approach to other designs and reliability measures are discussed as well. Finally, the usefulness of the proposed resampling-based testing strategies is demonstrated in an extensive simulation study and illustrated by real data applications.

Altered hair endocannabinoid levels in mothers with childhood maltreatment and their newborns.

The endocannabinoid (EC) system possesses anti-inflammatory properties and seems to be altered in trauma-exposed individuals. In an intergenerational approach, this study investigated the link between childhood maltreatment (CM) experiences and alterations in the EC system. Hair samples of N = 142 mothers and N = 91 newborns were analyzed, retrospectively assessing EC regulation during the last trimester of pregnancy with four ECs: 1-arachidonoylglycerol (1-AG), N-oleoylethanolamide (OEA), N-stearoylethanolamide (SEA), and N-palmitoylethanolamide (PEA). Compared to mothers without CM, hair of mothers with CM showed significantly higher levels of 1-AG and lower levels of SEA. Newborns of mothers with CM exhibited higher levels of 1-AG and OEA. Furthermore, the higher the severity of maternal CM, the lower were maternal SEA levels and the higher neonatal OEA levels. Findings indicate altered EC levels during the last trimester of pregnancy in mothers with CM and their developing fetus, highlighting potential intergenerational effects from one generation to the other.

Intergenerational gene × environment interaction of FKBP5 and childhood maltreatment on hair steroids.

BACKGROUND: The inconsistency in results of cortisol alterations after childhood maltreatment (CM) might arise due to the fact that no study so far considered the effects of environmental factors such as maltreatment load and genetic factors such as the influence of FKBP5 genotype on stress hormone regulation. This study analyzed the interaction between the single nucleotide polymorphism rs1360780 within the FKBP5 gene and the severity of maternal CM experiences (maltreatment load) on hair steroid levels of mother-infant-dyads. METHODS: Hair samples of N = 474 mothers and N = 331 newborns were collected < 1 week after parturition enabling a retrospective assessment of cortisol, cortisone, and dehydroepiandrosterone (DHEA) using mass spectrometry. The sum score of the Childhood Trauma Questionnaire operationalized the maternal maltreatment load. DNA from whole blood or buccal cells was used for FKBP5 genotyping. RESULTS: The higher the maltreatment load, the higher maternal hair cortisol and cortisone levels in T allele carriers of FKBP5 rs1360780 were observed. Hair cortisol and DHEA levels of newborns with the T allele were reduced with an increasing maternal maltreatment load, while there was an increase of hair cortisol and DHEA in newborns homozygous for the C allele. CONCLUSIONS: This study is the very first uncovering a gene (FKBP5) × environment (maltreatment load) interaction on hair steroids in mothers and their offspring, indicating an intergenerational transmission of hypothalamic-pituitary-adrenal axis alterations. These results may help to explain the inconsistency in previous findings on steroid hormone alterations after chronic and traumatic stress and should be considered in future studies.

Rank-based permutation approaches for non-parametric factorial designs.

Inference methods for null hypotheses formulated in terms of distribution functions in general non-parametric factorial designs are studied. The methods can be applied to continuous, ordinal or even ordered categorical data in a unified way, and are based only on ranks. In this set-up Wald-type statistics and ANOVA-type statistics are the current state of the art. The first method is asymptotically exact but a rather liberal statistical testing procedure for small to moderate sample size, while the latter is only an approximation which does not possess the correct asymptotic α level under the null. To bridge these gaps, a novel permutation approach is proposed which can be seen as a flexible generalization of the Kruskal-Wallis test to all kinds of factorial designs with independent observations. It is proven that the permutation principle is asymptotically correct while keeping its finite exactness property when data are exchangeable. The results of extensive simulation studies foster these theoretical findings. A real data set exemplifies its applicability.

Diabetes Mellitus and Its Effects on All-Cause Mortality After Radiopeptide Therapy for Neuroendocrine Tumors.

We aimed to assess the risk of developing diabetes mellitus and its effects on all-cause mortality after radiopeptide therapy for neuroendocrine tumors (NETs). METHODS: NET patients received somatostatin radiopeptide therapy with 90Y-DOTATOC or 177Lu-DOTATOC. The incidence of diabetes mellitus and its mortality were assessed using univariate and multivariate regression. RESULTS: Overall, 1,535 NET patients were enrolled and received 3,807 treatment cycles. After treatment, 72 patients developed diabetes mellitus, including 47 cases after 90Y-DOTATOC and 25 cases after combined treatment. The diabetes mellitus risk was higher before than after DOTATOC (estimate, 0.0032; P < 0.001), and overall survival was similar in patients with and without diabetes mellitus (hazard ratio, 1.13; 95% confidence interval, 0.91-1.39; n = 1,535; P = 0.27). CONCLUSION: Radiopeptide therapy does not appear to increase the risk of developing diabetes mellitus in NET patients, whereas diabetes mellitus does not appear to increase the mortality of NET patients undergoing receptor-targeted radiopeptide therapy.