Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.

Background: We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application. Patients and methods: We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features. Results: Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88. Discussion: We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

An efficient synthesis of epoxydiynes and a key fragment of neocarzinostatin chromophore.

[reaction: see text] A key structural feature of the Neocarzinostatin chromophore is a reactive epoxydiyne. We present here a new method for the preparation of epoxydiynes by the addition of an allenyl zinc bromide to a propargylic ketone.

Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer.

Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a "3+3" study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A ≥ 50% reduction in PSA was observed in 31.7% evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68% of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7% and remained stable in 31.8% of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR(-)CD11b(+)) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T- and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Early perinatal hospital discharge and parenting during infancy.

OBJECTIVE: To evaluate the relationship between early perinatal hospital discharge and several parenting outcomes during infancy, including breastfeeding, mother-infant interaction, and mother-infant attachment. STUDY DESIGN: A prospective, longitudinal, nonrandomized study of mother-infant dyads discharged 36 hours after birth (late discharge). METHODS: Demographic, perinatal, and psychosocial factors were determined from medical record review and maternal questionnaires. Questionnaires also assessed maternal perceptions of the hospital stay and breastfeeding rates. Mother-infant interaction was assessed at 3 months after birth using the NCAST Feeding Scale and at 9 months after birth using the NCAST Teaching Scale. Security of attachment was measured in the Ainsworth Strange Situation at 12 months after birth. RESULTS: Early and late discharge groups were similar with respect to major demographic, perinatal, and psychosocial characteristics and perceptions of the hospital stay. Even after adjusting for these factors in regression analyses, no significant association was found between early discharge and breastfeeding at 3 months, NCAST scores at 3 and 9 months, and security of attachment at 12 months. CONCLUSION: Parenting outcomes, such as breastfeeding, mother-infant interaction, and attachment, are not influenced by early perinatal hospital discharge.

Early discharge of the term newborn: a continued dilemma.

OBJECTIVE: To provide the pediatric practitioner with a summary of available data regarding the appropriate time of hospital discharge of the term newborn. METHODOLOGY: Published series on early discharge were critically reviewed. RESULTS: Heterogeneity and limitations of methodology and study design substantially limit conclusions that may be drawn from published studies. CONCLUSION: Early discharge recommendations of the American Academy of Pediatrics remain appropriate, and decisions regarding the timing of discharge of the well term newborn should be individualized and made by the practitioner based upon the medical, social, and economic aspects of each case.

Neonatal mortality and length of newborn hospital stay.

OBJECTIVE: To investigate the effect of hospital discharge time on neonatal mortality of term newborns. DESIGN: Infants who were discharged home at 5 days of age of younger and who subsequently died were compared with control infants using a retrospective case-control design. Descriptive information was collected from records of infants who were not discharged home from the hospital of birth (because of death or transfer to a tertiary care hospital) to determine the age at which their illnesses presented. METHODS: We reviewed death certificates for all infants with birth weights of 2500 g or greater born at 37 weeks' gestational age or greater who died in the first 28 days of life and who were born in one of four Utah counties (1985 through 1989). Of the 109,256 eligible births, 115 infants were found who had died in the neonatal period. Eighty-four infants had not been discharged home from the hospital of birth, 5 infants had had hospital stays of more than 5 days, 9 records could not be located, 17 presumed healthy infants were discharged from the hospital at 5 days of age or younger. These 17 infants were each matched with 3 control infants. Newborn nursery charts were reviewed to determine hospital discharge times for case and control infants. Descriptive information regarding the time of presentation of illness was collected for the other 89 infants. RESULTS: The mean age of hospital discharge was 43 +/- 21 hours for the 17 case infants and 47 +/- 25 hours for the 51 control infants. The odds ratio for neonatal mortality for discharge at less than 24 hours was 1.65 (95% confidence interval, 0.42 to 3.34) and for discharge at less than 48 hours was 1.16 (95% confidence interval, 0.4 to 3.34). Of the 84 infants who were not discharged home from the hospital of birth, 93% had been symptomatic by 12 hours of age, and 99% were symptomatic by 18 hours. CONCLUSIONS: Most full-term infants who die in the neonatal period are symptomatic within the first 18 hours after birth. We could not demonstrate an association between early hospital discharge and neonatal mortality in those infants who died after discharge home.

Imidazole therapy of coccidioidal meningitis in children.

The mortality related to coccidioidal meningitis (CM) has been reduced since the introduction of amphotericin B therapy, but children with CM continue to suffer significant morbidity. Some of this is related to the toxicity of the drug. We report nine children with CM treated with orally administered ketoconazole and intraventricularly administered miconazole. Four of them had been treated initially with amphotericin B with resultant failure in one and severe toxicity in all four. The other five children were treated only with imidazoles. All nine children had evidence of ventriculitis at the time of diagnosis and had ventriculoperitoneal shunts inserted for control of increased intracranial pressure. There was no relapse or recrudescence of CM in a follow-up period of 32 to 90 months on imidazole therapy. The coccidioidal complement-fixation antibody titers in the cerebrospinal fluid of the lateral ventricle became negative in all children 3 to 51 months after diagnosis (mean, 17 months). The serum antibody titers demonstrated a 16- to 256-fold decrease from their maximal levels. Four children are still receiving intraventricular miconazole whereas the others have not received miconazole for an average of 51 months. Therapy with the imidazoles was well-tolerated. The main morbidity was related to the shunts required for control of increased intracranial pressure. There was no evidence of hepatic toxicity and no clinical evidence of adrenal insufficiency although transient adrenal suppression was demonstrated at 4 but not at 24 hours after ketoconazole administration.

Loss of hepatitis B antibody in human immunodeficiency virus-positive hemophilia patients.

The presence of human immunodeficiency virus (HIV) antibody in hemophilia patients was correlated with the loss of existing antibody to hepatitis B surface antigen (HBsAb) or the inability to develop an antibody to hepatitis B after receiving commercially available hepatitis B vaccine. Of the 137 patients studied 66 were HIV-positive and 71 were HIV-negative. Evidence of HBsAb (n = 44) or exposure to hepatitis vaccine (n = 12) was found in 85% of HIV positive patients at some time during their care in our clinic. However, 20% demonstrated subsequent antibody loss and/or did not respond to hepatitis vaccine. Loss of HBsAb or vaccine nonresponse was restricted to patients less than 21 years of age (72% of all patients). This result contrasted to only a 3% loss of HBsAb or vaccine nonresponse in the HIV-negative patients who had acquired the HBsAb (n = 23) or were given the hepatitis vaccine (n = 29). This result suggests that loss or alterations of hepatitis B immunity occur in association with HIV infection or exposure.

Acute promyelocytic leukemia: report of a variant translocation, t(1;17).

A 4-year-old female with acute promyelocytic leukemia (APL) was found to have a variant form of the 15;17 translocation, which is diagnostic of APL. The karyotype of the malignant cells was 47,XX,t(1;11)(q25;q21),t(1;17)(p36;q21), + 8. This case is additional evidence that the breakpoint of #17 at q21 is the characteristic chromosomal aberration of APL. The present case is also unusual because of the young age of the patient.

Gonadotropin-releasing hormone infusion test in the distinction of hypopituitary patients from normal subjects.

We undertook a pilot study to determine whether infusion of gonadotropin-releasing hormone (GnRH) might improve the distinction of hypogonadotropinism from the normal state and might permit gonadotropin deficiency to be diagnosed in the prepubertal child. Normal prepubertal and pubertal boys had a greater luteinizing hormone (LH) reaction (delta LH 54 +/- 15 [SD] ng/ml and 165 +/- 23 ng/ml, respectively) to a 4-hour infusion (100 microgram/hour) than to a 100-microgram bolus of GnRH (19 +/- 9 and 52 +/- 35 ng/ml). These augmented responses were observed in boys with delayed puberty, but not in apparently hypogonadotropic males greater than or equal to 12 years old. LH (delta LH 445 to 1602 ng/ml) and FSH (delta FSH 718 to 2112 ng/ml) surges were induced consistently by GnRH infusion only in normal, postmenarchial females. In all, of 13 hypopituitary cases classified as hypogonadotropic on the basis of a subnormal response to GnRH infusion, 31% had a normal response to the GnRH bolus (P = 0.05). Thus, GnRH infusion testing seems to improve the distinction of hypogonadotropic patients from normal individuals, including boys with delayed puberty.

Keratosis follicularis spinulosa decalvans. An infant with failure to thrive, deafness, and recurrent infections.

A 10-month-old male infant had keratosis follicularis spinulosa decalvans, an X-linked dominant disorder. His cutaneous abnormalities consisted of generalized hyperkeratosis, spiny follicular papular lesions, universal alopecia, and hypoplastic nails. Ocular changes characteristic of the disease were also present. Unusual findings included deafness, failure to thrive, predisposition to bacterial infections without demonstrable immune defect, and transient hepatomegaly with abnormal liver function studies.

Perinatal screening for child abuse and neglect.

An increased awareness of the frequency and severity of child abuse and neglect in our society has prompted consideration of the feasibility of perinatal screening and early intervention for this problem. This article reviews the available information on screening and early intervention for high-risk parenting in the perinatal period. The advantages, disadvantages, and cost-effectiveness of screening and intervention for children and families at risk for abuse and neglect are also discussed.

Weight, length, head and chest circumference at birth in Phoenix, Arizona.

Standard percentile curves are presented for weight, length, head circumference and chest circumference at birth for a population of 27,963 singleton infants born between the gestational ages of 26 and 42 weeks at a large, private hospital in Phoenix, Arizona. At term, all four growth parameters were significantly greater in male than in female infants. These parameters were significantly reduced in infants born to mothers who smoked and increased in infants born to mothers with diabetes. Percentiles in all parameters were higher than in those of previous studies, suggesting that continued use of growth curves based on older data may result in misclassification of infants with respect to appropriateness of growth-for-gestational age.

Use of nonanatomical dolls in the sexual abuse interview.

Controversy exists regarding use of anatomically detailed dolls in child sexual abuse evaluations because of concerns that such dolls may provoke false positive demonstrations of sexually explicit behavior. This study shows that children referred for medical evaluation of sexual abuse will use sexually explicit behavior to demonstrate what has happened to them with nonanatomical dolls as frequently as when they are interviewed with anatomically detailed ones. Over a two-year period, 136 children (aged 24 months to 10 years) were interviewed by the same pediatric interviewer. During the first year sexually anatomically detailed dolls (SAD) were used, and in the subsequent year nonanatomic dolls (NAD) were used. Data was analyzed according to age, sex, and demonstration of sexually explicit behavior. There were 67 children in the NAD group and 69 in the SAD group. Of the NAD group, 72% showed sexually explicit behavior compared to 68% in the SAD group. Comparisons using chi-square analysis revealed no significant differences between NAD and SAD. Results indicated that in the sexual abuse interview setting, use of sexually detailed dolls did not increase children's use of sexually explicit behavior to describe what had happened to them when compared to use of nonanatomical dolls, and that use of either type of doll provides similar information in the interview setting.

A new measure for distress during child sexual abuse examinations: the genital examination distress scale.

OBJECTIVE: The primary aim was to develop a simple scale to quantify indices of emotional distress during the rectal-genital (anogenital) phase of a child sexual abuse examination. METHOD: A scale successfully developed to measure reactions of children to painful procedures, in particular bone marrow aspirations, was used as a model (Elliot, Jay, & Woody, 1987). This new scale was developed to have a simplified rating format, more relevant operational definitions and possibly a different set of behavioral categories. This new scale was developed using 300 children being examined for possible child sexual abuse. Intraclass correlation coefficients identified reliable items to use. Factor analysis and Cronbach alpha were employed to understand the internal structure of the scale. Paired t-tests, Pearson correlations and hierarchical regression were used to explore validity. RESULTS: A simple 7-item scale was developed along with two subscales representing agitated and verbally mediated distress. Ratings of distress were significantly greater during the anogenital phase than the general physical part of the examination. Increased distress was associated with positive physical findings. Ratings by the children that they disliked the physician looking at their bodies provided discriminant validity by correlating with increased scores for emotional distress during the anogenital segment of the examination. CONCLUSION: The Genital Examination Distress Scale (GEDS) has been developed for measuring the emotional distress of children during the anogenital component of child sexual abuse examinations. The GEDS has been provided for prudent use. Descriptive data offer a comparative standard for other programs and research.

Cryopreservation of adenovirus-transfected dendritic cells (DCs) for clinical use.

In this study, we examined the effects of cryoprotectant, freezing and thawing, and adenovirus (Adv) transduction on the viability, transgene expression, phenotype, and function of human dendritic cells (DCs). DCs were differentiated from cultured peripheral blood (PB) monocytes following Elutra isolation using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 6 days and then transduced using an Adv vector with an IL-12 transgene. Fresh, cryopreserved, and thawed transduced immature DCs were examined for their: 1) cellular concentration and viability; 2) antigenicity using an allogeneic mixed lymphocyte reaction (MLR); 3) phenotype (HLA-DR and CD11c) and activation (CD83); and 4) transgene expression based on IL-12 secretion. Stability studies revealed that transduced DCs could be held in cryoprotectant for as long as 75 min at 2-8°C prior to freezing with little effect on their viability and cellularity. Further, cryopreservation, storage, and thawing reduced the viability of the transduced DCs by an average of 7.7%; and had no significant impact on DC phenotype and activation. In summary, cryopreservation, storage, and thawing had no significant effect on DC viability, function, and transgene expression by Adv-transduced DCs.