A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.

BACKGROUND: Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. METHODS: We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). RESULTS: Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n=5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p<0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. CONCLUSION: Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.

BACKGROUND: Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer. METHODS: Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival. RESULTS: Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%. CONCLUSIONS: The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer.

BACKGROUND: To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation. RESULTS: Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%). CONCLUSIONS: Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.

Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva.

OBJECTIVE: To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva. METHODS: Patients with vulvar lesions amenable to surgery or chemoradiation (cohort 1) or those with metastatic measurable disease (cohort 2) received erlotinib 150 mg daily. Patients were monitored for toxicity. Responses were determined by digital photography or RECIST 1.1. Cohort 1 underwent pre and post treatment biopsies. EGFR immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and mutational analysis were performed. RESULTS: 41 patients were enrolled: 17 in cohort 1 and 24 in cohort 2. Notable grade 3 or 4 toxicities included allergic reaction (1), diarrhea/electrolyte abnormalities (3), ischemic colitis (1), and renal failure (3) and electrolyte abnormalities (n=2). Mean number of cycles for cohort 2 was 3.3. Overall clinical benefit rate was 67.5% with 11 (27.5%) partial responses (PR), 16 (40.0%) stable disease (SD), and 7 (17.5%) progressive disease. Responses were of short duration. All pre and post treatment biopsies exhibited 2-3+ EGFR staining. 5 of 14 patients (35%) were found to have EGFR amplification (n=3) or high polysomy/trisomy (n=2). These five patients had either a PR (n=3) or SD (n=2). Gain of function mutations were not been identified. CONCLUSIONS: This is the first reported controlled trial evaluating erlotinib for the management of vulvar carcinoma. Toxicities were acceptable given the lack of treatment options for these patients. Given the observed clinical benefits erlotinib may represent one of the most active agents available to treat vulvar SCC.

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice.

BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and ß-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

Varying forage type, metabolizable protein concentration, and carbohydrate source affects manure excretion, manure ammonia, and nitrogen metabolism of dairy cows.

Effects of forage source, concentration of metabolizable protein (MP), and type of carbohydrate on manure excretion by dairy cows and production of ammonia from that manure were evaluated using a central composite experimental design. All diets (dry basis) contained 50% forage that ranged from 25:75 to 75:25 alfalfa silage:corn silage. Diets contained 10.7% rumen-degradable protein with variable concentrations of undegradable protein so that dietary MP ranged from 8.8 to 12%. Starch concentration ranged from 22 to 30% with a concomitant decrease in neutral detergent fiber. A total of 15 diets were fed to 36 Holstein cows grouped in 6 blocks. Each block was a replicated 3 x 3 Latin square resulting in 108 observations. Manure output (urine and feces) was measured using total collection, and fresh feces and urine were combined into slurries and incubated for 48 h to measure NH3-N production. Feces, urine, and manure output averaged 50.5, 29.5, and 80.1 kg/d, respectively. Manure output increased with increasing dry matter intake (approximately 3.5 kg of manure/kg of dry matter intake), increased concentrations of alfalfa (mostly via changes in urine output), and decreased concentrations of starch (mostly via changes in fecal output). The amount of NH3-N produced per gram of manure decreased with increasing alfalfa because excreted N shifted from urine to feces. Increasing MP increased NH3-N produced per gram of manure mainly because of increased urinary N, but increased fecal N also contributed to the manure NH3. Manure NH3-N production per cow (accounts for effects on manure production and NH3-N produced per unit of manure) was least and milk protein yields were maximal for diets with high alfalfa (75% of the forage), moderate MP (11% of diet dry matter), and high starch (30% of diet dry matter).

Energy for living with cancer: preliminary findings of a cancer rehabilitation group intervention study.

PURPOSE/OBJECTIVES: To evaluate the acceptability and efficacy of a rehabilitation group intervention for people with cancer experiencing cancer-related fatigue (CRF) and examine the effects of the program on CRF distress. quality of life (QOL), and depression. DESIGN: Prospective, pre-/post-test intervention. SETTING: An outpatient area of a 551 -bed tertiary-care community hospital in the southeastern United States. SAMPLE: 20 participants have completed the program in four different groups. The preliminary mean age was 63.6 (range = 38-86). These participants had six different types of cancers, and 15 patients were receiving some form of cancer therapy during their participation in the program. METHODS: After providing informed consent participants completed the Cancer-Related Fatigue Distress Scale, the Center for Epidemiological Studies-Depression, the Functional Living Index-Cancer, and a demographic Information form. The intervention consists of eight weekly, 90-minute sessions with educational and sharing components. At the eighth session, participants were asked to complete the three instruments plus a program evaluation. MAIN RESEARCH VARIABLES: CRF distress, depression, QOL. FINDINGS: Preliminary results indicate that the program provided information, support, and management strategies for CRF. The mean for the program evaluations overall was 9.8 (0-10 scale, range = 9-10). Statistically significant differences were found for pre- and post-test fatigue distress and QOL scores. CONCLUSIONS: Preliminary findings indicate that this intervention is appropriate and beneficial for patients with cancer experiencing fatigue, even for those patients who are very debilitated. IMPLICATIONS FOR NURSING PRACTICE: The program can be used as a rehabilitation program to help people with cancer to manage the sequelae of their illness and treatments.

Uptake and excretion of organochlorine compounds in neonatal calves.

Intestinal absorption mechanisms of young calves change rapidly during the first 24 h postpartum and subsequently effect the absorption efficiencies of a wide range of compounds. This study was conducted to determine absorption efficiencies of (p,p'-dichlorodiphenyl)dichloroethylene (DDE), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), and 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD) when administered in colostrum to neonatal calves. Four male Holstein calves were given a single oral dose containing 100 mg each of DDE, PCB-153, and OCDD either 1 h (n = 2) or 65 h (n = 2) postpartum to determine whether time of exposure influenced the rate or extent of absorption. Another male calf received 100 mg each of DDE and OCDD 1 h postpartum. One gram of chromic oxide (Cr2O3) was administered as a digestion marker to dosed calves. Two male calves, receiving only colostrum, served as controls. Serum IgG concentrations indicated that the 1-h calves absorbed 20 to 37% of the ingested IgG and 65-h calves < 2%; therefore, the gut absorption mechanisms had changed by 65 h. Plasma DDE, PCB-153, and OCDD profiles did not differ based on time of exposure, suggesting that their mechanism of absorption was not influenced by the changing gut. Trapezoidal area under the curve to the last time point values indicated that, during the trial, relative plasma organochlorine concentrations amounted to PCB-153 > DDE > OCDD. Tissue concentrations were similar across treatment groups, with DDE and PCB-153 residues concentrating in adipose tissue and OCDD in the liver. Absorption efficiencies, calculated from fecal recoveries, were >97%, >74%, and >72% for DDE, PCB-153, and OCDD, respectively. These doses of DDE, PCB-153, and OCDD (2.5 +/- 0.1 mg/kg) did not produce signs of toxicosis based on detailed clinical observations, serum clinical chemistry, and gross and histological observations at necropsy. The results of this study indicate that DDE, PCB-153, and OCDD were absorbed and distributed similarly in calves exposed 1 or 65 h postpartum and did not induce toxicosis when administered in combination at these concentrations.

Retinoic acid resistance at late stages of human papillomavirus type 16-mediated transformation of human keratinocytes arises despite intact retinoid signaling and is due to a loss of sensitivity to transforming growth factor-beta.

In our in vitro model of human cell carcinogenesis, normal human foreskin keratinocytes (HKc) transfected with human papillomavirus type 16 DNA (HKc/HPV16) progress toward malignancy through several phenotypically defined and reproducible "steps" that include immortalization, growth factor independence (HKc/GFI), differentiation resistance (HKc/DR), and ultimately malignant conversion. While HKc/HPV16 are very sensitive to growth inhibition by all-trans-retinoic acid (RA) at early passages, they lose their sensitivity to RA during progression in culture. However, gel mobility shift assays using the retinoid response elements DR1 and DR5 showed no changes in binding activity of nuclear extracts obtained from HKc/HPV16 at different stages of in vitro progression. Similarly, Western blot analyses for retinoic acid receptor gamma-1 and the retinoid X receptors failed to reveal any decreases in the levels of these retinoid receptors throughout progression. In addition, luciferase activity driven by the SV40 promoter with a DR5 enhancer element was activated following RA treatment of HKc/DR that were resistant to growth inhibition by RA. Since RA induces transforming growth factor-beta2 (TGF-beta2) in normal HKc and HKc/HPV16, we investigated whether this response changed during progression. Again, RA induced TGF-beta2 mRNA in early and late passage HKc/HPV16, HKc/GFI, and HKc/DR approximately to the same extent, confirming that the RA signaling pathways remained intact during in vitro progression despite the fact that the cells become resistant to growth inhibition by RA. We then investigated the sensitivity of HKc/HPV16 to growth inhibition by TGF-beta. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-beta1 and TGF-beta2, the cells became increasingly resistant to both TGF-beta isotypes during in vitro progression. In addition, while both RA and TGF-beta produced a decrease in the levels of mRNA for the HPV16 oncogenes E6 and E7 in early passage HKc/HPV16, this effect was also lost at later stages of progression. Finally, blocking anti-TGF-beta antibodies partially prevented RA inhibition of growth and E6/E7 expression in early passage HKc/HPV16. Taken together, these data strongly suggest that inhibition of growth and HPV16 early gene expression in HKc/HPV16 by RA is mediated by TGF-beta and that a loss of RA sensitivity is linked to TGF-beta resistance rather than alterations in RA signaling.

Loss of transforming growth factor-beta (TGF-beta) receptor type I mediates TGF-beta resistance in human papillomavirus type 16-transformed human keratinocytes at late stages of in vitro progression.

Human keratinocytes (HKc) immortalized by human papillomavirus type 16 DNA (HKc/HPV16) progress toward malignancy through growth factor-independent (HKc/GFI) and differentiation-resistant stages (HKc/DR). This progression is associated with a loss of sensitivity to growth inhibition by both all-trans-retinoic acid (RA) and transforming growth factor-beta (TGF-beta). In the accompanying article (Borger et al., 2000, Virology 270, 397-407), we demonstrate that RA resistance in HKc/HPV16 arises despite functional nuclear retinoid receptors and that TGF-beta mediates growth inhibition by RA. To investigate the basis for the loss of TGF-beta sensitivity during in vitro progression of HKc/HPV16, we explored the expression of TGF-beta receptors type I and type II in independently derived HKc/HPV16 lines and their corresponding HKc/GFI and HKc/DR derivatives. While TGF-beta receptor type II mRNA levels were unchanged during progression, mRNA levels for TGF-beta receptor type I decreased dramatically as the cells became TGF-beta resistant. At the HKc/DR stage, loss of TGF-beta receptor type I mRNA, compared to low-passage cells, ranged from 55 to 87% in four HKc/HPV16 lines examined. Immunohistochemistry, using anti-TGF-beta receptor type I antibodies, confirmed a loss of TGF-beta receptor type I expression in HKc/DR. Reintroduction of the TGF-beta-receptor type I into TGF-beta-resistant HKc/DR completely restored growth inhibition by TGF-beta. Southern blot analysis of DNA extracted from normal HKc, HKc/HPV16, and HKc/DR ruled out any gross changes in the TGF-beta receptor type I gene. The activity of the TGF-beta receptor type I promoter, cloned upstream of a luciferase reporter gene, was decreased in HKc/DR, to an extent comparable to the decrease in mRNA levels for the TGF-beta receptor type I. Thus, TGF-beta resistance at late stages of HPV16-mediated transformation of HKc is the result of a loss of expression of TGF-beta receptor type I.

Kinetics of plasma fructose and glucose when lactose and fructose are used as energy supplements for neonatal calves.

Shortly after birth, plasma glucose and fructose concentrations of the neonate decline and thus leave blood sugar below the homeostatic mode. Two trials were conducted to determine the plasma glucose and fructose kinetics in control and supplemented calves for 108 h after birth. In the short-term trial, six Holstein calves were given 40 g of either fructose, lactose, or water (control) orally at 1 and 96 h after birth. Treatments were administered with a colostrum substitute (Life Boost) at 1 h and whole milk at 96 h. Rectal temperatures and changes in plasma glucose and fructose concentrations were monitored at close intervals for 12 h after supplementation. In the long-term trial, 15 Holstein calves were given 40 g of either lactose, fructose, or water (control) at 1 h after birth and at 12-h intervals for 81 h. Plasma glucose and fructose concentrations were determined before and 4 h after each of the seven feedings. Early postpartal feeding of fructose suppressed plasma glucose (approximately 50%), with a reciprocal rise in plasma fructose. Irrespective of treatment, plasma glucose concentrations did not stabilize (approximately 100 mg/dL) until 17 to 24 h after birth. After 24 h, lactose supplements increased concentrations of plasma glucose 4 h after supplementation (169.7 +/- 8.2 mg/dL), compared with those in calves that did not receive the additional lactose. After 24 h, fructose supplements did not affect plasma glucose, but plasma fructose concentrations increased (82.6 +/- 12.4 mg/dL) 4 h after administration. The response to fructose supplements declined by 11.4 mg x dL(-1) x d(-1). Fructose was not detected in the plasma of control or lactose-treated calves after 17 h after birth. Calves that received fructose supplements had rectal temperatures 8 and 10 h after birth that were higher than those of the other calves. The mechanisms of sugar metabolism change quickly following birth. Oral sugar supplements increase the total plasma sugar concentrations of treated calves.

Induction of HSP 32 gene in hypoxic cardiomyocytes is attenuated by treatment with N-acetyl-L-cysteine.

Increased synthesis of stress proteins may enhance myocardial viability during periods of low oxygen delivery. Our purpose was to determine if the oxidative stress protein heme oxygenase-1 [heat stress protein 32 (HSP 32)] was induced in hypoxic cardiomyocytes and whether this induction might be mediated by a redox-sensitive mechanism. Primary rat neonatal cardiomyocytes, cultured to express a tissuelike phenotype, responded to 12 h of hypoxia (< 0.5% ambient oxygen) with an approximately fivefold (range 3- to 7.5-fold; P < 0.05) increase in HSP 32 mRNA and a threefold (P < 0.05) increase in HSP 32 protein content. Exposure to 80 microM H2O2 for 3 h increased HSP 32 mRNA content to a similar extent. Expression of heme oxygenase-2 mRNA was unaffected by H2O2 or hypoxic treatments. Inclusion of 20 mM N-acetyl-L-cysteine in the medium during hypoxia reduced the increase in HSP 32 mRNA and protein expression by 25.50% compared with hypoxia alone. The data suggest that induction of HSP 32 protein may lead to an improved antioxidant defense in cardiomyocytes during hypoxia and that a redox-sensitive pathway mediates at least a portion of the hypoxic induction of the HSP 32 gene.

Induction of heme oxygenase-1 (HSP32) mRNA in skeletal muscle following contractions.

The capacity of preexisting antioxidant pathways to handle oxidative stress during exercise may be complemented by the synthesis of inducible heat stress proteins (HSP). Our purpose was to determine if the amount of mRNA for HSP32, a major oxidative stress protein, was increased in muscle after repetitive contractions. Reverse transcriptase-polymerase chain reaction analysis showed that HSP32 mRNA (normalized to alpha-actin mRNA) was increased about seven- and about fourfold (P < 0.35) immediately after 1 h of exhaustive running and after 3 h of muscle contractions (10 Hz nerve stimulation), respectively. Northern blot analysis revealed that HSP70 mRNAs were 3.5- to 15.5-fold above control value (P < 0.05), whereas the content of another oxidative stress protein mRNA (macrophage stress protein 23) was unchanged 0 h after contractions. The relative increase in HSP32 mRNA was found to be dependent on active tension generation; passive tension did not increase the HSP32-to-actin mRNA ratio. Increases in HSP32 mRNA may underlie an inducible antioxidant pathway in muscle responsive to metabolic stresses associated with repeated muscle contractions.

Selected critical care complications of cancer therapy.

In this article of critical care complications of radiation therapy, chemotherapy, and biological therapy, the authors focus on the pathophysiology of the toxicities, causative agents, and patient presentation. They provide an overview of the types of toxicities that advances practice and expert critical care nurses may encounter in the care of the critically ill patient who has received cancer therapy. The purpose of providing this information is to increase the awareness of potential causes for admission to the intensive care unit and to described the toxic effects that have an impact on the critical care nursing the patient receives. The nursing management of these problems follows the standard guidelines for patients with any of the particular organ system dysfunctions.

Congenital adrenal hyperplasia. I: Gender-related behavior and attitudes in female patients and sisters.

Thirty-five female patients with congenital adrenal hyperplasia (CAH) were compared to a group of 16 healthy sisters in regard to gender-related behavioral patterns, present attitudes, and plans for the future. A semi-structured interview with the subjects, ages 11 to 41 yr, and their mothers concentrated on four to five age stages. Results of retrospective data from single items as well as from several related composite scales ("interests and behavior," "appearance," "overall scores") revealed significant group differences: Both in mother-assessment and self-assessment, CAH patients showed a "more masculine" orientation than their sisters, but this was far from consistent across all age stages, especially for single items. Unexpectedly, the gender-behavior differences between CAH patients and sisters did not hold for certain items and scales of "social behavior" (e.g., assertiveness, dominance, acceptance in peer groups) and, in contrast to some of the existing literature, also not for "high-energy expenditure." With regard to expectations for the future, CAH patients had less of a "wish to have their own children" and a higher preference for "having a career versus staying at home." Age, socioeconomic status, intelligence, and presence or absence of a sister as possibly intervening psychosocial/demographic factors could not explain the group differences in behavior. Degree of genital masculinization (Prader stages) or "onset and quality" of therapy as measures of pre- and postnatal androgenization, respectively, could also not account for the degree of the "more masculine" orientation in the CAH group. Nevertheless, the overall results are compatible with earlier findings on the masculinizing effects of prenatal androgens on behavior in humans and point to a time period after sexual differentiation of the genitalia and before birth as the most likely one for the effects of prenatal hormones on behavioral masculinization in humans.

Congenital adrenal hyperplasia. II: Gender-related behavior and attitudes in female salt-wasting and simple-virilizing patients.

The salt-wasting (SW) and simple-virilizing (SV) forms of congenital adrenal hyperplasia (CAH) are characterized by distinct prenatal hormonal milieus. To test whether these hormonal milieus differentially influence the development of a "more masculine" behavioral pattern in female CAH patients (Dittmann et al., 1990), SW patients (N = 13) were compared both to SV patients (N = 20) and healthy sisters of both groups (N = 16). The data are based on semi-structured interviews in which subjects (11-41 yr) and mothers were asked about aspects of "Gender-related interests and behavior," "Level of activity," "Social behavior," (reflecting e.g., assertiveness, dominance, and acceptance by peer groups) and "Appearance"; these areas of interest were represented by composite scales. On most scales, and by both mother-assessment and self-assessment, SW patients differed significantly from both SV patients and sisters in having a "more masculine" orientation. SW patients also showed a higher "Level of activity." These SW group results probably account for much of the CAH/sister differences reported in the companion article (Dittmann et al., 1990). In contrast, SV patients differed from the sister sample on only a few scales. There were no significant differences between SV and SW subjects in the degree of virilization of the external genitalia (indicating no group difference in prenatal androgenization). SW patients were treated "earlier" and "better" after birth (indicating less postnatal androgenization). However, these medical conditions, as well as several psychosocial/demographic variables, could not explain the group behavioral differences. These results do not support a primarily psychosocial explanation of behavioral development in CAH patients, especially those with the SW condition; they rather suggest differential organizational effects of two different hormonal environments (SV vs. SW) during critical periods of prenatal CNS development.

Dermatoglyphics in congenital adrenal hyperplasia (CAH).

Dermatoglyphic findings were compared in 42 patients (32 females, 10 males) with Congenital Adrenal Hyperplasia (CAH) and 110 normal controls (70 females, 40 males). In CAH males, an excess of whorls (p less than 0.001), an increased total finger ridge count (p less than 0.05), and an increased frequency of patterns in the fourth interdigital area (p less than 0.025) was found. A main line A terminating high in the hypothenar area (p less than 0.05), and a missing c-triradius or an abortive main line C (p less than 0.05) was observed in CAH females. Both sexes displayed an increase in the frequency of small radially directed hypothenar patterns (p less than 0.05) and sydney lines (p less than 0.01).

[Puberty and growth development in patients with a 21-hydroxylase defect]. / Pubertäts- und Wachstumsentwicklung bei Patientinnen mit 21-Hydroxylase-Defekt.

Twenty six females suffering from congenital adrenal hyperplasia due to 21-hydroxylase-deficiency with and without salt wasting were evaluated to determine their growth patterns with special regard to their pubertal growth spurt. 17 patients have been substituted with hydrocortisone 20-25 mg/m2 and if necessary with 9 alpha-fluoro-cortisol 0.025-0.15 mg (group 1), 9 patients have got an additional cyproterone-acetate-therapy during their pubertal development (group 2). Group 1: A pubertal growth spurt was found in 14 females (82.4%) with a peak height velocity of 6.2 +/- 1.6 (SD) cm/yr. At the beginning of puberty the early treated girls showed a progressing retardation of bone age. Therefore the peak height velocity based on advancing bone age was elevated up to 8.7 +/- 1.4 (SD) cm/yr bone age (p = 0.01). Salt wasting (n = 10) did not seem to influence the pubertal growth velocity and the pubertal growth spurt (p = 0.1, p greater than 0.1), but the growth until cessation which was found to be markedly decreased (p less than 0.1). Group 2: Cyproterone-acetate suppressed symptoms of puberty but did not extinguish growth spurt. During 6.3 +/- 1.3 (SD) yrs of treatment bone age advanced only 4.2 +/- 0.7 (SD) yrs. However, in this period height increased by 20.8 +/- 6.4 (SD) cm which corresponds to a mean height velocity of 3.3 +/- 0.8 (SD) cm/yr, and 4.9 +/- 0.8 (SD) cm/yr bone age. Furthermore at puberty peak height velocity results in 4.5 +/- 0.7 (SD) cm/yr and in 10.4 +/- 4.6 (SD) cm/yr bone age.(ABSTRACT TRUNCATED AT 250 WORDS)

Interlaced versus progressive readout of television cameras for digital radiographic acquisitions.

A comparison was made of two methods for reading the TV camera target for digital radiographic acquisition, interlaced and progressive readout. Experiments were performed with a plumbicon TV camera to measure x-ray exposure requirements and resolution capabilities after readout for the two modes. Real time digital (30 frames per second, 256(2) matrix) and single-frame electrocardiogram gated images of the contrast-filled coronary arteries in a dog were acquired with both formats. Results demonstrate a reduction in patient exposure of up to four times for single-frame progressive readout images over interlaced acquisition for static images of comparable quality. Imaging of rapid motion objects (e.g., coronary arteries) with interlaced TV scanning results in "scalloping" of edges and resolution degradation. The short pulse width capability of progressive readout eliminates motion blurring and preserves object detail. Progressive readout is the preferred mode of TV camera readout for most digital radiographic applications due to more flexible x-ray techniques, superior images, and total utilization of the input x-ray flux for lower patient exposure.