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Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows signs of prenatal male hormone exposure at birth. In girls, androgen levels are low during pregnancy and childhood. A first physiologic rise of adrenal androgens is observed at the age of 6 to 8 years and reflects functional activation of the zona reticularis of the adrenal cortex at adrenarche, manifesting clinically with first pubic and axillary hairs. Early adrenarche is known as “premature adrenarche.” It is mostly idiopathic and of uncertain pathologic relevance but requires the exclusion of other causes of androgen excess (eg, nonclassic congenital adrenal hyperplasia) that might exacerbate clinically into virilization. The second modest physiologic increase of circulating androgens occurs then during pubertal development, which reflects the activation of ovarian steroidogenesis contributing to the peripheral androgen pool. However, at puberty initiation (and beyond), ovarian steroidogenesis is normally devoted to estrogen production for the development of secondary female bodily characteristics (eg, breast development). Serum total testosterone in a young adult woman is therefore about 10- to 20-fold lower than in a young man, whereas midcycle estradiol is about 10- to 20-fold higher. But if androgen production starts too early, progresses rapidly, and in marked excess (usually more than 3 to 5 times above normal), females will manifest with signs of virilization such as masculine habitus, deepening of the voice, severe acne, excessive facial and (male typical) body hair, clitoromegaly, and increased muscle development. Several medical conditions may cause virilization in girls and women, including androgen-producing tumors of the ovaries or adrenal cortex, (non)classical congenital adrenal hyperplasia and, more rarely, other disorders (also referred to as differences) of sex development (DSD). The purpose of this article is to describe the clinical approach to the girl with virilization at puberty, focusing on diagnostic challenges. The review is written from the perspective of the case of an 11.5-year-old girl who was referred to our clinic for progressive, rapid onset clitoromegaly, and was then diagnosed with a complex genetic form of DSD that led to abnormal testosterone production from a dysgenetic gonad at onset of puberty. Her genetic workup revealed a unique translocation of an abnormal duplicated Y-chromosome to a deleted chromosome 9, including the Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene. Learning Objectives Identify the precise pathophysiologic mechanisms leading to virilization in girls at puberty considering that virilization at puberty may be the first manifestation of an endocrine active tumor or a disorder/difference of sex development (DSD) that remained undiagnosed before and may be life-threatening. Of the DSDs, nonclassical congenital adrenal hyperplasia occurs most often. Provide a step-by-step diagnostic workup plan including repeated and expanded biochemical and genetic tests to solve complex cases. Manage clinical care of a girl virilizing at puberty using an interdisciplinary team approach. Care for complex cases of DSD manifesting at puberty, such as the presented girl with a Turner syndrome-like phenotype and virilization resulting from a complex genetic variation.

Background: After application of iodinated contrast media (CM), a pronounced deterioration of the microcirculation in skin and myocardium was reported. Clinically, the repeated application of CM, especially, led to an increase of the renal resistance index (RRI). With respect to the transiency of the RRI increase, it is reasonable to assume that the deterioration of blood flow could be due to transient blood stasis caused by reversible morphologic cell alterations due to osmotic discrepancies between CM and human blood. Therefore, the hypothesis was investigated whether CM are able to induce in vivo such blood stasis and cell deformations in the renal vasculature of well-hydrated pigs. Methods: The in vivo study was performed as a prospective randomized examination to compare the effects of two different CM in 16 pigs (German Landrace). Pigs were randomized to receive either Iodixanol (n = 8), or Iopromide (n = 8). Each animal received 10 injections separated by 5-min intervals via the suprarenal aorta at a rate of 10 mL/s according to the usual procedure during a cardiac catheter examination. Finally, the kidneys were explanted and processed for histology (H & E staining and fibrin staining according to Weigert) as well as for scanning electron microscopy (SEM) with regards to morphologic correlates explaining the changes in the microcirculation. Results: In each of the predefined four categories of vascular diameters, blood stasis were found, but clearly more often after application of Iopromide than after application of Iodixanol (p < 0.001). In addition, Iopromide induced more blood stasis in all of the examined kidney regions compared to Iodixanol (p = 0.0001). There were no obstructive events in the middle cortex following the application of Iodixanol. Except for the region around a puncture channel of a placed-in catheter probe, no fibrin was detected in Weigert’s fibrin-stained samples, neither around the histologically assessed thrombi nor in vessels with blood stasis. Complementary SEM analyses revealed in a few cases only a slight generation of fibrin and thrombi and deformations, such as echinocyte and “box-like” deformations. Conclusions: According to previous in vitro studies, pathological erythrocyte deformations, such as echinocyte and box-like formation of erythrocytes, were observed also in vivo. In addition, blood stasis and/or thrombi could be detected in histological samples from explanted kidneys from young pigs after repeated in vivo administration of CM. In only a few cases, mural platelet aggregates within minimal fibrin meshes occurred only after the application of Iopromide.

Context Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. Objectives To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). Design, Setting A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. Patients and Methods EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0–12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0–24 months) and 181 preterm babies, and 111 babies with atypical genitalia. Results The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6–11.5); in males 28–32 weeks 11.5 (9.2–12); in males 33–36 weeks 11.5 (10.5–12) and in full-term males 12 (10.5–12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. Conclusions EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research.

Zeitschrift für Hochschulentwicklung Volume Nr. 13 Issue Nr. 3

Background Localization of hyperfunctioning parathyroid glands in patients with previous cervical operations is not always successful with noninvasive methods such as ultrasound, sestamibi scan, or magnetic resonance imaging. The aim of our study was to evaluate the results of selective venous sampling (SVS) of intact parathyroid hormone (PTH) in patients undergoing surgery for primary (75%) or secondary (25%) hyperparathyroidism (HPT). Methods Between January 2000 and January 2006, SVS for PTH was performed in 51 consecutive patients with persistent or recurrent HPT or patients with previous cervical explorations. The results of SVS were compared with those of noninvasive localization studies. Results Successful surgical treatment was achieved in 47 of 51 patients (92%). SVS had a sensitivity of 83.3% for the correct localization of a parathyroid adenoma (79.5%) or hyperplastic parathyroid glands (91.6%). False-positive or indeterminate results of SVS were found in 6% and 2%, respectively, of the patients. Ultrasound detected enlarged parathyroid glands with a sensitivity of 33.3%, and sestamibi scan with a sensitivity of 57.1%. Conclusions Compared with noninvasive localization studies, SVS for PTH yielded the best results for recurrent or persistent HPT and for patients with previous neck explorations. SVS is strongly recommended in reoperative surgery for HPT with indeterminate results of noninvasive methods.

Studies in animals and humans suggest a role for peptide YY (PYY3-36) in regulating satiety. The physiologic role of PYY3-36, however, has not been investigated in detail.The present study was designed to examine PYY release in response to 2 meals differing in their calorie content and to relate the plasma levels to those obtained after exogenous infusion. In a second step, the effect of graded intravenous doses (0, 0.2, 0.4, and 0.8 pmol.kg(-1).min(-1)) of synthetic human PYY3-36 on food intake was investigated in healthy male volunteers in a double-blind, placebo-controlled fashion.Plasma PYY concentrations increased in response to food intake reflecting the size of the calorie load. Graded PYY3-36 infusions resulted in a dose-dependent reduction in food intake (maximal inhibition, 35%; P.001 vs control) and a similar reduction in calorie intake (32%; P.001). Fluid ingestion was also reduced by PYY (18% reduction; P.01). Nausea and fullness were the most common side effects produced by PYY, especially at the highest dose. Furthermore, subjects experienced less hunger and early fullness in the premeal period during PYY3-36 infusion at the highest dose (P.05).This study shows that intravenous infusions of PYY3-36 decrease spontaneous food intake; the inhibition is, however, only significant at pharmacologic plasma concentrations. Whether PYY3-36 has a physiologic role in the regulation of satiety in humans remains to be defined.

Das Ziel der Studie war eine Erfassung der Lebens-, Arbeits- und Karrierebedingungen von Arztinnen an den chirurgischen Universitatskliniken. An 261 operativ tatige Arztinnen der Fachrichtungen Viszeral-, Unfall- und Gefaschirurgie an 36 deutschen Universitatskliniken wurde ein Fragebogen verschickt. Die Antworten von 134 Chirurginnen (51,3%) wurden ausgewertet. Das Durchschnittsalter der befragten Chirurginnen lag bei 35,1 Jahren (27–54 Jahre). 78% der Chirurginnen waren in der Fachrichtung Viszeralchirurgie, 17% in der Unfallchirurgie und 5% in der Gefaschirurgie tatig. 72% waren promoviert und 9% habilitiert, 45% waren als Facharztinnen und 19% als Oberarztinnen beschaftigt. 80% gaben an, meistens oder immer mit ihrer beruflichen Situation zufrieden zu sein. 79% berichteten uber berufliche Hindernisse. Als haufigste Grunde fur eine Behinderung der Karriere wurden Dominanz der mannlichen Strukturen (80%), fehlendes Mentoring (70%), zu geringe operative Tatigkeit (67%) und eine geringere Chancengleichheit im Vergleich zu mannlichen Kollegen (60%) genannt. Zum Abbau der beschriebenen Karrierehemmnisse und zur Vermeidung einer Abwanderung an nichtuniversitare Einrichtungen ist eine Verbesserung der Kooperation zwischen den Chirurginnen, den Klinikleitungen und auch den staatlichen Institutionen erforderlich.

The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4+ Foxp3+ regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes. Conclusion: Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance. (HEPATOLOGY 2012;56:873–883)

The role of 5-hydroxytryptamine (5-HT), its enteric locus of action, and the receptor subtypes involved in the stimulation of in vivo phasic contractions in the colon were investigated by close intra-arterial infusions in conscious dogs. The contractile response to 5-HT was blocked completely by prior close intra-arterial infusion of atropine and reduced significantly by prior close intra-arterial infusions of tetrodotoxin and hexamethonium. The contractile response was, however, enhanced by the inhibition of nitric oxide (NO) synthase by a prior close intra-arterial infusion of N omega-nitro-L-arginine methyl ester. Prior close intra-arterial infusions of 5-HT1A/5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 receptor antagonists had no significant effect on the contractile response to 5-HT. By contrast, 5-HT3 receptor antagonist significantly and dose dependently inhibited the contractile response to 5-HT. We conclude that the in vivo phasic contractile response to 5-HT in the colon is mediated mainly by 5-HT3 receptors located on pre- and postsynaptic cholinergic enteric neurons. 5-HT receptors may also be localized on nonadrenergic, noncholinergic inhibitory motoneurons that use NO as a neurotransmitter.

The role of 5-hydroxytryptamine (5-HT), its enteric locus of action, and receptor subtypes involved in the regulation of jejunal contractions were investigated by close intra-arterial infusions in conscious dogs. Close intra-arterial infusions of 5-HT in short segments of the jejunum stimulated phasic contractions that were blocked completely by atropine, partially by tetrodotoxin, and not affected by hexamethonium. This response was also blocked significantly by 5-HT2A and 5-HT2C receptor antagonists but was not affected by 5-HT1A/5-HT1B, 5-HT3, and 5-HT4 receptor antagonists. Spontaneous phase III contractions were inhibited significantly by 5-HT2A and 5-HT2C receptor antagonists, not affected by 5-HT1A/5-HT1B and 5-HT3 receptor antagonists, and enhanced by 5-HT4 receptor antagonists. Repeated close intra-arterial infusions of 5-HT over several days stimulated giant migrating contractions. We conclude that in the conscious state, 5-HT acts on 5-HT2A and 5-HT2C receptors located on postsynaptic cholinergic neurons in the canine jejunum to stimulate phasic contractions and phase III activity. The 5-HT4 receptors in the canine small intestine may be localized on nonadrenergic, noncholinergic inhibitory neurons; these receptors suppress the amplitude and duration of phase III activity.

Summary OBJECTIVE We wished to investigate the circadian rhythm and pulsatility of parathyroid hormone (PTH) secretion in man, as conflicting results have been published. DESIGN and PATIENTS To investigate the circadian rhythm during daytime, we sampled (a) peripheral blood at hourly intervals in 12 healthy young men from 0900 h until 1700 h. For observation of pulsatility, we sampled (b) peripheral blood at 1-minute intervals for 1 hour in three healthy men and three healthy women (mean 27 7 years, range 21– 56 years) and (c) at 1-minute intervals for 30 minutes in 21 patients with surgically confirmed primary hyperparathyroidism (pHPT). MEASUREMENTS The serum levels of intact PTH were measured by two-site immunoradiometric assay and special care was taken to reduce intra-assay variability, especially at the normal PTH concentration. In series (a), ionized calcium, total calcium and phosphate were also determined. RESULTS A circadian rhythm during daytime was found for intact PTH in healthy men and women with a nadir at 0930 h and a peak in the afternoon. Ionized calcium and total calcium (protein-adjusted) decreased and phosphate increased in the afternoon. These changes were all statistically significant (P < 0– 02). Pulsatility of PTH: Statistical cluster analysis of the data showed no pulsatility either in healthy persons or in patients with primary hyperparathyroidism. In two healthy women and one healthy man slight changes of longer duration were discovered, but no complete pulses. In five patients with primary hyperparathyroidism, larger differences between the highest and lowest concentrations of intact PTH were found, but no complete pulses. CONCLUSIONS Our data show a significant circadian rhythm during daytime of intact PTH and only minor changes from minute to minute. The alterations in PTH-levels occurred at longer time intervals in healthy persons. In some patients with primary hyperparathyroidism, decreases of PTH-levels were found. The circadian rhythm of PTH may be due to slight changes in calcium or phosphate concentration.