Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

[From panel diagnostics to comprehensive genomic analysis : Infobesity or empowerment?] / Von der Paneldiagnostik zu umfassenden genomischen Analysen : Informationsüberfluss oder Zugewinn?

Precision oncology is obtaining a central role in the therapy of malignant diseases. The indication for targeted therapy is based on the identification of molecular targets for which next-generation sequencing (NGS) is commonly used nowadays. All approved predictive biomarkers and molecular targets, including gene fusions and copy number alterations, can be identified depending on panel design and method applied. Some clinical scenarios, however, may require more holistic genomic approaches, such as whole-genome/whole-exome and transcriptome analysis, which must be embedded in a clinical trial. Here, key aspects and applications of each method are summarized and discussed.

Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD).

Homologous repair deficiency (HRD) is present in many cancer types at variable prevalence and can indicate response to platinum-based chemotherapy and PARP inhibition. We developed a tumor classification system based on the loss of function of genes in the homologous recombination repair (HRR) pathway. To this end, somatic and germline alterations in BRCA1/2 and 140 other HRR genes were included and assessed for the impact on gene function. Additionally, information on the allelic hit type and on BRCA1 promoter hypermethylation was included. The HRDsum score including LOH, LST, and TAI was calculated for 8847 tumors of the TCGA cohort starting from genotyping data and for the subcohort of ovarian cancer also starting from WES data. Pan-cancer, deleterious BRCA1/2 alterations were detected in 4% of the tumors, while 18% of the tumors were HRD-positive (HRDsum ≥ 42). Across 33 cancer types, both BRCA1/2 alterations and HRD-positivity were most prevalent in ovarian cancer (20% and 69%). Pan-cancer, tumors with biallelic deleterious alterations in BRCA1/2 were separated strongly from tumors without relevant alterations (AUC = 0.89), while separation for tumors with monoallelic deleterious BRCA1/2 alterations was weak (AUC = 0.53). Tumors with biallelic deleterious alterations in other HHR genes were separated moderately from tumors without relevant alterations (AUC = 0.63), while separation for tumors with such monoallelic alterations was weaker (AUC = 0.57). In ovarian cancer, HRDsum scores calculated from WES data correlated strongly with HRDsum scores calculated from genotyping data (R = 0.87) and were slightly (4%) higher. We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.

BACKGROUND: Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood. MATERIALS AND METHODS: We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles. RESULTS: Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors. CONCLUSIONS: Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.

Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men.

The levels of dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS decrease with age after a peak around 25 yr. Animal studies as well as the first studies in humans have generated the idea that DHEA replacement in elderly subjects may have beneficial effects on well-being and cognitive functions. In the present experiment 40 healthy elderly men and women (mean age, 69 yr) participated in a double blind, placebo-controlled DHEA substitution study. For 2 weeks subjects took 50 mg DHEA daily, followed by a 2-week wash-out period and a 2-week placebo period. The treatment sequence was randomized in a cross-over design. After 2 weeks of DHEA or placebo, psychological and physical well-being as well as cognitive performance were assessed using several questionnaires and neuropsychological tests. All subjects had low DHEAS baseline levels. DHEA substitution lead to a 5-fold increase in DHEAS levels in women (from 0.67 +/- 0.1 to 4.1 +/- 0.4 micrograms/mL; P < 0.001) and men (from 0.85 +/- 0.1 to 4.5 +/- 0.4 micrograms/mL; P < 0.001). DHEA, androstenedione, and testosterone levels also increased significantly in both sexes (all P < 0.001). No significant changes were observed in insulin-like growth factor I or insulin-like growth factor-binding protein-3 levels. DHEA replacement had no strong beneficial effect on any of the measured psychological or cognitive parameters. Only women tended to report an increase in well-being (P = 0.11) and mood (P = 0.10), as assessed with questionnaires. They also showed better performance in one of six cognitive tests (picture memory) after DHEA. However, after Bonferroni alpha adjustment, this difference was no longer significant. No such trend was observed in men (P > 0.20). Likewise, no beneficial effects of DHEA substitution could be observed in any of the other tests of the neuropsychological test battery in either sex (all P > 0.20). In conclusion, the present data do not support the idea of strong beneficial effects of a physiological DHEA substitution on well-being or cognitive performance in healthy elderly individuals.

Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men.

Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study.

Energy requirement for eating in cattle.

We determined the energy requirement for the activity associated with eating in an experiment with four adult Hinterwälder steers weighing 640+/-25 kg BW (mean+/-SD), using indirect calorimetry in respiration chambers. Heat production was measured during 3 h with and 3 h without ad libitum access to wheat straw, and the energy cost of eating was calculated as the difference, which was on average 27+/-13 J/(min x kg BW) (mean+/-SD). Straw intake, the time spent for eating, and the number of jaw movements were recorded. Values for the energy cost of eating reported in the literature are similar to those in this study, and values for ruminating amount to approximately 27% of those for eating. The energy cost of eating (literature values) varies greatly between feeds and feed treatments, when related to the amount of feed ingested, but it was relatively constant when related to time spent eating and was similar for cattle, sheep, and horses, when related to BW or metabolic BW (35 J/[min x kg BW] or 124 J/ [min x kg BW.75]). Calculations indicated that in high-quality roughage 10% of the ME and in untreated straw approximately 30% of the ME provided by the feed are used for eating and ruminating. This might be the main reason for the lower efficiency of ME utilization in roughages. The energy requirement for eating and ruminating should therefore be considered as a distinct proportion of the total ME requirement.

A new approach to the treatment of laryngeal papilloma in adults.

Twenty-six cases of multiple laryngeal papillomatosis were treated by a newly developed grafting technique. The larynx was opened in the midline under local anaesthesia and the tumour mass was surgically resected. Mucous membrane along with the lamina propria was taken from patient's upper jaw and grafted over the wound, with the help of plain catgut on an atraumatic needle. Although our patients have been observed for only a short period of 5 years from 1972, no recurrence has been seen and good vocal cord function has remained.

Direct parameter specification and the concept of perception.

Stimuli that reach the sensory surface may result in perception, or serve to guide action. How are these two potential consequences of sensory stimulation related? I discuss three aspects of this problem. The conceptual aspect concerns the status of the concept of perception in an objective psychology. The methodological aspect pertains to the problem of how psychophysics is related to the assessment of performance measures. The functional aspect relates to the function(s) of perception for action control. I argue that (a) conceptually, the term perception belongs to a different level of description than the constructs of information-processing models: (b) methodologically, psychophysical judgements and performance measures are not necessarily converging operations: (c) functionally, sensory information can be used for the control of action without perception as a mediating stage (direct parameter specification). Taken together, this suggests that perception should be conceptualized not as a processing stage, but as a class of actions that serve to establish and update an internal representation of the environment.

[Parameters of trauma at posterior subglottic region by long term translaryngeal intubation (author's transl)]. / Schädigungsparameter an der Ringknorpelplatte bei Langzeitintubation

The mechanical lesion is the beginning of inflammation and destruction in the posterior subglottic region in some cases of long term translaryngeal intubated patients. Beside movement of the tube, it is the pressure upon the posterior cartilage which is dangerous. The circumstances of that danger are studied. Practical proposals for reduction of subglottic complications are discussed.

[Oral mucosal grafts in laryngeal reconstruction (author's transl)]. / Operationstechnik der freien Mundschleimhaut-Transplantation in den Kehlkopf

In many laryngofissure procedures large mucosal resections are necessary. Free grafts of oral mucosa have been used in over 50 patients over the past 3 years for glottic reconstruction, and these experiences are reported in detail. Its use in the management of papillomata of the adult larynx is stressed.

[Management of multiple laryngeal papillomas in cases of grown up persons]. / Behandlung der Larynxpapillomatose bei Erwachsenen

The method of grafting autogenous oral mucous flaps for glottic reconstruction allows a very radical resection of multiple laryneal papillomas. In 13 cases of operated grown up persons after a time between 6 and 37 months there has been no recurrence in the transplantated region and the vocal cords are normal in function.

Apparent distance reduction with moving stimuli (Tandem Effect): evidence for an attention-shifting model.

When two vertical rods move through a horizontal window in close succession, the Tandem Effect can be observed. It consists of a spatial illusion (distance between the rods looking smaller than it actually is) and a temporal illusion (under certain conditions both rods are seen simultaneously in the window, though the first rod has left the window before the second rod enters it). We report six experiments that explored the distance-reduction illusion and tested an attentional model of the effect. It assumes that attention is initially focused on the first rod and then shifted to the second, when it enters the window. The percept of the pair of rods is integrated from the first rod's position at the beginning, and the second rod's position at the end, of the focus shift. Consequently their subjective distance will be smaller than their physical distance by the distance that they travel during the focus shift. Experiments 1 and 2 established the Tandem Effect as an empirical phenomenon and showed that its size depends on stimulus parameters such as window size and movement speed. Experiments 3-5 tested specific predictions from the attentional model. Experiment 6 examined a further illusion, the Fröhlich Effect, and showed that it can be subsumed under the model. The experiments produced some unexpected effects and some predictions from the model were only partly confirmed. It is shown that the main findings can be combined into two quantitative functions that describe the course of focusing. One implication is that visual attention does not "move" from one object to another; rather all attention shifts originate in the fovea. We discuss several alternative interpretations of our data and show that they are less satisfactory than the attentional model.

Temporal, but not spatial, context modulates a masked prime's effect on temporal order judgment, but not on response latency.

Three experiments investigated a dissociation originally described by Neumann, Esselmann, and Klotz. Stimuli were geometric shapes, preceded by similar shapes that were masked by metacontrast. Each experiment consisted of three parts. In the reaction time (RT) part, participants saw an array of geometric shapes, one of which was marked by bars, and had to respond to the marked shape's position by pressing an appropriate button. A prime (a similar, but smaller stimulus) preceded either the marked or an unmarked stimulus. In the temporal order judgment (TOJ) part, the task was to judge the temporal order of the marked and the unmarked stimulus. In the detection part, detectability of the prime was tested. Although its detectability was zero or close to zero, the prime affected both RT and the apparent onset as measured by TOJ. The effect on RT was significantly larger than the effect on TOJ (Exp. 1). Increasing the spatial context (number of non-target stimuli in the display) did not affect this pattern (Exp. 2). By contrast, reducing the temporal context (range of stimulus onset asynchronies) abolished the prime's effect in the TOJ task, although the prime affected RT under identical conditions. It is concluded that partially different mechanisms mediate the prime's effect in the two tasks and that the effect of stimulus context on TOJ found in the Neumann et al. study was due to temporal, not spatial context.

[Diagnosis and therapy of seromucous otitis. Experience with 2766 operations on children]. / Diagnostik und Therapie beim Mucoserotympanon. Erfahrungen nach 2766 Eingriffen bei Kindern.

We compared tympanometric patterns with the type of ear effusion on 1693 ears of children with chronic seromucous otitis. There was no exact agreement between the tympanograms and the viscosity of the middle ear effusion. We inserted ventilating tubes in 943 of 2766 ears with SOM. A tube was only used if there was mucus in the middle ear. In cases of thin fluid we used myringotomy alone. A test to find the best tube is discussed. For a child with SOM the insertion of a ventilation tube is so helpful and complications so rare that in our opinion there is no better way of treatment. The complications are probably related more to the underlying disease than to the ventilation tube.

[The anatomy of the laryngeal ventricle and its importance in carcinoma of the vocal cords (author's transl)]. / Zur Morphologie des Sinus Morgagni und seine Bedeutung für das Stimmlippen-Karzinom.

An anatomical study was made of the sinus of Morgagni (laryngeal ventricle) in 10 normal larynges and 15 larynges with vocal cord carcinoma. The most striking difference in those patients with malignancy was the relatively greater goblet cell population found. It is assumed that these anatomical changes reflect a disturbed function of the laryngeal ventricle. The epithelial metaplasia and the high goblet cell count probably indicate an increased risk of vocal cord carcinoma.

[Laryngeal leukoplakias (author's transl)]. / Leukoplakien des Kehlkopfes. Histologisch-zytologische Klassifizierung.

A histologic and cytologic classification of laryngeal dysplastic leukoplakias is described. The basic knowledge has been gained by the experience in the diagnosis of portio-carcinoma. Histologic and cytologic illustrations of different dysplastic stages are shown. The final classification including the clinical description is achieved by cytology and histology.

[Study on clinic and etiology of human laryngoceles by help of Silopren -casts (author's transl)]. / Untersuchungen über Klinik und Atiologie menschlicher Laryngocelen anhand von Kunststoffausgusspräparaten.

In different papers the statistical number of the finding of a laryngocele is changing. This perhaps should be related to the fact that there is no equal definition. Therefore an own definition for the examination of 50 Silopren -casts from laryngeal autopsies is given. In 64% of the cases one or more sacculi laryngis were found. The sex-distribution was about 50%. By looking at the clinical history it seems that exogenic factors have an influence on the extent of laryngoceles.

[Intratympanic pressure changes during general anaesthesia (author's transl)]. / Veränderungen des Mittelohrdrucks in Allgemeinnarkose bei Verwendung von Lachgas.

A common observation during otologic surgery under general anaesthesia, notably with nitrous oxide, is tympanic membrane graft displacement due to elevated intratympanic pressure. It can be assumed that nitrous oxide increases the intratympanic pressure. The authors measured the intratympanic pressure changes with the Madsen Impedance measuring instrument Z073. The results of the measurements of 84 ears are discussed and the tendencies of the connection between pressure in the middle ear and the size of the mastoid bone are shown.