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.

[Drug-induced lupus erythematosus tumidus during treatment with adalimumab]. / Medikamenteninduzierter Lupus erythematodes tumidus unter Adalimumab-Therapie.

Patients treated with TNF-alpha inhibitors frequently have serum autoantibodies, but only a few develop clinically apparent lupus erythematosus. The TNF-alpha inhibitor adalimumab is a fully humanized antibody and seems to induce autoantibodies less frequently than other drugs of this group. We report on a patient with rheumatoid arthritis, who developed anti-histone antibodies and lupus tumidus after eight months on adalimumab therapy.

[A case of granulomatous rosacea coinciding with the use of etanercept: no relapse with infliximab]. / Ein Fall von granulomatöser Rosazea im zeitlichen Zusammenhang mit Etanercept: Kein Rezidiv unter Infliximab.

A woman with psoriasis vulgaris and psoriatic arthritis developed granulomatous rosacea after four weeks of therapy with etanercept. When this agent was stopped, her skin lesions rapidly resolved with topical therapy, suggesting a causal relationship between the skin lesions and drug intake. To the best of our knowledge, this is the first report on rosacea as granulomatous cutaneous adverse drug reaction caused by etanercept. No relapse of skin changes appeared under extended and successful anti-psoriatic therapy with infliximab.

[Human seminal plasma allergy type I]. / Typ-I-Allergie auf Seminalplasma.

Human seminal plasma allergy (HSPA) is a rare allergic reaction to specific protein fractions of seminal plasma, whereof PSA seems to be a relevant allergen. Predominantly Type I-immunoreactions can occur. The main symptoms are localized and generalized urticaria and sometimes anaphylactic symptoms. The diagnosis is based on history, skin tests and on the determination of specific IgE-levels for (un)fractionated seminal plasma. Here we report a patient with recurrent episodes of generalized urticaria after unprotected sexual intercourse and positive prick-test-reaction on seminal plasma.

Effects of (+/-)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats.

Kava pyrones extracted from pepper Piper methysticum are pharmacologically active compounds. Since kava pyrones exhibit anticonvulsive, analgesic and centrally muscle relaxing properties, the influence of a synthetic kava pyrone, (+/-)-kavain, on voltage-dependent ion channel currents was studied. Effects of (+/-)-kavain on voltage-activated inward currents were analysed in cultured dorsal root ganglion cells derived from neonatal rats. Voltage-activated Ca2+ and Na+ currents were elicited in the whole-cell configuration of the patch clamp technique. Extracellularly applied (+/-)-kavain dissolved in hydrous salt solutions reduced voltage-activated Ca2+ and Na+ channel currents within 3-5 min. As the solubility of (+/-)-kavain in hydrous solutions is low, dimethyl sulfoxide (DMSO) was added to the saline as a solvent for the drug in most experiments. When (+/-)-kavain was dissolved in DMSO, the drug induced a fast and pronounced reduction of both Ca2+ and Na+ currents, which partly recovered within 2-5 min even in the presence of the drug. The present study indicates that (+/-)-kavain reduces currents through voltage-activated Na+ and Ca2+ channels.

Long-term results (7 to 10 years) of endoscopic papillotomy for choledocholithiasis. Multivariate analysis of prognostic factors for the recurrence of biliary symptoms.

BACKGROUND: The long-term outcome after endoscopic papillotomy is poorly defined. The aim of this study was to determine the long-term results of this method in the treatment of common duct calculi and to determine which prognostic factors are associated with the relapse of biliary symptoms. METHODS: Between 1985 and 1988, 223 consecutive (149 women, mean age 67.9 years) patients underwent endoscopic papillotomy for duct stones; 127 had already undergone cholecystectomy or underwent this operation during the same hospitalization. Follow-up data were obtained retrospectively from the patients and patients' relatives and general practitioners. RESULTS: The procedure was successful in 217 of 223 cases (97%), of which 203 were followed-up; 2 patients died in the first month after treatment (0.89%). Mean follow-up for the 201 patients was 6.2 years, during which 31 relapsed (15%). Three significant prognostic factors for late complications were identified in a multivariate analysis. The recurrence rate of biliary symptoms in patients who were left with an in situ gallbladder was 20.2%, and 11% for those whose gallbladder was removed (p = 0.04). Patients with a bile duct 15 mm or greater in diameter were more prone to recurrence of symptoms than those with a bile duct 10 mm or less in diameter (41% vs. 10%, p = 0.025) and were especially at higher risk to develop recurrent stones (19.5% vs. 4.9%, p = 0.019). Stone recurrence, but not biliary symptoms as a whole, was more frequent in patients with a peripapillary diverticulum (p = 0.035). CONCLUSIONS: The long-term results of endoscopic papillotomy are comparable with those of surgical techniques. The prognostic factors associated with relapse of biliary symptoms as a whole are gallbladder left in situ and choledochal diameter. Bile duct size and peripapillary diverticula are associated with recurrent bile duct stones.

Angiotensin-converting enzyme inhibitors in preventing remodeling and development of heart failure after acute myocardial infarction: results of the German multicenter study of the effects of captopril on cardiopulmonary exercise parameters (ECCE).

Early action of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction (MI) has been shown in large scale clinical trials to reduce mortality over the first weeks. However, the mechanisms involved are yet unclear and several trials showed a tendency toward a small, albeit unexpected, rise in cardiogenic shock or mortality. Since cardiopulmonary exercise testing (CPX) has become a "gold standard" in assessing the severity of heart failure, we studied--after finishing a pilot trial--the effect of captopril versus placebo in 208 patients who were individually titrated (titrated dose, mean 46/69 mg/day after 7 days/4 weeks, respectively) in order to preserve their blood pressure in the acute phase of myocardial infarction; we followed the development of congestive heart failure (CHF) over 4 weeks by measuring oxygen consumption. After 4 weeks, overall oxygen consumption at the anaerobic threshold (VO2-AT; 13.7 vs 13.1), maximal oxygen consumption (VO2max 19.3 vs 18.9 mL/kg per min) and exercise duration (896 vs 839 sec) showed a nonsignificant difference in favor of the captopril group. The predefined, categorized, combined endpoint of severe heart failure or death (heart failure necessitating ACE inhibition, VO2max < 10 mL/kg per min, or death) was significantly reduced in the captopril group (n = 7/104) versus placebo (n = 18/104; p = 0.03). Differences were mainly caused by fewer CHF events (delta n = 10). We conclude that ACE inhibition with individualized dose titration markedly reduces the 4-week incidence of severe heart failure or death; > 10 patients per 100 treated gained major benefits from this therapy.

Effects of kawain and dihydromethysticin on field potential changes in the hippocampus.

1. The kava-pyrones kawain and dihydromethysticin are constituents of Piper methysticum which exert anticonvulsant, analgesic and anxiolytic properties. 2. In the present study the effect of these kava-pyrones were tested on field potential changes (fp) induced by omission of the extracellular Mg2+, recorded from the area CA1 and CA3 of the hippocampal slice preparation of guinea pigs. These fp are generated by an activation of NMDA receptors and voltage dependent calcium channels. 3. Kawain and dihydromethysticin reduced reversibly the frequency of occurrence of fp in a concentration range from 5 to 40 mumol/l and 10 to 40 mumol/l, respectively. 4. Reduction of the fp frequency after addition of subthreshold concentrations of 5 mumol/l kawain and 10 mumol/l dihydromethysticin indicated additive actions of both drugs. 5. Since the serotonin-1A agonist ipsapirone also exerts anxiolytic effects, subthreshold concentrations of kawain or dihydromethysticin were combined with a subthreshold concentration of ipsapirone in another set of experiments. Combining kawain and ipsapirone or dihydromethysticin and ipsapirone caused a reduction of the rate of fp to 0.76 and 0.81 of the baseline value, respectively. 6. The findings suggest that (i) single constituents of Piper methysticum may have additive actions, (ii) that the two components kawain and dihydromethysticin may enhance the effects of the anxiolytic serotonin-1A agonist ipsapirone and (iii) that activation of NMDA receptors and/or voltage dependent calcium channels may be involved in the elementary mechanism of action of some kava-pyrones.

[Chronic right heart failure after implantation of a cava filter]. / Chronische Rechtsherzbelastung nach Implantation eines Kavasperrfilters.

HISTORY AND CLINICAL FINDINGS: A 39-year-old woman complained of dyspnoea and increasing abdominal pressure sensation. A Greenfield filter had been implanted into her inferior vena cava (IVC) 4 years previously because of pulmonary embolism from a deep vein thrombosis after a hysterectomy with abscess formation. Physical examination revealed neck vein congestion, jaundiced sclerae, a tense abdominal wall, ascites and a soft machinery murmur in the paraumbilical region. INVESTIGATIONS: Transaminase activities were slightly raised (GOT 38 U/I, GPT 20 U/I), but total bilirubin and direct bilirubin were markedly elevated (2.9 mg/dl and 1.1 mg/dl, respectively). There was no evidence of cholestasis or decreased liver synthesis. Ultrasound showed marked dilatation of the IVC and hepatic veins, and echocardiography revealed right ventricular enlargement with grade II tricuspid regurgitation. Calculated pulmonary arterial systolic pressure averaged 50 mmHG. Colour-coded Doppler sonography demonstrated an aorto-caval shunt at the level of the filter in the IVC and penetration of a filter strut into the aortic lumen. TREATMENT AND COURSE: After removing the ascitic fluid by fluid and sodium restriction, and administration of an aldosterone antagonist and a loop diuretic, the A-V fistula was closed surgically and the filter removed. Three months after operation she was put on phenprocoumon (Quick value 20-30%). At the latest outpatient examination, 6 months after the operation, she was free of symptoms. CONCLUSION: As filter implantation in the IVC may produce severe complications, indications for it need to be demonstrated by further studies of its efficacy.

[Rickettsiosis of the typhus fever type. Its joint appearance with a left-ventricular thrombus and single-vessel coronary disease]. / Rickettsiose vom Fleckfiebertyp. Gemeinsames Auftreten mit einem linksventrikulären Thrombus und einer koronaren Ein-Gefäss-Krankheit.

A 44-year-old German fell ill in Libya, where he had been living for 10 years, with high fever, rigor and a nonitching centrifugally spreading macular rash, which had spared the head, hands and soles. In addition, a systolic cardiac murmur was heard. The Weil-Felix reaction had a titre rising within 3 days from 1:160 to 1:640, confirming the diagnosis of rickettsial disease, the total clinical picture indicating typhus. On treatment with chloramphenicol (1 g three times daily i.v.) the fever subsided within 5 days. On the ninth day treatment was changed to oral doxycyclin, 200 mg daily for 3 weeks. Echocardiography surprisingly revealed a floating thrombus, about 4 x 8 cm, attached to the hypo- and even akinetic apex of the left ventricle. In addition there was single-vessel coronary disease. Since the segmental contraction abnormality persisted after the typhus had been cured, a causal connection with the rickettsial disease is unlikely. The thrombus was removed at the time of a aortocoronary bypass operation: his course has been unremarkable since then.

[Ergospirometric studies of normal probands for an unsteady-state increment test program]. / Ergospirometrische Normalkollektivuntersuchungen für ein Unsteady-state-Stufentestprogramm.

One-hundred-sixteen healthy subjects (60 female and 56 male) with normal height (L) and weight (w) were selected to provide an even distribution of age (A, 20-70 years). All underwent an unsteady state cycle ergometer test with work increments of 20 watts each minute to exhaustion. A commercially available exercise testing system (EOS SPRINT, Jäger Corp., FRG) with gas analysis from a mixing chamber was used to study oxygen uptake (VO2), carbon dioxide output (VCO2), heart rate (HR), tidal volume (VT), breathing frequency (BR) and arterial oxygen tension (PO2) with special regard to the ventilatory anaerobic threshold (VAT) and maximum power output. For all parameters multiple regression equations were determined. Furthermore, heart rate reserve (HR-reserve), breathing reserve (VE-reserve), O2-pulse (VO2/HR), the dead space/tidal volume ratio (VD/VT) and the alveolar-arterial PO2-difference (AaDO2) were calculated. Day-to-day reproducibility was proven in 21 subjects. VO2max in females was 1584 +/- 300 ml/min (VO2max = -17 A + 10 L + 10 G + 58, r = 0.75, p < 0.0001), VO2AT 957 +/- 159 ml/min (VO2AT = 0.35 VO2max + 0.40 l/min, r = 0.77, p < 0.0001). The ratio VO2AT/VO2max was 50 +/- 7%. In male, VO2max was 2452 +/- 529 ml/min (VO2max = -23 A + 23 L + 9.5 G - 1395, r = 0.78, p < 0.0001), VO2AT 1209 +/- 213 ml/min (VO2AT = 0.29 VO2max + 0.51 l/min, r = 0.71, p < 0.0001), and VO2AT/VO2max 62 +/- 9%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiopulmonary capacity in patients before and after prosthetic valve replacement]. / Kardiopulmonale Leistungsfähigkeit bei Patienten vor und nach prothetischem Klappenersatz.

In this study we wanted to investigate if noninvasive cardiopulmonary exercise testing can be securely, accurately applied in patients with acquired cardiac valve disease pre- and postoperatively with any convenience. Furthermore, we looked if the cardiopulmonary exercise capacity (anaerobic threshold, etc.) was improved postoperatively (3 and 6 months) in 15 patients suffering from severe mitral valve disease as compared to the preoperative condition. The symptom-limited cardiopulmonary exercise testing was performed on a bike in a semi-supine position using a ramp program (+20 W/min). The following parameters were continuously monitored, and the breath-by-breath gas exchange values documented: cardiocirculatory parameters (heart rate; blood pressure; surface ECG; exercise capacity in Watts); gas-exchange parameters (O2-uptake VO2; CO2-production VCO2; respiratory anaerobic threshold VO2 AT; gas-exchange ratio VCO2/VO2; O2-pulse VO2/HR; aerobic capacity delta VO2/delta WR) and ventilatory parameters (respiratory rate; tidal volume Vt; minute ventilation VE; equivalent for O2: VE/VO2 and CO2: VE/VCO2). The 155 cardio-pulmonary exercise tests in 115 patients were practicable, safe (no emergency case) and accurate. In 100 patients late postoperatively (68.3 +/- 53.0 -102.9 +/- 41.2 months) after aortic or mitral valve replacement or both without signs of significant hemolysis or prosthetic valve dysfunction the NYHA classification was too imprecise to characterize the actual exercise capacity of the patients (e.g., NYHA class II: Weber class B to E). Patients with aortic valve prosthesis had a significantly better anaerobic threshold (57.4 +/- 19.1% pred. value max. VO2) as compared to those with mitral valve replacement (mean: 35.9% pred. value max. VO2).(ABSTRACT TRUNCATED AT 250 WORDS)

[Methodologic aspects of modern, computerized ergospirometry (CPX): ramp program, constant workload test and CO2 rebreathing method]. / Methodische Aspekte der modernen, computerisierten Ergospirometrie (CPX): Rampenprogramm, konstanter Belastungstest und CO2-Rückatmungsmethode.

The cardiopulmonary exercise testing (CPX) is a non-invasive method for the evaluation of the cardiopulmonary exercise capacity. Based upon the recent technical progress in gas analysers and personal computers today it is possible to perform CPX with acceptable time consumption, high practicability and high reproducibility of the results in many clinical areas. CPX is realized on a bike or on a treadmill. In bicycle CPX a ramp program (increase of x watts per minute) or a constant workload test (p.e. with 75% of the watts at anaerobic threshold) are performed. Furthermore, an estimation of the cardiac output using CO2-rebreathing method can be realized during a ramp program or a constant workload test. In this paper, also the CPX parameters of the ramp program, the constant workload test and the CO2-rebreathing method are defined and explained. The normal values of CPX are dependent of age, sex, body weight and exercise program. This should be kept in mind in interpreting the measured CPX data. Additionally, the performance of a routine CPX will be reported. Furthermore, the accuracy of the CPX parameters and the potential influences on the data will be discussed. Finally, problems during measurements and their analysis will be clarified.

[Cardiopulmonary capacity of patients with congenital heart defects in childhood, adolescence and adulthood]. / Kardiopulmonale Leistungsfähigkeit bei Patienten mit angeborenen Herzfehlern im Kindes-, Adoleszenten- und Erwachsenenalter.

Cardiopulmonary exercise capacity is a significant criterion of life quality. The evaluation of the exercise capacity is important to answer patient-questions concerning every day activity, choice of profession, sports-activity etc. We performed cardiopulmonary exercise testing in 38 patients (age 33.6 +/- 12.0 years, 18 women, 20 men) with different congenital heart disease (5 after surgical repair of tetralogy of fallot, 2 after Mustard-operation in transposition of the great arteries (TGA), 1 single ventricle, 14 atrial septal defect (ASD), 8 ventricular septal defect (VSD), 8 pulmonary valve stenosis (PS)) during outpatient routine control. All tests were performed on upright bicycle with continuous ramp program of 20 Watt increase/minute. Ventilatory values as O2-uptake, CO2-production, minute ventilation (VE) were measured breath-by-breath. Max. VO2 was reduced as average value for every patient group (tetralogy of fallot 60.2 +/- 20.3% pred., TGA 53.0 +/- 0.0% pred., single ventricle 35% pred., closed ASD 71.9 +/- 23.8% pred., ASD 62.7 +/- 30.0% pred., VSD 64.1 +/- 11.7% pred., PS 73.2 +/- 16.0% pred.). Anaerobic threshold was reduced in tetralogy of fallot (35.9 +/- 12.2% pred. max. VO2) and in single ventricle (28.3% pred. max. VO2). In comparison with clinical classification of exercise capacity we found for max. VO2 differences in 23/38 patients. 22/23 patients reported no exercise limitation but had reduced max. VO2. One patient had a normal max. VO 2 but complaints of exercise dyspnoea. For anaerobic threshold 18/38 patients had discrepancies in objective and subjective estimation of their exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiopulmonary exercise capacity in VVI stimulation in patients with high grade AV block]. / Kardiopulmonale Belastbarkeit unter VVI-Stimulation bei Patienten mit höhergradigen AV-Blockierungen.

VVI-pacemaker patients with high-grade atrioventricular block were subjected to cardiopulmonary exercise testing. An interindividual comparison was made between patients with intermittent intrinsic rhythm (n = 9) and patients with permanent VVI-stimulation (n = 15). Patients with intermittent sinus rhythm on exercise had no significant increase in exercise capacity as quantified by the O2-uptake at the anaerobic threshold. An intermittent sinus rhythm is of no relevance to therapeutic decisions, such as choosing the appropriate pacing mode. Exercise capacity is determined by multiple, partly peripheral factors.

[Predictive value of ergospirometry in preoperative assessment of risk factors before lung resections]. / Prädiktiver Wert der Spiroergometrie in der präoperativen Abschätzung von Risikopatienten vor Lungenresektionen.

Surgical resection for lung cancer provides the only real chance for cure. However, there is a high risk of postoperative complications including death for patients with pulmonary dysfunction. Therefore preoperative identification of patients at risk is necessary. Apart from history and physical examination three tests are currently used: 1. resting lung function (RFL), 2. invasive measurement of pulmonary vascular resistance (PVR) and 3. exercise testing with measurement of oxygen consumption (VO2). Main studies in the literature report the probability of abnormal tests for prediction of pulmonary complications (positive predictive value) and the probability of normal tests for prediction of uneventful outcome (negative predictive value) as follows: [table: see text] In conclusion, the "ideal" test predictive for morbidity and mortality after lung resection has not been found. The positive predictive values of RLF and PVR are disappointing, while the negative predictive values are acceptable. Measurement of VO2 is simple, noninvasive and might predict survivable morbidity, as suggested in the literature. Obviously, additional studies are necessary.

[Methodologic and clinical comparison of four different ergospirometry systems]. / Methodischer und klinischer Vergleich von vier verschiedenen Ergospirometriesystemen.

The clinician who uses cardio-pulmonary exercise testing (CPX) systems relies on the technical informations from the device producers. In this paper, the practicability, the accuracy and the safety of four different, available CPX systems are compared in the clinical area, using clinically orientated criteria. The exercise tests were performed in healthy subjects, in patients with cardiac and/or pulmonary disease as well as in young or old people. The comparison study showed, that there were partially large differences in device design and measurement accuracy. Furthermore, our investigation demonstrated that beneath repetitive calibrations of the CPX systems a frequent validation of the devices by means of a metabolic simulator is necessary. Problems in calibration can be caused by an inadequate performance or by unclean calibration gases. Problems in validation can be due to incompatibility of the CPX device and the validator. The comparison study of the four different systems showed that in the future standards for CPX testing should be defined.