Drug-induced myocarditis after nivolumab treatment in a patient with PDL1- negative squamous cell carcinoma of the lung.

Immunotherapy such as nivolumab is a new promising therapeutic option for advanced stage non small cell lung cancer (NSCLC). Due to the interference with the immune system previously unknown side effects are observed both in clinical studies and experience. Autoimmune phenomena effecting skin, gastrointestinal tract, endocrine glands, kidney and lung have been described. Up to now there is only limited information regarding potential cardiac side effects. We present a case of symptomatic drug induced myocarditis after nine cycles of nivolumab in a patient with efficient anticancer response.

[Cardiac sarcoidosis: diagnostic and therapeutic algorithms]. / Diagnostik und Therapie der kardialen Sarkoidose.

Sarcoidosis is a multisystemic granulomatous disorder which affects the respiratory system in the majority of the cases. Cardiac manifestations are found in up to 10 % of the affected cohort and show a large heterogeneity based on the ethnic background. Cardiac sarcoidosis are not only found in patients with rhythmogenic heart disease such as atrial and ventricular fibrillation but also in all phenotypes of cardiomyopathies. The overall morbidity and mortality caused by cardiac sarcoidois in Germany is unclear and no large prospective international studies are published on this topic. This consensus paper on diagnostic and therapeutic algorithms in cardiac sarcoidosis is based on a current literature search and forms a expert opinion statement under the hospices of the "Deutsche Gesellschaft für Pneumologie" and "Deutsche Gesellschaft für Kardiologie". It is the rationale of this statement to offer algorithms to facilitate clinical decision-making based on the individual case.

Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess.

BACKGROUND: Aspiration pneumonia (AP) and primary lung abscess (PLA), are diseases following aspiration of infectious material from the oropharynx or stomach. An antibiotic therapy, also covering anaerobic pathogens, is the treatment of choice. In this study we compared moxifloxacin (MXF) and ampicillin/sulbactam (AMP/SUL) concerning efficacy and safety in the treatment of AP and PLA. METHODS: Patients with pulmonary infections following aspiration were included in a prospective, open-label, randomized, multicenter trial. Sequential antibiotic therapy with MXF or AMP/SUL was administered until complete radiologic and clinical resolution. RESULTS: A total of 139 patients with AP and PLA were included, 96 were evaluable for efficacy (EE, 48 patients in each treatment group). The overall clinical response rates in both groups were numerically identical (66.7%). MXF and AMP/SUL were both well tolerated, even after long-term administration [median duration of treatment (range) in days MXF versus AMP/SUL: AP 11 (4-45) vs 9 (3-25), PLA 30.5 (7-158) vs 35 (6-90)]. CONCLUSION: In the treatment of aspiration-associated pulmonary infections moxifloxacin appears to be clinically as effective and as safe as ampicillin/sulbactam; but, however, having the additional benefit of a more convenient (400 mg qd) treatment.

A prediction model for bacterial etiology in acute exacerbations of COPD.

OBJECTIVES: Bacteria play a leading role in acute exacerbations of chronic obstructive pulmonary disease (COPD), but we lack predictors of bacterial etiology. We developed a prediction model for infection with gram-negative enteric bacteria (GNEB) and Pseudomonas aeruginosa. METHODS: Clinical presentation, sputum characteristics, microbial sputum patterns, lung function and previous and concomitant medication were prospectively recorded in patients with moderate to severe exacerbation of COPD. Risk factors for a specific bacterial etiology were calculated and a prediction model developed. RESULTS: A total of 193 patients with acute exacerbation were included. In 121 (62.6%) of them a microbial etiology could be identified, most frequently Haemophilus influenzae (32 strains), Streptococcus pneumoniae (22 strains) and P. aeruginosa (12 strains). Multivariate analysis identified severe airflow obstruction and use of systemic steroids as predictors for exacerbation due to gram-negative enteric bacilli and P. aeruginosa. A prediction model including FEV1 < 35% of predicted value, systemic steroid use and prior antibiotic therapy within preceeding 3 months had a negative predictive of 89%, being a helpful tool in excluding patients at risk of exacerbation due to gram-negative enteric bacilli and P. aeruginosa when all criteria are absent. CONCLUSION: A simple prediction model based on three factors may identify COPD patients at low risk for exacerbations with gram-negative enteric bacilli and P. aeruginosa. Bacterial Etiology in COPD Exacerbations.

[Serologic early diagnosis of pneumonia caused by Mycoplasma pneumoniae]. / Serologische Frühdiagnostik der Mykoplasmenpneumonie.

BACKGROUND AND OBJECTIVE: The definitive diagnosis of M. pneumoniae is encumbered by the lack of a rapid and cost-effective test of detection. The study aimed to determine if a single serological test within the first days of hospital admission may be relevant for the diagnosis of community-acquired pneumonia (CAP) caused by M. pneumoniae. PATIENTS AND METHODS: Patients with suspected of CAP were investigated for microbiological diagnosis based on respiratory samples (bronchoalveolar lavage, bronchial aspirate, sputum, throat rinse), blood culture and serology for detection of atypical organisms and viruses. Patients with M. pneumoniae antibody titers > or = 1:160 were further investigated by polymerase chain reaction (PCR) for detection of M. pneumoniae in respiratory samples. The group of CAP by M. pneumoniae (MP-CAP) included patients with serum titers > 1:160 of M. pneumoniae antibodies (based on a single antibody determination at admission). The control group (non-MP-CAP group) included patients with CAP by pathogens other than M. pneumoniae or with no definitive bacteriological diagnostic. RESULTS: Twenty adults with MP-CAP and 20 controls with non-MP-CAP were included. PCR was positive in 18/20 (90 %) of the MP-CAP group and negative in the 9/9 (100 %) investigated patients of the non-MP-CAP group. The duration of symptoms prior to hospital admission was rather long in both groups (mean 13.2 days in the MP-CAP group and 12,7 days in the non-MP-CAP group). The MP-CAP group was significantly younger (p = 0.002), had subsequently less associated comorbidities (p < 0.001) and less purulent sputum (p = 0.003) than the non-MP-CAP group. CONCLUSION: Single serology at admission with M. pneumoniae antibody titers > 1:160 may be useful for the diagnosis of CAP caused by M. pneumoniae in hospitalized patients with a long duration of symptoms (> 12 days).

[Diagnosis of haemoptoe/haemoptysis]. / Diagnostik bei Hämoptysen/Hämoptoe.

Haemoptysis and haemoptoe mainly differ in the amount of expectorated blood. Causes of haemoptysis are diverse and include bronchitis, bronchiectasis, carcinoma, tuberculosis and other infectious pulmonary disease. Haemoptysis almost exclusively involves bronchial arteries, rarely vessels of the pulmonary-artery circuit. Asphyxia rather than the loss of blood ist life-threatening. 20 - 30 % of bronchopulmonary bleeding happens without any identifiable cause, about 90 % of haemoptyses are self-terminating. Chest X-ray is an integral part in each evaluation, as is bronchoscopy. Fiberoptic bronchoscopy is easily performed, although rigid bronchoscopy considerably extends the armamentarium of diagnostic and therapeutic measures. (Pulmangio-) chest CT scan as well as echocardiography and angiographic procedures provide extended diagnostic and therapeutic options. Surgery may be required in severe bleeding complications or during stable disease as a diagnostic approach.

[Chronic eosinophilic pneumonia]. / Die chronische eosinophile Pneumonie (CEP).

HISTORY AND ADMISSION FINDINGS: A 43-year-old woman (patient 1) and a 58-year-old man (patient 2) presented with fever, nocturnal perspiration, dry cough, dyspnoea and general weakness. These symptoms had been present for several months. Repeated courses of antibiotic treatment as outpatients had failed. On admission their general condition was unremarkable. INVESTIGATIONS: The differential blood count revealed marked eosinophilia of 35% and 27%, respectively, and raised infection parameters. Results of laboratory tests were unremarkable. Conventional radiological films and CT of the thorax showed infiltrates, especially in the periphery. In both patients bronchoscopy revealed moderately severe bronchitis. Broncho-alveolar lavage and the peripheral blood count showed marked eosinophilia of 61% and 54%, respectively. Biopsies did not reveal necrosis, fungal infection, parasites, granulomas or vasculitis. DIAGNOSIS, TREATMENT AND COURSE: The described findings indicated a chronic eosinophilic pneumonia (CEP) in both patients. Treatment was initiated with high steroid dosage, namely 60 mg prednisolone equivalent daily, gradually reducing with improvement. The symptoms rapidly lessened and the radiological changes regressed after ca. 14 days. Intermittent recurrences were noted in both patients on reduction or termination, respectively, of the steroid treatment which had lasted for several months. CONCLUSIONS: CEP is an important disease to be considered in the differential diagnosis of unclear pulmonary infiltrates associated with an increased eosinophilia in both peripheral blood and the lungs. In some cases it may be necessary to continue steroid treatment over long periods, even years, to bring the pulmonary changes of CEP under control.

Ampicillin + sulbactam vs clindamycin +/- cephalosporin for the treatment of aspiration pneumonia and primary lung abscess.

Aspiration pneumonia, necrotising pneumonia and primary lung abscess are complications arising from the aspiration of infectious material from the oral cavity or stomach. There is limited information on optimal antibacterial therapeutic regimens. Patients with pulmonary infection following aspiration (n = 95) were included in a prospective, open, randomised, comparative multicentre trial to compare the safety, clinical and bacteriological efficacy of ampicillin + sulbactam vs. clindamycin +/- cephalosporin. Treated patients (n = 70) received sequential antibiotic therapy with either ampicillin + sulbactam (n = 37) or clindamycin (n = 33), with or without a second- or third-generation cephalosporin, administered until the complete resolution of clinical and radiological abnormalities. Definite or presumptive pathogens were isolated from 58 patients. Mean duration of therapy was 22.7 days for ampicillin + sulbactam and 24.1 days for clindamycin. In patients treated with ampicillin + sulbactam, the clinical response was 73.0% at the end of therapy and 67.5% 7-14 days after therapy. For clindamycin, the rates were 66.7% and 63.5%, respectively. Bacteriological response was similar in both treatment arms. Nine patients died (12.9%), with a Simplified Acute Physiology Score of > 30 points being the only significant predictive factor for therapeutic failure. Ampicillin + sulbactam and clindamycin +/- cephalosporin were both well-tolerated and proved equally effective in the treatment of aspiration pneumonia and lung abscess.

ABT-773: pharmacokinetics and interactions with ranitidine and sucralfate.

We assessed the pharmacokinetics and interaction of ABT-773 in 12 volunteers receiving ABT-773 alone or concomitantly with ranitidine or sucralfate. Data for 150 mg of ABT-773 were as follows: the maximum concentration of the drug in plasma (C(max)) was 318 ng/ml, its half-life was 5.66 h, and its area under the plasma concentration-time curve from 0 h to infinity (AUC(0- infinity )) was 1,662 ng. h/ml. Coadministration of ranitidine, reduced the C(max) (-25.7%) and AUC(0- infinity ) (-15.8%) significantly. Sucralfate had no impact on the bioavailability of ABT-773.

[Diagnosis and therapy of abscess forming pneumonia]. / Diagnostik und Therapie abszedierender Pneumonien.

Aspiration of oro-pharyngeal secretions and gastric content is the most frequent cause of formation of primary lung abscess. A compromised mental status (e.g. alcoholism, sedatives, stroke) and esophageal dysfunction (e.g. herniation, vomiting) are important risk factors. Aspiration pneumonia presents as a subacute disease and is usually not distinguishable from other causes of pneumonia, until typical radiological signs of cavitation and putrid sputum appear 8 to 14 days after the initial event of aspiration. Anaerobic bacteria play a pivotal role in an almost exclusively mixed spectrum of causative organisms. Aerobic pathogens are also frequently isolated, but whether they are an active part of infection or merely represent colonizers remains unclear in many instances. Differential diagnosis includes bronchial neoplasms, either as necrotizing carcinoma or as the cause of poststenotic cavernous pneumonia, other infectious diseases like tuberculosis, Pneumocystis carinii pneumonia or endocarditis with septic metastases, and lung artery embolism or vasculitis (M. Wegener). Fiberoptic bronchoscopy is extremely helpful in determining cause and etiology of the disease and should be carried out in all patients presenting with cavernous lung lesions. Bacteriological sampling should be performed using protected specimen brushing (PSB) technique. Broncho-alveolar lavage might serve as a less expensive but also less sensitive alternative measure. Since anaerobic bacteria resemble ubiquitous commensals of the oral cavity, sputum is of no use in anaerobic culture. Principal therapeutic strategy is antibiotic therapy for an extended period, usually four weeks to four months, unless radiologic changes and as well laboratory as clinical indicators of infection are completely resolved. Clindamycin, optionally supplemented with a second or third generation cephalosporin and Ampicillin/Sulbactam proved equally effective in treating aspiration pneumonia and primary lung abscess. The role of Moxifloxacin and other new flouroquinolones with their favorable pharmacodynamics is currently evaluated. Provided that antibiotics are prescribed for a sufficient period of time and patients' compliance is ensured, surgical procedures are limited to a negligible number of complications, e.g. recurrent severe hemoptysis, empyema or broncho-pleural fistula.

Acquisition of expression of the Pseudomonas aeruginosa ExoU cytotoxin leads to increased bacterial virulence in a murine model of acute pneumonia and systemic spread.

Pseudomonas aeruginosa is the nosocomial bacterial pathogen most commonly isolated from the respiratory tract. Animal models of this infection are extremely valuable for studies of virulence and immunity. We thus evaluated the utility of a simple model of acute pneumonia for analyzing P. aeruginosa virulence by characterizing the course of bacterial infection in BALB/c mice following application of bacteria to the nares of anesthetized animals. Bacterial aspiration into the lungs was rapid, and 67 to 100% of the inoculum could be recovered within minutes from the lungs, with 0.1 to 1% of the inoculum found intracellularly shortly after infection. At later time points up to 10% of the bacteria were intracellular, as revealed by gentamicin exclusion assays on single-cell suspensions of infected lungs. Expression of exoenzyme U (ExoU) by P. aeruginosa is associated with a cytotoxic effect on epithelial cells in vitro and virulence in animal models. Insertional mutations in the exoU gene confer a noncytotoxic phenotype on mutant strains and decrease virulence for animals. We used the model of acute pneumonia to determine whether introduction of the exoU gene into noncytotoxic strains of P. aeruginosa lacking this gene affected virulence. Seven phenotypically noncytotoxic P. aeruginosa strains were transformed with pUCP19exoUspcU which carries the exoU gene and its associated chaperone. Three of these strains became cytotoxic to cultured epithelial cells in vitro. These strains all secreted ExoU, as confirmed by detection of the ExoU protein with specific antisera. The 50% lethal dose of exoU-expressing strains was significantly lower for all three P. aeruginosa isolates carrying plasmid pUCP19exoUspcU than for the isogenic exoU-negative strains. mRNA specific for ExoU was readily detected in the lungs of animals infected with the transformed P. aeruginosa strains. Introduction of the exoU gene confers a cytotoxic phenotype on some, but not all, otherwise-noncytotoxic P. aeruginosa strains and, for recombinant strains that could express ExoU, there was markedly increased virulence in a murine model of acute pneumonia and systemic spread.

Effects of myelotoxic agents on cytokine production in murine long-term bone marrow cultures.

In long-term bone marrow cultures we studied the effect of the addition of the myelotoxic agents methotrexate (MTX) and ceftazidime (CEF) on the kinetics of cytokine production in the supernatant (SN) and on mRNA expression in the adherent stromal layer. In response to a medium change, a prompt and significant increase in colony-stimulating activity (CSA) and interleukin 6 (IL-6) concentrations in the SN occurred, peaking 12 h later. Two macrophage colony-stimulating factors (M-CSF) mRNA of 23 kb and 4 kb were identified. In response to the medium change, the 4.0-kb transcript increased significantly six h later. The 2.3-kb transcript expression was stronger than the 4-kb mRNA but did not cycle with medium change. At medium change, IL-6 mRNA was only minimally expressed; then a prompt increase occurred, which peaked six h later. The addition of 500 mg/ml (=915 microM) CEF to the culture caused a dose-dependent suppression of CSA and IL-6 supernatant concentrations and IL-6 and M-CSF mRNA expression. By contrast, 1 microM MTX had minimal effect on cytokine concentrations in the SN following medium change. mRNA expression was, however, suppressed. These results provide insights into the possible mechanisms whereby cytokines lead to increased myeloid cell proliferation following medium change. We also demonstrate that two myelotoxic agents have different effects on cytokine production. This information could be of value in developing rational approaches to the therapeutic use of cytokines in drug-induced neutropenia.

[Changes in the spectrum of the causative agents of community-acquired pneumonias (1982-1992)]. / Wandel im Erregerspektrum ambulant erworbener Pneumonien (1982-1992).

BACKGROUND AND OBJECTIVE: The picture of pneumonia acquired out of hospital is continually changing. Microbial aetiology as well as predisposing factors, course and prognosis of this disease were prospectively analysed over a period of 10 years. PATIENTS AND METHODS: In three prospective studies, undertaken between 1982 and 1992, data from 448 patients with out-of-hospital acquired pneumonia were analysed. Microbiological evidence was obtained through blood cultures, from purulent sputum or bronchial secretions, as well as by determining serum antibodies or antigens in urine. RESULTS: Proof of causative organism was achieved in 282 patients (64.1%), with identification of 337 different ones. The spectrum of causative microbes shifted during the study period from predominantly gram-positive bacteria to largely atypical organisms (from 12.5% during 1982/1983, to 36.7% in 1991/1992). Although pneumococci continued to dominate, Chlamydia pneumoniae appeared as an important cause of pneumonia, at 11.4% the most important atypical organism in 1991/1992. -Most patients (74.3%) had a chronic underlying disease. The death rate remained relatively constant at 12.9% during the 10-year period. CONCLUSION: The observed changes in microbial spectrum should be taken into account when specific antibiotic treatment is given. History as well as clinical, radiological and laboratory findings are of only limited value as pointers to the possible microbial cause.

[JOMOL--immunostimulation and rejection of tumor cells?]. / JOMOL--Immunstimulation und Verfremdung von Tumorzellen?

Jomol contains cell wall fragments of the bacterium Nocardia opaca composed of 40% oligopeptides, 40% lipids, 10-15% polysaccharides, and 5-10% peptidoglycans. Technetium labeled--Jomo tech--and Indium-labeled--Jomo in--preparations are used for diagnosing cancer. Jomol is promoted to cure any cancer, except Non-Hodgkin lymphoma and ovarian cancer. It is claimed that Jomol has no side effects, however chills and high fever have been observed. Following initial intensive therapy with daily injections of Jomol, a maintenance therapy is recommended to prevent relapses. One vial of Jomol or Jomo-tech costs 450.--DM. Dr. U. Ehrenfeld, an oral surgeon, developed the aqueous extract of Nocardia opaca and patented it in 1983 under the name of Jomol. Ehrenfeld is promoting Jomo-tech and Jomo-in for qualitative and semi-quantitative cancer diagnosis with whole body scintigraphy. The following action of mechanisms of Jomol are claimed: 1. Unspecific stimulation of cellular immune mechanisms, 2. xenogenization of tumor cells towards a bacterial surface by adhesion of Jomol and then attraction and activation of macrophages. Despite the positive claims of the promoters the preclinical and clinical investigations are insufficient or missing, therefore a routine treatment of malignancies with Jomol is not justified except in study protocols. Jomol is not registered at the Intercantonal Office for Drug Control in Switzerland and is not approved by the Public Health Department in Germany and is not reimbursed by most of the state health insurances.

[Neytumorin as biomodular onco-therapy--allegations without documentation]. / NEYTUMORIN als "biomodulare Onko-therapie" -Behauptungen ohne Belege.

NeyTumorin is a combination of peptides and proteins of 15 different organs from fetal and young pigs and cows. The list of indications ranges from cancer prevention to long-term treatment of malignancies. One vial of NeyTumorin-Sol costs DM 122.34. The therapy for a patient with a T1-2N0M0 cancer costs about DM 16,500 and an advanced stage up to over DM 100,000. The inventor of the Cytoplasmatic Therapy is K.E. Theurer. About 40 years ago, he founded the Vitorgan-Pharmaceutical Company which produces and distributes NeyTumorin. It is claimed that "physiological repair aids" from the cytoplasm of healthy animal organs induce a "hygiogenization" of the disturbed metabolism and NeyTumorin has immunogenic and immuno-modulatory effects which are important for the efficacy. The promotors classify NeyTumorin as a biological response modifier. The components of NeyTumorin are not defined. Preclinical investigations showing direct cytostatic and immunomodulatory effects are not sufficiently documented. Often extremely high concentrations of NeyTumorin were used. Clinical studies including prospective randomized trials are not conclusive because of false or insufficient documentation. There is no proof for either the claimed mechanism of action nor for a clinical efficacy.

[Regazell-Energen: bioactivator in tumor treatment? Documentation No. 26 D]. / Regazell-Energen: Bioaktivator in der Tumorbehandlung? Dokumentation Nr. 26 D.

Regazell-Energen (RE) is a combination of drinking vials which contain gelée royale, ginseng, hawthorn, wheatgerm extract solved in mead, and capsules filled with mixed pollen. RE is recommended for revitalization and regeneration, regulation and stimulation of the immune system and in the early metaphylaxis of treated cancer patients. Two courses during 40 days per year should be taken. RE has practically no side effects. Only individuals with pollen allergy or alcohol intolerance should be cautious. A package for a 14-day course costs 170 Swiss francs. RE is produced by Bio-Naturkraft in Poing, Munich, and research is supported by the German Society for Matrix Research. The president is Prof. H. Heine from the Institute of Anatomy of the anthroposophic University Witten-Herdecke. The bioactivator RE ist claimed to be a 'new, autonomous therapeutic system' to 'increase physical and mental well-being ... helping to overcome stress and immune defects'. Heine claims that RE acts decisively on the 'regulation of the matrix' and fights cancer by activating the fibroblast-macrophage system via the healthy tissue. The three clinical investigations on the effect of RE in the oncological aftercare contain severe flaws in the collection of data and interpretation.