[Economics and management of CAR T- cell therapy : Status quo and future perspectives]. / Ökonomie und Management bei der CAR-T-Zell-Therapie : Status quo und Ausblick.

BACKGROUND: Virtually no other topic has attracted more attention in oncology in recent years than chimeric antigen receptor (CAR) T­cell therapy (CAR T). On the one hand it opens up completely new treatment options for cancer patients, while on the other it generates treatment costs exceeding € 300,000 per treatment. OBJECTIVES: The aim of this work is to analyze the economic, procedural and organizational challenges of CAR T­cell therapy from the perspective of the service provider, the cost-bearer and the pharmaceutical manufacturer. MATERIAL AND METHODS: The current German diagnosis-related-group (G-DRG) catalog, the G­DRG tariff, of the German Federal Joint Committee (G-BA) guidelines and G­DRG coding principles were used to evaluate the reimbursement and remuneration system in Germany. Practical experiences of medical sites were integrated in the analysis. RESULTS: The findings demonstrate great economic challenges especially from the perspective of a CAR T site. Increasing certification and qualification efforts lead to financial pressure. Insufficient reimbursement and inadequate cost-covering for CAR T treatment result in budget restrictions for hospitals. CONCLUSION: High drug costs as well as enormous personnel and infrastructural requirements demand transparent and sufficient reimbursement for hospitals. Interaction between hospital and pharmaceutical manufacturer in the CAR T process might enable new means of cooperation.

[The national Network Genomic Medicine (nNGM) : Model for innovative diagnostics and therapy of lung cancer within a public healthcare system]. / Das nationale Netzwerk Genomische Medizin (nNGM) : Modell für eine innovative Diagnostik und Therapie von Lungenkrebs im Spannungsfeld eines öffentlichen Versorgungsauftrages.

BACKGROUND: Since 2012, the Network Genomic Medicine (NGM) has been providing a large number of lung cancer patients from referring partner sites with comprehensive molecular-pathological diagnostics on the single diagnostic platform at the University Hospital Cologne. In addition, the network headquarters in Cologne interprets the findings in close interdisciplinary coordination between pathologists and oncologists, provides information on innovative treatment options, and evaluates the personalized therapies using the central database. As part of one of its largest single grants in 2018, the German Cancer Aid (DKH) rolled out this interdisciplinary and intersectoral care model to all existing DKH-funded German comprehensive cancer centers at the time of the initial application. GOAL: Presentation of the treatment reality within the national Network Genomic Medicine (nNGM) with its core elements and actors (network centers and intersectoral clinical partners sites). METHODS: This article is based on our own experience in NGM and nNGM and includes a summary of the currently applicable guidelines for reimbursement and an overview of the treatment landscape in the field of molecular-pathological diagnostics in Germany. RESULTS: The focus of nNGM is on the implementation of innovative molecular diagnostics and personalized therapy in broad clinical routine in Germany. This is enabled by developing molecular-pathological diagnostics within the network centers on an ongoing basic, interdisciplinary counseling of referring partner sites, offering innovative clinical trials, and performing central evaluation. In particular, a focus of nNGM is the development of regional networks to treat the affected lung cancer patients close to home at the partner sites whenever possible. DISCUSSION: Interdisciplinary teams are essential for the success of a broad implementation of molecular-pathological diagnostics. nNGM addresses a severe deficit in German lung cancer care and in the future will be expanded to further network centers while meeting the defined quality criteria.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Estimation of skin phototypes with optical parameters: an experimental study using newly developed fibre optic detection device.

In an experimental study (October 2010 Mannheim Germany) with 99 Caucasian volunteers, the skin colour (L*, a*, b*) and the reflectance spectra of human skin were compared to the Fitzpatrick's sun-reactive skin photo types (SPT). For this purpose, the skin colour and the reflectance spectra of human skin were determined using non-invasive method with a newly developed fibre optic detection device. The device, based on reflectance spectroscopy, was designed and optimized using a commercial optical analysis Software. By means of the measured spectra of scattered light, the colour values and the absorption spectra of the skin were calculated. Neither any of the L*, a*, b* colour values nor any of the parameters of the absorbance spectra can be used alone to assess the skin type properly. Therefore, an ordinal logistic regression analysis was performed, using the statistical computing software r, to correlate the skin types with the measured optical parameters. It turned out that the detection device combined with the extended statistical analysis gives a better estimate of skin type in respect of the measured optical parameters than a procedure with only L*, a*, b* colour values. Even with the extended methodology, the procedure gives only a rough estimation of the skin type.

Hypergonadotropic hypogonadism in a patient with inv ins (2;4).

We report on a 30-year-old man with azoospermia, primary hypogonadism and minor dysmorphic features who carried a balanced insertional chromosome translocation inv ins (2p24;4q28.3q31.22)de novo. Molecular cytogenetic analyses of the chromosome breakpoints revealed the localization of the breakpoint in 4q28.3 between BACs RP11-143E9 and RP11-285A15, an interval that harbours the PCDH10 gene. In 4q31.22, a breakpoint-spanning clone (RP11-6L6) was identified which contains the genes LSM6 and SLC10A7. On chromosome 2, BACs RP11-531P14 and RP11-360O18 flank the breakpoint in 2p24, a region void of known genes. In conclusion, the chromosome aberration of this patient suggests a gene locus for primary hypogonadism in 2p24, 4q28.3 or 4q31.2, and three possible candidate genes (LSM6, SLC10A7 and PCDH10) were identified by breakpoint analyses.

Does a focal neurologic deficit contraindicate operation in a patient with endocarditis?

BACKGROUND: As many as 40% of patients with left-sided bacterial endocarditis will sustain a neurologic insult. The importance of a neurologic change as an indication or a contraindication for valve replacement remains controversial. METHODS: We performed a retrospective analysis of the records of 33 patients admitted to the University of Virginia Health Sciences Center between January 1, 1978, and June 30, 1996, with a diagnosis of endocarditis and a neurologic change. RESULTS: All 33 patients had echocardiographic or pathologic evidence of left-sided endocarditis; 23 were seen with focal neurologic findings and had a mortality rate of 22% (5 of 23), and 10 patients were seen with nonfocal, diffuse encephalopathy and had a mortality rate of 60% (6 of 10) (p<0.05). Of the 33 patients, 14 underwent operation and 19 were treated medically. The mortality rate was 21.4% (3 of 14) in the surgical group and 42.1% (8 of 19) in the medical group (p = not significant). In 71% (10 of 14) of the surgical patients, the operation was done within 1 week of the neurologic event. Additional neurologic deterioration occurred in 18.2% (2 of 11) of survivors in the surgical group and 9.1% (1 of 11) in the medical group (p = not significant). CONCLUSIONS: Choosing therapy for a patient with endocarditis and a neurologic change remains a difficult challenge. Initial findings of nonfocal, global dysfunction on examination are a predictor of a poor outcome. By comparing surgical and medical groups derived from the same series of patients, it is clear that patients with bacterial endocarditis and central nervous system changes face substantial mortality regardless of intervention. However, these data demonstrate that when compared with a similar group of medical patients, surgical patients who require and receive operation early in the course of their illness do comparatively well. Improving outcomes by delaying surgical intervention may serve to "select out" hardier patients but will lead to the death of patients who might benefit from such intervention.

Preservation with 8-bromo-cyclic GMP improves pulmonary function after prolonged ischemia.

BACKGROUND: Cyclic guanosine monophosphate (cGMP) is a potent second messenger for the nitric oxide pathway in the pulmonary vasculature. Increased cytosolic cGMP levels elicit pulmonary vasodilatation resulting in decreased pulmonary vascular resistance and maximized pulmonary function after ischemia-reperfusion injury. We hypothesized that the addition of a membrane-permeable cGMP analogue (8-bromo-cGMP) to a Euro-Collins (EC) preservation solution would ameliorate pulmonary reperfusion injury better than prostaglandin E1 injection alone after prolonged hypothermic ischemia. METHODS: All lungs from New Zealand White rabbits (weight, 3 to 3.5 kg) were harvested en bloc, flushed with EC solution, and reperfused with whole blood for 30 minutes. Group 1 lungs (immediate control) were immediately reperfused. Group 2 lungs (control) were stored inflated at 4 degrees C for 18 hours before reperfusion. Groups 3 and 4 lungs were flushed with EC solution containing 200 micromol/L 8-bromo-cGMP and stored at 4 degrees C for 18 and 30 hours, respectively. Fresh, nonrecirculated venous blood was used to determine single-pass pulmonary venous-arterial oxygen gradients at 10-minute intervals. Assays for cGMP, cyclic adenosine monophosphate, nitric oxide synthase activity, and myeloperoxidase were performed on all lung tissue samples. Wet to dry weight ratios were determined after 2 weeks of passive desiccation. RESULTS: Oxygenation (venous-arterial oxygen gradient), pulmonary artery pressure, pulmonary vascular resistance, and edema formation were significantly improved in groups 3 and 4 (addition of 8-bromo-cGMP to EC plus 18 or 30 hours of hypothermic ischemia). Hypothermic storage (groups 2, 3, and 4) decreased both nitric oxide synthase activity and myeloperoxidase levels compared with immediate reperfusion (group 1). CONCLUSIONS: These results suggest that the addition of a membrane-permeable cGMP analogue to an EC pulmonary flush solution improves pulmonary function after prolonged storage compared with EC and prostaglandin (E1) preservation alone. The finding of myeloperoxidase reduced levels after hypothermic storage and subsequent reperfusion may suggest a more important role for pulmonary hemodynamic control in mitigating pulmonary reperfusion injury.

[Federal investigations on the distribution and in vitro resistance of udder pathogenic bacteria in the milk of cows with subclinical mastitis]. / Bundesweite Untersuchung zur Erregerverteilung und In-vitro-Resistenz euterpathogener Bakterien in der Milch von Kühen mit subklinischer Mastitis.

1644 quarter milk samples of 948 dairy cows with subclinical mastitis, collected from 63 veterinary practices all over Germany origined by 262 livestocks with problems in udder health were examined semiquantitatively by "Aulendorfer Mastitistest" for cell count and additionally bacteriologically. Potentially udder pathogenic bacteria were tested for in vitro-sensitivity to penicillin G, ampicillin, oxacillin, cefacetril, tylosin, neomycin, gentamicin, polymyxin B and enrofloxacin. 24.5% of all tested milk samples were bacteriologically negative. In 35.3% of the bacteriological positive milk samples Staphylococcus (S) aureus was detected. Enterococci, Streptococcus (Sc.) uberis, Sc. dysgalactiae and Sc. agalactiae were found in 8.9%, 8.2%, 8.1% and 4.9% of all positive milk samples, respectively. G-streptococci were found only occasionally. Apathogenic bacteria like coagulase-negative staphylococci, micrococci, aerobic bacilli and coryneforms were detected in 45.0% of all positive milk samples. Enterobacteriaceae (E. coli, klebsiella spp., proteus spp. and other coliforms) were isolated in 3.3% of all cases and should be considered as insignificant for the subclinical mastitis of dairy cows in Germany. Against S. aureus cefacetril and oxacillin were mostly effective in vitro, whereas penicillin G was ineffective because 40% of these bacteria are penicillinase-positive. Streptococci and enterococci were mostly sensitive to cefacetril, oxacillin, penicillin G and ampicillin. Concerning the distribution of bacteria regional differences were recognized. Regional differences concerning in vitro-sensitivity were negligible. The results are discussed.

[Vojta's seven postural reactions in the detection of neuromotor disorders in infants. Experience with 2382 subjects]. / Le sette reazioni posturali di Vojta come depistage delle alterazioni neuromotorie del lattante. Esperienza su 2.382 soggetti.

The Authors examined 2.382 babies who were between 4 and 6 weeks old using the seven postural reactions proposed by Vojta for neuromotor screening. They followed the progress of 2.295 (96,35%) babies up to the age of 1 year. 100% of the babies judged to be normal after the first visit were normal after a year. The Authors describe the evolution of the babies who were abnormal at the first visit, and clarify the results obtained with early physiotherapeutic treatment.