Korrelation histologischer und nuklearmedizinischer Befunde der Tumorregression in behandelten bösartigen Lungentumoren

Zusammenfassung Die CT ist nach neoadjuvanter Radio-Chemo-Therapie zur Charakterisierung der Tumorregression nur begrenzt einsetzbar. Daher sollte die Wertigkeit der ¹⁸F-FDG-PET als molekulares, nichtinvasives bildgebendes Verfahren analysiert werden.Bislang 32/100 Patienten mit NSCLC Stadium IIIA/IIIB wurden in einer multizentrischen, randomisierten Therapiestudie (LUCAS-MD) untersucht. Prätherapeutisch erfolgten eine ¹⁸F-FDG-PET und eine Spiral-CT. Der neoadjuvante Therapieblock bestand aus 2–3 Zyklen Paclitaxel und Carboplatin sowie einer simultanen Radio-Chemo-Therapie. Es folgte eine zweite PET direkt vor der Operation mit Bestimmung des Glukosemetabolismus für Primärtumor und Lymphknotenmetastasen sowie eine PET-CT-Bildfusion. Der am OP-Präparat bestimmte Regressionsgrad wurde mit den PET-Befunden und dem Überleben der Patienten korreliert.In Lymphknoten von 10 Patienten mit kompletter Remission in der FDG-PET zeigte sich ein Regressionsgrad/RG III im OP-Präparat (Sensitivität 100%). Zu 94% wiesen die 16/32 Patienten mit kompletter Remission im Primärtumor RG IIb oder III auf, ein Patient RG IIa (falsch-negativ). Die Zweijahresüberlebenswahrscheinlichkeit bei kompletter Remission war nach 24 Monaten signifikant erhöht (76 vs. 20%, p=0,0079). Patienten mit RG III bzw. IIb lebten signikant länger als Patienten mit RG IIa bzw. I (63 vs. 36%, p=0,0123).Der RG korreliert mit der in der FDG-PET bestimmten metabolischen Remission. Die PET eilt metabolisch dem durch die CT bestimmten Tumoransprechen nach neoadjuvanter Behandlung deutlich voraus und ermöglicht wahrscheinlich eine prospektive Aussage über den Langzeittherapieerfolg von Patienten mit NSCLC im Stadium III.     

Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia

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Relative contributions of balance and voluntary leg-coordination deficits to cerebellar gait ataxia

Different cerebellar regions participate in balance control and voluntary limb coordination, both of which might be important for normal bipedal walking. We wanted to determine the relative contributions of balance versus leg-coordination deficits to cerebellar gait ataxia in humans. We studied 20 subjects with cerebellar damage and 20 control subjects performing three tasks: a lateral weight-shifting task to measure balance, a visually guided stepping task to measure leg- coordination, and walking. We recorded three-dimensional joint position data during all tasks and center of pressure coordinates during weight-shifting. Each cerebellar subject was categorized as having no detectable deficits, a balance deficit only, a leg-placement deficit only, or both deficits. We then determined the walking abnormalities associated with each of these categories. Five of 10 measures of gait ataxia were abnormal in cerebellar subjects with a balance deficit, but only 1 was abnormal in cerebellar subjects with a leg-placement deficit. Furthermore, subjects with a balance deficit performed worse than subjects with a leg-placement deficit on 9 of the 10 gait measures. Finally, performance on the balance task, but not the leg-placement task, explained a significant proportion of the variance in walking speed for the entire cerebellar group. We conclude that balance deficits are more closely related to cerebellar gait ataxia than leg-placement deficits. Our findings are consistent with animal literature, which has suggested that cerebellar control of balance and gait are interrelated, and dissociable from cerebellar control of voluntary, visually guided limb movements.     

CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza

Summary: We have outlined the carefully orchestrated process of CD4⁺ T‐cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T‐cell interaction with antigen‐presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4⁺ T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4⁺ effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4⁺ T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza.     

Interleukin-12/T cell stimulating factor,a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells

At least two subsets of CD4⁺ T helper cell lymphocytes termed T_h1 and T _h, 2 exist in the mouse and probably in humans. They are characterized by the secretion of different lymphokines and by their functional behavior. Dysregulated expansion of one or the other subset may be one reason for the development of certain diseases. Thus, it is of importance to define the signals involved in the differentiation and activation of the two T_h cell subsets. It is known and has been confirmed in this report that the cytokine interleukin (IL)-1 acts onT_h2 cells but not on T_h1 cells. We now report that a previously identified cytokine which was provisionally termed T cell stimulating factor is identical with IL-12 and exhibits a reciprocal behaviour to IL-1. IL-12 has several effects on T_h1 cells. It can induce the proliferation of certain T_h1 cells in combination with IL-2. Synthesis of interferon (IFN)-γ by T_h1 cells can be triggered by IL-2 plus IL-12. In contrast to the IFN-γ production observed after T cell receptor (TcR) CD3 stimulation of T_h1 cells with lectin Concanavalin A the IFN-γ production induced by IL-12+IL-2 is insensitive to the immunosuppressive drug cyclosporin A. Furthermore, IL-12 enhances the TcR/CD3-induced synthesis of IFN-γ of several T_h1 clones. Finally, IL-12 (+ IL-2) induces homotypic cell aggregation of T_h1 clones. This type of cell aggregation depends on the participation of LFA-1 and ICAM-1 molecules. In all activation systems with T_h1 cells no effect of IL-1 was demonstrable. In contrast, only IL-1 but not IL-12 served as a co-stimulatory signal for several T_h2 cell lines activated via the TcR/CD3 complex.     

Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children

BACKGROUND: Several studies have indicated linkage of chromosome 11q12-13 to asthma and associated traits. Among other candidate genes, the Clara cell protein 16 (CC16) gene maps to this region. CC16 is expressed in the bronchial epithelium and exhibits potent anti-inflammatory properties. A single-nucleotide polymorphism (SNP) in the CC16 gene (A38G) was previously associated with asthma. OBJECTIVE: We evaluated the role of the CC16 SNP in pediatric asthma and asthma severity in 2 German study populations. METHODS: The German Multicenter Allergy Study (MAS) cohort (n = 872, 94 asthmatic patients) and 112 allergic asthmatic children recruited in Freiburg, Germany, were included in the present study. Histamine provocations were performed at the age of 7 years in the MAS cohort to determine bronchial hyperreactivity; in the Freiburg study population a standardized exercise-induced decrease in FEV1 was evaluated. For genotyping, melting-curve analysis and restriction enzyme digestion were applied. RESULTS: No association of the CC16*38A allele with asthma could be observed in either study population. However, in asthmatic subjects (MAS cohort) PC(20)FEV(1) values were significantly lower in individuals homozygous or heterozygous for the CC16*38A allele compared with those in subjects with the CC16*38GG genotype (P <.05 and P <.03, respectively). Similarly, allergic asthmatic patients in the Freiburg cohort showed a significantly greater decrease in FEV1 after exercise when homozygous for the CC16*38A allele compared with that seen in asthmatic patients with the *38AG or *38GG genotype (P <.04 and P =.006, respectively). CONCLUSION: We conclude that the CC16*A38G SNP influences bronchial hyperreactivity and might be a genetic determinant of asthma severity in German children.     

Pancreatic mucinous noncystic (colloid) carcinomas and intraductal papillary mucinous carcinomas are usually microsatellite stable.

Pancreatic mucinous noncystic (colloid) carcinomas (MNCC) differ from the usual ductal adenocarcinomas in their mucin expression profile and share with many extrapancreatic mucinous carcinomas the expression of MUC2. Because mucinous carcinomas are frequently associated with mutations of the DNA mismatch repair genes, causing them to exhibit the so-called mutator phenotype, we decided to investigate whether MNCCs of the pancreas are characterized by microsatellite instability (MSI). Twelve carcinomas with a mucinous phenotype (8 mucinous noncystic carcinomas, 3 intraductal papillary-mucinous carcinomas with an invasive muconodular component, and 1 ductal adenocarcinoma with an extensive mucinous noncystic component) and 11 ductal adenocarcinomas were immunostained with monoclonal antibodies to the mismatch repair gene products hMLH1, hMSH2, and hMSH6. For MSI analysis, DNA was isolated from microdissected tissue, and five primary microsatellites (BAT 25, BAT 26, D5S346, D17S250, and D2S123) were analyzed. MSI was diagnosed in case a novel allele was found, compared with the normal tissue. The criterion for LOH was a 75% signal reduction. All carcinomas tested exhibited nuclear expression of mismatch repair gene products, except for one MNCC that also showed MSI at the molecular level. The data suggest that pancreatic carcinomas with a mucinous phenotype (MUC2+/MUC1-) do not appear to normally exhibit mutations in the mismatch repair genes and therefore differ in their carcinogenesis from those in other organs.     

DNA‐based immunotherapy: potential for treatment of chronic viral hepatitis?

Persistent HBV and HCV infection represent major causes of chronic liver disease with a high risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Conventional protein-based vaccines are highly efficacious in preventing HBV infection; whereas in therapeutic settings with chronically infected patients, results have been disappointing. Prophylactic vaccination against HCV infection has not yet been achieved due to many impediments including frequent spontaneous mutations of the virus with escape from immune system control. Using animal models it has been demonstrated that DNA-based immunisation strategies may overcome this problem because of their potential to induce immunity against multiple viral epitopes. DNA-based vaccines mimic the effect of live attenuated viral vaccines, eliciting cell mediated immunity in addition to inducing humoral responses. Efficacy may further be improved by addition of DNA encoding immunomodulatory cytokines and more recently, direct genetic modulation of antigen-presenting cells, such as dendritic cells (DC), has been shown to increase antigen-specific immune responses. This review focuses on immunological aspects of chronic HBV and HCV infection and on the potential of DNA- and DC-based vaccines for the treatment of chronic viral hepatitis.     

Recurrent high level parvovirus B19/genotype 2 viremia in a renal transplant recipient analyzed by real-time PCR for simultaneous detection of genotypes 1 to 3

Organ transplant recipients infected with parvovirus B19 frequently develop persistent viremia associated with chronic anemia and pure red cell aplasia. In this study, a male renal transplant recipient who had been infected with parvovirus B19/genotype 2 after renal transplantation at the age of 34 years is described. The patient was repeatedly treated with high dose intravenous immunoglobulin (IVIG) that resulted in the resolvement of symptoms but not in virus eradication. During an observation period of 33 months after transplantation three phases associated with high parvovirus B19 viremia were observed. Both the first and the second viremic phases were combined with severe anemia. Parvovirus B19 specific IgM-antibodies were initially detected at the beginning of the second phase in continually rising concentrations. Initially eradication of the virus by immunoglobulin therapy was reported after the first viremic phase [Liefeldt et al. (2002): Nephrol Dial Transplant 17:1840-1842]. Retrospectively this statement has to be corrected. It was based on the use of a qualitative PCR assay specific for parvovirus B19 genotype 1 associated with reduced sensitivity for detection of genotype 2. After sequence analysis of the viral DNA and adjustment of a real-time PCR assay (TaqMan) for quantitative detection of all three B19 virus genotypes analysis of consecutive serum samples allowed the demonstration of long lasting phases with reduced viral loads following IVIG-treatment. These results demonstrate that IVIG treatment of parvovirus B19-triggered anemia in transplant recipients offers an opportunity to resolve symptoms, but does not guarantee eradication of the virus. Since reactivation of parvovirus B19 infection can result in high virus load associated with the recurrence of symptoms repeated screening for viral DNA is recommended using the TaqMan system established for quantitative detection of all three genotypes of parvovirus B19.