Abdominale Tuberkulose

Zusammenfassung: Die Tuberkulose (Tbc) zählt immer noch zu den 15 häufigsten Todesursachen weltweit. Die pulmonale Tbc stellt die klassische Manifestation dar, während die abdominale Tbc etwas aus dem Blickfeld verschwunden ist. Eine Tbc kann sich im ganzen Gastrointestinaltrakt (am häufigsten in der Ileozökalregion), im Peritoneum, in den abdominalen Lymphknoten oder in jedem soliden Organ des Abdomens manifestieren. Als "Chamäleon" kann sie u.a. eine Neoplasie oder eine entzündliche Darmerkrankung imitieren. Klinisch zeigen sich unspezifische Symptome (Fieber, Gewichtsverlust, Schmerzen) oder auch gastrointestinale Blutungen, Perforationen, Obstruktionen oder Aszites, jeweils abhängig vom Ort des Befalls. Die Diagnosesicherung erfolgt meist aus einer Gewebebiopsie oder gelegentlich mit einer Feinnadelpunktion mittels Nachweis von Mycobacterium tuberculosis in Kultur oder PCR. Die Therapie besteht in der Regel aus einer initialen Vierertherapie mit Isoniazid, Rifampicin, Pyrazinamid und Ethambutol, die bei Abwesenheit von Resistenzen auf eine zweimonatige Behandlung mit Isoniazid, Rifampicin und Pyrazinamid reduziert werden kann, gefolgt von 4Monaten Isoniazid und Rifampicin. Die Patienten müssen während der Therapie wegen medikamentösen Interaktionen und Nebenwirkungen sowie der Möglichkeit eines Immunrekonstitutionssyndroms eng begleitet werden. Zwingend ist in jedem Fall der Ausschluss einer offenen pulmonalen Tbc, da sich daraus krankenhaushygienische und epidemiologische Konsequenzen ergeben

Abdominale Tuberkulose

Die Tuberkulose (Tbc) zählt immer noch zu den 15 häufigsten Todesursachen weltweit. Die pulmonale Tbc stellt die klassische Manifestation dar, während die abdominale Tbc etwas aus dem Blickfeld verschwunden ist. Eine Tbc kann sich im ganzen Gastrointestinaltrakt (am häufigsten in der Ileozökalregion), im Peritoneum, in den abdominalen Lymphknoten oder in jedem soliden Organ des Abdomens manifestieren. Als „Chamäleon“ kann sie u. a. eine Neoplasie oder eine entzündliche Darmerkrankung imitieren. Klinisch zeigen sich unspezifische Symptome (Fieber, Gewichtsverlust, Schmerzen) oder auch gastrointestinale Blutungen, Perforationen, Obstruktionen oder Aszites, jeweils abhängig vom Ort des Befalls. Die Diagnosesicherung erfolgt meist aus einer Gewebebiopsie oder gelegentlich mit einer Feinnadelpunktion mittels Nachweis von Mycobacterium tuberculosis in Kultur oder PCR. Die Therapie besteht in der Regel aus einer initialen Vierertherapie mit Isoniazid, Rifampicin, Pyrazinamid und Ethambutol, die bei Abwesenheit von Resistenzen auf eine zweimonatige Behandlung mit Isoniazid, Rifampicin und Pyrazinamid reduziert werden kann, gefolgt von 4 Monaten Isoniazid und Rifampicin. Die Patienten müssen während der Therapie wegen medikamentösen Interaktionen und Nebenwirkungen sowie der Möglichkeit eines Immunrekonstitutionssyndroms eng begleitet werden. Zwingend ist in jedem Fall der Ausschluss einer offenen pulmonalen Tbc, da sich daraus krankenhaushygienische und epidemiologische Konsequenzen ergeben

Optimization of a Novel Peptide Ligand Targeting Human Carbonic Anhydrase IX

BACKGROUND: Carbonic anhydrase IX (CA IX) is a hypoxia-regulated transmembrane protein over-expressed in various types of human cancer. Recently, a new peptide with affinity for human carbonic anhydrase IX (CaIX-P1) was identified using the phage display technology. Aim of the present study is to characterize the binding site in the sequence of CaIX-P1, in order to optimize the binding and metabolic properties and use it for targeting purposes. METHODOLOGY/PRINCIPAL FINDINGS: Various fragments of CaIX-P1 were synthesized on solid support using Fmoc chemistry. Alanine scanning was performed for identification of the amino acids crucial for target binding. Derivatives with increased binding affinity were radiolabeled and in vitro studies were carried out on the CA IX positive human renal cell carcinoma cell line SKRC 52 and the CA IX negative human pancreatic carcinoma cell line BxPC3. Metabolic stability was investigated in cell culture medium and human serum. Organ distribution and planar scintigraphy studies were performed in Balb/c nu/nu mice carrying subcutaneously transplanted SKRC 52 tumors. The results of our studies clearly identified amino acids that are important for target binding. Among various fragments and derivatives the ligand CaIX-P1-4-10 (NHVPLSPy) was found to possess increased binding potential in SKRC 52 cells, whereas no binding capacity for BxPC3 cells was observed. Binding of radiolabeled CaIX-P1-4-10 on CA IX positive cells could be inhibited by both the unlabeled and the native CaIX-P1 peptide but not by control peptides. Stability experiments indicated the degradation site in the sequence of CaIX-P1-4-10. Biodistribution studies showed a higher in vivo accumulation in the tumor than in most healthy tissues. CONCLUSIONS: Our data reveal modifications in the sequence of the CA IX affine ligand CaIX-P1 that might be favorable for improvement of target affinity and metabolic stability, which are necessary prior to the use of the ligand in clinical approaches

Table 2: Anti-tumor agents for targeting hypoxia-induced CA IX for therapy and diagnosis.

The expression of carbonic anhydrase (CA) IX is up-regulated in many types of solid tumors in humans under hypoxic and acidic microenvironment. Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis. Thus, the development of potent antitumor drugs targeting CA IX with minimal toxic effects is important for the target-specific tumor therapy. Recently, several promising antitumor agents against CA IX have been developed to treat certain types of cancers in combination with radiation and chemotherapy. Here we review the inhibition of CA IX by small molecule compounds and monoclonal antibodies. The methods of enzymatic assays, biophysical methods, animal models including zebrafish and Xenopus oocytes, and techniques of diagnostic imaging to detect hypoxic tumors using CA IX-targeted conjugates are discussed with the aim to overview the recent progress related to novel therapeutic agents that target CA IX in hypoxic tumors

PD-L1 receptor expression in vulvar carcinomas is HPV-independent

PD-L1 (programmed cell death 1 ligand) is expressed on many cancer cells and prevents tumor cell death by blocking T cell activity. PD-L1 overexpression has been reported in squamous cell carcinomas of head and neck and lung cancer. To better understand the role of PD-L1 expression in vulvar cancer, we analyzed PD-L1 expression by immunohistochemistry in 55 well-characterized squamous cell carcinomas of vulva. PD-L1 was found in 72.7% of tumors. 27.3% of vulvar carcinomas showed moderate or strong PD-L1 expression. PD-L1 expression was correlated with low tumor stage (p < 0.05). There was no association to other clinicopathological parameters, HPV status, and overall survival of vulvar carcinoma patients. In conclusion, PD-L1 overexpression is detectable in a substantial proportion of vulvar carcinomas in all stages independent of HPV and may be a suitable therapeutic target in these cancers

SOX2 Gene Amplification and Overexpression is Linked to HPV-positive Vulvar Carcinomas.

SOX2 (SRY-related HMG-box 2) belongs to the SOX gene family of high-mobility transcription factors indispensably involved in gene regulation in pluripotent stem cells and neural differentiation. SOX2 copy number increases have been frequently reported in various types of squamous cell cancer. To better understand the effect of SOX2 aberrations on vulvar cancer phenotype and patient prognosis, we analyzed SOX2 copy number changes using fluorescence in situ hybridization and SOX2 expression by immunohistochemistry in 55 squamous cell carcinomas of the vulva. SOX2 amplification was found in 20.8% of tumors; 27.3% of vulvar carcinomas showed SOX2 protein overexpression. SOX2 amplification was correlated with SOX2 overexpression in our data set (P<0.01). Amplification of the SOX2 locus was associated with high tumor grade (P<0.05) and human papillomavirus (HPV) positivity (P<0.01). SOX2-amplified tumors showed more frequently a basaloid phenotype than nonamplified carcinomas. SOX2 protein overexpression was also correlated with basaloid phenotype and positive HPV status of vulvar carcinomas (P<0.05, each). SOX2 amplification and expression were not associated with patient overall survival. In conclusion, SOX2 copy number increases are detectable in a substantial proportion of high-grade HPV-positive vulvar carcinomas with basaloid differentiation. Our study provides further evidence for different molecular alterations in HPV-positive and HPV-negative vulvar carcinomas