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

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

Radiation dosimetry of ¹⁸F-AzaFol: A first in-human use of a folate receptor PET tracer.

The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the &lt;sup&gt;18&lt;/sup&gt; F-AzaFol (3'-aza-2'-[ &lt;sup&gt;18&lt;/sup&gt; F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299-399 MBq) of &lt;sup&gt;18&lt;/sup&gt; F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6-60.5 μGy/MBq). &lt;sup&gt;18&lt;/sup&gt; F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance. ClinicalTrial.gov, NCT03242993, posted on August 8, 2017

NOTCH1 and PIK3CA mutation are related to HPV-associated vulvar squamous cell carcinoma

NOTCH1 and PIK3CA are members of important cell signalling pathways that are deregulated in squamous cell carcinomas of various organs. Vulvar squamous cell carcinomas (vulvSCC) are classically divided into two pathways, HPV-associated or HPV-independent, but the effect of NOTCH1 and PIK3CA mutations in both groups is unclear. We analysed two different cohorts of vulvSCC using Hybrid Capture-based Comprehensive Genomic Profiling and identified NOTCH1 and PIK3CA mutations in 35% and 31% of 48 primary vulvSCC. In this first cohort, PIK3CA and NOTCH1 mutations were significantly correlated with HPV infection (p < 0.01). Furthermore, mutations in both genes were associated with an advanced tumor stage and poorly differentiated status (p < 0.05). PIK3CA and NOTCH1 mutations were also associated with shorter patient survival which did not reach significance. In the second cohort of 735 advanced vulvSCC from metastatic site biopsies or from sites of unresectable loco-regional disease, NOTCH1 and PIK3CA mutations were reported in 14% and 20.3%, respectively. 4 of 48 (8%) and 22 of 735 vulvSCC (3.0%) featured genomic alterations (short variants and/or copy number changes and/or rearrangements) in both NOTCH1 and PIK3CA. NOTCH1 mutations were mostly located in the extracellular EGF-like domains, were inactivating and indicated that NOTCH1 functions predominantly as a tumor suppressor gene in vulvSCC. In contrast, PIK3CA mutations favored hotspot codons 1624 and 1633 of the gene, indicating that PIK3CA acts as an oncogene in vulvar carcinogenesis. In conclusion, NOTCH1 and PIK3CA mutations are detectable in a substantial proportion of vulvSCC and are related to HPV infection and more aggressive tumor behaviour

Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Item does not contain fulltextCarbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four-step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer