Vergleich von zwei dosisreduzierten Proteasehemmerkombinationen mit Indinavir/Ritonavir (400/100 mg vs. 600/100 mg) BID bei therapienaiven HIV-1 infizierten Patienten

Die in der Therapie der HIV-Infektion seit 1995/96 eingesetzten Proteaseinhibitoren werden seit einigen Jahren in verschiedenen Dosismodifikationen eingesetzt, es wird versucht die für den Patienten optimale Dosierung mit einer guten antiretroviralen Effizienz und einem akzeptablen Nebenwirkungsprofil zu finden. In der hier vorgelegten Dissertation wurde eine Dosisreduktion des Proteasehemmers Indinavir (IDV) bei HIV 1-infizierten therapienaiven Patienten untersucht. Es wurden mittels Randomisation die Dosierungen 600 mg IDV BID (bis in die) und 400 mg IDV BID jeweils in Kombination mit 100 mg Ritonavir als pharmakologischem Booster und 2 Nukleosidanaloga über einen Zeitraum von 48 Wochen verglichen. Hierbei zeigte sich eine gute Wirksamkeit in Bezug auf die Suppression der viralen Replikation (87 % der Patienten unterhalb der Nachweisgrenze von 50 Kopien/ml nach 48 Wochen in der On treatment-Analyse) und eine gute immunologische Wirksamkeit (Anstieg der Helferzellen um 173/µl nach 48 Wochen). Die Wirksamkeit war damit genauso gut wie in der zuvor eingesetzten Standarddosis von 800 mg IDV/100 mg RTV BID, die jedoch durch eine ausgeprägte IDV assoziierte Toxizität mit Abbruchraten aufgrund von Nierensteinen von über 30 % belastet war.Eine relevante Nephrotoxizität wurde in dieser Untersuchung ebensowenig beobachtet wie eine relevante Hauttoxizität, Anstiege von Bilirubin oder Blutfetten. Auch die subjektive Verträglichkeit der reduzierten IDV Dosen war besser im Vergleich zu 800/100 mg IDV/RTV BID. Die bessere Verträglichkeit korreliert mit verringerten IDV-Spitzenspiegeln. Trotz der Dosisreduktion konnten bei allen Patienten suffiziente Talspiegel nachgewiesen werden, die mit der Wirksamkeit der Substanz assoziiert sind.Die Abbruchrate in der COREDIR 2 Studie war sehr hoch (6 von 14 Patienten). Es war jedoch nur ein Therapieabbruch möglicherweise mit IDV assoziiert, während alle anderen Abbrüche durch andere Gründe wie Inhaftierung, lost to follow up oder ähnliches bedingt waren. Ein formaler Vergleich der beiden Dosisformen war daher nicht möglich, so dass die optimale Strategie für den Einsatz von dosisreduziertem IDV weiterhin unklar bleibt. Zusammenfassend stellt die Dosisreduktion von IDV einen wichtigen und sicher durchzuführenden Schritt zur Verbesserung der antiretroviralen Therapie dar. Trotz der mittlerweile bestehenden moderneren Möglichkeiten der antiretroviralen Therapie ist die Behandlung mit dosisreduziertem geboostertem Indinavir aufgrund ihrer vergleichsweise niedrigen Kosten eine sinnvolle Option in Ländern mit nur geringen finanziellen Ressourcen

Curative treatment in a patient with gastric cancer stage IV: a case report

Diel A, Rodermann E, Kienzle H-F, Meuthen D, Meuthen I. Curative treatment in a patient with gastric cancer stage IV: a case report. F1000Research. 2012;1: 34.A 39-year old patient with gastric adenocarcinoma stage IV failed to respond to preoperative chemotherapies containing 5-FU and cisplatin as well as 5-FU and irinotecan. After third-line chemotherapy with two cycles of docetaxel and cisplatin we confirmed a clinical partial response. A complete histologically confirmed remission was detected after complete resection of the tumor. Following two postoperative cycles of docetaxel and cisplatin, the tumor is still in complete remission after more than eight years

Overcoming EGFR G724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors

Acquired resistance to targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. Here, the authors show how the acquired EGFR G724S mutation induces resistance to third-generation EGFR inhibitors and why the mutant kinase remains susceptible to second-generation inhibitors

Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

PURPOSE Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p. T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p. T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor (MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P <= .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR. (C) 2019 by American Society of Clinical Oncolog

Evidence for PTGER4 ,PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 x 10(-04)) and on chromosome 8q24 at rs2585176 (P = 1.09 x 10(-09)). On chromosome 5p13 we found cis-eQTL effects with an up-regulation of PTGER4 expression in GC risk allele carrier (P = 9.27 x 10(-11)). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 x 10(-47)). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 x 10(-09)). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms

Dissecting the genetic heterogeneity of gastric cancer

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709</p