Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

• MeSH
• Deoxycytidine analogs & derivatives   administration & dosage   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Doxorubicin analogs & derivatives   administration & dosage   MeSH
• Phthalazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Gemcitabine MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   MeSH
• Ovarian Neoplasms * drug therapy   genetics   mortality   pathology   MeSH
• Paclitaxel administration & dosage   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use   adverse effects   MeSH
• Piperazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Polyethylene Glycols administration & dosage   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged MeSH
• Topotecan administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Children with hemophilia have a significantly higher risk of intracranial hemorrhage (ICH) compared to the normal population. Prophylaxis reduces the risk of ICH and earlier initiation of prophylaxis may now be feasible, especially in hemophilia A (HA). The aim of the study is to explore the potential for preventing ICH by earlier start of prophylaxis by assessing the natural course of ICH before the initiation of prophylaxis and describe timing and incidence (clinicaltrials gov. Identifier: NCT02979119). In total, 2,727 children (2,275 with HA; 452 with hemophilia B [HB]) were included from the PedNet Registry, followed from 28 days until 36 months of life. ICH was observed in 61 children (incidence 2.2%; 10 per 1,000 patient years), with 75% of cases occurring before 1 year of age. Cumulative incidence was significantly lower in HB (0.9%) compared to HA (2.5%) and in non-severe HA (0.7%) compared to severe HA (3.5%). ICH occurred early, with a rise at 3 months, and a median age of 7.0 months in severe HA and 5.4 months in severe HB. In 40% of children, ICH occurred before the diagnosis of hemophilia was established, underscoring the importance of early diagnosis. Assuming that prophylaxis would have been started at the time of diagnosis and preventing all ICH in children with severe HA, the number needed to treat with prophylaxis would be 44 patients to prevent one ICH. Hopefully, prophylaxis options allowing initiation early in life, ideally before 3 months of age for children with severe HA, will reduce the incidence of ICH in the future.

• MeSH
• Time Factors MeSH
• Child MeSH
• Hemophilia A * complications   drug therapy   epidemiology   MeSH
• Hemophilia B * complications   drug therapy   MeSH
• Incidence MeSH
• Intracranial Hemorrhages * prevention & control   epidemiology   etiology   diagnosis   MeSH
• Infant MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Registries MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

• MeSH
• Cell Tracking methods   MeSH
• Fluorine chemistry   MeSH
• Fluorocarbons MeSH
• Contrast Media MeSH
• Cell Movement MeSH
• Fluorine-19 Magnetic Resonance Imaging MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• radiologie, nukleární medicína a zobrazovací metody
• NML Publication type
• kolektivní monografie

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

• MeSH
• Chemotherapy, Adjuvant MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   administration & dosage   adverse effects   MeSH
• Carboplatin administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Endometrial Neoplasms * pathology   drug therapy   mortality   therapy   MeSH
• DNA Mismatch Repair * MeSH
• Paclitaxel * administration & dosage   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Feruloyl esterases (FAEs) are a crucial component of the hemicellulose-degrading enzyme family that facilitates the degradation of lignocellulose while releasing hydroxycinnamic acids such as ferulic acid with high added value. Currently, the low enzyme yield of FAEs is one of the primary factors limiting its application. Therefore, in this paper, we optimized the fermentation conditions for the expression of FAE BpFaeT132C-D143C with excellent thermal stability in Escherichia coli by experimental design. Firstly, we explored the effects of 11 factors such as medium type, isopropyl-β-D-thiogalactopyranoside (IPTG) concentration, and inoculum size on BpFaeT132C-D143C activity separately by the single factor design. Then, the significance of the effects of seven factors, such as post-induction temperature, shaker rotational speed, and inoculum size on BpFaeT132C-D143C activity, was analyzed by Plackett-Burman design. We identified the main factors affecting the fermentation conditions of E. coli expressing BpFaeT132C-D143C as post-induction temperature, pre-induction period, and post-induction period. Finally, we used the steepest ascent path design and response surface method to optimize the levels of these three factors further. Under the optimal conditions, the activity of BpFaeT132C-D143C was 3.58 U/ml, which was a significant 6.6-fold increase compared to the pre-optimization (0.47 U/ml), demonstrating the effectiveness of this optimization process. Moreover, BpFaeT132C-D143C activity was 1.52 U/ml in a 3-l fermenter under the abovementioned optimal conditions. It was determined that the expression of BpFaeT132C-D143C in E. coli was predominantly intracellular in the cytoplasm. This study lays the foundation for further research on BpFaeT132C-D143C in degrading agricultural waste transformation applications.

• MeSH
• Escherichia coli * genetics   metabolism   enzymology   MeSH
• Fermentation * MeSH
• Isopropyl Thiogalactoside metabolism   MeSH
• Carboxylic Ester Hydrolases * genetics   metabolism   chemistry   biosynthesis   MeSH
• Culture Media chemistry   MeSH
• Coumaric Acids metabolism   MeSH
• Lignin MeSH
• Recombinant Proteins genetics   metabolism   biosynthesis   chemistry   MeSH
• Enzyme Stability MeSH
• Temperature MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.

• MeSH
• Drug Resistance, Neoplasm * MeSH
• Docetaxel * pharmacology   therapeutic use   MeSH
• Epithelial-Mesenchymal Transition drug effects   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms * pathology   drug therapy   metabolism   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• Keywords
• pembrolizumab, studie KEYNOTE-826,
• MeSH
• Bevacizumab pharmacology   therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized pharmacology   therapeutic use   MeSH
• Immune Checkpoint Inhibitors pharmacology   therapeutic use   MeSH
• Clinical Studies as Topic MeSH
• Drug Therapy, Combination * methods   MeSH
• Humans MeSH
• Human Papillomavirus Viruses pathogenicity   MeSH
• Uterine Cervical Neoplasms * diagnosis   drug therapy   genetics   MeSH
• Paclitaxel pharmacology   therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

• Keywords
• balonkový katetr,
• MeSH
• Dinoprostone pharmacology   therapeutic use   MeSH
• Labor, Induced * methods   MeSH
• Catheterization methods   MeSH
• Catheters classification   MeSH
• Pregnancy Complications diagnosis   drug therapy   MeSH
• Humans MeSH
• Misoprostol pharmacology   therapeutic use   MeSH
• Pregnancy drug effects   MeSH
• Pregnant People MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Pregnancy drug effects   MeSH
• Female MeSH
• Publication type
• Review MeSH

• MeSH
• Adenocarcinoma * diagnosis   MeSH
• Progression-Free Survival MeSH
• Gemcitabine pharmacology   therapeutic use   MeSH
• Incidence MeSH
• Irinotecan * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Meta-Analysis as Topic MeSH
• Neoplasm Metastasis MeSH
• Pancreatic Neoplasms * surgery   drug therapy   classification   MeSH
• Albumin-Bound Paclitaxel pharmacology   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Alveolární echinokokóza (AE) je vzácné, ale závažné parazitární onemocnění jater, které často napodobuje maligní ložiska. V této kazuistice prezentujeme případ 76letého pacienta, u něhož byla AE diagnostikována náhodně při vyšetření pro renální insuficienci. Ultrazvukové vyšetření odhalilo mnohočetná hyperechogenní ložiska v játrech. Následné CT a MR jater zobrazily mnohočetná ložiska nepravidelných okrajů bez typické vaskularizace, největší o velikosti 71 × 38 mm. Laboratorní výsledky ukázaly zvýšené jaterní enzymy, CRP a renální insuficienci. Core cut biopsie jater potvrdila přítomnost pseudocystických struktur. Vzorky byly následně zaslány do Národní referenční laboratoře pro tkáňové helmintózy, která diagnózu AE potvrdila. Sérologické vyšetření bylo provedeno až po bioptickém vyšetření a potvrdilo přítomnost protilátek proti Echinococcus multilocularis. Pacient byl odeslán do infekční ambulance, kde byla zahájena léčba albendazolem v dávce 800 mg denně. Po rehydrataci a úpravě léčby došlo ke stabilizaci renálních funkcí a při kontrolních zobrazovacích vyšetřeních byl nález stacionární. Tento případ zdůrazňuje nutnost zařazení AE do diferenciální diagnostiky ložiskových procesů jater, zejména u pacientů bez onkologické anamnézy.

Alveolar echinococcosis (AE) is a rare but serious parasitic liver disease that often mimics malignant lesions. We present the case of a 76-year-old patient in whom AE was incidentally diagnosed during examination for renal insufficiency. Abdominal ultrasound revealed multiple hyperechogenic liver lesions. Subsequent MRI showed multiple irregularly bordered lesions without typical vascularization, the largest measuring 71 × 38 mm. Laboratory tests revealed elevated liver enzymes, CRP, and renal insufficiency. A core-cut liver biopsy confirmed the presence of pseudocystic structures. Samples were sent to the National Reference Laboratory for Tissue Helminthiases, which confirmed the diagnosis of AE. Serological testing was performed after the biopsy confirming the presence of antibodies against Echinococcus multilocularis. The patient was referred to an infectious disease clinic, where treatment with albendazole at a dose of 800 mg daily was initiated. After rehydration and adjustment of therapy, renal function stabilized, and follow-up imaging showed stable findings. This case highlights the need to include AE in the differential diagnosis of hepatic lesions, particularly in patients without an oncological history.

• MeSH
• Albendazole pharmacology   therapeutic use   MeSH
• Biopsy MeSH
• Diagnostic Imaging methods   MeSH
• Echinococcosis, Hepatic * diagnosis   drug therapy   MeSH
• Liver diagnostic imaging   pathology   MeSH
• Humans MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Case Reports MeSH