Sixteen polyketides belonging to diverse structural classes, including monomeric/dimeric tetrahydroxanthones and resorcylic acid lactones, were isolated from an organic extract of a fungal culture ...Setophoma terrestris (MSX45109) by bioactivity‐directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were new: penicillixanthone B (5), blennolide H (6), 11‐deoxyblennolide D (7), blennolide I (9), blennolide J (10), and pyrenomycin (16). The known compounds were: secalonic acid A (1), secalonic acid E (2), secalonic acid G (3), penicillixanthone A (4), paecilin B (8), aigialomycin A (11), hypothemycin (12), dihydrohypothemycin (13), pyrenochaetic acid C (14), and nidulalin B (15). The structures were elucidated by a set of spectroscopic and spectrometric techniques: the absolute configurations of compounds 1–10 were determined by ECD spectroscopy combined with time‐dependent density functional theory (TDDFT) calculations, whereas a modified Mosher's ester method was used for compound 16. The cytotoxic activities of compounds 1–15 against the MDA‐MB‐435 (melanoma) and SW‐620 (colon) cancer cell lines were evaluated. Compounds 1, 4, and 12 were the most potent, with IC50 values ranging from 0.16 to 2.14 μM. When tested against a panel of bacteria and fungi, compounds 3 and 5 showed promising activity against the Gram‐positive bacterium Micrococcus luteus, with MIC values of 5 and 15 μg mL–1, respectively.
Sixteen polyketides, six of them new, were isolated from a fungal culture (Setophoma terrestris). Cytotoxicity assays were used to develop structure–activity relationships amongst the series.
Synthetic biological approaches, such as site-directed biosynthesis, have contributed to the expansion of the chemical space of natural products, making possible the biosynthesis of unnatural ...metabolites that otherwise would be difficult to access. Such methods may allow the incorporation of fluorine, an atom rarely found in nature, into complex secondary metabolites. Organofluorine compounds and secondary metabolites have both played pivotal roles in the development of drugs; however, their discovery and development are often via nonintersecting tracks. In this context, we used the biosynthetic machinery of Trichoderma arundinaceum (strain MSX70741) to incorporate a fluorine atom into peptaibol-type molecules in a site-selective manner. Thus, fermentation of strain MSX70741 in media containing ortho- and meta-F-phenylalanine resulted in the biosynthesis of two new fluorine-containing alamethicin F50 derivatives. The fluorinated products were characterized using spectroscopic (1D and 2D NMR, including 19F) and spectrometric (HRESIMS/MSn) methods, and their absolute configurations were established by Marfey’s analysis. Fluorine-containing alamethicin F50 derivatives exhibited potency analogous to the nonfluorinated parent when evaluated against a panel of human cancer cell lines. Importantly, the biosynthesis of fluorinated alamethicin F50 derivatives by strain MSX70741 was monitored in situ using a droplet–liquid microjunction–surface sampling probe coupled to a hyphenated system.
Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived ...xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC(50) determination. The IC(50) values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC(50) determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clinical assessment.
Background
B‐rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF‐mutated melanoma patients. So far, the ...range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib).
Objective
The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib.
Methods
Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature.
Results
The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug‐induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%).
Conclusion
Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.
Linked article: This article is commented on E. Livingstone, pp. 630–631 in this issue. To view this article visit https://doi.org/10.1111/jdv.15527.
Background
Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence.
Methods
The study included patients between 3 and 20 years with clinically and radiologically ...confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m
2
weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3).
Results
All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression.
Conclusions
Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.
Clear cell sarcoma of the kidney: A review Gooskens, S.L.M; Furtwängler, R; Vujanic, G.M ...
European journal of cancer (1990),
09/2012, Letnik:
48, Številka:
14
Journal Article
Recenzirano
Abstract Clear cell sarcoma of the kidney (CCSK) is a rare renal tumour that is observed most often in children under 3 years of age. Only a few large series of CCSK have been reported and patients ...with CCSK are often included among patients with other types of childhood renal tumours. The purpose of this paper is to review the published series and case reports of CCSK and to create an up-to-date overview of clinical and histological features, genetics, treatment, and outcome.
Abstract Blastemal-type Wilms tumour (BT-WT) has been identified as a high risk histological subgroup in WT assessed after pre-nephrectomy chemotherapy in trials of the International Society of ...Paediatric Oncology (SIOP) Renal Tumour Study Group. Therefore, in SIOPWT2001, post-operative chemotherapy for BT-WT was intensified aiming to improve survival. Survival analysis of all unilateral BT-WT patients (SIOPWT2001) ( n = 238), was compared with historical BT-WT controls (SIOP93-01) ( n = 113). 351/4061 (8.6%) unilateral non-metastatic BT-WT patients (SIOP93-01/SIOPWT2001) were studied. Median age at diagnosis was 43 months (Inter Quartile Range (IQR) 24–68 months), stages: I ( n = 140, 40%), II ( n = 106, 30%), III ( n = 105, 30%). BT-WTs were higher staged, showed greater volume decrease after pre-operative chemotherapy and were diagnosed at an older median age compared to other WT patients. Patient characteristics did not differ substantially between SIOP93-01 and SIOPWT2001. Univariate analysis showed a 5-year event-free survival (EFS) of 80% (95% confidence interval (CI): 75–86%) (SIOPWT2001) compared to 67% in SIOP93-01 (95% CI: 59–76%; p = 0.006) and overall survival (OS) of 88% (95% CI: 83–93%) (SIOPWT2001) compared to 84% (95% CI: 77–91%; p = 0.4) in SIOP93-01. 95% of relapses were distant metastases (SIOP93-01/SIOPWT2001). Treatment protocol, age at diagnosis, tumour stage (III versus I/II) and volume (at surgery), were prognostic variables for EFS (uni- and multivariate Cox regression analysis). Independent prognosticators for OS were age at diagnosis, tumour stage and volume (at surgery). The most significant survival benefit of intensified treatment, was observed in Stage I (EFS 96% in SIOPWT2001 (OS 100%), 71% in SIOP93-01 (OS 90%)). BT-WT derived benefits from more intensive chemotherapy as reflected by a reduction in relapse risk. However, the benefit of the more intensive chemotherapy to improve OS was only observed in stage I BT-WTs, by adding doxorubicin.
Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven ...distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIalpha gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.
In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 ...paediatric cancer patients (58 % males; median age 8.3 years, interquartile range (IQR) 3.8–14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63 % of all patients and Ports in 20 %. One hundred forty-two patients (18 %; 95 % CI 16 to 21 %) experienced at least one BSI (179 BSIs in total; bacteraemia 70 %, bacterial sepsis 27 %, candidaemia 2 %). In 57 %, the BSI occurred in inpatients, in 79 % after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16 %) was an independent risk factor for all BSI and for Gram-positive BSI.
Conclusion
: This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles.
What is Known:
•
Paediatric cancer patients face an increased risk of nosocomial bloodstream infections
(
BSIs
).
•
In most cases
,
these BSIs are associated with the use of a long-term central venous catheter
(
Broviac
,
Port
),
severe and prolonged immunosuppression
(
e.g. neutropenia
)
and other chemotherapy-induced alterations of host defence mechanisms
(
e.g. mucositis
).
What is New:
•
This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients
.
•
It describes the epidemiology of nosocomial BSI in paediatric cancer patients mainly outside the stem cell transplantation setting during conventional intensive therapy and argues for prospective surveillance programmes to target and evaluate preventive bundle interventions
.
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