Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study).

There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma: Final results of the MARC-2 trial.

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs <65 years and 51.4% (95% CI, 34.7-65.7) vs 18.2% (95% CI, 5.7-36.3) for patients with body mass index (BMI) >25 vs ≤25 kg/m2 . A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most.

Deoxygenative Fluorination of Phosphine Oxides: A General Route to Fluorinated Organophosphorus(V) Compounds and Beyond.

Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1) occasional handling of toxic or pyrophoric PIII starting materials and 2) a dependence on hazardous fluorinating reagents such as XeF2 . Herein, we present a simple solution and introduce a deoxygenative fluorination (DOF) approach that utilizes easy-to-handle phosphine oxides as starting materials and effectively replaces harsh fluorinating reagents by a combination of oxalyl chloride and potassium fluoride. The reaction has proven to be general, as R3 PF2 , R2 PF3 , and RPF4 compounds (as well as various cations and anions derived from these) are accessible in good yields and on up to a multi-gram scale. DFT calculations were used to bolster our observations. Notably, the discovery of this new method led to a convenient synthesis of 1) new difluorophosphonium ions, 2) hexafluorophosphate salts, and 3) fluorinated antimony- and arsenic- compounds.

Monohydride-Dichloro Rhodium(III) Complexes with Chiral Diphosphine Ligands as Catalysts for Asymmetric Hydrogenation of Olefinic Substrates.

We report full details of the synthesis and characterization of monohydride-dichloro rhodium(III) complexes bearing chiral diphosphine ligands, such as (S)-BINAP, (S)-DM-SEGPHOS, and (S)-DTBM-SEGPHOS, producing cationic triply chloride bridged dinuclear rhodium(III) complexes (1 a: (S)-BINAP; 1 b: (S)-DM-SEGPHOS) and a neutral mononuclear monohydride-dichloro rhodium(III) complex (1 c: (S)-DTBM-SEGPHOS) in high yield and high purity. Their solid state structure and solution behavior were determined by crystallographic studies as well as full spectral data, including DOSY NMR spectroscopy. Among these three complexes, 1 c has a rigid pocket surrounded by two chloride atoms bound to the rhodium atom together with one tBu group of (S)-DTBM-SEGPHOS for fitting to simple olefins without any coordinating functional groups. Complex 1 c exhibited superior catalytic activity and enantioselectivity for asymmetric hydrogenation of exo-olefins and olefinic substrates. The catalytic activity of 1 c was compared with that of well-demonstrated dihydride species derived in situ from rhodium(I) precursors such as [Rh(cod)Cl]2 and [Rh(cod)2 ]+ [BF4 ]- upon mixing with (S)-DTBM-SEGPHOS under dihydrogen.

Management of an Extremely Low Birth Weight Infant with Bilateral Renal Obstruction Caused by Candida albicans Fungus Balls.

We report an extremely low birth weight infant with anuria caused by bilateral Candida albicans fungus balls it was treated with a combination of antifungal therapy, irrigation and pyelotomy. This lead to a recovery of renal function, after a follow-up of 77 month no more Candida was cultured from urine.

Difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and Selanes: Missing Links of Trichloroisocyanuric Acid/Potassium Fluoride Chemistry.

The TCICA/KF approach to oxidative fluorination of heteroatoms has emerged as a surprisingly simple, safe, and versatile surrogate to classically challenging fluorination reactions. Although polyfluorination (or chlorofluorination) of diaryl disulfides, diaryl diselenides, diaryl ditellurides, aryl iodides, and aryl(perfluoroalkyl)tellanes has been described, the application of this TCICA/KF methodology to aryl(perfluoroalkyl)sulfanes and selanes remains an area of unexplored chemical space. Accordingly, to address the "missing links" in the developing series of chalcogen-based substrate reactivity, we report mild syntheses of metastable difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and selanes. As only limited examples of these species exist in the current literature (accessible only by using F2 or XeF2 /HF), we have carried out detailed structural analyses, primarily using NMR and SC-XRD data. In addition, we investigate the effect of the perfluoroalkyl chain on the outcome of oxidative fluorination, and, finally, we provide preliminary evidence that difluoro(aryl)(trifluoro-methyl)-λ4 -sulfanes may act as fluorinating reagents.

Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands.

The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2 , Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.