Clinical specimens are each inherently unique, limited and non-renewable. As such, small samples such as tissue biopsies are often completely consumed after a limited number of analyses. Here we present a method that enables fast and reproducible conversion of a small amount of tissue (approximating the quantity obtained by a biopsy) into a single, permanent digital file representing the mass spectrometry-measurable proteome of the sample. The method combines pressure cycling technology (PCT) and SWATH mass spectrometry (MS), and the resulting proteome maps can be analyzed, re-analyzed, compared and mined in silico to detect and quantify specific proteins across multiple samples. We used this method to process and convert 18 biopsy samples from 9 renal cell carcinoma patients into SWATH-MS fragment ion maps. From these proteome maps we detected and quantified more than 2,000 proteins with a high degree of reproducibility across all samples. The identified proteins clearly separated tumorous kidney tissues from healthy tissue, and differentiated distinct histomorphological kidney cancer subtypes.

Our data demonstrate that quantification of plasma DNA is an accurate technique amenable to standardization, which might complement current methods for the prediction of patient survival. This approach might be considered for evaluation in large prospective studies.

PURPOSE For patients with resectable stage IIIA(N2) non–small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab. METHODS Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2 and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. RESULTS Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related. CONCLUSION The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non–small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.

PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI 5 2.30-6.09, p 5 2 3 10 25

Background:The aim of this study was to quantitatively assess the effect of anthropometric and biochemical variables and third-space effusions on paclitaxel pharmacokinetics in solid tumor patients. Materials and Methods: Plasma concentration-time data of paclitaxel were collected in patients with non^small cell lung cancer (n = 84), ovarian cancer (n = 40), and various solid tumors (n = 44), totaling 168 patients. Paclitaxel was given as a 3-hour infusion (n = 163) at doses ranging from 100 to 250 mg/m 2 , or as a 24-hour infusion (n = 5) at a dose of 135 or 175 mg/m 2 . Data were analyzed using nonlinear mixed-effect modeling. Results: A three-compartment model with saturable elimination and distribution was used to describe concentration-time data. Male gender and body surface area were positively correlated with maximal elimination capacity of paclitaxel (VM EL ); patient age and total bilirubin were negatively correlated withVM EL (P < 0.005 for all correlations).Typically, male patients had a 20% higher VM EL ; a 0.2 m 2 increase of body surface area led to a 9% increase of VM EL ; a 10-year increase of patient age led to a 5% decrease of VM EL ; and a 10-Amol increase of total bilirubin led to a 14% decrease of VM EL . Third-space effusions were not correlated with paclitaxel pharmacokinetics. Conclusions: This extended retrospective population analysis showed patient gender to significantly and independently affect paclitaxel distribution and elimination. Body surface area, total bilirubin, and patient age were confirmed to affect paclitaxel elimination. This pharmacokinetic model allowed quantification of the covariate effects on the elimination of paclitaxel and may be used for covariate-adapted paclitaxel dosing.Paclitaxel formulated in Cremophor EL is regularly administered to patients with non -small cell lung cancer (NSCLC), ovarian cancer, and breast cancer. The pharmacokinetics of paclitaxel were initially believed to be linear, but Sonnichsen and Gianni reported that paclitaxel pharmacokinetics were best described with a two-and three-compartment model, respectively, with saturable elimination and saturable distribution to the tissues (1, 2). Later, the formulation vehicle of paclitaxel, Cremophor EL, was reported to be the cause of the (apparent) nonlinear plasma behavior of paclitaxel, probably by entrapment of paclitaxel into micelles (3 -7). Generally, substantial interpatient variability of paclitaxel pharmacokinetic variables has been noted (8).Hepatic metabolism and biliary excretion are the most important elimination routes of paclitaxel and its metabolites (9). Paclitaxel has been shown to bind extensively to plasma proteins (from 95% to < 97%), with high central (mean = 13.8 L/m 2 ) and steady-state (mean = 182 L/m 2 ) volumes of distribution (10-13). However, data on specific tissue and compartment distribution of paclitaxel in humans following i.v. administration are limited. Paclitaxel concentrations in ascites have been analyzed in single patients, where the concentration ...

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5-Fluorouracil (5-FU) is dosed by body surface area, a practice unable to reduce the interindividual variability in exposure. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), we evaluated clinical evidence and strongly recommend TDM for the management of 5-FU therapy in patients with colorectal or head-and-neck cancer receiving common 5-FU regimens. Our systematic methodology provides a framework to evaluate published evidence in support of TDM recommendations in oncology.