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Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P

Background: The prognosis of patients with non-small cell lung cancer (NSCLC) is traditionally determined by anatomic staging using the Tumor, Node, Metastasis (TNM) staging system. TNM staging neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying NSCLC patients at increased risk of recurrence after curative-intent surgery remains an important unmet need as adjuvant therapies are available that may reduce the risk of recurrence and improve patient survival. Methods: Digital Display Precision Predictor (DDPP), based on differential RNA expression in tumor versus normal tissue, was used to interrogate gene sets to determine their association with disease-free survival (DFS) in patients with non-small cell lung cancer (NSCLC) who underwent curative-intent surgery. Findings: Low versus high DDPP score was significantly associated with shorter DFS (highest recurrence risk): HR=1.88, 95% CI [1.2-2.9] (p=0.006) in all patients (n=120) and in patients with TNM stages 1-2 (p= 0.00051) (n=83). For patients with stages 1-2 and low DDPP (n=29), adjuvant chemotherapy was associated with improved DFS (p= 0.0041). High co-overexpression of CTLA-4, PD-L1 and ICOS in normal lung (28 of 120 patients), hypothesized to reflect the host immune status, was also significantly associated with decreased DFS (p= 0.0013) suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (p=2.12E-11). Interpretation: We identified stage 1-2 NSCLC patients with high risk of recurrence who benefitted from adjuvant chemotherapy. Furthermore, identified a subset of NSCLC patients who may have poor post-surgery outcome related to an immunotolerant normal tissue profile that might be amenable to modulation by specific checkpoint blockade immunotherapies. Funding: European Union Frame Pprogram 6-funded project (Chemores FP6 Health, Grant 37 665). Declaration of Interest: Dr. Vladimir Lazar, Catherine Bresson, are full time employees of Worldwide Innovative Network (WIN) Association - WIN Consortium. Worldwide Innovative Network (WIN) Association - WIN Consortium is the owner of the patent family entitled Digital Display. The inventors are Dr. Vladimir Lazar, and Shai Magidi. Dr. Jean-Francois Martini, is a full-time employee and stockholder of Pfizer Inc. Dr. Susan Galbraith is a full-time employee and stockholder of AstraZeneca. Dr. Benjamin Solomon received honorarium for Advisory Board from AstraZeneca and Bayer. Shai Magidi receives consultancy from Worldwide Innovative Network (WIN) Association. Dr. Amir Onn receives consulting fees from Roche Israel, MSD Israel, Boehringer Ingelheim 552 and AstraZeneca. Dr. Enriqueta Felip receives advisory board and/or speaker’s bureau fee from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffman-LaRoche, Glaxi Smith Kline, Janssen, Medical Trends, Medscape, Merck Sharp & Dohme, Merck Serono, Peptomyc, Peervoice, Pfizer, Puma, Regeneron, Sanofi, Springer, Syneos Health, Takeda, Touch Medical; on the board of Grifols, Independent member. Receives research funding from Fundacion Merck Salud, Grant for Oncology Innovation (GOI) EMD Serono. Dr. Josep Tabernero declares scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. Dr. Gerald Batist collaborates in formal clinical trial contracts, IITs and in joint grants funded by Canadian and Quebec governments with Roche, Merck, Novartis, Astra-Zeneca, Bayer, Esperas, Aurka, Caprion, MRM. Pr. Angel Porgador declares scientific consultancy role for PiNK Biopharma. Dr. Razelle Kurzrock has received research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc., and Biological Dynamics, has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Dr. Richard L. Schilsky’s institution (ASCO) receives research grants in support of a clinical trial that he directs from the following companies: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, Lilly, Merck, Pfizer. Dr. Schilsky reports being a consultant to Cellworks, Clarify Precision Medicine, Bryologx, EQRx and Scandion Oncology. The remaining authors declare no competing interests. Ethical Approval: The bio-banking study was approved by the IMM’s Ethics Committee.

The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E−05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E−04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients’ treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).

9581 Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) algorithm in order to predict treatment response by comparing tumor and normal tissue biopsies on both genomic and transcriptomic platforms. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC (no EGFR or ALK alterations; no ROS1 alterations if tested; PD-L1 unrestricted; ≤2 prior therapy lines) were treated with avelumab, axitinib, and palbociclib (3+3 dose escalation design). Tumor and normal endobronchial mucosal biopsies were obtained on all patients for retrospective SIMS algorithm validation. Results: Fifteen patients were treated: 6 at dose level 1 (DL1); 6, dose level 2 (DL2); 3, dose level 3 (DL3). Three dose-limiting toxicities (DLTs) at least possibly drug-related occurred: 1 DLT at DL2 (Grade 3 (G3) infusion reaction); 2 patients with DLTs at DL3 (1 with G3 hand/foot syndrome and G3 fatigue and 1 with G5 respiratory failure). Among 14 evaluable patients, the partial response (PR) rate was 28.6% (4/14 patients including 2/6 patients at DL1; two PRs in patients who failed prior pembrolizumab; two PRs in patients with PD-L1 < 1%). The maximum tolerated dose was avelumab 10 mg/kg IV q2weeks, axitinib 5 mg PO BID continuous, palbociclib 75 mg PO daily on days 8-28 of a 28 day cycle (DL2). DL2 was above the recommended phase II dose (RP2D), since 5/6 patients treated at DL2 required later treatment delays and/or dose reductions, mostly due to neutropenia. To further evaluate DL1, 3 patients were added to this cohort (total of 6). Since no DLTs were seen at DL1, and 5 of 6 patients did not require dose reduction, DL1 (avelumab 10 mg/kg IV q2weeks, axitinib 3 mg PO BID continuous, palbociclib 75 mg PO daily on days 8-28 of a 28 day cycle) is the RP2D. Conclusions: The RP2D was determined to be dose level 1. This triplet showed antitumor activity in patients with NSCLC, including those progressing on prior pembrolizumab. SIMS algorithm correlates of response are being assessed. Clinical trial information: NCT03386929 .

The precision medicine (PM) revolution is well underway, and next-generation sequencing (NGS) is helping take cancer treatment to new levels. Finding actionable targets in real time is now a reality, and data from several clinical trials based on identified molecular alterations can be assessed and can help address the question of whether personalized treatment based on genomics produces superior survival outcomes compared with unselected treatment. Targeted treatment-based clinical trials have shown benefit in molecular subgroups of patients. Of further interest, it appears that genomics and immunotherapy are coupled to each other, since the immune system recognizes neo-antigens produced by the mutanome. Hence, some of the most important markers predicting response to immunotherapy are genomic markers, PDL1 amplification (for PD-1/PD-L1 checkpoint inhibitors), and tumor mutational burden. However, a number of challenges remain to be addressed if the use of molecular profiling-guided therapy in PM-designed clinical trials is to become the standard on which cancer treatment is based. In this chapter, we explore what it will take for PM trials that use molecular profiling as part of the eligibility criteria to be successful and the remaining hurdles that need to be overcome.

Background In prior published work, the Worldwide Innovative Network (WIN) Consortium described the Simplified Interventional Mapping System (SIMS) algorithm, based on the hypothesis that both genomic and transcriptomic data are important for matching to a tri-therapy regimen. To account for variation in transcription levels between different tissues, gene by gene tumor RNA levels are normalized against RNA levels in analogous biopsied normal tissue. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced NSCLC. Methods Patients with metastatic NSCLC (no EGFR or ALK alterations; no ROS1 alteration if tested; PD-L1 unrestricted; ≤2 prior therapy lines) were treated with avelumab, palbociclib, and axitinib (3 + 3 dose escalation design). After consent, biopsies of tumor and normal endobronchial mucosa were obtained on all patients for analysis on a central genomics/transcriptomics platform and retrospective SIMS algorithm validation. A safety monitoring committee reviews study conduct at least weekly. Results Twelve patients have been treated (3 at dose level 1; 6, dose level 2; 3, dose level 3). Three dose-limiting toxicities (DLTs) at least possibly drug related occurred: 1 DLT at dose level 2 (Grade 3 (G3) infusion reaction); 2 DLTs at dose level 3 (G3 hand/foot syndrome and a G5 respiratory failure). The partial response (PR) rate was 44% (4/9 patients who have reached restaging including 2/3 patients at dose level 1; two PRs are in patients who failed prior pembrolizumab). The maximum tolerated dose was avelumab 10 mg/kg IV q2weeks, axitinib 5 mg po bid, palbociclib 75 mg po daily (7 days off; 21 days on) (dose level 2). Conclusions The tri-therapy combination of avelumab, axitinib, and palbociclib is tolerable with early evidence of activity including in NSCLC patients who failed a prior checkpoint inhibitor. Expansion cohorts are being added to further explore safety of a recommended phase II dose. Transcriptomic and genomic correlates of response are being assessed. Clinical trial identification NCT03386929; First posted: December 29, 2017. Legal entity responsible for the study Worldwide Innovative Network (WIN) Association - WIN Consortium. Funding ARC Foundation for Cancer Research and Pfizer. Disclosure B. Solomon: Travel / Accommodation / Expenses: Elekta. A. Callejo: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boerhinger; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Speaker Bureau / Expert testimony: KYOWA KIRIN ; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Celgene. J. Bar: Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Genentech; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AbbVie; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Takeda; Advisory / Consultancy: Vascular Biogenics; Research grant / Funding (institution): MedImmune. G. Berchem: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene. L. Bazhenova: Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Loxo Oncology; Shareholder / Stockholder / Stock options: Epic Sciences; Research grant / Funding (institution): Beyondspring Pharma. P. Saintigny: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): HTG Diagnostics. E. Raymond: Full / Part-time employment: Genoscience; Full / Part-time employment: Scor; Advisory / Consultancy: Pharmaengine; Travel / Accommodation / Expenses: Merck. N. Girard: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Hoffmann-La Roche; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Takeda; Advisory / Consultancy: GSK; Advisory / Consultancy: AbbVie. R. Sulaiman: Full / Part-time employment: Physicians Laboratory . E. Rubin: Travel / Accommodation / Expenses: Roche. V. Lazar: Licensing / Royalties: Worldwide Innovative Network Association. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: ABBVIE; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Blue Print Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck MGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Domme; Advisory / Consultancy, Speaker Bureau / Expert testimony: NOVARTIS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: JANSSEN; Research grant / Funding (institution): Fundation Merck Salud; Research Grant / Funding (Institution): Grant For Oncology Innovation Emd Serono. A. Onn: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. B. Leyland-Jones: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Exelixis; Speaker Bureau / Expert testimony: Genentech; Speaker Bureau / Expert testimony: Puma; Travel / Accommodation / Expenses: NFCR; Travel / Accommodation / Expenses: AkesoGen. R. Kurzrock: Shareholder / Stockholder / Stock options, Co-founder: CureMatch; Shareholder / Stockholder / Stock options: IDbyDNA; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Soluventis; Advisory / Consultancy: Gaido; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: Xbiotech; Advisory / Consultancy: Acurate Therapeutics; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: NeoMed; Research grant / Funding (institution): uardant Health; Research grant / Funding (institution): Grifols; Research grant / Funding (institution): Konica Minolta; Research grant / Funding (institution): OmniSeq; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sequenom; Research grant / Funding (institution): Foundation Medicine. All other authors have declared no conflicts of interest.

Background: NSCLC is the leading cause of cancer death. Recently, much progress has been made to identify and target specific oncogenic drivers such as EGFR mutations and ALK translocations. Unfortunately, the majority of NSCLCs do not have a single driver, but instead harbor complex systems of molecular alterations. The advent of immunooncology has opened newer avenues for treating these patients, but still, many tumors are resistant. Therefore, selection of precise therapies targeting the appropriate pathways in these tumors is an important area of research. In previously published work, the Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) algorithm to match patients to a targeted drug triplet. The SIMS algorithm is based on the hypothesis that the use of both genomic as well as transcriptomic data is important in selecting an ideal tri-therapy regimen. Since the transcriptome varies widely between different types of normal tissue, the relative level of transcription of any given gene in a tumor must be normalized against the expected level of transcription of that gene in the analogous normal tissue. The SPRING trial is the first trial assessing a rational, SIMS-based tri-therapy regimen in advanced NSCLC. The drugs utilized for SPRING–avelumab (anti-PDL1), axitinib (VEGFR inhibitor) and palbociclib (CDK4/6 inhibitor)–were chosen because the SIMS genomic/transcriptomic analysis demonstrated that ~10% of NSCLCs have a combination of these targets. Methods: Patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations are being enrolled and treated with avelumab, palbociclib, and axitinib after informed consent. During phase I, any prior treatment is allowed. SPRING will assess the safety of the tri-therapy combination and determine the recommended phase II dose (RP2D) (3+3 dose escalation). Once the RP2D is found, the study will proceed directly to the phase II portion, which will permit only previously untreated patients in the metastatic setting. A biopsy of both tumor and normal tissue (by endobronchial mucosal biopsy) is obtained on all patients, both of which are analysed in a central genomics and transcriptomics platform. The SIMS algorithm is being validated retrospectively by determining the degree of genomic and transcriptomic matching and correlating with outcome. Results: The phase I study is open in USA, Israel, Spain and Luxembourg and has enrolled 12 patients to date and has progressed to cohort 3. The phase II portion is expected to open later in 2019. This research is supported by the EMD Serono/Pfizer alliance and ARC Foundation for cancer research. Citation Format: Benjamin Solomon, Enriqueta Felip, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Nicolas Girard, Raed Sulaiman, Catherine Bresson, Fanny Wunder, J Jack Lee, Jacques Raynaud, Eitan Rubin, Brandon Young, Vladimir Lazar, Amir Onn, Brian Leyland Jones, Razelle Kurzrock. Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium Phase I/II proof-of-concept study to explore the safety and efficacy of a tri-therapy approach using avelumab, palbociclib and axitinib in advanced/metastatic non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT223.

12011Background: Precision medicine has focused mainly on matching drugs to tumor DNA alterations. However, not all individuals have tractable genomic alterations.We initiated the WINTHER trial to ...

TPS11625 Background: Today, personalized cancer medicine implies matching the patient’s tumor genomic characteristics with molecularly and immune targeted agents. Although there are an increasing number of DNA aberrations that can now be matched to a cognate therapy, some patients do not display such druggable oncogene drivers. Methods: WINTHER is an open non-randomized study involving 6 cancer centers in France, Spain, Israel, Canada and USA applying genomic and also transcriptomic assays to guide treatment decisions. The novelty of the WINTHER approach lies in the use of tumor and matched normal tissue biopsies together and an algorithm for predicting efficacy of therapies. The aim is to provide a rational therapeutic choice for all of the patients enrolled in the study whether or not they harbor actionable DNA alterations. The study endpoint is the comparison of the progression-free-survival (PFS) under the WINTHER selected therapy to the PFS of the last therapeutic line. Patients included have refractory metastatic cancer of any histological type, with at least one prior therapeutic regimen and performance status of 0 to 1. Patients who have received a matched treatment based on a molecular anomaly as their immediate prior therapy were excluded. After consent, patients undergo a tumor and histologically-matched normal tissue biopsy. Extracted DNA and RNA of both tumor and normal from frozen tissues at the local center under common standard operating procedures are sent to centralized laboratories for omics investigations. DNA is investigated at Foundation Medicine Inc. and RNA at Gustave Roussy using Agilent technology. For RNA, the WINTHER algorithm is applied on the differential RNA expression data between tumor and normal tissues and establishes the list of drugs with the presumed higher score of efficacy for each patient. Patients with actionable genomic events enter in ARM A, and patients without any druggable anomaly of the DNA enter in ARM B and are treated using the WINTHER algorithm RNA-based treatment decision tool. To date, the trial has recruited 303 patients. Clinical trial information: NCT01856296.

Lack of increased urine calcium-oxalate supersaturation in long-term kidney transplant recipients. Nephrolithiasis is uncommon after kidney transplantation. However, calcium (Ca) supplementation, which has been proposed as a treatment of post-transplant osteopenia, might increase calciuria and bolster Ca stone formation. Therefore, in 24-hour urine of 82 normocalcemic long-term renal transplant recipients (RT) and in 82 healthy subjects (HS), we assessed some Ca nephrolithiasis risk factors and the Ca-salt saturation estimated by the ion-activity product index (AP) and relative supersaturation (RS). In RT, calciuria was lower (mean ± SD, 3.20 ± 2.25 vs. 4.61 ± 1.71 mmol/day; P < 0.001), urinary volume higher (2.41 ± 0.83 vs. 1.39 ± 0.53 liter/day; P < 0.001), oxaluria higher (419 ± 191 vs. 311 ± 79 µmol/day; P < 0.001) and citraturia lower (1.40 ± 1.36 vs. 3.77 ± 1.36 mmol/day; P < 0.001) than in HS. As a result, Ca-oxalate supersaturation was lower in RT than HS (AP, 1.07 ± 0.69 vs. 2.07 ± 1.13, P < 0.001; and RS, 0.62 ± 0.26 vs. 0.94 ± 0.21, P < 0.001), and was similar in subgroups of RT (N = 37) and HS (N = 37) matched for urinary volume, demonstrating that even without any larger urinary volume, Ca-oxalate saturation was not higher in RT than HS, and suggesting that opposite changes in Ca and oxalate in RT likely canceled their effects on lithogenic risk. In RT which had similar urinary pH and phosphate (P) than HS, Ca-P supersaturation was lower than in HS for brushite (AP, 3.25 ± 6.67 vs. 6.01 ± 4.85, P < 0.001; RS, -0.33 ± 0.76 vs. 0.48 ± 0.53, P < 0.001) and octacalcium phosphate (RS, -0.95 ± 0.72 vs. 0.21 ± 0.85, P < 0.001), and similar for apatite. Finally, fasting calciuria and calciuric response to a single oral Ca load were similar in RT (N = 19) and HS (N = 8). Together, these results argue strongly against a higher risk of Ca stone formation in RT than HS, even in case of Ca supplementation.

7524 Background: Combining three targeted therapies significantly improved outcomes in AIDS. A similar strategy could theoretically benefit patients with metastatic NSCLC, but a scientific method f...

Although hyperparathyroidism is a common feature in renal transplant recipients, the long-term course of parathyroid hormone (PTH) secretion in these patients is not well established, and the actual contribution of PTH to posttransplant bone disease remains incompletely understood. Therefore, we studied calcium-regulating hormones and serum osteocalcin, as a marker of bone remodeling, in 82 normocalcemic renal transplant recipients with good renal function who had received a graft 6 to 73 months previously and in 82 healthy subjects matched for age and sex. In all subjects, fasting serum and 24-hour urinary samples were collected. The transplant recipients had excessive PTH secretion (serum PTH, 6.9 +/- 0.5 pmol/L in recipients v 3.0 +/- 0.1 pmol/L in healthy subjects; P0.001) and high bone turnover (osteocalcin, 16.6 +/- 0.8 microg/L v 8.0 +/- 0.3 microg/L; P0.001). (Values are mean +/- SEM.) In addition, transplant recipients had a slightly higher ionized calcium than the healthy subjects, providing definite evidence of an inappropriate PTH secretion in renal transplant recipients. Furthermore, in subgroups of 25 recipients and 25 healthy controls matched for creatinine clearance, the results superimposed those obtained in the whole groups, suggesting that excessive PTH secretion and high bone turnover in renal transplant recipients did not merely reflect the moderately reduced renal function of some recipients. In the whole group of transplant recipients, PTH correlated positively with osteocalcin (r = 0.40; P0.001), suggesting that PTH contributes at least partly to posttransplant bone disease. Conversely, there was no correlation between serum PTH or osteocalcin and the delay from grafting. Therefore, our results provide no evidence for a spontaneous improvement of either persistent hyperparathyroidism or high bone turnover in normocalcemic long-term renal transplant recipients.

Since the effects of cyclosporine on mineral and bone metabolism are controversial, we studied calcium regulating hormones, calcium-phosphorus (Ca-P) metabolism, and bone remodeling, assessed by serum osteocalcin, in long-term renal transplant recipients (RT). Forty-seven normocalcemic patients with good renal function receiving cyclosporine (CT, n = 27) or not (NC, n = 20) were studied at baseline and after an oral Ca load. CT and NC had similar age, daily dose of steroids, GFR level, and duration of transplantation. Baseline evaluation included 24-hr urinary Ca, P, TRP, TmP/GFR, fasting serum intact PTH, 1,25-(OH)2D, 25OHD, osteocalcin, Ca, and P. Subjects of the two groups had excessive secretion of PTH, tubular P wasting, and high serum osteocalcin level, as is usual in RT. However, there was no difference between CT and NC regarding any baseline variable. Ten CT and ten NC, matched for duration of transplantation and serum PTH level, ingested 1g Ca to achieve an acute dynamic study of PTH secretion and Ca-P metabolism. In both CT and NC, this Ca load caused the same decreases in serum PTH (P < 0.001), NcAMP (P < 0.05), and urinary P (P < 0.001) and the same increases in serum and urinary Ca (P < 0.001), and in both TmP/GFR and TRP (P < 0.001). These results strongly suggest that cyclosporine treatment had no significant effect on calcium-regulating hormone secretion, P-Ca metabolism, and bone remodeling level. We therefore consider that cyclosporine is unlikely to have any prominent role in the abnormalities of bone endocrine and mineral metabolism that are common in long-term kidney recipients.

Persistent hyperparathyroidism and impaired tubular reabsorption of phosphate (P) are common after kidney transplantation. In order to assess the suppressibility of these abnormalities, we studied the effects of a single oral calcium (Ca) load (1 g) in 7 healthy subjects (HS) and in 14 normocalcemic long-term renal transplant recipients with good renal function (RT). In HS and RT, serum and urinary Ca were similar at baseline, and increased (p < 0.001) to the same extent after Ca ingestion. Serum parathyroid hormone (PTH) and nephrogenic cAMP (NcAMP) levels were higher at baseline in RT than HS (mean +/- SEM; respectively, PTH 7.8 +/- 0.8 vs. 3.5 +/- 0.6 pmol/l, p < 0.001, and NcAMP 24.8 +/- 2.3 vs. 13.9 +/- 2.3 nmol/l GFR, p < 0.01). After Ca, PTH (p < 0.001) and NcAMP (p < 0.01) decreased markedly in both RT and HS. Maximal changes in PTH and NcAMP were larger in RT than HS (PTH - 3.3 +/- 0.4 vs. -2.1 +/- 0.03 pmol/l, p < 0.01, and NcAMP -18.2 +/- 3.3 vs. -8.1 +/- 2.6 nmol/l GFR, p < 0.05). Although PTH levels remained significantly higher in RT than HS from baseline to the end of the study (p < 0.001), PTH decreased to the normal range in RT after Ca load. Moreover, NcAMP reached similar values in RT and HS after Ca (16.0 +/- 3.3 vs. 13.2 +/- 2.8 nmol/l GFR at the end of the survey, NS).(ABSTRACT TRUNCATED AT 250 WORDS)