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Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium × phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or ‘damage’ of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients.Kidney International (2008) 73, 384–390; doi:10.1038/sj.ki.5002696; published online 28 November 2007 [ABSTRACT FROM AUTHOR]

To further explore the clinical applicability of the calcium (Ca) isotope marker (CIM), we determined the 44Ca/42Ca isotope ratio in blood serum and urine. This ratio is expressed in the conventional δ-notation (as defined in the text below) specifically as CIM-serum for serum and as CIM-urine for urine. Our study tested the hypothesis that CIM values can differentiate between positive and negative bone mineral balance (BMB) across a diverse clinical population considering variables such as age, gender, and diet. The threshold values (CIM-serum: −0.85 ± 0.06 ‰ and CIM-urine: 0.23 ± 0.06 ‰) established in the OsteoGeo study (NCT02967978 , Eisenhauer et al., 2019) were evaluated in 2320 participants as part of a surveillance study referred to as Osteolabs study. The earlier study revealed women with osteoporosis had an average CIM-serum value of −0.91 ± 0.21 ‰ (N = 24) and a CIM-urine value of 0.18 ± 0.33 ‰ (N = 71) that are significantly below the threshold values (p = 0.02 for urine, one-sided Wilcoxon rank test, p < 0.001 for serum, one-sided Student's t -test). Diseases affecting BMB such as osteoporosis, acute and chronic kidney disease (CKD), hyperthyroidism, breast cancer, prostate cancer, and myeloma were associated with significantly lower average CIM values, falling below the equilibrium thresholds and indicating negative BMB. In contrast, patients receiving osteoprotective treatments such as denosumab, Romosozumab, bisphosphonates, or hormone replacement therapy for certain diseases, had CIM values above the equilibrium thresholds indicating a positive BMB. Additionally, Ca supplements taken by some of the patients ((N = 22 (serum), N = 49 (urine), median dose: 500 mg) showed a Ca isotope composition approximately 1 ‰ higher than that from a normal diet. Consequently, their CIM values need to be adjusted to account for the amount and duration of supplementation to be comparable to those with a normal diet. Participants taking vitamin D (237 women; 58 men) showed no significant difference from the average values of the study group. Counterintuitively, the possible impact of malnutrition on individual BMB was most pronounced in vegans, who exhibited the highest average CIM-urine values compared to patients on a normal diet (p < 0.001, N = 17). The results of this study were consistent with the registered OsteoGeo study (NCT02967978) and other earlier published Ca isotope-based studies on BMB. We confirm that the CIM threshold values determined in the OsteoGeo study are generally valid for this much larger and diverse surveillance study group covering a diverse population encompassing various medical conditions and therapies. • First report on the application of CIM in the serum and urine of 2320 participants • CIM correlates with all metabolic diseases affecting musculoskeletal metabolism • Diseases negatively affecting BMB fall below CIM thresholds • Osteoprotective treatment positively affecting BMB fall above the CIM thresholds [ABSTRACT FROM AUTHOR]

Background: Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods: The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m² every 3 weeks but was reduced to 220 mg/m² owing to toxicity. Results: A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P=0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion: Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA. [ABSTRACT FROM AUTHOR]

Background: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. Patients and methods: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. Results: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. Conclusions: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. [ABSTRACT FROM AUTHOR]

Background Whether carcinomas of the ampulla of Vater should be classified with biliary tract tumors and treated in a similar manner remains unknown. We sought to compare the outcomes of similarly staged periampullary adenocarcinomas (AAs) and analyze the chemotherapy responsiveness of AAs. Patients and methods A total of 905 patients with resected periampullary adenocarcinomas were identified from a prospective surgical registry from 1988 to 2010. A second cohort of 64 metastatic AA patients from 1992 to 2009 who received either front-line fluoropyrimidine-based or gemcitabine-based chemotherapy was also identified. Results Overall survival (OS) for AAs was similar to survival with duodenal adenocarcinomas, but was significantly different from both extrahepatic biliary and pancreatic adenocarcinomas (P < 0.001 for each comparison). In multivariate analysis, AAs had a significantly improved OS in comparison with extrahepatic biliary adenocarcinomas (HR = 1.97, P = 0.006). Fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy for metastatic AAs resulted in a significant improvement in time to progression (P = 0.001) but only a trend toward benefit for OS (P = 0.07) in multivariate analysis. Conclusions Differences in the natural history of ampullary and extrahepatic biliary adenocarcinomas exist. Analyses of metastatic ampullary adenocarcinomas suggest that fluoropyrimidine-based chemotherapy may represent a more appropriate front-line chemotherapy approach. [ABSTRACT FROM PUBLISHER]

Many chronic illnesses affect bone health, and commonly lead to mineralization abnormalities in young people. As cortical and trabecular bone may be differentially affected in certain diseases, an imaging technique that allows for detailed study of the bone structure is required. Peripheral quantitative computed tomography (pQCT) overcomes the limitations of dual energy X-ray absorptiometry (DXA) and is perhaps more widely available for use in research than bone biopsy. However, in contrast to DXA, where there are large reference datasets, this is not the case for pQCT. Fifty-five children and young adults aged 7 to 30 years had the non-dominant tibia scanned at the 3% & 4% sites for trabecular bone mineral density and the 38% site for cortical bone mineral density and bone mineral content. Image acquisition and analysis was undertaken according to the protocols of two of the largest reference datasets for tibial pQCT. The Z-scores generated were compared to examine the differences between protocols and the differences from the expected median of zero in a healthy population. The trabecular bone mineral density Z-scores generated by the two protocols were similar. The same was true for cortical mineral content Z-scores at the 38% site. Cortical bone mineral density was significantly different between protocols and likely affected by differences in the ethnicity of our cohort compared to the reference datasets. Only one reference dataset extended from childhood to young adulthood. Only trabecular bone mineral density, periosteal and endosteal circumference Z-scores from one methodology were not significantly biased when tested for deviation of the median from zero. pQCT is a useful tool for studying trabecular and cortical compartments separately but, there are variations in pQCT scanning protocols, analysis methodology, and a paucity of reference data. Reference datasets may not be generalizable to local study populations, even when analysed using identical analysis protocols. • pQCT is a useful tool for assessing trabecular and cortical compartments separately. • There is a marked variation in the literature in methods and scanning protocols. • There are few reference datasets to use as comparators. • Reference datasets may not be generalizable to local study populations. [ABSTRACT FROM AUTHOR]