Search

Validation of the Kidney Disease Quality of Life (KDQOL) Cognitive Function subscale.BackgroundFormal cognitive function testing is cumbersome, and no self-administered instruments for estimating cognitive function in persons with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have been validated. The goal of this study was to determine the validity of the Kidney Disease Quality of Life Cognitive Function scale (KDQOL-CF) for the assessment of cognitive impairment in persons with kidney disease.MethodsWe administered the KDQOL-CF to 157 subjects, 79 with ESRD and 78 with CKD participating in a cross-sectional study of cognitive function. Scores on the Modified Mini-Mental State Exam (3MS) were considered the gold standard measure of global cognitive function. Performance characteristics of the KDQOL-CF were assessed using correlation coefficients, Bland-Altman plots, and receiver operating characteristic curves.ResultsMedian scores on the KDQOL-CF were 73 (interquartile range 60–87) for subjects with ESRD and 87 (interquartile range 73–100) for subjects with CKD (P < 0.0001). Scores on the KDQOL-CF were directly correlated with scores on the 3MS (r = 0.31, P = 0.0001). Defining global cognitive impairment as a 3MS score

Objectives: To assess the prevalence of cognitive impairment in persons with chronic kidney disease (CKD) and its relation to the severity of CKD. Design: Cross-sectional study. Setting: University-affiliated ambulatory nephrology and dialysis practices. Participants: Eighty subjects with CKD Stages III and IV not requiring dialysis (CKD) and 80 subjects with CKD Stage V on hemodialysis (end-stage renal disease (ESRD)) with a mean age±standard deviation of 62.5±14.3. Measurements: Three standardized cognitive tests, the Modified Mini-Mental State Examination (3MS), Trailmaking Test B (Trails B), and California Verbal Learning Trial (CVLT). Glomerular filtration rate was estimated in subjects with CKD using the six-variable Modification of Diet in Renal Disease equation. Results: There was a graded relation between cognitive function and severity of CKD. Mean scores on the 3MS, Trails B, and CVLT immediate and delayed recall were significantly worse for subjects with ESRD than for subjects with CKD or published norms (P

This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of treatment of liver-dominant metastatic gastrointestinal cancer using (90)Y glass microspheres.Between June 2010 and November 2012, 30 adult patients (22 men, eight women; median age 61 years) with metastatic chemotherapy-refractory unresectable colorectal (n = 15), neuroendocrine (n = 9), intrahepatic cholangiocarcinoma (n = 3), pancreas (n = 2), and esophageal (n = 1) carcinomas underwent 45 lobar or segmental administrations of (90)Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for 6 months after each treatment. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Time to maximum response, response duration, progression-free survival (hepatic and extrahepatic), and overall survival were measured.Median target dose and activity were 111.6 Gy and 2.5 GBq per treatment session, respectively. All but three clinical AE were grade 1 or 2 in severity. Serious AE included an unplanned hospital admission for carcinoid crisis, grade 3 vomiting, and grade 4 gastric ulcer. Patients with colorectal cancer had hepatic objective response rate (ORR) of 27 % and a disease control rate (DCR) of 73 %. Median progression-free and overall survival were 1.0 and 4.9 months, respectively. Patients with neuroendocrine tumors had hepatic ORR and DCR of 78 % and 100 %, respectively. Median progression-free survival was 18.5 months for this cohort.Y glass microspheres device has a favorable safety profile and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.

Congenital localized absence of the skin has been observed in various subsets of inherited epidermolysis bullosa (EB). Pyloric atresia is a rare disorder that has been seen in association with EB. Ureterovesical junction obstruction is a condition unique to the association between pyloric atresia and EB. The authors describe 2 premature male siblings with pyloric atresia, congenital localized absence of the skin, urinary obstruction, and EB at birth. Electron microscopic study of the biopsy specimen from the first sibling revealed characteristic findings of EB simplex. However, prenatal diagnosis of the next sibling was made by integrin B4 mutations and the electron microscopic study of the biopsy specimen after delivery confirmed junctional EB (JEB). These cases emphasize this unusual combination of defects and limitations of electron microscopy.

Background: Although sleep complaints are commonly reported in persons with end stage renal disease (ESRD), little is known about the prevalence of sleep complaints in chronic kidney disease (CKD), and the relation of sleep quality to the severity of kidney disease. Methods: We administered the Kidney Disease Quality of Life (KDQOL) sleep scale to 156 subjects, 78 with ESRD and 78 with CKD. Glomerular filtration rate (GFR) was estimated using the six variable Modification of Diet in Renal Disease (MDRD) equation and used to stratify subjects with CKD as mild-moderate (GFR >25 ml/min/1.73 m2) and advanced (GFR

To assess the prevalence of cognitive impairment in persons with chronic kidney disease (CKD) and its relation to the severity of CKD.Cross-sectional study.University-affiliated ambulatory nephrology and dialysis practices.Eighty subjects with CKD Stages III and IV not requiring dialysis (CKD) and 80 subjects with CKD Stage V on hemodialysis (end-stage renal disease (ESRD)) with a mean age+/-standard deviation of 62.5+/-14.3.Three standardized cognitive tests, the Modified Mini-Mental State Examination (3MS), Trailmaking Test B (Trails B), and California Verbal Learning Trial (CVLT). Glomerular filtration rate was estimated in subjects with CKD using the six-variable Modification of Diet in Renal Disease equation.There was a graded relation between cognitive function and severity of CKD. Mean scores on the 3MS, Trails B, and CVLT immediate and delayed recall were significantly worse for subjects with ESRD than for subjects with CKD or published norms (P.001 for all comparisons). Scores on the Trails B (P.001) and CVLT immediate (P=.01) and delayed (P.001) recall were significantly worse for subjects with CKD not requiring dialysis than for published norms. In addition, the fraction of subjects with impairment on the 3MS and Trails B increased with decreasing kidney function.Cognitive impairment is associated with the severity of kidney disease. Further studies are needed to determine the reasons for cognitive impairment in subjects with CKD and ESRD.

Infection with Borrelia burgdorferi, the cause of Lyme disease, has been accompanied by a puzzling delayed antibody (Ab) response to B. burgdorferi antigens (Ags) including the abundant organism-specific outer surface proteins, such as the 31-kD OspA. In humans the response to nonspecific B. burgdorferi Ags has required 3–6 weeks. The response to OspA has rarely been detected by conventional methodology until months after infection, despite demonstrable T cell reactivity. Tick inoculation and low-dose intradermal inoculation animal models have been characterized by a comparable response to OspA. Using more sensitive biotin-avidin immunoblots and immune complex (IC) dissociation techniques, we demonstrated in humans that Ab to OspA is formed early but may remain at low levels or bound in IC. To see if this was a universal biologic response, animal models were analyzed by these methods. The results with mice, monkeys and rabbits show that IC Ab to OspA may be detected at the onset of infection. The data suggest that these animal models may be used to understand the immune response to B. burgdorferi and the pathogenesis of Lyme disease. With attention to unique B. burgdoferi Ags, these results are likely to have both clinical and diagnostic importance.

3507 Background: TheBRAF V600 mutation occurs in 5-10% of metastatic CRC, predicts poor prognosis, and may predict lack of response to standard therapy. The combination of inhibitors of BRAF (dabrafenib; D) and MEK (trametinib; T) has shown significant efficacy in BRAF-mutant melanoma. The safety, efficacy, and pharmacodynamic effects of this combination were studied in BRAF-mutant CRC patients (pts). Methods: BRAF mutant CRC pts were enrolled to an initial efficacy cohort of 26 pts and a subsequent pharmacodynamic (PD) expansion cohort that included biopsies of 15 pts at screening and at steady state. So far, 36 pts have enrolled, including 10 in the PD cohort. Eligible pts had previously-treated BRAFV600E mutant stage IV CRC. Pts were treated with D (150mg BID) and T (2mg QD). Additional analyses were performed on available archival tissues. Results: Data are available for 36 pts: ECOG performance status 0 (58%) or 1 (42%), 81% had received ≥ 2 prior chemotherapy regimens, 36% had received prior EGFR inhibitor treatment, and 83% had ≥ 1 biologic therapy. Among 34 pts with >1 restaging assessment as of November 2012, 1 (3%) achieved a complete response (confirmed, on study >12m), 3 (9%) achieved a partial response (1 confirmed to date), and 18 (53%) had stable disease (SD). Minor responses were seen in 7/18 pts (39%) with SD. Median PFS was 3.5 mo (95% CI: 1.8-4.9); overall duration on study range: 0.03–15.2 mo 7 pts (24%) remained on study for ≥6 cycles with 9 pts still on study. The most frequent AEs, any grade, included pyrexia (67%), nausea (56%), fatigue (53%), chills (47%), vomiting (39%), headache (31%), peripheral edema (31%), anemia (28%), and decreased appetite (28%). 2 pts (6%) discontinued due to AEs. Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ±29%) and relative (69% ±28%, normalized to total ERK) reduction in pERK. Conclusions: Further investigation is needed, as this combination is tolerable at full monotherapy doses of each drug, with manageable toxicities, and has activity in a subset of BRAF mutant pts. Updated safety, efficacy, and correlative data will be presented. Clinical trial information: NCT01072175.

3528 Background: BRAF V600 mutations occur in 10-15% of CRC and may predict lack of response to standard chemotherapy and anti-EGFR treatment. There have been no significant recent changes in the treatment of CRC. Novel therapeutic strategies for BRAF mutant CRC are critically needed. To collect preliminary efficacy data, an expansion cohort of 25 BRAF mutant CRC patients (pts) was included in part 2 of a phase I/II study evaluating the combination of dabrafenib (BRAFi) and trametinib (MEKi). Methods: Eligible pts had BRAF V600 mutant CRC, measurable disease per RECIST 1.1, and previous treatment with anti-cancer therapies. Pts were treated with established dose of dabrafenib (150mg BID) and trametinib (2mg QD). Results: Data for 23 pts are available at data cut-off: median age 54 years, 74% female, ECOG performance status 0 (48%) or 1 (52%). 39% had received prior EGFR inhibitor treatment. 74% had received ≥ 2 prior chemotherapy regimens; 48% had ≥ 1 biologic therapy. 48% had ≥ 3 metastatic sites. Three of the 23 pts were non-evaluable at data cut-off as they had not reached the first restaging assessment. Among the 20 evaluable pts, 1 (5%) achieved partial response and 10 (50%) stable disease. Minor responses (>10% to

e19046 Background: Pyrexia (fever) is a common adverse event associated with combined BRAF and MEK inhibition (dabrafenib and trametinib). Although the mechanism of fever is unclear, we explore pyrexia as a pharmacodynamic marker for clinical response. Methods: A phase II international trial with dabrafenib and trametinib in metastatic melanoma (MM) and colorectal cancers (CRC) harboring BRAF mutations is ongoing. Twenty-nine patients (pts) were enrolled at UCSF between January 2011 and January 2012. Fevers were graded based on temperature and coinciding symptoms, and an episode of pyrexia was defined as a temperature of >100 °F at least once a day for one or more consecutive days. Tumor assessments were performed every 8 weeks (wks). Results: To date, 13 pts with MM and 5 with CRC had tumor assessments up to 24 wks. In MM, pyrexia was reported 2 or more times in 7 pts; 5 had none, and 1 reported one episode of Grade 1 pyrexia. Episodes occurred 2-4 wks after starting treatment, and time between subsequent recurrences ranged from 1 to 25 wks. Neutrophil counts showed early fluctuations, but none had neutropenia. Of the 7 pts with recurring fevers, 5 had partial responses and 2 had stable disease at 8 wks. Of the 6 pts with nonrecurring or no fevers, 2 had partial responses at 8 wks, and 1 progressed. At 24 wks, all 7 pts with ≥ 2 fever episodes remained progression-free, whereas 0/6 pts with < 2 fever episodes were progression-free (p < 0.001). Pts without progression continued to have recurring fevers (median = 4). There were no differences by disease stage (12 of 13 with M1c) or mutation status (10 with V600E; 2 with V600K; 1 with V600E + V601I). While pts with CRC had pyrexia, no association between pyrexia and response was noted; however, only 5 pts are included in this analysis. Conclusions: In this limited analysis of pts with MM, recurrent fevers were associated with durable response (≥ 24 wks). These results suggest that pyrexia could be a marker for inflammation and antitumor activity. Further studies are underway to characterize cytokine profiles and immune responses. [Table: see text]

To the Editor: The diagnosis of a new Lyme disease infection by conventional assays may be difficult in persons who have antibodies to or immunologic memory of Borrelia burgdorferi proteins. This w...