Discordant Mismatch Repair Protein Immunoreactivity in Lynch Syndrome-Associated Neoplasms: A Recommendation for Screening Synchronous/Metachronous Neoplasms.

OBJECTIVES: Lynch syndrome (LS) predisposes individuals to developing synchronous and metachronous LS-associated neoplasms (LSANs). Mismatch repair protein (MMRP) immunohistochemistry (IHC) is widely used to identify LS, but its utility in patients with synchronous/metachronous lesions has not been studied. We studied MMRP IHC in patients with LS with more than one LSAN to provide screening recommendations in patients with synchronous/metachronous neoplasms. METHODS: All patients with LS diagnosed at The Ohio State University Wexner Medical Center from 2009 through 2014 with more than one LSAN and available tumor tissue for immunostaining were identified. Tumors were stained for MLH1, MSH2, MSH6, and PMS-2 proteins, and immunoreactivity was scored as intact or lost. RESULTS: Thirteen patients with LS with 29 synchronous and/or metachronous primary LSANs were identified. Neoplasms involved large and small intestine (n = 19), ampulla (n = 1), endometrium (n = 1), and skin (sebaceous neoplasms, n = 8). Nine (69%) of 13 patients showed concordant MMRP results in all tumors, and four (31%) showed discordant MMRP results. CONCLUSIONS: LS diagnosis could have been missed in 31% of the study cases if only the LSAN exhibiting intact MMRP expression was screened. Accordingly, our findings support the recommendation to perform LS screening in all primary, synchronous, and metachronous intestinal and endometrial cancers if a previous tumor screened intact.

A modified Lynch syndrome screening algorithm in colon cancer: BRAF immunohistochemistry is efficacious and cost beneficial.

OBJECTIVES: Somatic BRAF mutation in colon cancer essentially excludes Lynch syndrome. We compared BRAF V600E immunohistochemistry (IHC) with BRAF mutation in core, biopsy, and whole-section slides to determine whether IHC is similar and to assess the cost-benefit of IHC. METHODS: Resection cases (2009-2013) with absent MLH1 and PMS2 and prior BRAF mutation polymerase chain reaction results were chosen (n = 57). To mimic biopsy specimens, tissue microarrays (TMAs) were constructed. In addition, available biopsies performed prior to the resection were available in 15 cases. BRAF V600E IHC was performed and graded on TMAs, available biopsy specimens, and whole-section slides. Mutation status was compared with IHC, and cost-benefit analysis was performed. RESULTS: BRAF V600E IHC was similar in TMAs, biopsy specimens, and whole-section slides, with only four (7%) showing discordance between IHC and mutation status. Using BRAF V600E IHC in our Lynch syndrome screening algorithm, we found a 10% cost savings compared with mutational analysis. CONCLUSIONS: BRAF V600E IHC was concordant between TMAs, biopsy specimens, and whole-section slides, suggesting biopsy specimens are as useful as whole sections. IHC remained cost beneficial compared with mutational analysis, even though more patients needed additional molecular testing to exclude Lynch syndrome.

Progressive renal light chain amyloidosis with the absence of detectable free monoclonal light chains after an autologous hematopoietic stem cell transplant for amyloid light chain amyloidosis.

Amyloid light chain amyloidosis involving the kidneys is not uncommon in patients with monoclonal gammopathy. The mainstay of treatment of amyloid light chain amyloidosis is autologous hematopoietic stem cell transplantation. Evidence that the autologous hematopoietic stem cell transplantation has been successful is the absence of free monoclonal light chains in serum and urine. Herein, we report 2 cases of progressive renal amyloid light chain amyloidosis after autologous hematopoietic stem cell transplantation, documented by kidney biopsy, despite the absence of monoclonal protein in the serum and urine. Kidney function declined progressively in both patients. During that time, numerous immunofixation and protein electrophoresis test results were negative for monoclonal protein, both in serum and urine, concealing the progression of the amyloidosis. We conclude that close monitoring of kidney function is warranted following autologous hematopoietic stem cell transplantation in patients with amyloid light chain amyloidosis, even with negative results from monoclonal protein testing. Unexplained, worsening renal function warrants a kidney biopsy to assess whether retreatment of the monoclonal gammopathy is indicated.

Bicarbonate kinetics and predicted energy expenditure in critically ill children.

BACKGROUND: To determine nutrient requirements by the carbon oxidation techniques, it is necessary to know the fraction of carbon dioxide produced during the oxidative process but not excreted. This fraction has not been described in critically ill children. By measuring the dilution of (13)C infused by metabolically produced carbon dioxide, the rates of carbon dioxide appearance can be estimated. Energy expenditure can be determined by bicarbonate dilution kinetics if the energy equivalents of carbon dioxide (food quotient) from the diet ingested are known. OBJECTIVE: We conducted a 6-h, primed, continuous tracer infusion of NaH(13)CO(3) in critically ill children fed parenterally or enterally or receiving only glucose and electrolytes, to determine bicarbonate fractional recovery, bicarbonate rates of appearance, and energy expenditure. DESIGN: Thirty-one critically ill children aged 1 mo-20 y who were admitted to a pediatric intensive care unit at a tertiary-care center were studied. Patients were stratified by age, BMI, and severity score (PRISM III). RESULTS: Fractional bicarbonate recovery was 0.69, 0.70, and 0.63, respectively, for the parenterally fed, enterally fed, and glucose-electrolytes groups, and it correlated with the severity of disease in the parenteral (P < 0.01) and glucose-electrolytes (P < 0.05) groups. Rates of appearance varied between 0.17 and 0.19 micromol . kg(-1) . h(-1) With these data and estimates of the energy equivalents of carbon dioxide (a surrogate for respiratory quotient), energy expenditure was determined. CONCLUSIONS: The 2001 World Health Organization and Schofield predictive equations overestimated and underestimated, respectively, energy requirements compared with those obtained by bicarbonate dilution kinetics. Bicarbonate kinetics allows accurate determination of energy needs in critically ill children.

Adaptation to a long term (4 weeks) arginine- and precursor (glutamate, proline and aspartate)-free diet.

BACKGROUND & AIMS: It is not known whether arginine homeostasis is negatively affected by a "long term" dietary restriction of arginine and its major precursors in healthy adults. To assess the effects of a 4-week arginine- and precursor-free dietary intake on the regulatory mechanisms of arginine homeostasis in healthy subjects. METHODS: Ten healthy adults received a complete amino acid diet for 1 week (control diet) and following a break period, six subjects received a 4-week arginine, proline, glutamate and aspartate-free diet (APF diet). The other four subjects continued for 4 weeks with the complete diet. On days 4 and 7 of the first week and days 25 and 28 of the 4-week period, the subjects received 24-h infusions of arginine, citrulline, leucine and urea tracers. RESULTS: During the 4-week APF, plasma arginine fluxes for the fed state, were significantly reduced. There were no significant differences for citrulline, leucine or urea fluxes. Arginine de novo synthesis was not affected by the APF intake. However, arginine oxidation was significantly decreased. CONCLUSIONS: In healthy adults, homeostasis of arginine under a long term arginine- and precursor-free intake is achieved by decreasing catabolic rates, while de novo arginine synthesis is maintained.

Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis.

BACKGROUND: The value of measuring serial antineutrophil cytoplasmic autoantibody (ANCA) titers in guiding therapy among patients with ANCA-associated vasculitis is controversial. METHODS: We measured serial titers of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA by antigen-specific enzyme-linked immunosorbent assays (ELISAs) in 48 patients with ANCA-associated vasculitis who were followed up during remission at the Massachusetts General Hospital from 1990 through 2000 (mean follow-up, 46.2 months). We retrospectively assessed disease activity by Birmingham Vasculitis Activity Score (BVAS). RESULTS: We found 21 episodes of fourfold or greater ANCA titer rises in 17 patients who were in complete remission (BVAS=0). Among eight patients who had 10 such titer rises and were not given increased immunosuppression, (group I), all suffered relapses after each episode (mean interval, 5.8 months), whereas among 11 patients, each with one titer rise, who received preemptive increased immunosuppression, (group II), only two relapses occurred, at 3 and 6 months. The difference in the cumulative incidence of relapses in a 1-year period between the two groups was 82% (P=0.0002). Changes in ANCA titers were also used to help guide therapy in the other 31 patients in the study; patients with slight titer rises often received incremental increases in immunosuppression, whereas those with falling titers received incremental decreases. The overall outcome in the entire group was favorable; 46 patients were alive at the end of the study; two died of unrelated diseases. CONCLUSION: Serial measurements of PR3- and MPO-ANCA titers in patients with ANCA-associated vasculitis during remission can help predict relapses, and preemptive increases in immunosuppression following fourfold titer rises reduces the risk of relapses. Moreover, adjustment of immunosuppression based on lesser titer changes appears to result in a favorable outcome.