Kouichi Haraguchi

Adult T-Cell Leukemia in a Liver Transplant Recipient That Did Not Progress after Onset of Graft Rejection

A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T- cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.

Masked t(15;17) APL with the insertion of PML–RARα fusion gene in 4q21

Most cases of acute promyelocytic leukemia (APL) are characterized by the reciprocal translocation t(15;17); however, several complex variant translocations have also been reported. Here we report complex cytogenetic abnormalities without t(15;17) assayed by the G-banding method in a 62-year-old woman with the typical morphology and clinical features of APL. Based on spectral karyotyping and FISH analyses, we confirm the insertion of a cryptic chromosomal segment containing the PML/RARalpha fusion gene. The patient achieved complete remission after treatment with all-trans retinoic acid (ATRA) alone. Although the mechanism of this cryptic variant insertion is not known, we conclude that the insertion of PML-RARalpha fusion into 4q21 seems not to alter the effectiveness of treatment with ATRA.

Clinical significance of cutaneous adverse reaction to mogamulizumab in relapsed or refractory adult T-cell leukaemia-lymphoma

Altrock, P.M., Liu, L.L. & Michor, F. (2015) The mathematics of cancer: integrating quantitative models. Nature Reviews Cancer, 15, 730–745. Gerstung, M., Papaemmanuil, E. & Campbell, P.J. (2014) Subclonal variant calling with multiple samples and prior knowledge. Bioinformatics (Oxford, England), 30, 1198–1204. Gibson, C.J., Lindsley, R.C., Tchekmedyian, V., Mar, B.G., Shi, J., Jaiswal, S., Bosworth, A., Francisco, L., He, J., Bansal, A., Morgan, E.A., Lacasce, A.S., Freedman, A.S., Fisher, D.C., Jacobsen, E., Armand, P., Alyea, E.P., Koreth, J., Ho, V., Soiffer, R.J., Antin, J.H., Ritz, J., Nikiforow, S., Forman, S.J., Michor, F., Neuberg, D., Bhatia, R., Bhatia, S. & Ebert, B.L. (2017) Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. Journal of Clinical Oncology, JCO2016716712. [Epub ahead of print] Li, H. & Durbin, R. (2010) Fast and accurate longread alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England), 26, 589–595. Link, D.C. & Walter, M.J. (2016) ‘CHIP’ping away at clonal hematopoiesis. Leukemia, 30, 1633– 1635. McKerrell, T., Park, N., Moreno, T., Grove, C.S., Ponstingl, H., Stephens, J., Understanding Society Scientific Group, Crawley, C., Craig, J., Scott, M.A., Hodkinson, C., Baxter, J., Rad, R., Forsyth, D.R., Quail, M.A., Zeggini, E., Ouwehand, W., Varela, I. & Vassiliou, G.S. (2015) Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Reports, 10, 1239–1245. Rowland, J.H. & Bellizzi, K.M. (2014) Cancer survivorship issues: life after treatment and implications for an aging population. Journal of Clinical Oncology, 32, 2662–2668. Welch, J.S., Ley, T.J., Link, D.C., Miller, C.A., Larson, D.E., Koboldt, D.C., Wartman, L.D., Lamprecht, T.L., Liu, F., Xia, J., Kandoth, C., Fulton, R.S., McLellan, M.D., Dooling, D.J., Wallis, J.W., Chen, K., Harris, C.C., Schmidt, H.K., Kalicki-Veizer, J.M., Lu, C., Zhang, Q., Lin, L., O’Laughlin, M.D., McMichael, J.F., Delehaunty, K.D., Fulton, L.A., Magrini, V.J., McGrath, S.D., Demeter, R.T., Vickery, T.L., Hundal, J., Cook, L.L., Swift, G.W., Reed, J.P., Alldredge, P.A., Wylie, T.N., Walker, J.R., Watson, M.A., Heath, S.E., Shannon, W.D., Varghese, N., Nagarajan, R., Payton, J.E., Baty, J.D., Kulkarni, S., Klco, J.M., Tomasson, M.H., Westervelt, P., Walter, M.J., Graubert, T.A., DiPersio, J.F., Ding, L., Mardis, E.R. & Wilson, R.K. (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell, 150, 264– 278. Young, A.L., Challen, G.A., Birmann, B.M. & Druley, T.E. (2016) Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nature Communications, 7, 12484. Zhu, L., Finkelstein, D., Gao, C., Shi, L., Wang, Y., Lopez-Terrada, D., Wang, K., Utley, S., Pounds, S., Neale, G., Ellison, D., Onar-Thomas, A. & Gilbertson, R.J. (2016) Multi-organ mapping of cancer risk. Cell, 166, 1132–1146.e7.

Serum prohepcidin levels are potential prognostic markers in patients with multiple myeloma

Prohepcidin is the prohormone of hepcidin. Anemia is one of the main clinical features in patients with multiple myeloma (MM) and hepcidin may be associated with iron homeostasis in these patients. However, the clinical significance of prohepcidin is not fully understood. In this retrospective study, we measured serum prohepcidin levels using an immunoassay technique to study its clinical significance in 39 MM patients. Serum prohepcidin levels in patients with MM were weakly correlated with alkaline phosphatase (ALP) levels (r=0.32, P=0.048), calculated by Spearman’s rank correlation, but not with other clinical data, including hemoglobin, serum iron or ferritin. In addition, patients with severe renal insufficiency [creatinine clearance (CCr) <50 ml/min] had significantly higher prohepcidin levels compared with patients with mild or no renal insufficiency (CCr ≥50 ml/min, P=0.047). In contrast, low serum prohepcidin levels less than 110 ng/ml were an independent predictor of poor overall survival [hazard ratio (HR), 5.29; 95% confidence interval (CI), 1.65–17.03] in addition to serum creatinine levels of at least 2 mg/dl (HR, 5.32; CI, 1.10–25.64), serum calcium (HR, 3.53; CI, 1.01–12.33) and ECOG performance status grade 4 (HR, 4.15; CI, 1.32–13.09) in the multivariate analysis using Cox proportional hazards model. In the subset of 31 MM patients with CCr ≥50 ml/min, low serum prohepcidin (HR, 5.65; CI, 1.60–19.95) was an indicator of poor prognosis in multivariate analysis. These results indicate that serum prohepcidin levels may be associated with ALP and renal function but not iron homeostasis, in MM patients. In addition, lower serum prohepcidin levels are potential independent indicators of poor overall survival in MM patients regardless of renal function.

Long-term survival of pancreatic cancer patients treated with multimodal therapy combined with WT1-targeted dendritic cell vaccines

ABSTRACT Background/Aim: Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors with a dismally poor prognosis. Although surgical resection remains the only potentially curative treatment, most PDAs are not surgically resectable at diagnosis. Therefore, multimodal therapy is urgently needed to improve the long-term survival of PDA patients. Methods: Six eligible PDA patients underwent multimodal therapy comprising dendritic cells (DCs) pulsed with Wilms’ tumor 1 (WT1) peptide (DC/WT1-I) restricted by the human leukocyte antigen (HLA) class I (A*24:02 or A*02:06) allele, chemotherapy, radiation, and/or surgery. Patient laboratory data, DC/WT1-I-specific delayed-type hypersensitivity (DTH) reactions, and WT1-specific immune responses were analyzed to assess the prognostic markers of multimodal therapy. Results: Compared to 2-treatment type combinations, multimodal therapy involving 3 to 4 treatment types was significantly associated with longer overall survival (p = 0.0177). Moreover, after 7 DC/WT1-I vaccinations, the progression-free survival (PFS) of PDA patients with a neutrophil to lymphocyte ratio (NLR) or C-reactive protein (CRP) level less than the median was superior to that of PDA patients with values above the median (p = 0.0246). PDA patients with an overall survival (OS)>1000 days had significantly more lymphocytes after one DC/WT1-I vaccination course than did those with an OS<1000 days. Conclusion: Multimodal therapy involving the DC/WT1-I vaccination may benefit patients with advanced PDA. However, comparing the limited number of PDA patients in terms of survival is difficult because the patients were at different disease stages and received different treatments. Further studies are needed to evaluate the clinical benefits of this multimodal therapy.