Toshinori Okuda

A Phase I Trial of Arterial Infusion Chemotherapy with Gemcitabine and 5-Fluorouracil for Unresectable Advanced Pancreatic Cancer after Vascular Supply Distribution via Superselective Embolization

BACKGROUND We previously reported that arterial infusion chemotherapy improved the response rate and survival of the patients with pancreatic cancer at advanced stages in an open trial. We conducted a Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for advanced pancreatic cancer after vascular supply distribution via superselective embolization. METHODS Patients were treated after arterial embolization for hemodynamic change to restrict the blood flow into the pancreas (mainly to the great pancreatic artery and the caudal pancreatic artery). Arterial infusion chemotherapy consisted of gemcitabine in doses that were increased from 600 to 1000 mg/m(2) in subsequent cohorts on Day 1 plus continuous infusion of 5-fluorouracil 300 mg/m(2)/day on Days 1-5 every 2 weeks. Result Twelve patients were enrolled. The maximum tolerated dose of gemcitabine was determined to be Level 3 (1000 mg/m(2)). Only very mild hematological and non-hematological toxicities were noted. The overall response rate was 33.3%. The median survival time was 22.7 (95% CI; 9.5-24.5) months and the 1- and 2-year overall survival rates were 83.3 and 25.0%, respectively. CONCLUSION Arterial infusion chemotherapy using 1000 mg/m(2) gemcitabine on Day 1 and 300 mg/m(2)/day 5-fluorouracil on Days 1-5 every 2 weeks warrants a Phase II study.

Single‐stage endoscopic treatment for mild to moderate acute cholangitis associated with choledocholithiasis: a multicenter, non‐randomized, open‐label and exploratory clinical trial

Two‐stage treatment involving stone removal after drainage is recommended for mild to moderate acute cholangitis associated with choledocholithiasis. However, single‐stage treatment has some advantages. We aimed to assess the efficacy and safety of single‐stage endoscopic treatment for mild to moderate acute cholangitis associated with choledocholithiasis.

Reversible skin and hair depigmentation during chemotherapy with dasatinib for chronic myeloid leukemia

1 Sakabe J, Yoshiki R, Sugita K et al. Connexin 26 (GJB2) mutations in keratitis-ichthyosis-deafness syndrome presenting with squamous cell carcinoma. J Dermatol 2012; 39: 814–815. 2 Jan AY, Amin S, Ratajczak P et al. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol 2004; 122: 1108–1113. 3 Lee JR, Derosa AM, White TW. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes. J Invest Dermatol 2009; 129: 870–878. 4 Homeida L, Wiley RT, Fatahzadeh M. Oral squamous cell carcinoma in a patient with keratitis-ichthyosis-deafness syndrome: a rare case. Oral Surg Oral Med Oral Pathol Oral Radiol 2015 Apr; 119(): e226– e232. 5 Lee SW, Tomasetto C, Sager R. Positive selection of candidate tumor-suppressor genes by subtractive hybridization. Proc Natl Acad Sci USA 1991; 88: 2825–2829.

Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial.

BACKGROUND AND STUDY AIMS Endoscopic bile duct stone (BDS) removal is a well-established treatment; however, the preference for basket or balloon catheters for extraction is operator-dependent. We therefore conducted a multicenter prospective randomized trial to compare catheter performance. PATIENTS AND METHODS We enrolled patients with a BDS diameter ≤ 10 mm and common bile duct diameter ≤ 15 mm. Participants were randomly assigned to groups that were treated with basket or balloon catheters between October 2013 and September 2014. The primary endpoint was the rate of complete clearance of the duct; the secondary endpoints were the rate and time to complete clearance in one endoscopic session. RESULTS We initially enrolled 172 consecutive patients; 14 were excluded after randomization. The complete clearance rates were 92.3 % (72/78) in the balloon group and 80.0 % (64 /80) in the basket group. The difference in the rates between the two groups was 12.3 percentage points, indicating non-inferiority of the balloon method (non-inferiority limit -10 %; P < 0.001 for non-inferiority). Moreover, the balloon was superior to the basket (P = 0.037). The rate of complete clearance in one endoscopic session was 97.4 % using the balloon and 97.5 % using the basket (P = 1.00). The median times to complete clearance in one endoscopic session were 6.0 minutes (1 - 30) and 7.8 minutes (1 - 37) in the balloon and basket groups, respectively (P = 0.15). CONCLUSIONS For extraction of BDSs ≤ 10 mm, complete endoscopic treatment with a single catheter is more likely when choosing a balloon catheter over a basket catheter.University Hospital Medical Information Network Trials Registry: UMIN000011887.

Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/β and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.

Spontaneous cholesterol crystal embolism to lymph node

A 65-year-old male diagnosed with hypertension and hypertrophic cardiomyopathy in April 2010 at a different hospital was administered angiotensin II receptor blocker and low-dose aspirin. Although laboratory data at that time showed eosinophilia (2,860/lL), further examination was not performed. He had a history of smoking 1.5 packs of cigarettes a day for 45 years, but no history of diabetes mellitus. He developed cerebral infarction in January 2012, but recovered uneventfully with conservative treatment, including statins for dyslipidemia. He was subsequently referred to our hospital to investigate the eosinophilia. On physical examination, he had several swollen lymph nodes in bilateral inguinal regions, but no cutaneous lesion was observed. Laboratory data were as follows: WBC 10,600/ lL, eosinophil 840/lL, Hb 11.2 g/dL, Plt 8.8 9 10/lL, FDP 12.0 lg/mL, LDH 352 U/L, BUN 17.5 mg/dL, Cr 1.00 mg/dL, IgE 8,600 IU/mL, ACTH 15.3 pg/mL and cortisol 9.4 lg/dL, as well as negative test results for ANA and MPO-ANCA. The urinalysis showed proteinuria and microhematuria. Parasite eggs were not detected in the feces. Bone marrow examination showed 9.1 % eosinophils among all nucleated cells without dysplasia, and FIP1L1-PDGFRa and BCR-ABL chromosomal aberrations were not detected by FISH analysis. Chest and abdominal CT showed several enlarged inguinal lymph nodes up to 18 mm in the minor axis. Although he stated that he had recognized these inguinal masses about 10 years previously and that they had not changed markedly in size, we performed biopsy from the right inguinal lymph node. Histopathological findings revealed needle-shaped clefts in the lumen of arterioles with multinucleated giant cell infiltration surrounded by normal lymphoid follicles (Fig. 1a–c). Perivascular inflammatory cell infiltration, mainly of eosinophils, was also observed. Flow cytometric analysis of lymph node showed no abnormality. The diagnosis of cholesterol crystal embolism (CCE) to lymph node was made. As he presented no other clinical manifestations of CCE, no further therapeutic intervention was performed. CCE is a rare systemic disease caused by occlusion of small arteries by cholesterol crystals released from atheromatous plaques of the aorta or major branches. Chest CT in this patient also showed calcification and wall thickness of the thoracic aorta, which can be a source of cholesterol crystals (Fig. 2). The common manifestations of CCE are characteristic skin lesions, such as livedo reticularis, cyanosis or ulceration, renal impairment, and gastrointestinal disorder. CCE involvement of lymph node is extremely rare. Only a few preand postmortem cases of CCE to lymph node have been reported to date [1, 2]. CCE usually occurs following an invasive vascular procedure, or anticoagulant or thrombolytic therapy, but it can also occur spontaneously. We surmised that the CCE in this patient was spontaneous, as he had not undergone any such intervention during this clinical course. The exact time at which the CCE developed was unclear, but pathological findings of lymph nodes showing CCE with giant cell infiltration and no signs of fibrosis suggested that it had been a relatively recent event. Hence, we suspect that the A. Fujimi (&) A. Hashimoto Y. Kanisawa Department of Hematology and Oncology, Oji General Hospital, 3-4-8 Wakakusa-cho, Tomakomai 053-8506, Japan e-mail: Akihito.fujimi@ojihosp.or.jp

A Prospective Multicenter Study Evaluating Bleeding Risk after Endoscopic Ultrasound-Guided Fine Needle Aspiration in Patients Prescribed Antithrombotic Agents

Background/Aims Although the risk of bleeding after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is low, the safety of EUS-FNA in patients prescribed antithrom-botic agents is unclear. Therefore, this study evaluated the incidence of bleeding after EUS-FNA in those patients. Methods Between September 2012 and September 2015, patients who were prescribed antithrombotic agents underwent EUS-FNA at 13 institutions in Japan were prospectively enrolled in the study. The antithrombotic agents were managed according to the guidelines of the Japanese Gastrointestinal Endoscopy Society. The rate of bleeding events, thromboembolic events and other complications within 2 weeks after EUS-FNA were analyzed. Results Of the 2,629 patients who underwent EUS-FNA during the study period, 85 (62 males; median age, 74 years) patients were included in this stduy. Two patients (2.4%; 95% confidence interval [CI], 0.6% to 8.3%) experienced bleeding events. One patient required surgical intervention for hemothorax 5 hours after EUS-FNA, and the other experienced melena 8 days after EUS-FNA and required red blood cell transfusions. No thromboembolic events occurred (0%; 95% CI, 0.0% to 4.4%). Three patients (3.5%; 95% CI, 1.2% to 10.0%) experienced peri-puncture abscess formation. Conclusions The rate of bleeding after EUS-FNA in patients prescribed antithrombotic agents might be considerable.

Thrombocytopenia and Anemia with Anti-c-Mpl antibodies Effectively Treated with Cyclosporine in a Patient with Rheumatoid Arthritis and Chronic Renal Failure.

A 61-year-old woman with rheumatoid arthritis who was undergoing hemodialysis for end-stage renal failure was transferred to our hospital due to severe thrombocytopenia and anemia. A bone marrow biopsy showed the complete absence of megakaryocytes and erythroblasts. Cyclosporine treatment resulted in the improvement of her megakaryocyte and erythroblast levels, and a decrease in her serum level of anti-c-Mpl (thrombopoietin receptor) antibodies. After this initial improvement, her anemia progressively worsened, despite the continuous administration of immunosuppressive therapy with cyclosporine. Her platelet and leukocyte counts remained stable. This is the first report of a probable case of anti-c-Mpl antibody-associated pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura.

Reply to Kadayifci et al.

We appreciate the comments made by Dr. Kadayifci regarding our study inwhich we concluded that complete endoscopic treatment with a single catheter is more likely when choosing a balloon catheter over a basket catheter for the extraction of bile duct stones ≤10mm [1]. In the basket group, the basket catheter was switched to a balloon catheter when the endoscopist had judged the duct clearance to be complete by the basket catheter. First, the balloon was inflated at the perihilar bile duct and pulled to the bottom of the bile duct, and then balloon-occluded cholangiography (BOC) was performed. During this procedure, if a stone emerged from the papilla of Vater, this was judged to be “incomplete clearance.” In addition, when a defect on BOC was confirmed to be a stone by subsequent endoscopic observation, the outcome was also judged to be “incomplete clearance.” Therefore, “residual stones on BOC (n=9)” were confirmed during this procedure. These failure cases meant that duct clearance had not been completed by basket catheter alone. “Complete clearance by the assigned catheter” in the basket group represented the result obtained by the basket catheter alone, not by the basket catheter plus the balloon catheter. Therefore, we think that using the balloon after the basket for stone extraction was not a confounding factor of our study. As mentioned by Dr. Kadayifci, it is sometimes difficult to check stone removal by direct endoscopic observation after balloon sweep of the duct. Therefore, the performance of the balloon catheter may be overestimated. The actual success rate of each catheter might be lower than the rates determined in our study because BOC and balloon sweep were used to confirm duct clearance in both groups. For true comparison of the two catheters, other modalities, such as peroral cholangioscopy, should be used to evaluate the efficacy of individual catheters. However, it was not realistic to use cholangioscopy to evaluate residual stones in our study because participants included patients with normal common bile ducts, with diameters ≤8mm in general. In addition, evaluating the end point by the same method in both groups is crucial in a randomized controlled trial. When considering clinical trial feasibility, BOC was selected to evaluate the end point in both groups to minimize the methodological bias. However, we identified this issue as a limitation of our study.

[Successful treatment with dose-adjusted EPOCH-R for triple-hit lymphoma having BCL2, BCL6 and MYC translocations].

Double- and triple-hit lymphomas (DHL/THL), high-grade B-cell lymphomas with an extremely poor prognosis, are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint. The successful use of dose-adjusted (DA) EPOCH-R in patients with MYC-positive lymphoma and Burkitt lymphoma (BL) was recently reported. A 74-year-old man with acute renal dysfunction and hyperkalemia was transferred to our emergency center by ambulance. PET-CT revealed a left renal hilar mass enveloping the abdominal para-aortic domain and bladder and hydronephrosis. High (18)F-FDG uptake revealed lymph node, peritoneum, and multiple bone metastases. Analysis of the bone marrow aspirate revealed abnormal lymphoid cells with deeply basophilic cytoplasm and numerous vacuoles resembling Burkitt cells. Chromosomal analysis revealed a complex chromosomal karyotype, including t(14;18)(q32;q21), and FISH analysis confirmed split BCL2, BCL6, and MYC signals. Bone marrow biopsy revealed diffusely infiltrating large abnormal lymphoid cells with a CD10⁺, CD20⁺, BCL2⁺, BCL6⁺, c-MYC⁺ and MUM1(-) immunophenotype. B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and BL, was diagnosed. The patient achieved a partial response after eight courses of DA-EPOCH-R chemotherapy. Our experience suggests that DA-EPOCH-R may be an effective treatment for DHL/THL.