No benefit of endoscopic sphincterotomy before biliary placement of self-expandable metal stents for unresectable pancreatic cancer.

BACKGROUND & AIMS: Endoscopic sphincterotomy (ES) is performed routinely before self-expandable metallic stents (SEMS) are placed in malignant distal biliary strictures to prevent postprocedural pancreatitis. However, it is not clear whether ES actually prevents pancreatitis or affects other adverse events (AEs). We conducted a noninferiority trial to examine the necessity of ES before SEMS placement. METHODS: Two hundred patients with distal biliary strictures caused by unresectable pancreatic cancer were assigned randomly to groups that received ES or did not receive ES (non-ES) before SEMS placement, at 25 hospitals in Hokkaido, Japan, from August 2010 through November 2012. The primary outcome was early AEs (≤30 d) specifically related to the presence or absence of ES (pancreatitis, bleeding, or perforation). Secondary outcomes measured included the effect of ES omission on time to SEMS dysfunction and patient survival times. RESULTS: The proportions of patients with early AEs were 9.2% in the non-ES group and 10.4% in the ES group (a difference of 1.2%, noninferior). The median times to SEMS dysfunction was longer than 594 days in the non-ES group and 541 days in the ES group (P = .88). The median overall survival times were 202 in the ES group vs 255 days in the non-ES group; P = .20). CONCLUSIONS: ES before SEMS does not affect the incidence of AEs, SEMS patency, or patient survival times. Our data provide no evidence for a benefit of ES to patients undergoing SEMS placement for a biliary stricture caused by pancreatic cancer. UMIN clinical trials registry number: 000004044.

[A Case of Acute Lymphoblastic Leukemia with Adult-Onset Still's Disease-Like Erythema].

A 62-year-old woman developed B lymphoblastic leukemia (B-ALL) in April 2010, and achieved complete remission after hyper-CVAD/high-dose-MA therapy combined with rituximab. ALL recurred in December 2011, and remission was again achieved with the Japan Adult Leukemia Study Group (JALSG) ALL202 protocol combined with rituximab. Owing to a fever and rash that persisted from July 2012, the patient was examined again. On examination, redness was observed in the pharynx, and poorly defined oval erythemas were seen on the cheeks, posterior region of the neck, and upper arms. Blood test results showed high levels of ferritin, tumor necrosis factor (TNF)-α, an d C-reactive protein (CRP), and mild hepatosplenomegaly was identified on abdominal computed tomography (CT), indicative of an adult-onset Still's disease-like condition. Prednisolone therapy was initiated in August 2012, and remission was achieved. A second recurrence of ALL developed in September 2012, and although remission was again achieved using the JALSG ALL202 protocol, a third recurrence of ALL occurred in April 2013, and the patient could not be saved. In this case, adult-onset Still's disease-like erythema developed during the remission phase of ALL.

[A case of primary testicular diffuse large B-cell lymphoma with a p53 gene point mutation].

A 52-year-old man with bilateral swelling in the scrotum was referred to the department of urology in our hospital in January 2013. Pathological examination of the scrotum revealed diffuse large B-cell lymphoma(DLBCL). Immunohistochemical staining revealed p53 overexpression, and polymerase chain reaction-single strand conformation polymorphism(PCRSSCP) revealed a point mutation in exon 7 of the p53 gene. Rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone(R-CHOP)therapy and intrathecal prophylaxis were initiated. After three courses of R-CHOP therapy, high-dose cytarabine was administered, followed by peripheral blood stem cell harvesting. Busulfan, etoposide, and Ara-C(BEA)therapy was then administered, followed by autologous peripheral blood stem cell transplantation(auto- PBSCT). Primary testicular lymphoma(PTL)is a rare, clinically aggressive form of extranodal lymphoma, and there is a high incidence rate of relapse in the central nervous system(CNS). The vast majority of cases are histologically DLBCL. The p53 mutation is an independent marker of poor prognosis in patients with DLBCL treated with R-CHOP therapy. Our patient has been disease free for 17 months after auto-PBSCT with high-dose chemotherapy, which results in a greater level of penetration into the CNS.

[Subcutaneous myeloid sarcoma in a patient with essential thrombocythemia that transformed into acute myeloid leukemia].

Since November 2008, an 80-year-old man had been administered hydroxyurea and aspirin for the treatment of essential thrombocythemia (ET). In January 2012, his white blood cell count was markedly elevated, and he was treated with busulfan and cytarabine. In October 2012, he was hospitalized because of fever and general malaise, and a central venous port was placed in the right anterior chest owing to difficulty obtaining peripheral vascular access. Approximately 2 weeks after port placement, a subcutaneous mass was observed near the port. The patient died in November 2012 owing to exacerbation of the original disease. Autopsy revealed transformation to acute myeloid leukemia( AML; M2 subtype) and myeloid sarcoma (MS) in lymph nodes and the right anterior chest. The incidence of transformation of ET to AML is low, and MS as a comorbidity is rare. However, the risk of MS complications should be considered in patients with hematological malignancies due to recent increases in the use of central venous ports in such cases.

[Polycythemia vera developed after a major molecular response to imatinib mesylate treatment in a patient with chronic myelogenous leukemia].

A 68-year-old man complained of dizziness and was referred to our hospital by his primary physician for evaluation of an elevated leukocyte count. In April 2002, soon after the chronic phase of chronic myeloid leukemia had been diagnosed, he was treated with imatinib. In March 2010, imatinib treatment was completed and the BCR/ABL fusion gene had become undetectable by real time quantitative PCR. Subsequently, leukocyte counts and the hematocrit gradually rose. In August 2012, a bone marrow aspirate showed hypercellular marrow with marked erythroid hyperplasia and the presence of the JAK2 gene V617F mutation. He was diagnosed with polycythemia vera. Phlebotomy and chemotherapy were started in addition to imatinib administration. Shortly thereafter complete blood counts returned to normal levels.

[Successful treatment with combination of plasma exchange and chemotherapy for CD5-positive primary hepatosplenic diffuse large B-cell lymphoma complicated with acute liver injury].

Primary hepatosplenic CD5-positive diffuse large B cell lymphoma (CD5⁺ DLBCL) has recently been characterized as showing hepatosplenomegaly without lymphadenopathy, a portal and intrasinusoidal pattern of infiltration in the liver, and bone marrow invasion by lymphoma cells, without intravascular involvement. A 45-year-old man presented with fever and malaise in June 2013. Computed tomography showed hepatosplenomegaly and multiple liver tumors without lymphadenopathy. An ultrasonography-guided needle biopsy of the liver mass revealed portal and intrasinusoidal infiltration of CD5⁺CD20⁺ lymphoma cells and large numbers of destroyed hepatocytes. These findings were diagnostic of primary hepatosplenic CD5⁺ DLBCL. Upon admission, lymphoma cells also appeared in the peripheral blood and serum hepatocyte growth factor (HGF) was markedly elevated. A bone marrow biopsy revealed extensive invasion by lymphoma cells. Seven days after admission, his laboratory data showed elevated aminotransferase and serum creatinine levels. Therefore, dose-reduced CH(O)P, with rituximab (R-CHOP) therapy, plasma exchange, and continuous hemodiafiltration, was initiated. The patient achieved complete remission after 4 courses of R-CHOP therapy. HGF is useful for predicting acute liver damage. If the HGF level is high, remission induction therapy, with plasma exchange, is necessary at an early stage.

Successful treatment of an essential thrombocythemia patient complicated by Sweet's syndrome with combination of chemotherapy and lenalidomide.

A 79-year-old man had been followed up since July 2003 based on a diagnosis of essential thrombocythemia (ET). The patient visited our hospital after developing a high fever and rash in August 2010, and Sweet's syndrome was diagnosed based on skin biopsy results. The bone marrow aspirate showed features like those of myelodysplastic/myeloproliferative neoplasm (MDS/MPN, unclassifiable). Administration of metenolone and azacitidine was initiated in March and May 2011, respectively, but the rash associated with Sweet's syndrome showed exacerbation. Ranimustine was therefore administered starting in July 2011 to control the blood cell count, but the rash associated with Sweet's syndrome persisted. Combination therapy with lenalidomide was initiated in September 2012, and resulted in control of the blood cell count and marked improvement of Sweet's syndrome.

[Three cases of lenalidomide-resistant IgA myeloma for which a response was regained after the addition of clarithromycin].

BiRd combination therapy, which comprises clarithromycin (CAM: Biaxin®), lenalidomide (LEN: Revlimid®), and dexamethasone ( DEX), is a highly effective treatment for newly diagnosed symptomatic myeloma. However, its efficacy against recurrent myeloma refractory to combination therapy with LEN and DEX(Rd therapy) remains unclear. Here, we report on BiRd therapy administered to three patients with IgA myeloma exacerbated during Rd therapy and for whom transplantation was not indicated, by adding CAM to the Rd regimen. Because the IgA levels increased again after Rd therapy in all patients, treatment was switched to BiRd therapy. In all cases, the IgA levels decreased after switching to BiRd therapy, with no exacerbation or hematological or non-hematological toxicity observed. Thus, BiRd therapy may represent a therapeutic option for symptomatic myeloma resistant to Rd therapy.

[Combined modality therapy for a patient with primary adrenal lymphoma].

A 71-year-old man with malaise, anorexia, and weight loss was referred to our hospital from a clinic. Abdominal computed tomography(CT)revealed bilateral adrenal masses. An ultrasound-guided percutaneous needle biopsy of the adrenal grand indicated diffuse large B-cell lymphoma. A rapid adrenocorticotropic hormone(ACTH)test revealed primary adrenal failure. Rituximab-cyclophosphamide/doxorubicin/vincristine/prednisolone(common name, R-CHOP)therapy accompanied by intrathecal treatment was initiated along with steroid replacement therapy. After the fourth courses, a CT scan showed a reduction of the adrenal masses, and there was no[18F]-fluorodeoxyglucose(FDG)uptake in the adrenal masses. The patient has remained in metabolic complete remission. Subsequently, both adrenal lymphomas were irradiated. The patient has been disease-free for 6 months after the diagnosis of primary adrenal lymphoma. The combined modality of chemoradiation therapy plus intrathecal treatment could be effective for primary adrenal lymphoma with a poor prognosis.

[Acute promyelocytic leukemia presenting with central nervous system involvement at initial diagnosis].

We describe a rare case of acute promyelocytic leukemia (APL) presenting with central nervous system (CNS) involvement at the time of initial diagnosis. A 58-year-old male was hospitalized with palpitations, dyspnea, high grade fever, photophobia, and disturbance of consciousness in March 2010. APL was diagnosed by bone marrow (BM) examination. The cytogenetic analysis of BM cells demonstrated t(15;17)(q22;q11), and PML-RARA chimeric gene was detected by reverse transcriptase-polymerase chain reaction assay. Magnetic resonance imaging of the brain revealed several high intensity regions in the cerebrum and cerebellum. CNS involvement was diagnosed based on the appearance of APL blasts in cerebrospinal fluid (CSF). The patient was treated with all-trans retinoic acid (ATRA), and systemic chemotherapy consisting of idarubicin and cytarabine according to the Japan Adult Leukemia Study Group (JALSG) APL 204 protocol. He was then treated with continuous intrathecal administration of cytotoxic drugs (methotrexate, cytarabine, prednisolone) after systemic chemotherapy, achieving complete remission (CR) in both BM and the CNS. To date, he has been maintained in complete molecular remission in both BM and the CSF for 28 months, to date.

[Hematologic improvement with deferasirox following tandem antithymocyte globulin treatment in a transfusion-dependent patient with severe aplastic anemia].

A 62-year-old man with transfusion-dependent severe aplastic anemia received immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine A in April 2010. However, his transfusion dependency did not improve. As more than 100 red blood cell (RBC) transfusions had been performed, he was administered iron chelation therapy (ICT) with deferasirox (DFX) to improve iron overload starting in July 2011. Consequently, both RBC and platelet transfusion dependency gradually improved concomitant with a decrease in serum ferritin. The bone marrow (BM) biopsy findings before administration of DFX showed severe iron accumulation and strong positive immunostaining for 8-OHdG, a marker of oxidative stress due to free iron. One year after ICT, the number of BM hematopoietic cells was increased and both iron deposition and oxidative stress were decreased. These findings suggest that DFX may contribute to hematological improvement in patients with IST-refractory aplastic anemia.

[Follicular lymphoma complicated with myelofibrosis and macroglobulinemia at initial presentation].

A 49-year-old woman presented with pharyngeal and cervical lymph node swelling in December 2010. Biopsy of the pharynx demonstrated follicular lymphoma which secreted large volumes of immunoglobulin M (IgM) and transforming growth factor-ß (TGF-ß). Bone marrow aspiration yielded a dry tap, and bone marrow biopsy demonstrated myelofibrosis associated with lymphoma cells on admission. The plasma concentration of TGF-ß was elevated and monoclonal IgM gammopathy was detected. After only one course of chemotherapy with CHOP plus rituximab, remission of both lymphoma and myelofibrosis was achieved. Bone marrow aspiration became possible, and TGF-ß and IgM levels normalized. Thus, the myelofibrosis was reversible.

[Primary myelofibrosis complicated by acquired hemophilia A and subsequent development of acute myeloid leukemia].

A 77-year-old man diagnosed with primary myelofibrosis (PMF), successfully controlled by thalidomide and prednisolone, was referred to us for massive subcutaneous bleeding involving the face, body, and all four limbs. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer, resulting in a diagnosis of acquired hemophilia A (AHA) for which he was treated with prednisolone and cyclophosphamide on admission. He developed right femoral intramuscular hemorrhage soon after immunosuppressive therapy and was treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he suffered complications of respiratory failure with increasing throat hemorrhaging. Recombinant activated factor VII (rFVIIa) was administered combined with methylprednisolone pulse therapy. Bleeding, including respiratory failure, was ameliorated with rFVIIa. Immunosuppressive rituximab therapy resolved AHA with marked efficacy. He died of Pneumocystis jiroveci pneumonitis. Autopsy showed transformation from PMF to acute myeloid leukemia.

[Bendamustine-rituximab therapy is effective for transformed follicular lymphoma with significant expression of p53].

We describe a patient with transformed follicular lymphoma(FL), expressing p53 but remaining in complete remission(CR) due to bendamustine-rituximab(BR)therapy. She was a 64-year-old female diagnosed with stage IV FL(grade 3A)in July 2007 when she was admitted with right lower abdominal pain and body weight loss. Colonoscopy revealed Bauhin' valve lymphoma of the terminal ileum, and computed tomography(CT)scan showed lymphadenopathy, involving the cervical, mediastinal para-aortic lymph nodes and right tonsil. She received chemotherapy with eight courses of CHOP therapy with rituximab and achieved CR. Two and a half years later, mediastinal lymph node swelling relapsed, and ibritumomab tiuxetan therapy induced the second CR. After ten months, however, a third relapse occurred as a submucosal tumor(SMT)of the stomach. Gastric SMT biopsy showed diffuse large B cell lymphoma(DLBCL)transformation with immunohistochemical expression of p53. Although gastric SMT disappeared after radiotherapy, which achieved the third CR, lymph node swelling was detected again in the para-aortic and-iliac artery lymph nodes in September 2011. Subsequently, she was treated with five courses of BR therapy, because bendamustine had been reported to be effective for p53 gene-deficient B cell neoplasms. The therapy was successful and achieved the fourth CR, demonstrating that BR therapy was effective for p53-expressing DLBCL.

[A case in which chromosome 5q deletion syndrome resistant to lenalidomide therapy transformed to refractory anemia with excess blasts].

An 80-year-old man was admitted to our hospital because of pancytopenia. Bone marrow examination revealed an increase in the number of dysplastic cells indicating trilineage dysplasia. A 5q13q31 deletion was the only genetic abnormality found, and consequently, 5q deletion syndrome was diagnosed. Although lenalidomide therapy was initiated, it had to be discontinued because of Stevens-Johnson syndrome, which occurred during the second course of treatment. There was no discernible hematological improvement, and bone marrow aspiration showed transformation to refractory anemia with excess blasts-2(RAEB-2)after lenalidomide therapy. However, by changing the therapy to azacitidine, cytogenetic remission was achieved.

[Clinicopathological features of intestinal complications in non-Hodgkin's lymphoma -a single institution analysis-].

We evaluated the clinicopathological features of patients who developed intestinal complications following surgery for gastrointestinal non-Hodgkin's lymphoma (NHL) and determined the risk factors for complications. We retrospectively analyzed 28 patients with gastrointestinal NHL who were treated at our institution between January 2007 and June 2012. Seven patients (25.0%) underwent surgery for bleeding, perforation, or ileus caused by the gastrointestinal NHL, particularly those with involvement of the jejunum or ileum. Half the patients with small intestinal NHL required surgery for complications; patients with this form of NHL were therefore considered to be at a high risk of complications. Those with semicircular ulcerative lesions, a protruding deformity, or systemic NHL involving the small intestine were also considered to be at a particularly high risk of intestinal complications.

[Complete response by rituximab monotherapy in a patient with leukemic mantle cell lymphoma diagnosed by fluorescence in situ hybridization analysis].

An 85-year-old male was admitted to a hospital with abdominal discomfort in October, 2010. Severe splenomegaly and mild para-aortic lymphoadenopathy were detected. In addition, an increase in atypical lymphocytes was noticed by bone marrow analyses with weak positive staining of cyclin D1. Subsequently, the fluorescence in situ hybridization(FISH)method confirmed cyclin D1 reconstruction, and the fusion signals of the BCL1 and IgH genes were detected, thus providing a definitive diagnosis of leukemic mantle cell lymphoma. After treatment with rituximab monotherapy, the Ki-67 index was stabilized to within 10%, and complete response was obtained.

[Chronic hepatitis C presenting with hepatic involvement by chronic lymphocytic leukemia responding to polyethylene glycol interferon-α-2b].

Hepatic involvement by chronic lymphocytic leukemia(CLL)is common, but rarely presents with liver injury. We report a case of chronic hepatitis C(CH-C)in a patient who had suffered from liver injury as a result of hepatic involvement by CLL. A 74-year-old man was hospitalized because of an examination confirming him positive for leukocytosis. Computer tomography scan showed mild hepatosplenomegaly, lymph node swelling of the neck and axilla, and abdominal lymphadenopathy. He was diagnosed as CLL by bone marrow examination. His laboratory data revealed hepatis C virus(HCV)antibody-positive, and elevated levels of both aminotransferase and HCV-RNA. Liver biopsy demonstrated significant CLL involvement of portal areas and a mild T lymphocyte invasion of centrilobular and portal areas. After treatment with polyethylene glycol interferon (PEG-IFN)-α-2b for CH-C, the CLL count was decreased in both peripheral blood and the liver. The hematological response was significantly correlated with the disappearance of HCV-RNA. The patient has maintained a sustained virological response(SVR)status for the past 9 months after PEG-IFN-α-2b administration. Thus, PEG-IFN-α-2b therapy could be effective not only for CH-C but also for hepatic involvement of CLL as seen in our patient.

HOPS-R01 phase II trial evaluating neoadjuvant S-1 therapy for resectable pancreatic adenocarcinoma.

Although neoadjuvant therapy (Nac) is recommended for high-risk resectable pancreatic cancer (R-PDAC), evidence regarding specific regimes is scarce. This report aimed to investigate the efficacy of S-1 Nac for R-PDAC. In a multicenter phase II trial, we investigated the efficacy of Nac S-1 (an oral fluoropyrimidine agent containing tegafur, gimeracil, and oteracil potassium) in R-PDAC patients. The protocol involved two cycles of preoperative S-1 chemotherapy, followed by surgery, and four cycles of postoperative S-1 chemotherapy. Two-year progression-free survival (PFS) rates were the primary endpoint. Overall survival (OS) rates and median survival time (MST) were secondary endpoints. Forty-nine patients were eligible, and 31 patients underwent resection following Nac, as per protocol (31/49; 63.3%). Per-protocol analysis included data from 31 patients, yielding the 2-year PFS rate of 58.1%, and 2-, 3-, and 5-year OS rates of 96.8%, 54.8%, and 44.0%, respectively. MST was 49.2 months. Intention-to-treat analysis involved 49 patients, yielding the 2-year PFS rate of 40.8%, and the 2-, 3-, and 5-year OS rates of 87.8%, 46.9%, and 33.9%, respectively. MST was 35.5 months. S-1 single regimen might be an option for Nac in R-PDAC; however, the high drop-out rate (36.7%) was a limitation of this study.

[Effective treatment by both anti-androgen therapy and chemotherapy for a patient with advanced salivary duct carcinoma].

Salivary ductcarcinoma (SDC)is a high-grade malignant tumor arising predominantly in the parotid gland. Androgen receptor(AR)expression was mainly restricted to SDC in salivary cancer. We report successful treatment of a patient with advanced SDC using an endocrine chemotherapy. A 76-year-old man was hospitalized with lumbalgia and swelling of left submandibular region. Radiological examination indicated a tumor in left submandibular gland and metastatic tumors in lumbar vertebra, accompanied by swollen lymph nodes of the neck, mediastinum. Needle biopsies of both vertebral tumor and cervical lymph node revealed SDC. Positive nuclear staining was observed against AR in tumor cells of our patient by immunohistochemical analysis. He obtained a partial response after 1 course of treatment with both anti-androgen therapy and palliative chemotherapy using paclitaxel. In contrast to previous reports of poor response to chemotherapy alone and short-term survival of patients with SDC, our patient has demonstrated that chemotherapy combined with anti-androgen therapy may be an effective modality as a therapeutic regimen for SDC.