Takakazu Higuchi

Secondary resistance to imatinib mesylate in a patient with unresectable duodenal GIST without mutations in exons 9, 11, 13, or 17 of the c-kit protooncogene.

after 6 months of the therapy, but developed massive gastrointestinal bleeding and tumor regrowth, which indicated acquired secondary resistance to the treatment. Up to 80%–90% of metastatic GISTs have been reported to have mutated KIT. KIT mutations have been found in exon 11 in 50%–77% of sporadic GISTs. Exon 9 mutations are found in 3%–18% of GISTs, and a few GISTs have mutations in exons 13 and 17.1 In one study, patients with an exon 11 mutation of the c-kit gene had a significantly higher rate of response to imatinib mesylate therapy (72%) than patients whose tumor had an exon 9 mutation (32%), or no detectable mutation (12%), and the time to treatment failure was also longer in patients with an exon 11 mutation.3 Furthermore, imatinib mesylate is ineffective in patients with GISTs which have mutations in exons 13 and 17.4 It may be important to analyze c-kit gene mutation, especially in exon 11, in order to predict the effectiveness of imatinib mesylate on the suppression of GISTs and the possible acquisition of drug resistance. The present patient, who did not show any mutations in exon 11, or in exons 9, 13, or 17, exhibited acquired secondary resistance to imatinib therapy. Considerable mechanisms of resistance to imatinib therapy in GIST patients may include c-kit gene amplification, increased expression of KIT, activated expression of P-glycoprotein (which is a product of the multidrug resistant gene), activation of signal transduction downstream from KIT, or the acquisition of a growth mechanism other than that associated with KIT.

Transition of Polycythemia Vera to Chronic Neutrophilic Leukemia

Two cases of polycythemia vera (PV) had transition to a hematological condition compatible with chronic neutrophilic leukemia (CNL) 17 and 8 years after diagnosis, respectively. One patient was treated with carboquone followed by hydroxyurea (HU) and the other with HU during PV phase. On transition, both had neutrophilia with white blood cell count above 40,000/microl, elevated neutrophil alkaline phosphatase activity, splenomegaly, normal karyotype without bcr-abl rearrangement. Busulfan was temporally effective in controlling the neutrophil count. However, one patient progressed to the so-called spent phase and the other subsequently had multiple transitions between PV and CNL. These cases may represent a form of uncommon evolution of PV and support the contention that CNL is a type of myeloproliferative disorder and that at least some CNL cases have derangement at the hematopoietic stem cell level.

Hypocomplementemia and Hematological Abnormalities in Immunoblastic Lymphadenopathy and Immunoblastic Lymphadenopathy-Like T Cell Lymphoma

Serum complement levels and hematological data were evaluated in five patients with immunoblastic lymphadenopathy (IBL) and four with IBL-like T cell lymphoma (IBL-T). Anemia with Hb values below 10.0 g/dl was seen in four patients. A direct Coombs test was positive in five patients and the bone marrow of two of these showed features of pure red cell aplasia. Seven patients were thrombocytopenic with platelet counts below 100 x 10(9)/l. Six of the seven patients had splenomegaly. Platelet-associated IgG was elevated in all three thrombocytopenic patients examined. Whole complement activity (CH50) was reduced in eight patients (89%) at presentation and subsequently normalized in five who were treated either with prednisolone (two patients with IBL) or with multidrug combination chemotherapy (three with IBL-T). One patient achieved complete remission and four partial remission. Remission was accompanied by normalization of hematological abnormalities and elevation of complement activity to the normal range in all cases. These results suggested that complement-mediated mechanisms are responsible, at least in part, for some of the hematological abnormalities observed in IBL and IBL-T and that hypocomplementemia is a common abnormality with significance as a laboratory marker for the disease activity.

CASE REPORT: Primary hepatic lymphoma associated with chronic liver disease

We report on a case of primary hepatic lymphoma that developed in a patient with chronic hepatitis C. Given that Japan is an area endemic for both hepatitis B and C viruses, we reviewed 51 Japanese cases of primary hepatic lymphoma, addressing the question as to whether the Japanese cases have unique characteristics and whether there is a causal relationship to the presence of chronic liver disease. Primary hepatic lymphoma most commonly affected middle‐aged males. Presenting symptoms and physical findings were non‐specific. Aminotransferases tended to stay in the low range compared with marked increases in lactate dehydrogenase. Sixteen patients (31%) had chronic liver disease, eight had liver cirrhosis and eight had chronic hepatitis, suggesting that there is a possible aetiological link between chronic liver disease and primary hepatic lymphoma.

Clinical outcome in patients with small intestinal non-Hodgkin lymphoma

The clinical features and outcome of small intestinal lymphoma remain unclear. We retrospectively analyzed 23 patients who had non-Hodgkin lymphoma with a small intestinal lesion. With a median follow-up of 37 months, the 5-year overall survival and failure-free survival (FFS) were 64% and 60%, respectively. In a univariate analysis, a worse performance status at the start of treatment and the occurrence of abdominal symptoms or perforation during treatment were associated with poor survival. Perforation often resulted in a dismal prognosis in patients with uncontrollable lymphoma, but not in patients with lymphoma in remission. The role of surgery in small intestinal lymphoma remains equivocal. In the current study, surgery before other therapies favorably influenced FFS, and all patients who underwent complete resection of the small intestinal lesion had extremely favorable results. Further studies are warranted to establish optimal therapeutic strategies.

Disseminated intravascular coagulation complicating acute lymphoblastic leukemia: A study of childhood and adult cases

A high incidence of disseminated intravascular coagulation (DIC) in adult patients with acute lymphoblastic leukemia (ALL) is reported. However, studies comprising both childhood and adult patients are sparse and the clinical relevance of DIC in ALL patients has been a conflicting issue. Coagulation profiles at presentation and within seven days after starting remission-induction therapy of 44 childhood and 51 adult ALL patients were studied. At presentation, two childhood (5%) and 11 adult (22%) patients had DIC (p<0.05). After starting therapy, four of 27 childhood (15%) and 14 of 33 adult (42%) patients screened for coagulopathy developed DIC (p<0.05). Overall, six of the 44 children (14%) and 25 of the 51 adults (49%) were complicated with DIC (p<0.001). In the adult cases, DIC was more frequently complicated with FAB subtype L2 than L1 (p<0.05). All hemorrhages seen in the childhood cases were minor hemorrhages. In the adult patients, two patients with DIC had WHO grade 3 hemorrhage and the other hemorrhagic complications were minor hemorrhages. While milder induction therapies starting with corticosteroid given for childhood cases should be taken into consideration when comparing the incidences of DIC after therapy, the findings indicated that childhood and adult ALL may differ in the procoagulant characteristics. Morphological distinction between L1 and L2 appears to have relevance in the procoagulant activity in adult ALL. DIC complicating ALL is generally mild, however, sometimes causes severe hemorrhages in adults.

Disseminated intravascular coagulation in acute lymphoblastic leukemia at presentation and in early phase of remission induction therapy

Abstract A high frequency of disseminated intravascular coagulation (DIC) in adult acute lymphoblastic leukemia (ALL) has been reported; however, its clinical relevance and characteristics have not been fully determined. We studied 67 adults with newly diagnosed ALL between 1982 and 1996 to clarify these questions. DIC was diagnosed in ten of 64 patients (16%) who underwent coagulation study at presentation and in 14 of 40 patients (35%) screened for DIC within 7 days after starting remission induction therapy. Overall, 24 of 67 patients (36%) had DIC during this period. Hemorrhagic symptoms were generally mild, while two patients required red blood cell transfusions. Patients who developed DIC had higher white blood cell counts and more frequently a palpable spleen than those who did not. There was no difference in age, French-American-British subtype, karyotype, immunophenotype, lactate dehydrogenase level, percentage of blasts in bone marrow, or frequency of lymphadenopathy or hepatomegaly between patients who had DIC and those who did not. Fibrinolysis tended to be milder in DIC complicating ALL than in that complicating acute promyelocytic leukemia; however, there was no difference in other coagulation parameters between these two subtypes. An etiological link between CD34 expression in common ALL patients and DIC was suggested.

Current cigarette smoking is a reversible cause of elevated white blood cell count: Cross-sectional and longitudinal studies

While cigarette smoking is a well-recognized cause of elevated white blood cell (WBC) count, studies on longitudinal effect of smoking cessation on WBC count are limited. We attempted to determine causal relationships between smoking and elevated WBC count by retrospective cross-sectional study consisting of 37,972 healthy Japanese adults who had a health check-up between April 1, 2008 and March 31, 2009 and longitudinal study involving 1730 current smokers who had more than four consecutive annual health check-ups between April 1, 2007 and March 31, 2012. In the cross-sectional study, younger age, male gender, increased body mass index, no alcohol habit, current smoking, and elevated C-reactive protein level were associated with elevated WBC count. Among these factors, current smoking had the most significant association with elevated WBC count. In subgroup analyses by WBC differentials, smoking was significantly associated with elevated counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Ex-smoking was not associated with elevated WBC count. In the longitudinal study, both WBC and neutrophil counts decreased significantly in one year after smoking cessation and remained down-regulated for longer than next two years. There was no significant change in either WBC or neutrophil count in those who continued smoking. These findings clearly demonstrated that current smoking is strongly associated with elevated WBC count and smoking cessation leads to recovery of WBC count in one year, which is maintained for longer than subsequent two years. Thus, current smoking is a significant and reversible cause of elevated WBC count in healthy adults.

Coagulation patterns of disseminated intravascular coagulation in acute promyelocytic leukemia.

Coagulation patterns of 19 newly‐diagnosed acute promyelocytic leukemia (APL) patients with disseminated intravascular coagulation (DIC) at presentation were studied. Seventeen patients had hemorrhagic complications, of which four were fatal. Fatal hemorrhages were related with lower fibrinogen level and lower platelet count. DIC of the APL patients without infection was characterized by low fibrinogen and normal antithrombin III (ATIII) level. Thrombin–ATIII complex level was elevated in all patients examined. Patients with infection had higher fibrinogen levels than those without infection and some patients had reduced ATIII level. Ten remission inductions were tried with multidrug chemotherapy and seven with all‐trans retinoic acid (ATRA). Complete remission was achieved in seven of ten inductions with chemotherapy and in all seven inductions with ATRA. Two patients treated with chemotherapy had fatal hemorrhage after starting therapy but none treated with ATRA.

Overlap of IgG4-related Disease and Multicentric Castleman's Disease in a Patient with Skin Lesions

A 59-year-old man presented with multiple dark red erythemas with induration, anemia, and polyclonal hypergammaglobulinemia. A skin biopsy revealed the infiltration of lymphocytes and plasma cells and he was initially diagnosed with multicentric Castlemans disease (MCD). Glucocorticoid treatment was only partially effective. Four years later, the patients bilateral lacrimal glands gradually became enlarged and a biopsy revealed dense lymphocyte and plasma cell infiltration with an IgG4+/IgG+ plasma cell ratio of 70%. The patient was diagnosed with IgG4-related disease (RD). Rituximab only had a slight effect. This case demonstrates that overlapping features of IgG4-RD and MCD may present in a single patient, which suggests a shared pathogenesis.