Molecular analysis of liquid cytological samples collected by bronchoscopy with radial endobronchial ultrasonography and guide sheath.

A 64-year-old man who underwent sigmoid resection for Stage 4 colon cancer had a growing nodule on the left upper lobe during follow-up. Surgical resection revealed primary pulmonary adenocarcinoma. Subsequently, a new nodule appeared in the contralateral S(1)b, for which endobronchial ultrasonography with a guide sheath (EBUS-GS) was performed for diagnosis. However, histopathologic examinations were inconclusive. Gene analysis of the liquid samples from this lesion revealed KRAS mutation, which on hindsight was not detected in the metachronous left upper lobe cancer but was detected in the resected sigmoid colon. Hence, the right upper lobe nodule was diagnosed by bronchoscopy as colon cancer metastasis, confirmed after wedge resection. For specimen obtained by EBUS-GS, search for gene mutation in the liquid specimen is useful as an ancillary test especially when histological diagnosis is equivocal. Thus, developments on diagnostic tools using liquid samples are highly expected in the future.

Recombinant human soluble thrombomodulin safely and effectively rescues acute promyelocytic leukemia patients from disseminated intravascular coagulation.

We treated individuals for disseminated intravascular coagulation (DIC) caused by acute promyelocytic leukemia (APL) (n=9) using human soluble thrombomodulin (rTM) in combination with all-trans retinoic acid (ATRA) and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM-treated patients. Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL.

Thrombomodulin enhances the antifibrinolytic and antileukemic effects of all-trans retinoic acid in acute promyelocytic leukemia cells.

This study found that levels of thrombomodulin (TM) were downregulated in freshly isolated leukemia cells from patients with acute promyelocytic leukemia (APL, n = 7) and acute myelogenous leukemia (n = 14), as compared with CD34(+)/CD38(-) hematopoietic stem/progenitor cells and CD34(-)/CD33(+)/CD11b(-) promyelocytes isolated from healthy volunteers (n = 3). Exposure of APL NB4 cells to recombinant human soluble TM (rTM, 1500 ng/mL) inhibited clonogenic growth of these cells by approximately 30%, and induced expression of CD11b, a marker of myeloid differentiation, on their surfaces, in association with upregulation of nuclear levels of myeloid-specific transcription factor CCAAT/enhancer binding protein ε. These antileukemic effects of rTM were mediated by thrombin/activated protein C-dependent mechanisms, as hirudin, an inhibitor of thrombin and a blocking antibody against endothelial receptor for protein C to which activated protein C binds, hampered the ability of rTM to induce expression of CD11b in NB4 cells. This study also found that rTM downregulated expression of Annexin II, a receptor for both plasminogen and tissue plasminogen activator, and inhibited plasmin activity in APL cells. Interestingly, rTM significantly enhanced the ability of all-trans retinoic acid to induce growth arrest, differentiation and apoptosis, and inhibited plasmin activity in APL cells. Taken together, these results suggest that administration of rTM should be considered for treatment of individuals with disseminated intravascular coagulation associated with APL.