Cholangiocellular Carcinoma Associated with Multiple Liver Cysts

A 46-year-old woman visited our outpatient clinic complaining of dull right hypochondrial pain. Ultrasonography revealed four cysts in the right lobe of the liver. Arteriography and CT could not determine whether these cysts were benign or malignant. Because one of these cysts contained chocolate-colored fluid, amebic abscess was suspected, and the cyst was drained. No amebae were found in the cultured exudate, and fresh bleeding continued; therefore, laparotomy was performed. A tumor was present on the surface of the liver. Right lobectomy was performed. The resected specimen contained one nonepithelialized cyst which was invaded by surrounding cholangiocellular carcinoma and three epithelialized cysts. Preoperative diagnosis of this kind of cholangiocellular carcinoma seems to be very difficult. Recently cholangiocellular carcinoma associated with developmental cysts has been classified as a new entity different from cystadenocarcinoma. Cholangiocarcinoma, which belongs to this group, seems to deserve special attention.     

Vasopressin responsiveness of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia

OBJECTIVE: Vasopressin (AVP) is reported to be an important factor for regulating cortisol secretion in patients with Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia (AIMAH). Recently, there have been several case reports of subclinical Cushing's syndrome due to AIMAH, in which the pathophysiological role of AVP has been unknown. The aim was to conduct an extensive investigation of AVP in the autonomous secretion of cortisol in subclinical Cushing's syndrome due to AIMAH. PATIENTS AND MEASUREMENTS: Five cases of AIMAH with subclinical Cushing's syndrome underwent prospective study including physical examination, imaging (MRI, CT and 131I-adosterol scintigraphy) and endocrinological evaluation that comprised basal plasma cortisol levels and urinary excretions of steroid metabolites, a dexamethasone suppression test and an AVP stimulation test. In case 1, left adrenalectomy was performed and the pathological diagnosis of AIMAH was established. An in vitro experiment using the cultured AIMAH adrenal cells was conducted to investigate cortisol secretion and expression of the V1-AVP receptor, mRNA by RT-PCR. RESULTS: All five cases were discovered incidentally to have bilateral adrenal nodules. Imaging by MRI and CT revealed large multinodular lesions in both adrenal glands, which showed positive uptake on 131I-adosterol scintigraphy. Although the basal values of plasma cortisol and urinary excretions of steroid metabolites were within normal limits, autonomous secretion of cortisol was assumed to occur because of lack of suppression during dexamethasone suppression. The five patients had no overt signs of Cushing's syndrome, and they were therefore diagnosed with subclinical Cushing's syndrome due to AIMAH. In all five patients, AVP stimulated cortisol secretion in vivo, whereas desmopressin acetate failed to affect cortisol secretion. In case 1, AVP stimulated cortisol secretion from cultured AIMAH adrenal cells, but this secretion had no relationship with cAMP production. In addition, over-expression of V1-AVP receptor mRNA in AIMAH tissue was determined by RT-PCR. CONCLUSION: Patients with subclinical Cushing's syndrome due to AIMAH commonly exhibit cortisol responsiveness to AVP, and this is probably mediated through activation of overexpressed V1-AVP receptors.     

Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status

Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph⁺MPAL) is a rare type of acute leukemia having myeloid and lymphoid features. In the present study, we describe the successful treatment of a 71-year-old Japanese female patient with Ph⁺MPAL by the alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutations. The patient survived in her third complete remission (CR) for over 4 years. In her first CR, the patient was treated with multiple-agent chemotherapy and underwent maintenance therapy with imatinib and monthly vincristine and prednisolone (VP). At the first relapse, an examination of the bone marrow revealed a transformation into acute lymphoblastic leukemia and an F317L mutation in BCR-ABL1 gene, which responded preferentially to nilotinib over dasatinib. She achieved second CR, and nilotinib with VP therapy was selected for maintenance treatment. At second relapse, BCR-ABL1 mutational analysis revealed Y253H mutation instead of F317L mutation, resulting in resistance to nilotinib. The patient achieved third CR with dasatinib and VP therapy, and maintained CR with this treatment. This suggests that appropriate alternation of TKIs may contribute to long-term survival in elderly patients with Ph⁺MPAL.     

s‐Afadin binds more preferentially to the cell adhesion molecules nectins than l‐afadin

l‐Afadin was originally purified from rat brain as an actin filament (F‐actin)‐binding protein that was homologous to the AF‐6 gene product. Concomitantly, s‐afadin that did not show an F‐actin‐binding capability was copurified with l‐afadin. Structurally, s‐afadin lacks the C‐terminal F‐actin‐binding domain but has two short sequences that were not present in l‐afadin. The properties and roles of l‐afadin have intensively been investigated, but those of s‐afadin have poorly been understood. We show here an additional difference in their biochemical properties other than binding to F‐actin between l‐afadin and s‐afadin. Both l‐afadin and s‐afadin bound to nectins, immunoglobulin‐like cell adhesion molecules, whereas s‐afadin more preferentially bound to nectins than l‐afadin. The PDZ domain of l‐afadin and s‐afadin was essential for their binding to nectin‐3. The dilute domain of l‐afadin negatively regulated its binding to nectin‐3, but the deletion of the C‐terminal F‐actin‐binding domain of l‐afadin did not increase the binding of l‐afadin to nectin‐3. These results indicate that the s‐afadin‐specific C‐terminal inserts may be involved in its preference of binding to nectin‐3 and raise the possibility that there are proteins other than nectins that more preferentially bind s‐afadin than l‐afadin.     

Simple in vitro migration assay for neural crest cells and the opposite effects of all‐trans‐retinoic acid on cephalic‐ and trunk‐derived cells

Here, we describe a simple in vitro neural crest cell (NCC) migration assay and the effects of all‐trans‐retinoic acid (RA) on NCCs. Neural tubes excised from the rhombencephalic or trunk region of day 10.5 rat embryos were cultured for 48 h to allow emigration and migration of NCCs. Migration of NCCs was measured as the change in the radius (radius ratio) calculated from the circular spread of NCCs between 24 and 48 h of culture. RA was added to the culture medium after 24 h at embryotoxic concentrations determined by rat whole embryo culture. RA (10 μM) reduced the migration of cephalic NCCs, whereas it enhanced the migration of trunk NCCs, indicating that RA has opposite effects on these two types of NCCs.