Monoclonal antibody MCS-2 as the marker of phorbol diester-induced myeloid differentiation in acute undifferentiated leukemia

Leukemic cells from 32 cases of acute leukemia were cultured in vitro with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) to study their differentiative potential. Three cases of acute undifferentiated leukemia (AUL) were studied intensively. We found that culturing of leukemic cells with TPA can induce changes in cell surface antigens. In particular, MCS-2, a "pan" granulocyte/monocyte marker, was inducible in vitro in AUL and in acute myelogenous leukemia, while it was not inducible in acute lymphoblastic leukemia. BA-2 (recognizing the Mr 24,000 protein) and TA-1 (recognizing the Mr 170,000 and Mr 95,000 proteins) were also inducible in cases of AUL, acute myelocytic leukemia, and acute monoblastic leukemia, although these antigens are not limited only to leukemias of the myelomonocytic lineage. Our studies also indicate that undifferentiated cells could be induced to nonspecific esterase and sometimes to chloroacetate esterase reactivity while losing terminal deoxynucleotidyl transferase. Morphological studies in these cases revealed cytological maturation following TPA treatment. In most cases, these changes were also partially inducible by culturing cells in medium alone or with the addition of dimethyl sulfoxide but not to the extent that was demonstrated by TPA. Our studies showed that MCS-2 is a very good, specific marker of acute nonlymphocytic leukemia. A potential use for TPA to aid in the subclassification of patients with AUL is also suggested.     

Hereditary Apolipoprotein A-1 Amyloidosis With Glu34Lys Mutation Treated by Liver Transplantation: A Case Report

Hereditary apolipoprotein A-1 (ApoA-1) amyloidosis is a rare disease characterized by progressive deposition of amyloid fibrils in the kidney, heart, and liver. We observed a 45-year-old male patient with liver failure. Liver dysfunction was detected at 30 years of age during an annual health check-up. At 35 years of age, renal dysfunction was also found. At 40 years of age, the pathologic findings of the liver revealed amyloid deposition. A testis biopsy specimen taken at 42 years of age to identify the cause of male infertility showed amyloid accumulation. At 43 years of age, the amyloid results and genetic profile led to a definitive diagnosis of hereditary ApoA-1 amyloidosis caused by Glu34Lys mutation. A family history was absent. Liver failure showed Budd-Chiari–like formation, including enlargement of the caudate lobe and liver congestion. Although the patient showed end-stage liver cirrhosis and renal failure, only liver transplant was performed considering the burden for a living donor. The enlarged liver (4.9 kg) showed amyloid deposition in parenchyma and the space of Disse. Amyloid also accumulated in the giant spleen. The APOA1 mutation Glu34Lys is extremely rare, and in this case hepatic failure was successfully treated by liver transplant to both replace organ function and reduce production of the amyloidogenic ApoA-1–variant protein. Careful observation for reaccumulation of amyloidosis in the organ is required.     

Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.     

Is the Gauer-Henry reflex important for immersion diuresis in men?

BACKGROUND: This study examines the relationship between the threshold for plasma vasopressin concentration [PVP] responses and diuresis (Gauer-Henry reflex), and tests the hypothesis that water intake would not influence diuresis. METHODS: Eight men (19-25 yr) underwent four treatments: euhydration in air (Eu-air), euhydration in water immersion (Eu-H2O), and with prior 3.6% hypohydration in air (Hypo-air), and hypohydration in immersion (Hypo-H2O). Ad libitum drinking was allowed during the 3-h experimental and 1-h recovery periods. RESULTS: Drinking was greatest during the first 10 min: 3.5 ml x kg(-1) with Hypo-air (450 ml x 3 h(-1)) and only 1.7 ml x kg(-1) (p < 0.05) with Hypo-H2O (235 ml x 3 h(-1)). At 1 h, concomitant [PVP] decreased from a control level of 6.6+/-1.5 to 4.0+/-1 .0 pg x ml(-1) (delta = 2.6 pg x ml(-1), p < 0.05) with Hypo-air, and from 5.9+/-0.6 to 2.3+/-0.2 pg x ml(-1) (delta = 3.6 pg x ml(-1), p < 0.05) with Hypo-H2O. Urine flow was unchanged from control level (<1.0 ml x min(-1)) with Hypo-air, Hypo-H2O, and Eu-air, but increased to 4-5 ml x min(-1) with Eu-H2O. Neither water intake volume nor urine flow was related to the magnitude of [PVP] depression. Regression of Uosm/Posm ratio on [PVP] and urine flow indicated that [PVP] above 2 pg x ml(-1) did not affect urine flow. Thus, ad libitum water intake in previously hypohydrated subjects did not affect urine flow or the decrease in [PVP]. The threshold [PVP] to initiate significant diuresis was about 2 pg x ml(-1), and significant diuresis can occur with no change in [PVP] maintained at about 1 pg x ml(-1) during immersion in euhydrated subjects. CONCLUSIONS: Thus, it appears that the Gauer-Henry reflex is not the major mechanism for immersion-induced diuresis. Clearly, other diuretic factors are also involved.     

Molecular-pathological Analysis of a Patient with Three Synchronous Squamous Cell Carcinomas in the Aerodigestive Tract

A case of synchronous squamous cell carcinomas in the soft palate,larynx and esophagus is reported, along with findings of molecular-pathologicalanalysis. A biopsy sample from the aryngeal carcinoma revealedwell differentiated squamous cell carcinoma harboring two pointmutations at codons 144 and 148 of the p53 gene but not at codon299, and more than 50% of the cancer cells showed accumulationof p53 protein immunohistochemically. The esophageal tumor,which was moderately differentiated squamous cell carcinoma,showed immunoreactivity for p53 within the nuclei of 25–50%of cancer cells with a missense mutation at codon 299 but notat codon 144 or 148. This cancer also showed immunoreactivityfor transforming growth factor alpha. On the other hand, thepoorly differentiated squamous cell carcinoma in the soft palateshowed negative immunoreactivity for p53 and no point mutationin exons 5 to 8 of the gene. These results suggest that thethree synchronous squamous cell carcinomas arose as independentevents.     

A compound tumor in the adrenal medulla--pheochromocytoma combined with ganglioneuroma: a case report

We report a case of a compound adrenal medullary tumor. A 63-year-old woman was referred to our hospital for examination of a right adrenal tumor, incidentally found by abdominal computed tomography (CT). CT and magnetic resonance imaging (MRI) revealed a round heterogeneous tumor, 5 cm in diameter, on the upper pole of the right kidney. A view of the total body scan demonstrated the uptake into the tumor after the injection of 123I-metaiodobenzyl-guanidine. Serum and urinary adrenaline levels were slightly elevated, and urinary excretion of vanillylmandelic acid was markedly elevated. Her blood pressure was normal. From these findings, the tumor was suspected to be a pheochromocytoma of the right adrenal gland and was resected reteroperitoneally. Pathological diagnosis was a compound adrenal medullary tumor, which was composed of pheochromocytoma and ganglioneuroma. This combination of the adrenal medullary tumor is extremely rare, and to date this case may be the sixth case in the Japanese medical literature.     

Vascular ultrasound in obstetrics

The usefulness of the vascular ultrasound in the field of obstetrics is now well recognized. Intima-media thickness (IMT) and elastic property of the common carotid artery are affected by pregnancy and vary with complications. Flow-mediated vasodilation (FMD) of the brachial artery reflects the vascular endothelial function and is reported to be useful in the management of complicated pregnancy, especially pre-eclampsia. For the screening of deep vein thrombosis of the lower extremities in the perinatal period, compression ultrasonography (CUS) is useful.     

Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (-/-) mice.

Breast cancer resistance protein (BCRP) is a recently identified ATP-binding cassette transporter, important in drug disposition and in the development of multidrug resistance in cancer. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be human BCRP inhibitors. The objective of the present study was to evaluate the potential for in vivo pharmacokinetic interactions by comparing the pharmacokinetics of topotecan (a model BCRP substrate) after oral administration of 2 mg/kg topotecan with and without different doses of the flavonoids chrysin or 7,8-benzoflavone (BF) in rats and mdr1a/1b (-/-) mice. Coadministration of 50 mg/kg GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9, 10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] with 2 mg/kg topotecan significantly increased the area under the plasma concentration-time curve and bioavailability of topotecan by more than 4-fold in these animals, indicating the importance of BCRP in the bioavailability and disposition of topotecan in rats. Chrysin (50 microM) and BF (5 microM) significantly inhibited the BCRP-mediated transport of topotecan in BCRP-overexpressing MCF-7 MX100 cells (MCF-7 cells selected with mitoxantrone) to a level comparable to that observed with 10 microM fumitremorgin C (a potent BCRP inhibitor). However, neither chrysin nor BF significantly altered topotecan pharmacokinetics in rats or in mdr1a/1b (-/-) mice after oral coadministration of doses up to 50 mg/kg. The reason(s) for this lack of in vitro-in vivo association may be the lack of potent inhibition activity of the flavonoids against mouse or rat BCRP, as evidenced by our observation that these flavonoids have only weak, if any, inhibition activity against mouse Bcrp1-mediated transport of topotecan in MDCK-Bcrp1 cells.