Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry.

BACKGROUND: We investigate rates of pathologic complete response (pCR) and tumor expression of ER, PgR, HER2 discordance after neoadjuvant chemotherapy using Japanese breast cancer registry data. PATIENTS AND METHODS: Records of more than 300,000 breast cancer cases treated at 800 hospitals from 2004 to 2013 were retrieved from the breast cancer registry. After data cleanup, we included 21,755 patients who received neoadjuvant chemotherapy and had no distant metastases. pCR was defined as no invasive tumor in the breast detected during surgery after neoadjuvant chemotherapy. HER2 overexpression was determined immunohistochemically and/or using fluorescence in situ hybridization. RESULTS: pCR was achieved in 5.7% of luminal tumors (n = 8730), 24.6% of HER2-positive tumors (n = 4403), and 18.9% of triple-negative tumors (n = 3660). Among HER2-positive tumors, pCR was achieved in 31.6% of ER-negative tumors (n = 2252), 17.0% of ER-positive ones (n = 2132), 31.4% of patients who received trastuzumab as neoadjuvant chemotherapy (n = 2437), and 16.2% of patients who did not receive trastuzumab (n = 1966). Of the 2811 patients who were HER2-positive before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 340 (3.4%) of the 9947 patients with HER2-negative tumors before treatment had HER2-positive tumors afterward. Of the 10,973 patients with ER-positive tumors before treatment, 499 (4.6%) had ER-negative tumors after neoadjuvant chemotherapy, whereas 519 (9.3%) of the 5607 patients who were ER-negative before treatment had ER-positive tumors afterward. CONCLUSION: We confirmed that loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer. We also confirmed that in practice, differences in pCR rates between breast cancer subtypes are the same as in clinical trials. Our data strongly support the need for retest ER, PgR, HER2 of surgical sample after neoadjuvant therapy in order to accurately determine appropriate use of targeted therapy.

Pancreatic beta-cell-type-specific transcription of the insulin gene is mediated by basic helix-loop-helix DNA-binding proteins.

The pancreatic beta-cell-specific expression of the insulin gene is mediated, at least in part, by the interaction of unique trans-acting beta-cell factors with a cis-acting DNA element found within the insulin enhancer (5'-GC CATCTG-3'; referred to as the insulin control element [ICE]) present in the rat insulin II gene between positions -100 and -91. This sequence element contains the consensus binding site for a group of DNA-binding transcription factors called basic helix-loop-helix proteins (B-HLH). As a consequence of the similarity of the ICE with the DNA sequence motif associated with the cis-acting elements of the B-HLH class of binding proteins (CANNTG), the ability of this class of proteins to regulate cell-type-specific expression of the insulin gene was addressed. Cotransfection experiments indicated that overexpression of Id, a negative regulator of B-HLH protein function, inhibits ICE-mediated activity. Antibody to the E12/E47 B-HLH proteins attenuated the formation, in vitro, of a previously described (J. Whelan, S. R. Cordle, E. Henderson, P. A. Weil, and R. Stein, Mol. Cell. Biol. 10:1564-1572, 1990) beta-cell-specific activator factor(s)-ICE DNA complex. Both of these B-HLH proteins (E12 and E47) bound efficiently and specifically to the ICE sequences. The role of B-HLH proteins in mediating pancreatic beta-cell-specific transcription of the insulin gene is discussed.

Insulin gene expression in nonexpressing cells appears to be regulated by multiple distinct negative-acting control elements.

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located between nucleotides -340 and -91 relative to the transcription start site. Transcription from the enhancer is controlled by both positive- and negative-acting cellular factors. Cell-type-specific expression is mediated principally by a single cis-acting enhancer element located between -100 and -91 in the rat insulin II gene (referred to as the insulin control element [ICE]), which is acted upon by both of these cellular activities. Analysis of the effect of 5' deletions within the insulin enhancer has identified a region between nucleotides -217 and -197 that is also a site of negative control. Deletion of these sequences from the 5' end of the enhancer leads to transcription of the enhancer in non-insulin-producing cells, even though the ICE is intact. Derepression of this ICE-mediated effect was shown to be due to the binding of a ubiquitously distributed cellular factor to a sequence element which resides just upstream of the ICE (i.e., between nucleotides -110 and -100). We discuss the possible relationship of these results to cell-type-specific regulation of the insulin gene.

Beneficial effect of FR183998, a Na+/H+ exchanger inhibitor, on porcine pancreas allotransplantation retrieved from non-heart-beating donors.

Activation of Na(+)/H(+) exchanger (NHE) may have an important role in the ischemia/reperfusion injury by producing intracellular calcium overload. Recent studies have shown a beneficial effect of an NHE inhibitor on the ischemia/reperfusion injury in the heart. In this study, we examined the effect of FR183998, a potent NHE inhibitor, in porcine pancreas allotransplantation from non-heart-beating Landrace pig donors (NHBDs). The four experimental groups included: untreated with no preservation (group 1; n = 3), treated with no preservation (group 2; n = 5), untreated with preservation (group 3; n = 6), and treated with preservation (group 4; n = 4). The preservation was made in ice-cold University of Wisconsin (UW) solution for 24 hours. The groups treated received 1 mg/kg FR183998 before donor cardiac arrest and 10 mg in the UW solution flush in situ. Serum blood glucose, insulin, and amylase were measured daily. An intravenous glucose tolerance test (IVGTT) was performed on the postoperative day (POD) 7 when pigs were sacrificed for histological examination. Graft survival rates on that day in groups 1,2,3, and 4 were 3 of 3; 5 of 5; 3 of 6; and 4 of 4, respectively. The mean K values of IVGTT in groups 3 and 4 were 0.78 +/- 0.10 and 1.27 +/- 0.16, respectively, which were significantly different (P < .05). Upon histological examination, pancreatic tissue in group 3 showed more severe edema and necrosis than other groups. FR183998 may be considered beneficial for ischemia/reperfusion injury to pancreatic grafts from NHBDs.

Excessive portal flow causes graft nonfunction in small size liver transplantation: an experimental study in pigs.

We investigated the effects of portocaval shunt (PCS) on excessive portal flow in producing sinusoidal microcirculatory injury in small-for-size liver transplants in pigs. The posterior segment of a whole liver (25%) was transplanted orthotopically. The pigs were divided two groups: group A, graft with PCS (n = 11), and group B, graft without PCS (n = 11). The PCS was a side-to-side anastomosis of the portal vein and the inferior vena cava. In group A, eight pigs survived for more than 4 days; all pigs except for one died of graft nonfunction within 24 hours in group B. The portal flow after reperfusion decreased in group A, but increased about three times greater in group B than that before the operation (P < .01). In group B, destruction of the sinusoidal lining and bleeding in the periportal areas were observed after reperfusion, findings that were not recognized in group A. These results suggest that graft nonfunction after small-for-size liver transplantation may be attributable to excessive portal flow producing sinusoidal microcirculatory injury.

Selective inhibition of cyclic AMP phosphodiesterase from various human tissues by milrinone, a potent cardiac bipyridine.

We observed the effects of milrinone, an inotropic agent prescribed to treat congestive heart failure, on cyclic nucleotide messenger systems in various human tissues in vivo. Cyclic nucleotide phosphodiesterases (PDEs) from the human heart were separated into three isoforms, FI, FII and FIII, by DEAE-cellulose chromatography. Milrinone proved to be a potent and selective inhibitor of human cardiac FIII PDE, a "low Km" enzyme for cyclic AMP (cAMP-PDE). The IC50 value for the inhibition of FIII PDE was 0.42 microM, while those of FI and FII PDEs, "high Km" enzymes, were 38 and 19 microM, respectively. Kinetic studies showed that milrinone inhibited the activity of FIII PDE, competitively with respect to cAMP, and the Ki was 0.15 microM. Milrinone in doses to 100 microM had no effect on human cardiac cAMP-dependent protein kinase and adenylate cyclase. The activity of cAMP-PDEs from human platelets and the aorta, as well as that from heart, were potently inhibited by milrinone, with much the same IC50 values. Cyclic AMP-PDEs from human kidney, liver and lung were not readily inhibited by milrinone, and the IC50 values of cAMP-PDEs from these tissues were about 7-30-fold higher than that from heart. On the other hand, papaverine had a relatively lesser selectivity for any of the cAMP-PDEs. All these results suggest that milrinone exerts inotropic effects by inhibiting cAMP-PDE selectively in the human heart tissues and that this compound can be used to evaluate different forms of cAMP-PDEs present in human tissues.

Identification and characterization of isoenzymes of cyclic nucleotide phosphodiesterase in human kidney and heart, and the effects of new cardiotonic agents on these isoenzymes.

The present study was done to identify and characterize the isoenzymes of cyclic nucleotide phosphodiesterase (PDE) and to determine their intracellular distribution in human kidney and heart. The in vitro effects of new cardiotonic agents, namely, NSP-805 (4,5-dihydro-5-methyl-6-[4-[(2-methyl-3-oxo-1-cyclopentenyl)amino] phenyl]-3(2H)-pyridazinone), TZC-5665 (6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]- 2 -methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone ) and its metabolites, OPC-18790 ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2 -hydroxypropoxy]-2-(1H)-quinolinone), MS-857 (4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone ) and E-1020 (1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate), on these human PDE isoenzymes were also investigated. PDE isoenzymes were separated from cytosolic and particulate fractions of homogenates of human kidney and heart by DEAE-Sepharose chromatography. PDE isoenzymes were identified by their elution characteristics, substrate specificities, sensitivities to regulation by effectors and by the use of isoenzyme-specific inhibitors. In a cytosolic fraction from kidney, Ca2+/calmodulin-dependent PDE (CaM-PDE), cyclic GMP-stimulated PDE (cGS-PDE), cyclic GMP-inhibited PDE (cGI-PDE) and two forms of cyclic AMP-specific PDE (cAMP-PDE) were resolved. One form of cAMP-PDE (cAMP-PDE alpha), which was eluted at a lower ionic strength than cGI-PDE during DEAE-Sepharose chromatography, was newly recognized in human tissues, though the other form (cAMP-PDE beta), which eluted later than cGI-PDE, had been previously isolated.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictive value of remnant-like particle cholesterol as an indicator of coronary artery stenosis in patients with normal serum triglyceride levels.

OBJECTIVE: We designed the present study to evaluate the association of various lipid and fibrinolytic components with coronary artery stenosis with respect to the triglyceride (TG) level. METHODS: Levels of TG, remnant-like particle cholesterol (RLP-C), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein-(a), uric acid, blood glucose, tissue plasminogen activator (t-PA), t-PA inhibitor type 1, antithrombin III, and protein C were measured in 208 patients who underwent diagnostic coronary angiograms. PATIENTS: Of these 208 patients, 59 were hypertriglyceridemic (150 mg/dl or higher) and 149 were normotriglyceridemic. RESULTS: Both LDL-C and HDL-C showed significant differences between patients with and those without coronary artery stenosis in both hypertriglyceridemic and normotriglyceridemic patient subgroups. However, RLP-C showed a significant difference in the normotriglyceridemic patient subgroup (p=0.012) but not in the hypertriglyceridemic patient subgroup (p=0.736). CONCLUSION: Our current retrospective study disclosed that RLP-C levels are closely associated with coronary artery stenosis in patients with normal TG levels.

Rhabdomyolysis and myocardial damage induced by palytoxin, a toxin of blue humphead parrotfish.

A 55-year-old man had rhabdomyolysis and myocardial damage induced by palytoxin. Weakness and myalgia of four extremities occurred five hours after eating a fish. Rhabdomyolysis developed and the serum creatine phosphokinase (CK) was elevated to 40,000 IU/l on the 3rd day. Gastric lavage with activated charcoal and forced mannitol-alkaline diuresis therapy were performed. The patient recovered with no complication such as renal failure. In this case, palytoxin was suggested to induce myocardial damage which was demonstrated by an elevation of the myosin light chain level and a change in electrocardiogram.

[Recovery from pancytopenia and liver dysfunction after administration of thiamazole for hyperthyroidism].

A 45-year-old woman was referred to our hospital because of hyperthyroidism complicated by atrial fibrillation and heart failure. Laboratory data revealed pancytopenia, with a white blood cell count of 2,600/microliter, red blood cell count of 330 x 10(4)/microliter, and platelet count of 6.2 x 10(4)/microliter. The patient had normal transaminase levels, but tests for hepaplastin and cholinesterase showed values of 34% and 1.4 U/ml, respectively, indicating liver dysfunction. There was also decreased excretion of indocyanine green. After initiation of treatment with 30 mg thiamazole and 20 mg propranolol daily, the patient's thyroid function normalized and the other abnormal laboratory findings such as pancytopenia and liver dysfunction also disappeared. Pancytopenia is a rare complication of hyperthyroidism. In this case, various laboratory abnormalities were normalized by antithyroid therapy alone, indicating that the hyperthyroidism itself was closely related to the pathogenesis of pancytopenia and liver dysfunction.

[Primary non-Hodgkin's lymphoma of the uterine cervix complicated by acute renal failure due to ureter obstruction].

An 80-year-old woman was referred to our hospital because of irregular genital bleeding. An abnormal mass was found in the uterine cervix, and diagnosed as non-Hodgkin's lymphoma, diffuse large B cell type. Soon after admission, the patient became anuric and was given a diagnosis of acute renal failure due to obstruction of the ureter. She was immediately placed on dose-reduced CHOP and radiotherapy of 15 Gy. As a result, not only did the malignant lymphoma go into remission, but diminished renal function was alleviated. Because malignant lymphoma of the uterus is extremely rare, it exact biocharacteristics are not well understood. We are unaware of any previous report concerning uterine lymphoma complicated by renal failure.

[Primary myelofibrosis with fatal mesenteric arterial thromboembolism caused by antiphospholipid syndrome].

A 60-year-old woman was admitted to our hospital in February 1993 due to dizziness, dyspnea, abdominal pain, and high susceptibility to bleeding. Physical examination revealed livedo reticularis of the foot, but did not detect hepatosplenomegaly. Examination of the peripheral blood detected pancytopenia, leukoerythroblastosis, and tear-drop erythrocytes. Primary myelofibrosis (PMF) was diagnosed on the basis of bone marrow biopsy findings. Antiphospholipid syndrome (APS) was confirmed by positive response to anti-cardiolipin antibody and recurrent splenic infarction. Because of factor XIII deficiency, the patient experienced severe gingival bleeding after tooth extraction. Her condition was complicated by mesenteric arterial thromboembolism and she died of sepsis 5 years after onset. Although the incidence of immunopathy in PMF patients is high, few studies to date have focused on APS patients presenting with a variety of severe embolic symptoms. Our patient required careful monitoring due to bleeding tendency and thromboemboli.

[Blastic form of acute erythremia: report of an autopsy case].

We report an autopsy case of acute erythremia which terminated in generalized infiltration of immature blasts similar to proerythroblasts. A 61-year-old man was admitted because of general fatigue and fever in June, 1990. Mild anemia and severe thrombocytopenia were noted. The bone marrow was hypocellular with 25.5% blasts similar to proerythroblasts and 36.5% erythroblasts, many of which were polynuclear and megaloblastoid. The blasts were cytochemically negative for POX, but positive for PAS staining. Therefore he was diagnosed as having acute erythremia. Partial remission was achieved by BHAC-EV therapy. But three months later, his marrow was replaced by 52.7% blasts as seen in admission. Those blasts were negative for lymphoid, myelocytic, megakaryocytic markers and antiglycophorin A, but positive for OKT 9. Electron microscopy revealed that some of blasts had characteristics of immature erythroblasts. In spite of low dose Ara-C therapy, he died of sudden gastrointestinal bleeding in December, 1990. The autopsy disclosed widespread infiltration of blasts, involving liver, spleen, lung, kidney and stomach. It was interesting that dysplasia had been confined to erythroid lineage throughout his clinical course. He seemed to be a rare case of blastic form of acute erythremia which should be distinguished from erythroleukemia.

[Pharmacokinetics of BHAC, VP-16 and Ara-C derived from BHAC in a hemodialysed patient with AMMoL].

Although recently the occurrence of a malignant neoplasma as a complication of uremia is becoming more frequently, pharmacokinetics of antitumor agents are not precisely studied in patients with impaired renal function. In this report we investigated pharmacokinetics of enositabine (BHAC), arabinosylcytosine (Ara-C) and etoposide (VP-16) in a patient on maintenance hemodialysis who suffered from acute myelomonocytic leukemia and treated by BHAC-EV regimen. Pharmacokinetic parameters of BHAC in uremia were not different from that in patients with normal renal function, and hemodialysis did not affect on the plasma level of BHAC. No significant accumulation of Ara-C was seen in uremia, but there remained the possibility that Ara-C could be removed by hemodialysis. So BHAC was able to be used in uremic patients safely. Since VP-16 was proved to be not a hemodialyzable but an accumulative substance and prolongation of plasma half life was prompt in uremia, VP-16 should be administered to uremic patients very cautiously. From these results BHAC-EV regimen was presumed to be a safely, well tolerated and beneficial regimen in uremic patients.

[Pure red cell aplasia complicated with polyarthritis, angitis, and acute renal failure].

A case of pure red cell aplasia (PRCA) with various complications polyarthritis, angitis, acute renal failure and DIC was successfully treated with steroid pulse therapy was described. A 55-year-old woman was hospitalized with a 9-month of intermittent but progressive joint pain, morning stiffness, general fatigue, and fever. Her initial laboratory evaluation revealed a hemoglobin of 4.4 g/dl and absence of reticulocyte. Her bone marrow aspirate showed no erythroblast which was compatible with a diagnosis of PRCA. Marked leukocytosis and thrombocytosis, positive antinuclear antigen, elevation of gammaglobulin and C-reactive protein and the presence of polyarthritis and angitis which was confirmed by renal angiography, indicated an underlying autoimmune disorders. Steroid pulse therapy was administered at 500 mg/day for 3 days, resulting in the complete response in both red cell aplasia and above findings. PRCA is known to be associated with systemic lupus erythematosus and rheumatoid arthritis very rarely, but this case did not fulfill the criteria of known collagen diseases, and there is no previous report representing PRCA with various complications such as polyarthritis, angitis and acute renal failure. This case may help us to understand more about the relationship between PRCA and autoimmune disorders.

[Interferon therapy of idiopathic thrombocytopenic purpura].

The authors evaluated the efficacy of a daily administration of recombinant human alpha 2a interferon (IFN), given at a dose of 300MU for 12 consecutive days, in patients with steroid-nonresponsive or -dependent idiopathic thrombocytopenic purpura (ITP). Nine patients received courses of IFN therapy. Mean platelet counts rose from 1.39 to 10.9 x 10(4)/microliters and PAIgG decreased from 151.7 to 59.7 ng/10(7) cells. The maximum rise in platelet counts occurred from 10 to 42 days (mean 19.1) after the initiation of IFN. Complete response (CR) was achieved in 3 of 13 courses (23.1%), and partial response (PR) in 8 (61.5%). One CR case continued for longer than 20 months without further treatment, but intermittent IFN therapy was necessary for the other. The increment of the platelet counts was transient in all of the partial responders. No severe side effect requiring interruption of the course of IFN was experienced. Both serum IgG and PAIgG significantly correlated with the increment of platelet counts, therefore the mechanism of IFN on ITP was presumed to be associated with the inhibition of autoantibody production. Daily administration of IFN appears to be an effective and safe treatment protocol for refractory ITP.

[High-dose cepharanthin therapy of idiopathic thrombocytopenic purpura].

Clinical efficacy of oral high-dose cepharanthin (40-60 mg/day) was evaluated in nine patients with idiopathic thrombocytopenic purpura who were unable to discontinue the administration of adrenocorticosteroids or immunosuppressive drugs. Mean platelet counts significantly (p less than 0.05) rose from 4.5 +/- 0.9 x 10(4)/microliters to 8.9 +/- 4.2 x 10(4)/microliters without any side effects. Two to five months after the initiation of this therapy, 4 patients, including 3 who could discontinue adrenocorticosteroids, kept their platelet counts over 10 x 10(4)/microliters. It was suggested that the oral administration of cepharanthin could be a beneficial and safe strategy for ITP.

[Successful low-dose etoposide therapy for a case of myelofibrosis with chronic myelogenous leukemia megakaryocytic predominance type].

A 38-year-old woman presented with ear pain and vertigo. No hepatosplenomegaly or lymphadenopathy were found, but her platelet counts markedly rose to 414 x 10(4)/microliters with an increase of megakaryocytes in the bone marrow (859/microliters). Cytogenetic assay revealed positive Ph1 chromosome and rearrangement of the break point cluster region (bcr). Although platelet counts remained under 100 x 10(4)/microliters after the administration of carboquone, a high fever and pancytopenia appeared 31 months later. Bone marrow biopsy showed marked myelofibrosis which was improved by low dose etoposide. This case was thought to be Ph1 positive ET, but it was more compatible with CML megakaryocytic predominance type according to the newly proposed "Hannover criteria for myeloproliferative disorders" and cytogenetic assay.

[A case of hemophagocytic syndrome with multiple myeloma].

A case with multiple myeloma complicated with hemophagocytic syndrome (HS) is presented. Because pancytopenia, liver dysfunction and increase of mature histiocytes in the bone marrow appeared rapidly a diagnosis of HS was made. The patient died of multiple organ failure, despite steroid therapy. Autopsy revealed marked invasion of hemophagocytic histiocytes not only into the bone marrow but also into many other organs such as the liver, lymph nodes and kidneys. HS is a histiocyte proliferative disorders, which is likely to be seen in immunocompromised hosts, but there is no previous report about HS and multiple myeloma.