An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

Uterine contractions increase fetal heart preload.

OBJECTIVE: The preload index (PLI) has been shown to increase in the recipient fetus of twin-twin transfusion syndrome in the presence of uterine contractions. The objective of this study was to determine whether there are changes in PLI in the presence of uterine contractions in normal fetuses. METHODS: Inferior vena cava blood flow was measured using Doppler sonography in 45 normal fetuses at 18-41 weeks' gestation in the presence of uterine contractions and during quiescence and the PLI was compared between groups. RESULTS: There was a highly significant difference (P < 0.0001) between the mean +/- SD PLI in fetuses in the absence (0.235 +/- 0.07) and in the presence (0.534 +/- 0.183) of uterine contractions. CONCLUSION: Uterine contractions appear to increase fetal preload conditions in normal pregnancy.

Roles of the telencephalic cells and their chondroitin sulfate proteoglycans in delimiting an anterior border of the retinal pathway.

The axons of the retinal ganglion cells run on the diencephalotelencephalic boundary on their way to the tectum; however, they do not invade the telencephalon anteriorly. To investigate the mechanisms that prevent the retinal axons from entering the telencephalic territory, the effects of the telencephalic cells were examined on the outgrowth of the retinal axons in vitro; the retinal outgrowth was selectively inhibited by the cellular substrate derived from the telencephalon. The responsible factor for the selective inhibition was, furthermore, found in the telencephalic membranes and the fraction of peripheral membrane molecules from the telencephalon. Because the inhibitory effect was destroyed by chondroitinase ABC but not by heat, this inhibition was attributable to the carbohydrate chains of chondroitin sulfate proteoglycans (CSPGs) adhering to the membranes of the telencephalic cells. To understand the function of the telencephalic CSPGs on the retinal pathfinding in vivo, their carbohydrate chains [chondroitin sulfate glycosaminoglycan (CS-GAG)] were removed from the embryonic brains by intraventricular injection of chondroitinase ABC; the removal of CS-GAG resulted in an anterior enlargement of the optic tract. The results indicate that the telencephalic cells delimit the anterior border of the optic tract with their CSPGs and prevent the retinal axons from aberrantly entering the anterior territory.

Characterization of growth-restricted fetuses with breakdown of the brain-sparing effect diagnosed by spectral Doppler.

OBJECTIVE: To characterize serial findings of the middle cerebral artery (MCA) and umbilical artery (UA) flow patterns, their relationship to each other, and neonatal outcomes in growth-restricted fetuses. METHODS: Serial pulsatility indices (PIs) from MCA and UA Doppler waveforms were measured in 41 growth-restricted fetuses until Cesarean delivery. We found three patterns, as follows: phase 1 (n = 27), UA PI < MCA PI (no brain-sparing effect); phase 2 (n = 11), UA PI > MCA PI (brain-sparing effect); phase 3 (n = 3), both PIs elevated with the absence of end-diastolic flow or presence of reverse end-diastolic flow, which was designated as the 'breakdown of the brain-sparing effect'. Umbilical cord blood gas data at delivery were compared between each group. RESULTS: Age at delivery and body weights were significantly different for each phase. The mean body weights in all phases were significantly diminished from Japanese standard body weights, indicating growth restriction. The phase 3 pH and base excess were significantly different from those of the other two phases. CONCLUSIONS: Growth-restricted fetuses which suffered from the state of breakdown of the brain-sparing effect were delivered early with severe growth restriction and mild metabolic acidosis. The change from decreased to increased MCA PI along with increasing UA PI may predict a severely growth-restricted infant.

Acute profound sensorineural hearing loss as the initial manifestation of acute leukemia--report of a case.

This paper reports an unusual case in which acute lymphocytic leukemia presented acute profound sensorineural hearing loss as the initial manifestation of the disease. The patient is a 55-year-old woman who complained of left hearing loss of sudden onset. Pure tone audiometry revealed profound sensorineural hearing loss of the left ear at mid and low frequencies. The patient was tentatively diagnosed as idiopathic sudden deafness and admitted for the treatment, but her laboratory data indicated that she was at an advanced stage of leukemia. The patient's hearing loss did not improve subjectively until she deceased 1 year after the admission. The mechanism producing acute hearing loss in leukemic patients is reviewed and discussed, and the importance of differentiating possible underlying diseases before we diagnose idiopathic sudden deafness is stressed.

Impaired interleukin-2 production in T-cells from a patient with Wiskott-Aldrich syndrome: basis of clinical effect of interleukin-2 replacement therapy.

Interleukin-2 production may be one of the underlying causes of Wiskott-Aldrich syndrome immunodeficiency and recombinant interleukin-2 administration (or an infusion of T-cells expanded by CD3 stimulation and rIL-2) is able, to some extent, to restore defective T-cell function.

CTG triplet repeat expansion in a laryngeal carcinoma from a patient with myotonic dystrophy.

A 66-year-old Japanese man with myotonic dystrophy (DM) underwent total laryngectomy for laryngeal carcinoma. The size of the expanded DNA fragment (EF) from the leukocytes and normal laryngeal tissues of this patient was only slightly longer than that in normal subjects. EF, however, was markedly longer in the laryngeal carcinoma. These findings support the hypothesis that elongation of the CTG repeat in the DM kinase gene occurs during acquired cell proliferation.

Postpartum microangiopathic hemolytic anemia: cases of successful and dismal outcome assisted with plasma therapy.

Microangiopathic thrombosis, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), seem to occur with certain stresses, including pregnancy. This report documents the clinical outcome with or without plasma therapy and dismal outcomes of two cases with postpartum microangiopathic thrombosis. One carried a pregnancy to successful cesarean delivery and suffered from postpartum TTP/HUS followed by plasma therapy-assisted recovery. Another developed postpartum TTP/HUS and was complicated with subarachnoid hemorrhage. Submission to plasma therapy should always be considered in a woman with postpartum microangiopathic thrombosis.

Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells.

We investigated the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the role of PPARgamma in cell growth in human gastric cancer cells. Reverse transcription-polymerase chain reaction, Northern blot and Western blot analyses showed that a human gastric cancer cell line, MKN45, expressed PPARgamma mRNA and protein. Luciferase assay in MKN45 cells showed that troglitazone, a selective ligand for PPARgamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter. Troglitazone or pioglitazone, selective ligands for PPARgamma, inhibited the growth of MKN45 cells in a dose-dependent manner. Co-incubation of MKN45 cells with troglitazone induced DNA ladder formation. These results suggest that human gastric cancer cells express PPARgamma and that activation of PPARgamma inhibits cell growth and induces apoptosis in gastric cancer cells.

Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system.

We identified a novel member of the Ikaros gene family, which has critical roles in the development of lymphoid lineages. This gene, which we named Eos, was expressed predominantly in the developing central and peripheral nervous system. Eos protein could interact with itself and Ikaros protein through its C-terminal portion in the yeast two hybrid assay. These findings suggested that Eos may have important roles in neural development similarly to the Ikaros family in the development of hemolymphoid tissue.

Differences in mossy and climbing afferent sources between flocculus and ventral and dorsal paraflocculus in the rat.

Sources of mossy and climbing fiber inputs to the flocculus (FL), ventral paraflocculus (VP) and/or dorsal paraflocculus (DP) were identified in the vestibular ganglion, medulla oblongata and pons of 19 Wistar rats after 26 local injections of horseradish peroxidase, wheat-germ agglutinin-conjugated horseradish peroxidase, fast blue or diamidino yellow into the FL, VP and/or DP. There were large differences in the sources of mossy fibers to the FL and VP/DP. Labeled neurons after injections into the FL were observed mainly in the ipsilateral vestibular ganglion, bilaterally in the vestibular and prepositus hypoglossal nuclei, and in the caudal part of the nucleus reticularis tegmenti pontis. Labeled neurons were rarely observed in the pontine nuclei after localized injections into the FL. By contrast, after injections into the VP and/or DP, numerous labeled neurons were observed in the pontine nuclei with a contralateral predominance and in the rostral part of the nucleus reticularis tegmenti pontis bilaterally, but not in the vestibular nuclei in either side. Sources of climbing fibers to the FL and paraflocculus were completely contralateral to the injection side. After injection into the FL, labeled neurons were observed in the caudal dorsal cap and ventrolateral outgrowth of the inferior olivary nucleus. After injections into the VP, labeled neurons were observed mainly in the rostral dorsal cap, ventral medial accessory olivary nucleus (MAO) and caudal half of the ventral leaf of the principal olivary nucleus. After injections into the DP, labeled neurons were observed in the ventral MAO and caudal half of the ventral leaf of the principal olivary nucleus. These differences in the sources of mossy and climbing fiber inputs may suggest functional differences between the FL and VP/DP. The present results are consistent with our previous observations in monkey that the FL and VP/DP exhibit quite different mossy fiber input organizations.

Kinetic analysis of cell proliferation using bromodeoxyuridine labeling and in situ detection of dying cells in the tympanic membrane and middle ear cholesteatoma.

Using specimens from the posterior-superior quadrant of the human tympanic membrane, meatal skin, retroauricular skin and middle ear cholesteatoma, epidermal cell proliferation was studied by cultures in FC43 emulsion containing bromodeoxyuridine (BrdU), and cell death was detected by in situ labeling of nuclear DNA fragmentation (TUNEL staining). The culture of specimens with BrdU revealed labeling in the basal cell layer and/or the layer immediately above it. The counts of BrdU-labeled cells both at and beside the malleus handle and at the annulus were significantly higher than those in the tympanic membrane, meatal skin, retroauricular skin and cholesteatoma, indicating the existence of epidermal proliferation centers in the annulus and malleus handle. TUNEL-positive cells were observed in the uppermost layer of the epidermis, and counts of dying cells did not show any significant differences among specimens from the different areas. From these observations, we conclude that addition of newly proliferated cells at the proliferation center and uniform cell death cause epidermal cell migration over the tympanic membrane and ear canal. In addition, no proliferation center was seen in the epidermis of cholesteatoma, suggesting a disturbance of epidermal cell migration. Furthermore, BrdU-labeling at the margin of persistently perforated tympanic membranes from patients with chronic otitis media revealed that, at the perforation margin, the counts of BrdU-labeled cells were not higher than those of the normal tympanic membrane. In addition, a few BrdU-labeled cells were observed in the lamina propria and mucosal cell layer, indicating that persistent perforation of the tympanic membrane results from the failure of proliferating cells to increase at the margin of the perforation.

[Hearing acuity in the elderly in Japan].

In Japan, the elderly population has progressively increased. It is therefore expected that various social services for the elderly will be demanded. As most of the elderly have hearing impairment due to presbycusis, it is difficult to communicate smoothly with them. To provide the various social services, it is necessary to investigate hearing acuity in the elderly. Accordingly, the Hearing Research Group, which belongs to the Research Project on Aging and Health in the Ministry of Health and Welfare of Japan, investigated the hearing acuity of people 65 years old, or more. One thousand one hundred ninety two subjects were divided into five groups, Group A consisted of 170 males and 216 females between 65 and 69 years old, Group B, 186 males and 158 females between 70 and 74; Group C, 147 males and 140 females between 75 and 79; Group D, 63 males and 61 females between 80 and 84; and Group E, 29 males and 22 females 85 years old or more. We examined the 175 subjects 80 years old or more. Therefore, it is considered that this study could indicate the present condition of hearing acuity of the elderly of Japan. The average hearing levels measured at seven frequencies (125, 250 and 500Hz, and 1, 2, 4, and 8KHz) were 35.0dB in group A, 42.1 in group B, 46.1 in group C, 52.1 in group D, and 55.6 in group E. There were no differences in the average hearing level between males and females in any group. The audiogram pattern indicated a gradually descending curve in most subjects in all groups. The average speech discrimination rate was 75.4% in group A, 70% in group B, 63.8% in group C, 59.7% in group D, and 52.1% in group E. The percentage of subjects showing a short increment sensitivity index of more than 70% was 45.2% in group A, 49.3% in group B, 47.9% in group C, 51.6% in group D, and 59.7% in group D. In conclusion, hearing loss due to aging tended to be more progressive at higher frequencies while hearing acuity of frequencies covering normal speech was preserved. However, the speech discrimination rate decreased relative to changes in the pure tone hearing level. It was considered that the pathology of hearing loss due to aging begins with retrocochlear changes and cochlear factors are added to retrocochlear changes with aging.

Apoptosis of germinal centers in postnatal development of rabbit tonsil.

The purpose of this study was to clarify the relationship between the morphological maturation of the germinal center of newborn rabbit tonsil and the appearance of apoptosis in it. Germinal centers were observed using immunostaining. Apoptosis is shown to be scarce in immature type of germinal center, but abundant in mature type. The findings suggest apoptosis to have an important function in the germinal center of the tonsil.

Cell dynamics in the germinal center of the human tonsil.

Apoptosis of the human tonsillar germinal center was studied by means of immunocytochemical methods. It is generally accepted that the germinal center of the lymphoid tissues plays an important role both in cell proliferation and cell death. Although many studies on cell proliferation have been reported, the cell death mechanism is not yet well understood. According to recent studies, apoptosis is the result of programmed, not pathological cell death, and it plays an important role in the maintenance, immunity and development of life. The present study showed that the tingible body was a mass of nuclear chromatin of dead cells, and that cells with a tingible body are macrophages, called tingible-body macrophages. The purpose of this study was to examine the relationship between tingible-body macrophages and apoptosis. The structure of tingible-body macrophages were observed by immunostaining methods.

Successful pregnancy in a patient with pseudomyxoma peritonei arising from ovarian mucinous cystadenocarcinoma treated with cisplatin.

A 24-year-old Japanese woman clinically showing pseudomyxoma peritonei arising from ovarian mucinous cystadenocarcinoma FIGO stage Ic is reported. She received intra-abdominal administrations of cisplatin five times following left oophorectomy. After being free of disease for 6 months, she conceived and carried two pregnancies to successful deliveries at 34 and 37 weeks, respectively. At the Cesarean sections, there were no abnormal findings except for right ovarian mucinous cystadenoma. She has had no evidence of recurrence by the time of the 60-month postoperative examination.