Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study.

Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.

A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L.

BACKGROUND: Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC. PATIENTS AND METHODS: The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05. RESULTS: Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%-53%; P = 0.031). The median PFS was 7.5 (6.2-12.3) months, while OS did not reach the median value. Major adverse event was grade 3-4 neutropenia in 34 patients (87%). There was no treatment-related death. CONCLUSIONS: In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.

A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.

BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

Mechanism for negative poisson ratios over the alpha- beta transition of cristobalite, SiO2: A molecular-dynamics study

The adiabatic elastic constants ( C(ij)) of cristobalite have been evaluated successfully over the temperature range of 300-1800 K using the molecular-dynamics method with a fluctuation formula. Cristobalite shows a negative Poisson ratio over this temperature range. However, the mechanisms differ between the alpha and beta phases. In the cubic beta phase, C44 exhibits a value extremely close to C11 rather than C12, in contrast to the Cauchy relation. This predicts a remarkable property that the longitudinal and transverse velocities coincide for the acoustic waves propagating along the [100] direction.

Diagnosis of an "isodense" pituitary microadenoma by dynamic CT scanning. Case report.

A case of Nelson's syndrome with an adrenocorticotropic hormone-secreting pituitary chromophobe microadenoma is presented to demonstrate the potential capability of rapid sequential (dynamic) computerized tomography (CT) scanning for the diagnosis of a pituitary microadenoma that was isodense with the adjacent pituitary gland on conventional enhanced CT scanning. The dynamic CT scans showed transient high density in this microadenoma contrasting with the pituitary gland in the early-enhancement phase, and thereafter the contrast density was indistinguishable from that of the pituitary gland in the delayed-enhancement phase. For the detection of pituitary microadenoma, dynamic CT combined with subsequent delayed CT scanning can provide diagnostic and localizing information.

Calcification in glioblastoma multiforme of the cervical spinal cord.

A patient having glioblastoma accompanied with calcification in the cervical spinal cord is presented. A calcifying lesion, detected on preoperative x-ray computed tomograms, was histologically confirmed as calcified areas in the tumor tissue. We discuss the difficulty in differentiating glioblastomas containing calcified masses from benign tumors with areas of calcification and present our hypothesis regarding the cause of calcification in the tumor tissue.

[Familial primary intracranial malignant lymphoma].

A 76-year-old female developed depression and loss of appetite. On admission, in June of 1987, she was disoriented. Computed tomography (CT) revealed enhanced masses without perifocal edema in the cerebellar vermis and left occipital lobe. The cerebellar tumor was subtotally removed through a suboccipital craniectomy. Histological examination disclosed malignant lymphoma of the diffuse, large cell type. The patient underwent postoperative irradiation, and no other tumors were detected by whole-body CT or gallium scans. Her 51-year-old son had been admitted to another hospital in April of 1987, with complaints of depression and change in mental status. Neurological examination revealed right hemiparesis, and CT demonstrated an enhanced left frontal paraventricular mass and severe perifocal edema. The histological diagnosis was malignant lymphoma, and the patient received postoperative irradiation and chemotherapy. A few cases of familial extracranial malignant lymphoma have been described. However, to the authors' knowledge, this is the first reported occurrence of familial primary intracranial malignant lymphoma.

[Intrathecal administration of amikacin in postoperative refractory meningitis].

The intrathecal administration of amikacin (AMK) (50--100 mg/day) was effective for 3 cases of postoperative refractory meningitis caused by gentamicin (GM) resistant organisms. The infecting pathogen of case 1 was K. pneumoniae and that of case 2 was S. epidermidis, while no pathogen was cultured in case 3. The causative pathogens in the former were eradicated only with AMK. No therapeutic response was gained with GM, but with AMK in the latter. High tone hearing impairment was observed in case 1 and transient vomiting was observed in case 3. However, these side effects were trivial for the severity of disease. It is suggested in these 3 cases that the high dose intrathecal administration of AMK may be extremely useful in the treatment of postoperative refractory meningitis which has shown no response to GM.

[Electroencephalographic changes during experimental plateau waves].

The present study was designed to induce plateau waves by electrical stimulation of the brain stem and examine the changes in EEG during the plateau waves. Experiments were carried out on 10 adult mongrel dogs which were slightly anesthetized, immobilized and artificially respired. Electroencephalogram (EEG), intracranial pressure (ICP), systemic blood pressure (SBP) and cerebral perfusion pressure were simultaneously recorded on the electromagnetic tape after transorbital puncture of the intracavernous internal carotid artery. EEGs were recorded from cortical electrodes, and were analyzed by a frequency analysis. At the stage of increased ICP, the mesencephalic reticular formation was stimulated. Stimulation parameters, i.e., intensity, duration and frequency, were 0.1 mA, 1 msec and 40 - 50 Hz, respectively. The total duration of each period was 5 seconds. Spontaneous plateau waves occurred in 2 dogs associated with subarachnoid hemorrhage, subdural hematoma and intraventricular hemorrhage. Plateau waves were induced by electrical stimulation in the mesencephalic reticular formation in one of two dogs with spontaneous plateau waves. Twenty-one repetitions of electrical stimulation induced ten plateau waves. Two plateau waves were induced during slow EEG associated with desynchronization of EEG. Eight plateau waves were induced during fast EEG activity with no changes in EEG before and after the stimulation. In addition, plateau waves occurred immediately after short duration (5 seconds) of electrical stimulation. It seems that CBV increases during plateau waves are due to rapidly occurring neurogenic vasodilatation of cerebral vessels, later augmented by increases in cerebral metabolism. In conclusion, plateau waves are produced in a rigid condition within the cranial cavity by stimulation of the brainstem reticular formation which influences cortical activation and cerebral vasodilatation.

[Hyponatremia due to excess natriuresis].

Nine cases with hyponatremia were precisely examined during the past 2 years. Seven of them showed normal plasma volume, serum aldosterone and pituitary function, although ADH was detected. Therefore, those seven cases were diagnosed without dilutional hyponatremia due to SIADH (a syndrome of inappropriate secretion of antidiuretic hormone). The mechanism of hyponatremia of such a type has not been yet explained definitely, but it may be referring to excess natriuresis. Only each one case of hyponatremia due to hypopituitarism and dilutional hyponatremia due to SIADH was verified in this series. SIADH showing high plasma volume value was thought to be rare. Differential diagnosis between SIADH and hyponatremia due to excess natriuresis is essential and simple. Non-invasive plasma volume measurement using RISA is significantly useful for it. For the hyponatremia due to excess natriuresis, water restriction is not necessary, but digestive supply of NaCl is needed.

[Pressure waves induced by electrical stimulation of upper pons and lower midbrain in dogs with experimental subarachnoid hemorrhage].

Neurogenic mechanisms of pressure waves were investigated by means of electrical stimulation of the upper pons and the lower midbrain of 32 dogs in which subarachnoid hemorrhage had experimentally been made. The dogs were slightly anesthetized, immobilized and artificially respired. After subarachnoid infusion of red blood cells, continuous recordings of systemic blood pressure (SBP), intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were made simultaneously. At the stage of increased ICP, pressure waves were induced by electrical stimulation of the upper pons and the lower midbrain from 6 to 12 mm rostral to external auditory meatus. Stimulation parameters, i.e., intensity, duration and frequency, were kept constant at 0.1 mA, 1 msec and 40-50 Hz, respectively, throughout experiments. The induced pressure waves were classified into three types: fast, slow and plateau waves. Fast waves had a duration of 10-30 sec, being associated with a marked increase in SBP. They were induced by stimulation of 41 points in various portions of the pontine and mesencephalic tegmentum. Slow waves had a duration of 30 sec to 3 min, being associated with no change or a decrease in SBP. They were induced by stimulation of 12 points in the rostral pontine reticular formation and the mesencephalic reticular formation. Plateau waves had a duration of 3 min or more, being associated with no change or a decrease in SBP. They were induced by stimulation of 2 points in the mesencephalic reticular formation 2 mm lateral to the red nucleus, where slow waves had been induced at the early stage.(ABSTRACT TRUNCATED AT 250 WORDS)

The Development of a Remote Patient Monitoring System using Java-enabled Mobile Phones.

A remote patient monitoring system is described. This system is to monitor information of multiple patients in ICU/CCU via 3G mobile phones. Conventionally, various patient information, such as vital signs, is collected and stored on patient information systems. In proposed system, the patient information is recollected by remote information server, and transported to mobile phones. The server is worked as a gateway between hospital intranet and public networks. Provided information from the server consists of graphs and text data. Doctors can browse patient's information on their mobile phones via the server. A custom Java application software is used to browse these data. In this study, the information server and Java application are developed, and communication between the server and mobile phone in model environment is confirmed. To apply this system to practical products of patient information systems is future work.

Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits.

This study was undertaken to evaluate the potential of HMG-CoA reductase inhibitors, pravastatin sodium (hereafter abbreviated to pravastatin) and simvastatin, for induction of myopathy and influence on the ubiquinone content of skeletal and cardiac muscles and other tissues in the rabbit. Both drugs were administered orally to New Zealand White rabbits (n = 5) at the dose of 50 mg/kg per day for 14 days. Serum cholesterol levels in the pravastatin- and simvastatin-treated groups were reduced significantly by 47% an 58% on day 14 (P < 0.05), respectively, as compared with the control group, but the difference between the two treatment groups was not significant. In animals of the simvastatin-treated group, abnormal elevations of creatine kinase (CK) and lactate dehydrogenase (LDH) levels were observed, in association with severe lesions in skeletal muscles, but not cardiac muscle. The ubiquinone content in skeletal muscle in this treatment group was not affected, even in the muscles that had severe lesions, whereas that in liver and cardiac muscle was significantly reduced compared with the control group. The results suggest that there is no direct correlation between myopathy and the decrease of ubiquinone content in skeletal muscles. In contrast, the animals in the pravastatin-treated group did not show any changes in CK and LDH levels, ubiquinone content in liver and muscles, or in histopathological features of muscle fibers. The difference between the adverse effects seen with the two drugs could be attributed to physicochemical properties: simvastatin permeates the plasma membrane because of its hydrophobic nature, whereas pravastatin does not, because it is hydrophilic.

Novel catalytic mechanism of nucleophilic substitution by asparagine residue involving cyanoalanine intermediate revealed by mass spectrometric monitoring of an enzyme reaction.

l-2-Haloacid dehalogenase from Pseudomonas sp. YL catalyzes the hydrolytic dehalogenation, in which Asp(10) acts as a nucleophile to attack the alpha-carbon of l-2-haloalkanoates to form an ester intermediate, which is subsequently hydrolyzed to produce d-2-hydroxyalkanoates. Surprisingly, replacement of the catalytic residue, Asp(10), by Asn did not result in total inactivation of the enzyme (Kurihara, T., Liu, J.-Q., Nardi-Dei, V., Koshikawa, H., Esaki, N., and Soda, K. (1995) J. Biochem. 117, 1317-1322). In this study, we monitored the D10N mutant enzyme reaction by ion-spray mass spectrometry, and found that the enzyme shows a unique structural change when it was incubated with the substrate, l-2-chloropropionate. LC/MS and tandem MS/MS analyses revealed that Asn(10) attacks the substrate to form an imidate, and a proton and d-lactic acid are eliminated to produce a nitrile (beta-cyanoalanine residue), followed by hydrolysis to reproduce Asn(10). This is the first report of the function of Asn to catalyze nucleophilic substitution through its conversion to beta-cyanoalanine residue as an intermediate structure. Also, these results demonstrate that mass spectrometry is remarkably useful in monitoring enzyme reactions.

[A giant cell glioblastoma--a case report].

Discussed is an 8-year-old girl with a history of convulsive seizures. A sharply demarcated tumor, measuring 3 X 4 cm, was located in the right frontal lobe. The mass grey and cystic in the center, and microscopic specimen demonstrated bizarre, irregular, giant cell with a long vesicular nuclei and spindle-shaped cell. A perivascular pseudo-rosette formation also was seen, and silver impregnation revealed reticulin network and extracellular collagen fibers. The pathological entity of an intracranial giant celled glioblastoma remains controversial. This entity is considered a giant celled glioblastoma by some and a monstrocellular sarcoma by others. In this that the authors experienced, a CT scan showed a ring that formed a high density area and low density in the center at the right frontal lobe. Also reviewed and discussed are the historical aspects of a giant celled glioblastoma and radiologic problems that have been encountered.