A case of recurrent stomach cancer treated with 5-fluorouracil responding to weekly paclitaxel therapy

We report a patient with unresectable stage IV stomach cancer with metastasis to the paraaortic lymph nodes who achieved an effective response to neoajuvant chemotherapy, which allowed curability-B resection, and in whom weekly paclitaxel (TXL) therapy for postoperative recurrence was very effective in improving QOL. The patient was a 65-year-old man. After preoperative PMFE therapy, CEA decreased from 68.1 ng/ml to 0.8 ng/ml, and CA19-9 from 15,000 U/ml to 190 U/ml. The paraaortic lymph nodes disappeared, and stomach wall thickening decreased. The overall response to treatment was evaluated as a partial response (PR). After surgery, the patient was given TS-1, but became unable to take oral medication because of retroperitoneal and lymph node recurrence. Since the cancer appeared to be resistant to 5-fluorouracil (5-FU), the patient was treated by weekly TXL therapy. Increased appetite and weight gain were observed from the middle of the first course of therapy, and CEA decreased from 28.2 ng/ml to 4.9 ng/ml, and CA19-9 from 15,000 U/ml to 2,000 U/ml. Abdominal CT scans demonstrated shrinkage of the tumor. Although the patient died 1 year and 8 months after the initial examination, he was able to take oral medication and maintain good QOL for 10 months after the start of TXL therapy. Only grade 1 side effects (alopecia and leukopenia) were observed throughout the course. These results suggest that TXL therapy is effective also for 5-FU-resistant stomach cancer, and exhibits effects early even in patients in a poor general condition, causing only mild side effects, with early improvements in QOL.     

Acute myelogeneous leukemia (M5a) that demonstrated chromosomal abnormality of robertsonian 13;21 translocation at onset

A 27-year-old woman had congenital lissencephaly syndrome and mental retardation. She had a fever of unknown origin and visited her local physician. Blood test indicated leukocytosis, so she was referred to our hospital for detailed examination. She was diagnosed to have acute myelogeneous leukemia (M5a). The chromosome analysis in blast cells revealed Robertsonian 13;21 translocation. Complete remission was obtained by induction chemotherapy. As normal karyotype (46, XX) was observed in the chromosome analysis of bone marrow cells after remission, it was considered that the patient had acquired Robertsonian 13;21 translocation complicated by acute myelogeneous leukemia.     

Diamond-Blackfan Anemia in Japan: Clinical Outcomes of Prednisolone Therapy and Hematopoietic Stem Cell Transplantation

The epidemiology and treatment outcomes for Diamond-Blackfan anemia (DBA) were surveyed in a cohort of 54 children (M/F = 26:28) registered in Japan from 1988 to 1998. The annual incidence was 4.02 cases per million births, the median age at diagnosis was 60 days, and 59% of the cases presented by 3 months of age. Three patients had a familial occurrence. All patients received prednisolone (PSL), and cyclosporin A (CsA) was added to the therapy in 17 patients. Forty-seven patients received transfusions, and 13 underwent hematopoietic stem cell transplantation (HSCT). The cumulative probabilities of a medication-free or a transfusion-free state prior to HSCT were 36% and 69%, respectively, at more than 5 years after diagnosis. Thirteen patients were weaned from PSL therapy without HSCT, and CsA was not associated with weaning from therapy. Transfusion and medication were stopped at 249 days and 933 days after diagnosis in 34 and 13 patients, respectively, who achieved a state of independence. No initial findings predicted the treatment dependence. More than 20% of patients experienced sustained hemosiderosis and/or adverse effects of PSL. The ages and reticulocyte counts at diagnosis of the patients who underwent HSCT were lower than in the patients who did not. HSCT led to the highest success (85%) of all previous reports, even though 5 alternative donors were included in our study. Two cord blood transplants from unrelated donors failed. These findings suggest the need for developing an integral treatment strategy including selective HSCT for refractory DBA.     

Functional MRI mapping of brain activation during visually guided saccades and antisaccades: cortical and subcortical networks

Antisaccade tasks require a subject to inhibit a saccade toward a briefly appearing peripheral target and instead to immediately generate a saccade to an equivalent point in the opposite hemifield. Using functional magnetic resonance imaging (fMRI), we investigated the neural networks required to inhibit reflexive saccades and to voluntarily generate saccades. The results demonstrated that saccade and antisaccade tasks often bilaterally activate frontal, parietal and supplementary eye fields, lenticular nuclei and occipital cortex. Additional activation of bilateral dorsolateral prefrontal cortices, supramarginal gyri, anterior cingulate cortices and thalamus was observed during antisaccade tasks. These results indicate that fronto-parietal and fronto-striato-thalamo-cortical circuits are involved in antisaccade tasks. The fronto-parietal circuit is thought to be related to the planning of saccadic eye movements that involve attentional control, while the fronto-striato-thalamo-cortical circuits connect to cortical region as a feedback network. We speculate that the abnormalities in spatial attention and eye movement control observed in schizophrenia stem from dysfunctions in the fronto-parietal and fronto-striato-thalamo-cortical circuits.     

Pupillary light reflex in panic disorder

BACKGROUND: Although many previous studies reported abnormalities of autonomic function in patients with panic disorder (PD), almost all targets in those studies primarily focused on cardiovascular autonomic functions. In the present study, we determined whether PD patients exhibited abnormalities in the pupillary autonomic nervous system (ANS). METHODS: Before and after audiovisual stimulation (AS), which induced mental stress through exposure to video images of high stress experiences, such as driving motor vehicles, the pupillary light reflex (PLR) was measured by infrared pupillometer in 13 remitted PD patients and twenty age- and gender-matched normal controls (NC). RESULTS: Before and after AS, there were no significant differences in initial pupillary diameters in dark conditions (D1), pupillary diameters at maximum constriction (D2) or constriction ratios (CR: (D1-D2)/D1) between PD and NC subjects. However, the CR ratio (CR before/CR after) was significantly higher in the PD group than in the NC. CONCLUSIONS: These findings suggest that even remitted PD patients may have a dysfunctional PLR regulation with experimental stressors such as AS.     

Endogenous 5-HT inhibits firing activity of hippocampal CA1 pyramidal neurons during conditioned fear stress-induced freezing behavior through stimulating 5-HT1A receptors

This study examines the activity of hippocampal CA, pyramidal neurons during conditioned fear stress (CFS)-induced freezing behavior in unanesthetized, unrestrained rats. The firing frequency of hippocampal CA1 pyramidal neurons was significantly decreased when conditioned rats exhibited freezing behavior. Firing frequency returned to the baseline after freezing behavior disappeared. The selective 5-hydroxytryptamine (5-HT)1A antagonists, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), and N-tert-butyl-3-[4-(2-methoxyphenyl)piperazine-1-yl]-2-phenylpropamide (WAY-100135) and 5-HT depletion with parachlorophenylalanine (PCPA) completely abolished the decrease in firing frequency during CFS-induced freezing behavior. These results suggested that endogenous 5-HT inhibited the firing activity of hippocampal CA1 pyramidal neurons during CFS-induced freezing behavior mainly through stimulating 5-HT1A receptors.     

Steroid-induced diabetes mellitus and related risk factors in patients with neurologic diseases

STUDY OBJECTIVE: To determine the frequency of steroid-induced diabetes mellitus (SDM) and the related risk factors in patients with neurologic diseases who receive high doses of steroids. DESIGN: Retrospective chart review. SETTING: Neurology ward of a university-affiliated hospital. PATIENTS: Twenty-five patients with neurologic diseases who received prednisolone 30-60 mg/day orally after breakfast for more than 2 weeks. MEASUREMENTS AND MAIN RESULTS: Plasma glucose concentrations were determined immediately before and 2 hours after each meal. Steroid-induced diabetes mellitus was diagnosed if the patient had either a fasting glucose concentration of 126 mg/dl or greater, or a random glucose concentration of 200 mg/dl or greater. The patients were divided into two groups on the basis of whether SDM had developed (13 patients) or not (12 patients). Ages, body mass indexes, cumulative total doses and daily doses of prednisolone, duration of therapy, and serum cholesterol and triglyceride concentrations were compared between the groups. Thirteen of the 25 patients were identified with SDM, and all of them had plasma glucose concentrations of 200 mg/dl or greater 2 hours after lunch. Mean age (59.1 +/- 10.2 yrs) and cholesterol concentration after prednisolone treatment (226.8 +/- 36.4 mg/dl) in the SDM group were significantly higher than those values in the non-SDM group (41.3 +/- 18.0 yrs and 188.1 +/- 27.2 mg/dl, respectively, p<0.01). CONCLUSIONS: A close relationship among postprandial hyperglycemia, advanced age, and hypercholesterolemia is a characteristic of SDM in patients with neurologic diseases. Therefore, monitoring the plasma glucose concentration 2 hours after lunch may be useful to detect SDM in these patients.     

The improved dissolution and prevention of ampoule breakage attained by the introduction of pretreatment into the production process of the lyophilized formulation of recombinant human Interleukin-11 (rhIL-11)

Lyophilized protein formulations sometimes pose problems such as the formation of a cloudy solution upon reconstitution. Ampoule or vial breakage can also occur during the production processes of lyophilized pharmaceutical products. Various efforts have been made to overcome those difficult problems. In this study, we introduce a particular temperature program into the production process of a recombinant human Interleukin-11 (rhIL-11) lyophilized formulation containing sodium phosphates (Na2HPO4/NaH2PO4, pH 7.0) and glycine in an attempt to improve its dissolution properties and to prevent ampoule breakage from occurring. The formulation was pretreated by nucleating ice and maintaining the solution overnight at a temperature of -6 degrees C. The solution was then completely frozen at a lower temperature. This pretreatment proved successful in not only producing a lyophilized cake which readily disintegrated and dissolved in the reconstitution media, but also prevented ampoule breakage from occurring during the production processes. In contrast, a lyophilized cake produced without the pretreatment created a cloudy solution particularly when reconstituted using water for injection contaminated with aluminum (Al3+), although the solution became transparent within 20-30 min. The pretreatment induced the crystallization of sodium dibasic phosphate (Na2HPO4) in the freeze-concentrate whereas direct freezing without the pretreatment did not crystallize the salt. Thermal analyses (DSC and TMA) showed that amorphous sodium dibasic phosphate in the freeze-concentrate became crystallized upon heating, accompanied by an increase in volume, which probably caused the ampoule breakage that occurred without the pretreatment. Although power X-ray diffraction (PXRD) experiments suggested that, with or without the pretreatment, glycine assumed the beta-form and sodium phosphate stayed amorphous in the final products, an electrostatic interaction between dibasic phosphate anions and rhIL-11, a highly cationic protein, would only exist in the lyophilized cake produced without the pretreatment. This interaction is highly likely because aluminum facilitates the formation of a cloudy solution upon reconstitution possibly by using the divalent anions which effectively reduce electrostatic repulsions between aluminum and the protein to form an aggregate structure that is not readily soluble. The pretreatment would circumvent the interaction by crystallizing the sodium salt before freezing creating a relatively soluble lyophilized cake that is much less sensitive to aluminum.     

Zonal differences in DNA synthesis and in transglutaminase activity between perivenous versus periportal regions of regenerating rat liver

We investigated a relationship within zonal differences in DNA synthesis and in transglutaminase (TGase) activity between perivenous versus periportal regions of regenerating rat liver. Using the digitonin/collagenase perfusion technique, hepatocyte subpopulations were isolated from each region at various time points after partial hepatectomy. The amounts of DNA synthesis as well as the levels of TGase mRNA and activity in each subpopulation were measured. Although increased DNA synthesis was observed in both subpopulations with a peak at 24 h after partial hepatectomy, the amount of DNA synthesis in periportal hepatocytes (PPH) was twice as much as that in perivenous hepatocytes (PVH). In PVH, TGase activity peaked at 24 h after partial hepatectomy with a preceding increase in its mRNA expression at 12 h, whereas TGase activity in PPH at 24 h was one-half of that in PVH. As TGase is known to have a growth-arresting activity, our data indicate that relatively higher TGase activity in PVH at 24 h after partial hepatectomy might correlate with relatively lower DNA synthesis in this region compared to periportal region.