A case report of chemotherapy with thalidomide, celecoxib and gemcitabine in the treatment of patients with brain metastases from lung cancer

Chemotherapy for the treatment of brain metastases arising from non-small cell lung cancer (NSCLC) has been limited by poor efficacy and high toxicity. Especially in heavily pretreated patients with brain metastases, further chemotherapy is known to be extraordinarily difficult. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Most current preclinical experiments evaluate antiangiogenic drugs used singly or in combination with other antiangiogenic drugs and/ or cytotoxic drugs. Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. In preclinical experiments, cyclooxygenase (COX) -2 plays an important role in the formation of brain edema. Glioma-infiltrating microglia are a major source of PGE2 production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors. Here we report a case of lung cancer patient with brain metastases who had been treated with chemotherapy and whole-brain radiation therapy (WBRT). He was treated with thalidomide, celceoxib and gemcitabine, after which brain metastases have almost completely disappeared. He tolerated extremely well. This combination may play an important role for patients with NSCLC and brain metastases.     

The relationship between sleep disturbance and morale in Japanese elderly people

BACKGROUND: Complaints of sleep disturbance are common in elderly individuals. The quality of life (QOL) for people who have insomnia is thought to be worse than for those who do not have insomnia. In this study we investigated the influence of disturbed sleep on morale in elderly people who live independently. METHODS: A survey of the necessity of public nursing care for all those aged over 65 years was performed in Kumamoto city, Japan. Three hundred subjects from the elderly population living at home without special care were sampled at random and they filled out a questionnaire regarding sleep, psychiatric symptoms and attitudes towards their own aging. RESULTS: A logistic regression analysis found psychiatric symptoms and problems keeping awake to be independently related to a negative attitude towards one's own aging. Neither sleep, sex nor age demonstrated any relationship with the negative attitudes of elderly individuals. CONCLUSION: Excessive daytime sleepiness is related to poor morale regardless of both the quality and quantity of sleep and psychiatric symptoms.     

Multiple recurrences of cerebellar hemangioblastoma after 20 years from initial total removal of the tumor

Cerebellar hemangioblastoma develops alone or develops as part of von Hippel-Lindau disease. Moreover, multiple hemangioblastomas are found in 10-15%. It was reported that some hemangioblastomas recur with multiple recurrence in long time follow-up period. A 51 years old male was referred to our hospital because of headache and found a cerebellar tumor which was totally removed and diagnosed as hemangioblastoma pathologically. He presented no deficit after first surgery, but he did not come our hospital. In May 2000, he was referred to our hospital because of headache again and found five cerebellar tumors on MRI. Angiography showed markedly tumor stain. Retinal and spinal lesions were not seen. Two of five tumors was removed. The remaining three small tumors were received gamma knife surgery. In December 2000, because of cyst enlargement, one tumor was removed and the cyst was opened. In June 2001, he presented right hearing disturbance due to enlargement of cerebellar pontine angle tumor. The tumor was removed after tumor embolization, but hearing disturbance and slight dizziness remained. The remaining 5 mm tumor is followed.     

Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression

The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulators of NGF in cardiomyocytes, we found that endothelin-1 specifically upregulated NGF expression in primary cultured cardiomyocytes. Endothelin-1-induced NGF augmentation was mediated by the endothelin-A receptor, Gibetagamma, PKC, the Src family, EGFR, extracellular signal-regulated kinase, p38MAPK, activator protein-1, and the CCAAT/enhancer-binding protein delta element. Either conditioned medium or coculture with endothelin-1-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. NGF expression, cardiac sympathetic innervation, and norepinephrine concentration were specifically reduced in endothelin-1-deficient mouse hearts, but not in angiotensinogen-deficient mice. In endothelin-1-deficient mice the sympathetic stellate ganglia exhibited excess apoptosis and displayed loss of neurons at the late embryonic stage. Furthermore, cardiac-specific overexpression of NGF in endothelin-1-deficient mice overcame the reduced sympathetic innervation and loss of stellate ganglia neurons. These findings indicate that endothelin-1 regulates NGF expression in cardiomyocytes and plays a critical role in sympathetic innervation of the heart.     

Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474

ZD6474 is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 inhibits angiogenesis and growth of a wide range of tumor models in vivo. Gefitinib ("Iressa") is a selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation. Here, the ability of gefitinib and ZD6474 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro, and a strong correlation was noted between the IC(50) values of gefitinib and ZD6474 (r = 0.79). No correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression. The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of an ATP-binding site (exon 19) in the EGFR was detected (delE746-A750-type deletion). To clarify the involvement of the deletional mutation of EGFR in the cellular sensitivity to ZD6474, we examined the effect of this agent on HEK293 stable transfectants expressing deletional EGFR that designed as the same deletion site observed in PC-9 cells (293-pDelta15). These cells exhibited a 60-fold higher sensitivity to ZD6474 compared with transfectants expressing wild-type EGFR. ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold compared with cells with wild-type EGFR. In conclusion, the findings suggested that a small in-frame deletion in the EGFR increased the cellular sensitivity to ZD6474.     

Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft models

ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor (VEGF) receptor-2 (KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 has been shown to inhibit angiogenesis and tumor growth in a range of tumor models. Gefitinib ("Iressa") is an selective EGFR tyrosine kinase inhibitor (TKI) that blocks signal transduction pathways. We examined the antitumor activity of ZD6474 in the gefitinib-sensitive lung adenocarcinoma cell line, PC-9, and a gefitinib-resistant variant (PC-9/ZD). PC-9/ZD cells showed cross-resistance to ZD6474 in an in vitro dye formation assay. In addition, ZD6474 showed dose-dependent inhibition of EGFR phosphorylation in PC-9 cells, but inhibition was only partial in PC-9/ZD cells. ZD6474-mediated inhibition of tyrosine residue phosphorylation (Tyr992 and Tyr1045) on EGFR was greater in PC-9 cells than in PC-9/ZD cells. These findings suggest that the inhibition of EGFR phosphorylation by ZD6474 can contribute a significant, direct growth-inhibitory effect in tumor cell lines dependent on EGFR signaling for growth and/or survival. The effect of ZD6474 (12.5-50 mg/kg/day p.o. for 21 days) on the growth of PC-9 and PC-9/ZD tumor xenografts in athymic mice was also investigated. The greatest effect was seen in gefitinib-sensitive PC-9 tumors, where ZD6474 treatment (>12.5 mg/kg/day) resulted in tumor regression. Dose-dependent growth inhibition, but not tumor regression, was seen in ZD6474-treated PC-9/ZD tumors. These studies demonstrate that the additional EGFR TKI activity may contribute significantly to the antitumor efficacy of ZD6474, in particular in those tumors that are dependent on continued EGFR-signaling for proliferation or survival. In addition, these results provide a preclinical rationale for further investigation of ZD6474 as a potential treatment option for both EGFR-TKI-sensitive and EGFR-TKI-resistant tumors.     

A 7-year-old boy with mycoplasmal infection requiring extracorporeal membrane oxygenation

A 7-year-old boy with Down syndrome developed severe acute respiratory distress syndrome after a respiratory infection with Mycoplasma pneumoniae with an unusually high agglutination titre (1:10240). Initially, mechanical ventilation and nitric oxide inhalation were used, but these did not improve the alveolar-arterial oxygen gradient. Extracorporeal membrane oxygenation for 152 h improved the lung condition. CONCLUSION: our case suggests that Mycoplasma pneumoniae should be considered as an aetiological agent in acute respiratory distress syndrome. Extracorporeal membrane oxygenation might have a valuable role in the management.     

Improved generation of HLA class I/peptide tetramers

As a tetrameric major histocompatibility complex (MHC) class I-peptide complex (tetramer) is capable of detecting antigen-specific cytotoxic T lymphocyte (CTL) by flow cytometry, significant information about the generation of in vivo immunity can be obtained. It is, however, difficult to make a soluble wild type of MHC class I heavy chain by the prokaryotic expression system. Therefore, we developed a new method for making soluble mutant HLA-A*2402 heavy chain. In this method, signal sequences were deleted, and the codon was changed to silent mutated nucleotide sequences that bacteria could use as preferable codon. When purified mutant HLA-A*2402 molecules were examined for the protein generation by SDS-polyacrylamide gel electrophoresis (PAGE) and western blotting using anti-HLA class I monoclonal antibody (mAb) as compared with wild type, a large amount of mutant heavy chain could be detected. In contrast, the expression of wild-type stable HLA-A*2402 heavy chain molecule was not detected in this system. Consequently, by using mutant HLA-A*2402/peptide tetramers, CTL precursors (CTLp) that specifically recognize antigenic peptide derived from the X;18 chromosomal translocations of synovial sarcoma were detected in patients' PBL.     

No clinical correlation between bilirubin levels and severity of retinopathy of prematurity

PURPOSE: To evaluate the hypothesis that bilirubin has a protective effect against the development of severe retinopathy of prematurity (ROP). METHODS: An assessment of 76 infants born at 24 and 25 weeks' gestation and admitted to the level III neonatal intensive care unit at Saitama Children's Medical Center was made. Indirect ophthalmoscopy fundus examinations were performed on all infants to identify the degree and progression to threshold ROP. We analyzed the daily bilirubin levels and grouped the patients according to the severity of ROP based on the infant's worst ROP examination. The first group was comprised of infants with less than stage 3 ROP and infants with stage 3 ROP. The second group was infants with less than prethreshold ROP or prethreshold ROP, and infants with threshold ROP. Next, we divided the infants into 3 groups: less than prethreshold ROP, prethreshold ROP, and threshold ROP. The daily changes in serum bilirubin concentrations during the first 14 days of life were determined for each infant. Three groups (less than prethreshold ROP, prethreshold ROP, and threshold ROP) were comparable as to their basic data, clinical characteristics, and treatments. RESULTS: ROP was found in 76 infants. There were no statistical differences in the clinical characteristics and treatments, excluding the duration of phototherapy, among the 3 groups. During the first 14 days of age, there were no significant differences in the daily mean bilirubin concentrations according to the groups separated by severity of ROP. CONCLUSION: These results indicate that there is no distinct protective effect of bilirubin on the development of severe ROP.