Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia

Chromosomal translocations involving the immunoglobulin heavy chain gene ( IgH ) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1 (6p25)- IgH nor MAFB (20q11)- IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma. (Cancer Sci 2003; 94: 350-354)     

Preoperative pulmonary function as a predictor of respiratory complications and mortality in patients undergoing lung cancer resection

OBJECTIVE: We evaluated preoperative pulmonary function as a predictor of respiratory complications and mortality in patients undergoing lung cancer resection to confirm the guideline of the British Thoracic Society: lung cancer surgery in patients with predictive postoperative FEV(1.0) (%FEV(1.0)ppo) > 40% and predictive postoperative diffusion capacity for carbon monoxide (%DL(co)ppo) > 40% can be carried out with average risk. METHODS: We retrospectively studied 356 consecutive patients who underwent pulmonary resection at our Department from January 1992 to December 2001. Preoperative pulmonary function tests included vital capacity (VC), %VC, forced expiratory volume in one second (FEV(1.0)), FEV(1.0)%, diffusion capacity for carbon monoxide (DL(co)), predictive postoperative FEV(1.0) (FEV(1.0)ppo), postoperative respiratory function expressed as a percentage of the predicted normal value (%FEV(1.0) ppo, %DL(co)ppo). Postoperative complications were divided into 2 groups: respiratory complications (pneumonia, atelectasis, etc) and other complications (bronchopleural fistula, prolonged air leak, arrhythmia, etc). RESULTS: Postoperative deaths occurred in 14 (3.9%) patients. Postoperative respiratory complications developed in 27 (7.6%) patients. Pneumonectomy (p < 0.001), preoperative chemotherapy (p < 0.01) and advanced stage (p < 0.05) were identified as risk factors of postoperative deaths. Patients undergoing lobectomy with FEV(1.0) > or = 1,500 ml did not die of respiratory complications. Patients undergoing pneumonectomy with FEV(1.0)ppo > or = 800ml/m2 did not die of respiratory complications. Patients undergoing pneumonectomy with %FEV(1.0)ppo < 40% and %DL(co)ppo < 40% did not survive. Five of the 7 patients who died of respiratory complications were treated with preoperative chemotherapy. The values of their %DL(co)ppo were all less than 40%. By multivariate analysis, %FEV(1.0)ppo was significant independent factor associated postoperative death. CONCLUSIONS: We conclude that the guideline is useful for the selection for surgery of lung cancer patients. If preoperative chemotherapy is performed, the measurement of %DL(co) is recommended before surgery.     

Proximal metatarsal osteotomy for hallux valgus: comparison of outcome for moderate and severe deformities

BACKGROUND: We compared the results of a distal soft-tissue procedure with a proximal crescentic osteotomy of the first metatarsal for moderate and severe hallux valgus. MATERIALS AND METHODS: The series consisted of 54 feet treated with this procedure. The average followup was 30 months. Fifty-four feet were divided into two groups including Group M (moderate) (24 feet, preoperative hallux valgus angle of 40 degrees or less and preoperative intermetatarsal angle of less than 18 degrees) and Group S (severe) (30 feet, preoperative hallux valgus angle of greater than 40 degrees or preoperative intermetatarsal angle of 18 degrees or greater). RESULTS: The difference between Group M and S was not significant with regard to the age of patients, duration of followup, or postoperative pain and function scores on the American Orthopaedic Foot and Ankle Society scale. However, postoperative alignment score in Group M was significantly greater than that in Group S (p = 0.038). Postoperative hallux valgus and intermetatarsal angles in Group S were significantly greater than those in Group M, respectively (p = 0.025, p = 0.001). The prevalence of recurrent hallux valgus (hallux valgus angle of 20 degrees or greater) in Group S was significantly higher than that in Group M (p = 0.013). CONCLUSION: This procedure is an effective method for relieving pain and improving function regardless of the severity of hallux valgus. However, the correction of moderate hallux valgus is likely to be better than that of severe hallux valgus.     

Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor.

Involvement of nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-kappaB is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. In addition, we found the phosphorylation of p65 subunit of NF-kappaB in addition to the phosphorylation of IkappaBalpha and the activation of NF-kappaB DNA binding and that various target genes of NF-kappaB including bcl-x(L), XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IkappaB kinase inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP). When myeloma cells were treated with ACHP, the cell growth was efficiently inhibited with IC(50) values ranging from 18 to 35 mumol/L concomitantly with inhibition of the phosphorylation of IkappaBalpha/p65 and NF-kappaB DNA-binding, down-regulation of the NF-kappaB target genes, and induction of apoptosis. In addition, we observed the treatment of ACHP augmented the cytotoxic effects of vincristine and melphalan (l-phenylalanine mustard), conventional antimyeloma drugs. These findings indicate that IkappaB kinase inhibitors such as ACHP can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of NF-kappaB.     

Effect of Combined H-1 and H-2 Histamine Receptor Antagonists on Late Asthmatic Response in an Asthmatic Patient

A curious inhibitory effect of histamine H-1 and H-2 antagonists on isolated late asthmatic response (LAR) in an asthmatic patient was observed.

When given alone, neither the H-1 nor the H-2 antagonist had an effect on LAR. The combination of drugs, however, provided marked inhibition of LAR. These findings suggest that histamine contributes to some types of LAR.     

Overexpression of transforming growth factor-β3 immunohistochemical staining in extramammary Paget''s disease, but downregulated expression in Bowen''s disease

BACKGROUND: The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex, with some reports indicating a tumor inhibition role and others indicating a tumor promotion role. In particular, TGF-beta3 is thought to play a key role in controlling epithelial homeostasis. Immunopositive p53 has been demonstrated in a variety of human malignant tumors and its role in oncogenesis and tumor progression is thought to be important. Extramammary Paget's disease (EPD) and Bowen's disease are skin cancers of unknown histogenesis. OBJECTIVE: To clarify the role of TGF-beta3 and p53 in EPD and Bowen's disease and to better understand the origin of these disorders. METHODS: Specimens were obtained from 12 patients with EPD and 12 patients with Bowen's disease seen at our clinic between 1993 and 2000. TGF-beta3 and p53 immunohistochemical staining was performed. RESULTS: In three of the 12 EPD patients and five of the 12 Bowen's disease patients, positive p53 staining was detected. In contrast, TGF-beta3 overexpression was detected in all EPD patients, whereas downregulated TGF-beta3 expression was detected in all Bowen's disease patients. CONCLUSIONS: The present data suggest different roles for TGF-beta3 in abnormal epidermal cells in EPD and Bowen's disease. Thus, TGF-beta3 expression may be modulated differently via a p53-dependent or -independent pathway in the pathogenesis of EPD and Bowen's disease. Moreover, high TGF-beta expression appears to be a useful indicator of tumor activity in EPD.     

Effects of olopatadine in limited scleroderma with peripheral eosinophils

Scleroderma and eosinophilia often occur together, though the pathogenesis is unclear. We investigated the effect of olopatadine hydrochloride in a series of cases of limited scleroderma (LS). Ten patients with LS and positive eosinophil counts (LSE) were enrolled (average age, 85 years; six men and four women). Serum concentrations of the anti‐Scl‐70 antibody were positive. Olopatadine hydrochloride was prescribed at 10 mg/day for 3 weeks. Serum concentrations of the anti‐Scl‐70 antibody significantly decreased, but changes in eosinophil numbers and percentages in peripheral blood were not significant. Factor analysis suggested a correlation between serum concentrations of the anti‐Scl‐70 antibody and complement C⁴. Olopatadine could be effective in reducing anti‐Scl‐70 antibodies in the elderly with LSE.     

A Clinicopathological Study of Idiopathic Normal Pressure Hydrocephalus

Background : Since Hakim and Adams introduced the clinical entity of normal pressure hydrocephalus (NPH) in 1965, postmortem studies of idiopathic NPH have been few in number. Several autopsy cases reported with clinically probable "idiopathic NPH" were diagnosed with Alzheimer's disease (AD) or Binswanger's disease (BD) neuropathologically. Therefore, the neuropathological study of pathologically confirmed idiopathic NPH remains to be completed both quantitatively and qualitatively.
Methods : Out of 239 autopsy cases in Fukushimura Hospital, 13 patients had been diagnosed clinically as having NPH. After excluding seven cases diagnosed neuropathologically with other diseases or secondary NPH, we investigated the clinicopathological findings of six patients with idiopathic NPH.
Results : Four patients presented with the complete classic triad consisting of progressive dementia, gait disturbance, and urinary incontinence. All cases exhibited progressive ventricular enlargement with periventricular lucency by computed tomography images. We found (1) diffuse marked dilatation of the lateral ventricles of unknown etiology, and (2) the changes of ependymal cells and subependymal tissue around the callosocaudate angle. Furthermore, no complications were suspected neuropathologically in all cases, such as AD, BD, or Lewy body disease.
Conclusion : We experienced six autopsy cases with pathologically confirmed idiopathic NPH. They had two pathological features of NPH but no other pathological disorders that might cause NPH. Several "idiopathic NPH" cases reported previously have been diagnosed neuropathologically with other disorders. However, the presented cases could be clearly distinguished from such "idiopathic NPH." Therefore, our cases should be defined as idiopathic NPH neuropathologically. By accumulating more cases and investigating further we hope to elucidate the pathogenesis and further develop treatment for idiopathic NPH.     

Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetics with hypertension.

Angiotensin II type-1 receptor blockers (ARBs) are regarded as first-line treatments for type-2 diabetes with hypertension. Despite the availability of various types of ARBs, there are no comparative studies of their effects on patients with diabetes. In this open-label prospective crossover study, we compared the effects of olmesartan (20 mg/day) and telmisartan (40 mg/day). Twenty Japanese early-stage type-2 diabetes patients with hypertension treated with valsartan (80 mg/day) for at least 8 weeks were recruited to this study. At study entry, valsartan was changed to olmesartan (20 mg/day) or telmisartan (40 mg/day) and administered for 8 weeks. The drugs were then switched and treatment was continued for another 8 weeks. We analyzed the blood pressure lowering effects of each drug by 24-h ambulatory blood pressure monitoring at 0, 8, and 16 weeks. Simultaneously, we measured metabolic parameters and inflammation markers. Olmesartan lowered mean systolic and diastolic blood pressure more significantly than did telmisartan. While there were no differences between the groups in metabolic parameters, including HbA1c and adiponectin, the decreases in serum interleukin-6 and highly sensitive C-reactive protein were more significant by olmesartan treatment. Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti-inflammatory effects than telmisartan.