Aprindine blocks the sodium current in guinea-pig ventricular myocytes

Summary Aprindine is a class Ib antiarrhythmic agent. We studied effects of aprindine (3 µmol/l) on the Na⁺ current using whole cell voltage clamp (tip resistance = 0.5 , [Na]_i and_o = 10 mmol/l at 18°C). Aprindine revealed tonic block (Kd_rest = 37.7 µmol/l, Kd_i = 0.74 µmol/l; n = 4). Aprindine, shifted inactivation curve to hyperpolarizing direction by 11.4 ± 3.5 mV (n = 4) without changes in slope factor. In the presence of 3 µmol/l aprindine, aprindine showed phasic block, i.e., duration-dependent block at 2 Hz (64% ±3070 at 1.5 ms, 82%±6% at 20 ms, 93%±7% at 200 ms; n = 4). Short single prepulse also produced aprindine-induced phasic block (12% at 1.5 ms, 22% at 100 ms; n = 2). After removal of fast inactivation of Na⁺ current by 3 mmol/l tosylchloramide sodium, aprindine revealed phasic block, independent of holding potential. The recovery time constant from aprindine-induced phasic block was 4.8 s at holding potential = –100 mV and 5.0 s at holding potential = –140 mV. This use-dependent block of aprindine had pH dependency. Under acidic condition (pH 6.0), 3 µmol/l aprindine showed smaller use-dependent block (14% ± 7% at 2 Hz; n = 4) comparing with either at pH 7,4 (68% ± 13%; n = 4) or at pH 8.0 (90% ±12%; n = 4).The results suggest that aprindine could bind to the receptor via activation process through channel pore, resulting in decrease of Na⁺ current, and egress from the receptor through the lipid bilayer. These effects might be attenuated under acidic condition due to changes in intracellular ratio of charged to neutralized form of drug molecule. Send offprint requests to: R. Sato at the above address     

Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer.

PURPOSE: The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 expression in human non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Clinicopathologic features and immunohistochemical expression of Skp2 and p27 proteins were studied in 138 patients with NSCLC. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. To analyze the role of Skp2 in vitro, NSCLC cells were transfected with an Skp2-expressing vector or small interfering RNA. RESULTS: Skp2 was overexpressed in males, smokers, patients with squamous cell carcinomas, and patients with poorly differentiated cancers (P = .034, < .0001, < .0001, and .002, respectively). The multivariant analysis revealed that Skp2 expression is an independent prognostic factor for survival in NSCLC. An inverse relationship of Skp2 with p27 expression was observed (P = .012), and patients with both a higher expression of Skp2 and a lower expression of p27 showed a significantly unfavorable prognosis (P = .0002). In vitro ectopic expression of Skp2 in NSCLC cells reduced the protein level of p27. Conversely, induction of Skp2 siRNA increased the protein level of p27, leading to growth inhibition in NSCLC cells. CONCLUSION: Skp2 overexpression is closely associated with the suppression of p27 and the aggressiveness in NSCLC. It also could be a therapeutic target in NSCLC.     

Functional impact of breast cancer by age at diagnosis.

PURPOSE: To explore changes in physical and psychosocial function before and after breast cancer by age at diagnosis. PATIENTS AND METHODS: A total of 122,969 women from the Nurses' Health Study (NHS) and NHS 2, ages 29 to 71 years, who responded to pre- and postfunctional status assessments were included; 1,082 women were diagnosed with breast cancer between 1992 and 1997. Functional status was measured using the Medical Outcomes Study Short Form 36 (SF-36). Mean change in health-related quality of life (HRQoL) scores was computed across categories representing the combination of incident breast cancer (yes or no) and age at diagnosis (< or = 40, 41 to 64, or 65+ years). RESULTS: Compared with women < or = 40 years without breast cancer, women with breast cancer experienced significant functional declines. Young (age < or = 40) women who developed breast cancer experienced the largest relative declines in HRQoL (as compared with middle-aged and elderly women) in multiple domains including physical roles (-18.8 v -11.5 and -7.5 points, respectively), bodily pain (-9.0 v -2.7 and -2.7 points), social functioning (-11.3 v -4.3 and -4.4 points) and mental health (-3.1 v 0.0 and +0.4 points). Much of the decline in HRQoL among elderly (age > or = 65) women with breast cancer was age related. CONCLUSION: Young women may fare worse than middle-aged or elderly women in both physical and psychosocial dimensions after breast cancer diagnosis. The needs of women facing breast cancer may be better understood within a life stage framework.     

Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy.

PURPOSE: To assess the predisposing factors and clinical characteristics of pelvic insufficiency fractures (PIF) in postmenopausal women with pelvic irradiation. MATERIAL AND METHODS: A total 335 postmenopausal patients with cervical cancer of the intact uterus treated with radiation therapy between 1983 and 1998 were reviewed. Total external dose was delivered between 45 and 50.4 Gy with parallel opposed anteroposterior portals. Total brachytherapy dose at point A was delivered between 10 and 36 Gy. PIF were diagnosed by bone scintigraphy and confirmed by computed tomography. The cumulative incidence of symptomatic PIF was estimated by actuarial methods. Potential risk factors (age, weight, type II diabetes, delivery, menopause, total external dose, total brachytherapy dose) were assessed. RESULTS: Fifty-seven (17.0%) of 335 patients were diagnosed as having PIF. Forty-seven patients were symptomatic and ten were asymptomatic. Parameters carrying a significant association with PIF were body weight 49 kg or below (P=0.044) in stepwise logistic regression analysis. The cumulative incidence of symptomatic PIF at 5 years was 17.9% calculated by the Kaplan-Meier method. A body weight of 49 kg or below and more than three deliveries were identified as having a significant effect on symptomatic PIF in univariate analysis (P=0.021, P=0.003, log-rank test) and Cox life table regression analysis (P=0.038, P=0.013). Five patients required narcotic agents and eight patients required hospital admission. CONCLUSIONS: We should consider reducing the dose contribution to the sacrum and sacroilac joints, without underdosing the tumor, especially in postmenopausal women with many deliveries or low body weight.     

Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers.

PURPOSE: Loss of function or expression of the mismatch repair gene MLH1 has been implicated in experimentally acquired resistance to cisplatin (CDDP) and other anticancer agents. The clinical significance of MLH1 expression was evaluated in advanced thoracic squamous cell carcinoma of the esophagus (ESCC) treated by neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: We investigated MLH1 and P53 expression by immunohistochemistry in the surgical specimens of 107 patients who had undergone preoperative chemotherapy using CDDP along with 5-FU and ADM. These findings were correlated with the clinical outcome for this treatment. Biopsy samples before chemotherapy in 20 of these patients, and another 43 surgical specimens without chemotherapy, were also examined as control samples. RESULTS: In surgical specimens of ESCC, low MLH1 expression was not frequent without chemotherapy, whereas it was commonly observed after chemotherapy (14 versus 37%, P = 0.0057). Comparison between samples before and after chemotherapy revealed that MLH1 expression was unchanged during chemotherapy in 12 of 20 patients (60%) but was from high to low in 8 of 20 patients (40%). In the surgical specimen after neoadjuvant chemotherapy, MLH1 expression was not correlated with any clinicopathological factors, including the response to chemotherapy. However, low MLH1 showed poorer prognosis than high MLH1 (5-year survival 40.6 versus 19.3%, P = 0.0393), and in multivariate analysis, MLH1 was an independent prognostic factor for this multimodal treatment, following lymph node metastasis and clinical response to chemotherapy. Positive p53 expression, which was not affected by chemotherapy, was weakly associated with a poor response and clinical outcome, although this trend was not significant. CONCLUSIONS: In advanced ESCC, expression of MLH1 is reduced during CDDP-based chemotherapy, and this may partly account for poor postoperative survival.     

Prediction of nodal metastasis by comparative genomic hybridization in biopsy specimens from patients with superficial esophageal squamous cell carcinoma.

PURPOSE: Selection of appropriate protocols for treatment of superficial esophageal squamous cell carcinoma (SESCC) is dependent on lymph node metastasis status. Therefore, it is important to know whether lymph node metastasis is present before treatment. EXPERIMENTAL DESIGN: In this study, we examined the relation between DNA sequence copy number aberrations detected by comparative genomic hybridization and lymph node metastasis in 26 surgically resected SESCCs (training samples). We then assessed whether the genetic information is predictive for nodal status in biopsy specimens from eight newly enrolled patients with SESCC (blinded samples). RESULTS: Pathological examination revealed that 17 of 26 training samples (65.4%) did not have associated lymph node metastasis. Gains of 8q24 and/or 20q12-qter were observed in 12, including all (nine of nine) with nodal metastasis. Fourteen training samples did not have gain of either 8q24 or 20q12-qter. Of the blinded samples, two showed no gain of 8q24 or 20q12-qter, and as anticipated the postoperative pathological examination revealed no nodal metastasis. The remaining six blinded samples had gains of 8q24 and/or 20q12-qter, and lymph node metastasis was detected by postoperative examination in four of these tumors. CONCLUSIONS: Absence of gains of 8q24 and/or 20q12-qter appears to be associated with absence of lymph node metastasis in patients with SESCC; therefore, less invasive surgery can be chosen.     

Transarterial Infusion of Cisplatin and Doxorubicin in Bladder Cancer: Original Article

Forty-five patients (median age 63 years) with muscle invasive bladder cancer were treated with transcatheter intraarterial infusion (TAI) of cisplatin (CDDP) and doxorubicin. They received a total of 114 courses (median 3 courses per patient) of TAI. Complete response was obtained in 20 patients (44%), partial response in 17 (38%), stable disease in 6(13%), and progression of disease in 2 patients (5%). The overall response rate was 82% at a median follow-up of 36 months. The actuarial survival of the patient population was 72% at 5 years; 36 patients were alive and 9 had died of cancer progression. The treatment was generally extremely well tolerated without major complications. The current study also revealed the fact that papillary carcinomas were more sensitive to this therapy than were non-papillary tumors. Overall, response rate and local control were significantly higher in low-grade than in high-grade tumors. The observed high complete response and good survival rate suggest that intraarterial CDDP and doxorubicin might be highly effective for localized invasive bladder cancer.     

Two cases of intrapulmonary lymph node presenting as a peripheral nodular shadow: Diagnostic differentiation from lung cancer

We present two cases of intrapulmonary lymph node. The patients were a 44-year-old woman and a 71-year-old man each with a small peripheral nodule in the lung. On computed tomography (CT) scans, both nodules were spiculated. Since histological diagnosis could not be obtained by bronchoscopic examination or CT-guided needle biopsy, they underwent video-assisted thoracoscopic surgery. Histological examination of the resected material revealed that both nodules were composed of lymph node. Intrapulmonary lymph node has until recently been assigned no clinical significance; however, differential diagnosis of this lesion from lung cancers and other metastatic tumors is now clinically important.