Phase I and initial phase II results from a trial investigating weekly docetaxel and carboplatin given neoadjuvantly and then concurrently with concomitant boost radiotherapy for locally advanced squamous cell carcinoma of the head and neck

BACKGROUND: The current Phase I/II study assessed induction docetaxel/carboplatin given weekly for 4 weeks, followed by weekly docetaxel/carboplatin and concomitant boost radiotherapy (CB-XRT) for locally advanced head and neck squamous cell carcinoma. METHODS: Twenty patients with Stage III or IV (M0) disease of the oropharynx, supraglottic larynx, or hypopharynx were enrolled. Patients initially received docetaxel 20 mg/m2 and carboplatin area under the curve (AUC) 2 weekly x 4. Patients with stable (SD) or responding disease subsequently received dose-escalated docetaxel (10-20 mg/m2 in sequential patient cohorts) and carboplatin AUC 1 weekly x 5 with CB-XRT (1.8 gray [Gy] every day x 15 days, followed by 1.8/1.5 Gy twice per day x 13 days). RESULTS: All patients were evaluable, and 15 patients (5 patients with Stage III disease, 10 patients with Stage IV disease) completed all planned therapy. The target docetaxel dose level of 20 mg/m(2) weekly with radiotherapy was achieved with no dose-limiting toxicities. The most frequent maximum toxicities during chemoradiotherapy were Grade 3 mucositis, dysphagia, and/or pain. Primary site responses after induction included 4 patients with partial responses, 11 patients with SD, and 5 patients with disease progression. Fifteen patients (75%) continued to receive chemoradiotherapy, with 14 patients attaining a complete response (CR). Overall, a clinicopathologic neck CR after chemoradiotherapy was achieved in 9 of 10 patients. One patient had persistent primary disease and underwent salvage surgery, whereas another died of unrelated causes before neck assessment. Thirteen patients remain free of any disease event, with a median follow-up of 15 months (range, 3-29 months). CONCLUSIONS: This regimen was feasible, safe, and particularly well tolerated. Early Phase II outcomes revealed promising activity in patients completing all treatment. Initial induction response results suggested that further investigation of this regimen with more aggressive induction therapy is warranted.     

Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo

About 97% of synovial sarcomas harbor the SYT-SSX fusion gene by chromosomal translocation. We found that the histone deacetylase (HDAC) inhibitor FK228 significantly suppressed the growth of synovial sarcoma cells as compared with that of osteosarcoma. The 50% growth inhibition IC50 value we obtained for FK228 was 0.02-0.2 nM, and it indicates that its suppression effect on synovial sarcoma cells is the highest of any of the HDAC inhibitors yet reported. It was not likely that the growth suppression of FK228 depends on the doubling time of these cells. Introduction of SYT-SSX cDNA into HEK293 cells enhanced the sensitivity of the cells for FK228. Immunostaining of the FK228-treated cells using an anti-acetyl-histone H3 antibody showed that FK228 inhibits deacetylation of histone. In a mice assay, the growth of synovial sarcoma cells was markedly inhibited by FK228 treatment, and the invasion of tumors into surrounding tissues was suppressed. These results suggest that FK228 may be useful in developing therapeutic strategies to treat synovial sarcoma.     

Immunohistochemical expression of multidrug resistance proteins as a predictor of poor response to chemotherapy and prognosis in patients with nodal diffuse large B-cell lymphoma

BACKGROUND/AIMS: The aim of this study was to determine whether expression of P-glycoprotein (P-gp), multidrug-resistance-related protein 1 (MRP1), and lung resistance protein (LRP) was related to the response to induction chemotherapy and prognosis in untreated diffuse large B-cell lymphoma (DLBCL). METHODS: We assessed immunohistochemical expression of P-gp, MRP1 and LRP, using formalin-fixed and paraffin-embedded specimens of lymph node in 41 patients with DLBCL. Association between expression of these three proteins and their impact on clinical outcome and prognosis was statistically evaluated. RESULTS: P-gp was positive in 37% of subjects, MRP1 in 63%, and LRP in 68%. The complete remission rates achieved in the group expressing these multidrug resistance (MDR) proteins was significantly lower than in the group not expressing them (20 versus 58%; p = 0.025 in P-gp, 23 versus 80%; p < 0.001 in MRP1 and 32 versus 69%, p = 0.043 in LRP, respectively). Furthermore, the patients expressing LRP had a shorter overall survival rate than those that did not (median of 26 months versus median not reached; p = 0.013). CONCLUSIONS: These findings suggest that the three MDR proteins are important predictive factors for the clinical outcome and prognosis in patients with DLBCL.     

Infrequent Ha-ras mutations and absence of Ki-ras,N-ras,and p53 mutations in 4-nitroquinoline 1-oxide-induced rat oral lesions

The alkylating agent 4-nitroquinoline 1-oxide (4-NQO) is a powerful carcinogen and induces squamous cell hyperplasia, squamous cell dysplasia, papilloma, and squamous cell carcinoma (a) in rat oral epithelia. Oral cancers induced by a single application of 4-NQO develop through a multistage process in a way similar to the development of this cancer in humans. In this study, mutations in exons 1 and 2 of Ki-ras, N-ras, and Ha-ras and exons 4–7 of p53 were examined by polymerase chain reaction (a) -single strand conformation polymorphism (a) analysis, followed by PCR-direct sequencing for the confirmation of mutations. Samples for the mutation analysis were obtained from dysplasias, papillomas, and SCCs on the tongue epithelia induced in F344 rats by adding 4-NQO (20 ppm) to their drinking water for 8 wk. The Ha-ras mutations (⁶¹A→T transversions in the second position) were found in five of 29 (17%) samples (one dysplasia and four SCCs). However, no mutations were detected in either Ki-ras, N-ras, or p53 under two different conditions of PCR-SSCP analysis. We suggest that some neoplasms in oral carcinogenesis induced by 4-NQO may involve Ha-ras mutations but not mutations in Ki-ras, N-ras, or p53. The 4-NQO-induced rat oral carcinogenesis model may provide a system for evaluation of the mechanisms of multistage oral carcinogenesis associated with Ha-ras mutation without Ki-ras, N-ras, or p53 mutation. © 1995 Wiley- Liss, Inc.     

Overall survival of high-risk prostate cancer patients who received neoadjuvant chemohormonal therapy followed by radical prostatectomy at a single institution

Background

The optimal treatment for high-risk prostate cancer (PCa) remains to be established. We previously reported favorable, biochemical recurrence-free survival in high-risk PCa patients treated with a neoadjuvant gonadotropin-releasing hormone agonist or antagonist and estramustine phosphate (EMP) (chemohormonal therapy; CHT) followed by radical prostatectomy (RP). We conducted a retrospective study to elucidate the clinical benefit of neoadjuvant CHT for high-risk PCa patients.

Methods

We reviewed the clinical and pathological records of 1254 PCa patients who underwent RP and bilateral pelvic lymphadenectomy between July 1996 and April 2016 at Hirosaki University. According to the D’Amico risk classification, we focused on 613 patients in the high-risk group. The high-risk PCa patients were further divided into two groups based on whether the patients received neoadjuvant CHT before RP (EMP group) or not (non-EMP group). The endpoint was overall survival (OS) after surgery.

Results

The 5- and 10-year OS rates were 98.5 and 92.6%, respectively. The 10-year OS rate in the EMP group was significantly higher compared to the non-EMP group (P = 0.021). In multivariate analysis, administration of neoadjuvant CHT, lymph node involvement, and castration-resistant PCa status were significantly associated with OS.

Conclusions

RP with neoadjuvant CHT using EMP for high-risk PCa patients provided excellent long-term OS.

     

Differential effects of methamphetamine and cocaine on behavior and extracellular levels of dopamine and 3,4-dihydroxyphenylalanine in the nucleus accumbens of conscious rats

The stress-induced hyperthermia procedure, in which effects of drugs on basal (T₁) and stress-induced body temperature (T₂) are measured, predicts anxiolytic drug effect. Serotonergic drugs alter these responses and here, we studied the role of 5-HT_1A receptors in stress-induced hyperthermia by using 5-HT_1A receptor knockout mice. Three strains (129/Sv, Swiss Webster and C57Bl6) were used because genetic background can significantly modulate the null phenotype. We found that GABA-ergic drugs with an anxiolytic profile and stimulate ₂ subunit containing GABA_A receptors, including diazepam and L838,417, result in reduced ΔT (ΔT = T₂ − T₁). The ₁ subunit containing GABA_A receptor was found to be primarily involved in regulation of basal body temperature T₁ and its stimulation can induce hypothermia. In addition, stimulation of 5-HT_1A receptors by buspirone results in a reduced ΔT, while stimulation of 5-HT₇ receptors primarily results in hypothermia. The null mutation of 5-HT_1A receptors resulted in differences in drug-sensitivity that was further modulated by the genetic background. In particular, the null mutation on the SW and C57Bl6 backgrounds resulted in differential diazepam/L838,417 and 5-CT responses respectively. This indicates an interaction between the 5-HT_1A receptor and genetic background and demonstrates the importance of selecting the background strain in a receptor knockout model.     

Inhibitory effects of sudanese medicinal plant extracts on hepatitis C virus (HCV) protease

One hundred fifty-two methanol and water extracts of different parts of 71 plants commonly used in Sudanese traditional medicine were screened for their inhibitory effects on hepatitis C virus (HCV) protease (PR) using in vitro assay methods. Thirty-four extracts showed significant inhibitory activity (>/=60% inhibition at 100 microg/mL). Of these, eight extracts, methanol extracts of Acacia nilotica, Boswellia carterii, Embelia schimperi, Quercus infectoria, Trachyspermum ammi and water extracts of Piper cubeba, Q. infectoria and Syzygium aromaticum, were the most active (>/=90% inhibition at 100 microg/mL). From the E. schimperi extract, two benzoquinones, embelin (I) and 5-O-methylembelin (II), were isolated and found as potent HCV-PR inhibitors with IC(50) values of 21 and 46 microM, respectively. Inhibitory activities of derivatives of I against HCV-PR as well as their effects on other serine proteases were also investigated.Copyright 2000 John Wiley & Sons, Ltd.     

Health care financing, expenditure and supply in great urban centers in the state of São Paulo (Brazil)

Challenges to implantation of SUS doutrinary and operative principles in great urban centers, have stimulated the developing of strategies focused on cities over 100.000 inhabitants and had raised researches on this setting. This article approaches health financing and expenditure evolution in S?o Paulo cities over 500.000 inhabitants, excluded the state capital, from 2000 to 2006. These data were compared with health services production. The main data sources were Seade Foundation, Siops and Datasus database. Conclusions pointed out to an increase in health expenditure higher than global income and expense increasing. The low PSF coverage and the increasing of middle and high complexity procedures production found in this study might reflect the tradictional medical-assistance model reproduction. Indicators dissimilarity presented by different cities bring up the necessity of case studies, as simple as multiple ones, in order to better understand and to identify the determinants of these differences.     

Ridaifen-SB8, a novel tamoxifen derivative,induces apoptosis via reactive oxygen species-dependent signaling pathway

Tamoxifen is an anticancer agent widely used for treatment of estrogen receptor (ERα)-positive breast cancer. We previously developed a novel synthesis of tamoxifen and its derivatives, named Ridaifens (RIDs). Some of them, including RID-SB8, exhibited a stronger anticancer activity than tamoxifen in ERα-positive MCF-7 cells while having lost the affinity for ERα, suggesting an ERα-independent anticancer mode of action. In this study, we investigated the underlying mechanism by which RID-SB8 exerts anticancer activity. As expected, anticancer activity of RID-SB8 was not influenced upon knockdown of ERα expression in MCF-7 cells. RID-SB8 exerted similar anticancer effects on thirteen ERα-negative cancer cell lines including human gliosarcoma SF539 cells. In SF539 cells, RID-SB8 triggered loss of mitochondrial membrane potential (ΔΨ_m) and progression of apoptosis accompanied by activation of caspases and translocation of apoptosis-inducing factor (AIF) to the nucleus. Furthermore, it induced reactive oxygen species (ROS), and a ROS scavenger, N-acetylcysteine (NAC), canceled loss of ΔΨ_m and progression of apoptosis triggered by RID-SB8. Using fifteen human cancer cell lines, we demonstrated a significant correlation between RID-SB8 concentration required for ROS production and that required for cytotoxic effect across these cell lines, but such correlation was not observed for tamoxifen. Finally, the selective induction of ROS and cytotoxic effect on cancer cells by RID-SB8 were confirmed. From these results, we concluded that RID-SB8 exerts an anticancer effect via a mode of action distinct from tamoxifen, and that RID-SB8 could become a promising anticancer lead compound which selectively induces ROS formation and apoptosis in cancer cells.