Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway.

The discovery of epidermal growth factor receptor (EGFR) mutations in never-smokers has been the most relevant finding ever in non-small cell lung cancer. When patients whose tumors bear the sensitizing mutations are treated with the tyrosine kinase inhibitors gefitinib or erlotinib, we witness response rates and durations never before reported, including complete responses. At the same time, the presence of EGFR mutations has raised numerous new questions, tantalizing data, and new challenges for treatment. This is particularly true as we try to generalize the findings in lung cancer to other malignancies. The indiscriminate use of gefitinib or erlotinib in the general lung cancer population results in meager survival benefit for patients. Similarly, the tyrosine kinase inhibitors have limited activity in a variety of tumor types with EGFR overexpression. This has led to the question of whether EGFR remains a viable target in patients other than those whose tumors contain mutations, and whether the modest activity of cetuximab in colorectal cancer and head and neck cancer represents all that we can expect from inhibition of this pathway in the absence of mutation. Mechanisms of pathway activation other than mutation have been discovered in recent years, and include overexpression mediated by gene amplification or by amplification of a dinucleotide repeat in the EGFR promoter, mutation of an extracellular region on EGFR generating a mutant protein termed EGFRvIII, and enhanced signaling due to heterodimerization with other members of the EGFR family, particularly overexpression of HER2/HER3. The extent to which these paths to EGFR activation will confer sensitivity to the tyrosine kinase inhibitors or to EGFR monoclonal antibodies is being explored. Thus far, published clinical data suggest that there is little room for the administration of gefitinib or erlotinib in the absence of EGFR mutations. The five articles in this edition of CCR Focus will address the various mechanisms of EGFR pathway activation and provide insight into the potential for translation into clinical relevance.     

Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling

Background  

Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations.     

Breast metastases as the first sign of recurrence of a cutaneous melanoma

Malignant melanoma is the most rapidly increasing cancer in the world. Metastatic disease occurs in 20% of patients, and prognosis in these cases is poor. We report the case of a woman who presented breast metastasis as the first sign of recurrence of a melanoma.     

Whole brain irradiation and temozolomide based chemotherapy in melanoma brain metastases

Introduction Whole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma in terms of symptom palliation, especially when extracranial systemic disease is present. Temozolomide (TMZ) has shown efficacy in the treatment of metastatic melanoma. The objective was to evaluate the potential benefit in survival of two different schedules of total dose and fractionation (20 Gy/5 fractions vs 30 Gy/10 fractions) and further TMZ based chemotherapy. Materials and method We have conducted a retrospective study in a group of twenty-one patients (RTOG Recursive Partitioning Analysis class II) of the use of WBRT with 20 Gy/5 fractions (n=11) and 30 Gy/10 fractions (n=10). All patients received further TMZ based chemotherapy administered as a single chemotherapeutic agent or in combination with chemo-immunotherapy. Results Prognostic variables such as: age, Karnofsky performance status, extracranial metastases and number of brain metastases, were analyzed in both groups of treatment without statistically significant differences. The median survival time (MST) for WBRT 20 Gy group was 4 months (CI 95%: range 2–6 months) and for WBRT 30 Gy group was 4 months (CI 95%: range 0–7 months) without statistically significant differences (Log rank p=0.74). There was one complete response and two partial responses. Conclusions The results suggest that MST was not significantly affected by the total dose/fractionation schedule.     

Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma.

PURPOSE: Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin's lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has demonstrated efficacy in rituximab-na?ve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL. PATIENTS AND METHODS: Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m(2) weekly for 4 weeks) or time to progression (TTP) of < or = 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m(2) intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients. RESULTS: Fifty-seven patients were treated. The median age was 54 years, 74% had tumors > or = 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier-estimated TTP was 6.8 months (range, 1.1 to > or = 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively. CONCLUSION: Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.     

A comparative study of HER2/neu amplification and overexpression using fluorescencein situ hybridization (FISH) and immunohistochemistry (IHC) in 101 breast cancer patients

The HER2/neu protooncogene is expressed in the breast, ovarian, gastric and prostatic tumors. Studies done in a number of laboratories have demostrated that 25%–30% of breast cancer contain overexpression of HER2/neu gene. A comparative analysis of the amplification and overexpression of HER2/neu using fluorescencein situ hybridization (FISH) and immunohistochemistry (IHC) was performed to determine the correlation between both techniques. In this study, FISH with HER2/neu probe (Path Vysion) is compared to immunohistochemistry (rabbit anti-human c-erbB-2-DAKO) in a series of 101 prospective human breast cancer specimens. Among 25 patients with score of IHC 3+, 23 (92%) were detected amplified by FISH and in two cases we found overexpression (3+) but without gene amplification. Out of 46 cases with 2+ by IHC, we found 43 not amplified, two moderately amplified (<10 copies) and one highly amplified (>10 copies) (6.5%). No patient with IHC O or 1+, presented amplification of HER2/neu. A good correlation between both techniques was found. FISH technique should have clinical utillity overoat in cases with 2+.     

嘈杂语噪声下汉语整句识别的同质性研究

目的 获得嘈杂语噪声背景下汉语短句识别率一信噪比(Performance-Intensity,P-I)函数的斜率和50%的得分所对应的信噪比(记为SNR50),并对所有短句的同质性进行评估和调整.方法 采用16张(每张20句)新编嘈杂语噪声下汉语普通话短句识别表作为测试材料.选取年龄为21～25岁之间、听力/言语发育正常且日常以汉语普通话为交流方式的48名受试者按"随机区组设计"在-1、-4、-7、-10 dB四种信噪比条件下进行言语识别率的心理声学测量.使用Statistica7.0软件进行P-I函数拟合和统计分析.结果 320句语句在嘈杂语噪声下的言语识别P-I函数曲线的阈值呈正态分布,斜率呈不规则分布.剔除P-I函数强健性增长(斜率＞55%/dB)的语句,并保留阈值变异度在±2σ内的语句,精选出同质性良好的240句.结论 逐个调整每句的SNR以实现同质性,可为编制"等言语识别阈级"的句表奠定扎实的心理声学基础.     

Children with cochlear implants who live in monolingual and bilingual homes.

OBJECTIVE: To determine if exposure to a second language impacts the ability of children with cochlear implants to develop spoken English skills. STUDY DESIGN: Matched-pairs comparison of postoperative speech perception and speech/language data of children from monolingual and bilingual homes with cochlear implants. SETTING: Tertiary medical facility. SUBJECTS: Twelve matched pairs of children with unilateral cochlear implants who reside in monolingual or in bilingual homes. Pairs were matched for age of implantation, cochlear anatomy, educational setting, and device type. All subjects received their implant before the age of 6 years. INTERVENTION: Subjects participated in routine speech perception and speech and language assessments at various postimplantation time intervals. MAIN OUTCOME MEASURES: Matched-pairs t tests and mixed-model analyses were used to evaluate and compare scores obtained by the 2 groups on the Peabody Picture Vocabulary Test, The MacArthur-Bates Communicative Development Inventory: Words and Gestures, The Oral and Written Language Scales, The Infant-Toddler Meaningful Auditory Integration Scale, and the Student Oral Language Observation Matrix. RESULTS: No significant differences were found between the scores of children living in bilingual homes when compared with the scores obtained by children living in monolingual homes at any interval tested. CONCLUSION: This study supports the belief that exposure to a second language at home does not impair primary language acquisition for some young children with cochlear implants. The study suggests that some children with cochlear implants can learn multiple spoken languages and that parents of such children do not need to avoid using a minority language with their child who has a cochlear implant.     

Cost-Utility Analysis of Rimonabant in the Treatment of Obesity

Objective:  To estimate the incremental cost-utility ratio (ICUR) of rimonabant 20 mg/day in the treatment of obesity from a third-party payer's perspective.
Methods:  Pooled data from three randomized clinical trials were used to develop a decision tree with five treatment alternatives: 1- and 2-year treatment with rimonabant, 2-year placebo, 1-year rimonabant followed by 1-year placebo, and no treatment. All alternatives, except no treatment, were accompanied by lifestyle interventions. Treatment benefits included gains in quality-adjusted life-years (QALYs) and reduced incidence of type-2 diabetes mellitus and coronary heart disease (CHD). Drug acquisition cost was based on the average wholesale price of a comparator drug minus 15%. One-way and probabilistic sensitivity analyses were conducted to assess the stability of the base-case results.
Results:  One-year rimonabant and 1-year rimonabant followed by placebo were extendedly dominated. Rimonabant for 2 years showed an average weight reduction of 8.49 kg, a body mass index reduction of 2.98 kg/m² and reduced waist circumference by 8.24 cm (placebo: 3.55 kg, 1.22 kg/m², 4.18 cm). Two-year rimonabant was associated with a relative reduction in the 5-year incidence of CHD by 7.15% and of diabetes by 9.28%. Incremental benefits (costs) were 0.0984 QALYs ($5209) compared to no treatment and 0.0581 QALYs ($4182) compared to placebo, producing ICURs of $52,936/QALY (95% confidence interval $39K–$69K) and $71,973/QALY ($51K–$98K), respectively.
Conclusions:  Rimonabant combined with lifestyle interventions has the potential to decrease the rate of obesity-related comorbidities and improve health-related quality of life, albeit at considerable cost.     

Factors influencing the participation of gastroenterologists and hepatologists in clinical research

Background  

Although clinical research is integral to the advancement of medical knowledge, physicians face a variety of obstacles to their participation as investigators in clinical trials. We examined factors that influence the participation of gastroenterologists and hepatologists in clinical research.