Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.     

Yellow fever 17-D vaccine is neurotropic and produces encephalitis in immunosuppressed hamsters

Immunosuppressed (cyclophosphamide) adult golden hamsters inoculated intraperitoneally (i.p.) with wild-type Asibi yellow fever virus (YFV) developed a rapidly fatal illness. Histopathologic and immunohistochemical studies of tissues from these animals showed typical hepatic changes of severe yellow fever (inflammation, hepatocyte necrosis, and steatosis) without brain involvement. In contrast, 50% of immunosuppressed hamsters receiving the YFV-17D-attenuated vaccine developed a slowly progressive encephalitic-type illness. Brain tissue from these latter animals revealed focal neuronal changes, inflammation, and YFV antigen-positive neurons; however, the liver and spleen appeared normal. YFV was isolated from brain cultures of many of these animals. Immunocompetent (non-immunosuppressed) hamsters inoculated with both viruses developed a subclinical infection. Results of this study indicate that wild-type YFV is hepatotropic in immunosuppressed hamsters, whereas the attenuated YFV-17 is primarily neurotropic. These findings support current recommendations against yellow fever vaccination of immunosuppressed/immunocompromised people and suggest that this hamster model might be useful for monitoring the safety of other live-attenuated YFV vaccines.     

Host feeding pattern of Culex quinquefasciatus (Diptera: Culicidae) and its role in transmission of West Nile virus in Harris County, Texas

The vertebrate hosts of 672 blood-engorged Culex quinquefasciatus Say, collected in Harris County, Texas, during 2005, were identified by nucleotide sequencing PCR products of the cytochrome b gene. Analysis revealed that 39.1% had acquired blood from birds, 52.5% from mammals, and 8.3% were mixed avian and mammalian blood meals. Most frequent vertebrate hosts were dog (41.0%), mourning dove (18.3%), domestic cat (8.8%), white-winged dove (4.3%), house sparrow (3.2%), house finch (3.0%), gray catbird (3.0%), and American robin (2.5%). Results are interpreted in conjunction with concurrent avian and mosquito West Nile virus (WNV) surveillance activities in Harris County. We conclude that Cx. quinquefasciatus is an opportunistic feeder and principal mosquito vector of WNV in this metropolitan area; however, transmission by other mosquito species or by other modes of infection, such as ingestion, must account for the high WNV infection rates among local blue jays and American crows.     

Hindlimb claudication reflects impaired nitric oxide-dependent revascularization after ischemia

Although vascular remodeling is important in preventing tissue damage and restoring muscle function, there is no evidence of a relationship between vascular remodeling and muscle function after peripheral vascular occlusion. Nitric oxide (NO) has been implicated in the process of vascular remodeling in hindlimb ischemia. Thus, development of alterations in hindlimb gait after ischemia may be associated with impaired nitric oxide-dependent, vascular blood flow recovery. We evaluated hindlimb gait as an index of ischemia-induced revascularization and tested the effects of NO synthase inhibition on both hindlimb blood flow and hindlimb gait locomotion. After 14 days of ischemia, the ischemic hindlimb showed no significant differences in gait locomotion compared to the sham-operated hindlimb. However, hindlimb ischemia drastically reduced hindlimb blood flow from 46+/-3 mL/min/100 g to 12+/-2 mL/min/100 g which reverted to 33+/-5 mL/min/100 g after 14 days of ischemia. eNOS mRNA expression levels at 3, 7, 14, and 28 days after initiation of ischemia, were increased by 50+/-5%, 100+/-10%, 140+/-8% and 270+/-12% respectively and eNOS protein expression levels at 7, 14, and 28 days, were increased by 28+/-3%, 62+/-6% and 80+/-16% respectively. However, eNOS inhibition caused by l-NAME treatment prevented blood flow recovery and correction of abnormal gait locomotion in rats. Thus, the duration of the stride-swing phase increased and the stride length decreased. The knee joint angle decreased during flexion and extension with eNOS inhibition. In conclusion, ischemia-induced revascularization is associated with recovery of both hindlimb blood flow and normal gait locomotion. Moreover, prevention of NO synthesis, a key messenger in ischemia-induced revascularization, is associated with impairment in hindlimb locomotion. Thus, gait locomotion represents a functional model that could be used to evaluate the degree of ischemia-induced revascularization.     

Reducing Internalizing Symptoms Among High-Risk,Hispanic Adolescents: Mediators of a Preventive Family Intervention

Familias Unidas is a family-focused preventive intervention that has been found to reduce drug use and sexual risk behaviors among Hispanic adolescents. In some trials, Familias Unidas has also been found to be efficacious in reducing adolescent internalizing symptoms (i.e., depressive and anxiety symptoms), even though the intervention did not specifically target internalizing symptoms. This study examines potential mediators or mechanisms by which Familias Unidas influences internalizing symptoms, specifically the role of intervention-targeted improvements in parent-adolescent communication and reductions in youth externalizing behaviors. A total of 213 Hispanic eighth grade students with a history of externalizing behavior problems and their primary caregivers were recruited from the public school system. Participants, with a mean age of 13.8 years, were randomized into the Familias Unidas intervention or community practice control condition and assessed at baseline, 6, 18, and 30 months post-baseline. A cascading mediation model was tested in which the Familias Unidas intervention was hypothesized to decrease adolescent internalizing symptoms through two mediators: improvements in parent-adolescent communication leading to decreases in externalizing behaviors. Findings show that the intervention had significant direct effects on youth internalizing symptoms at 30 months post-baseline. In addition, the cascading mediation model was supported in which the Familias Unidas intervention predicted significant improvements in parent-adolescent communication at 6 months, subsequently decreasing externalizing behaviors at 18 months, and ultimately reducing youth internalizing symptoms at 30 months post-baseline. Implications for prevention interventions are discussed.