Management of Sorafenib-Related Adverse Events: A Clinician’s Perspective

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). It is being evaluated in phase II and III clinical trials, which include treatment as a single agent (locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer [DTC]), as part of multimodality care (HCC), and in combination with chemotherapeutic agents (metastatic breast cancer). Sorafenib-related adverse events (AEs) that commonly occur across these tumor types include hand–foot skin reaction (HSFR), rash, upper and lower gastrointestinal (GI) distress (ie, diarrhea), fatigue, and hypertension. These commonly range from grade 1 to 3, per the Common Terminology Criteria for Adverse Events (CTCAE), and often occur early in treatment. The goal for the management of these AEs is to prevent, treat, and/or minimize their effects, thereby enabling patients to remain on treatment and improve their quality of life. Proactive management, along with ongoing patient education (before and during sorafenib treatment), can help to effectively manage symptoms, often without the need for sorafenib dose modification or drug holidays. Effective management techniques for common sorafenib-related AEs, as well other important disease sequelae not directly related to treatment, are presented. Recommendations and observations are based on physician/author experience and recommendations from published literature

Perceived Discrimination, Race and Health in South Africa

To assess the levels of perceived acute and chronic racial and non-racial discrimination in South Africa, their association with health, and the extent to which they contribute to racial differences in physical and mental health, data were used from a national probability sample of adults, the South African Stress and Health Study (SASH). All Black groups in South Africa (African, Coloured and Indian) were two to four times more likely than Whites to report acute and chronic experiences of racial discrimination. Africans and Coloureds report higher levels of ill health than Whites, but acute and chronic racial discrimination were unrelated to ill health and unimportant in accounting for racial differences in self-rated health. In contrast, all Black groups had higher levels of psychological distress than Whites, and perceived chronic discrimination was positively associated with distress. Moreover, these experiences accounted for some of the residual racial differences in distress after adjustment for socioeconomic status. Our main findings indicate that, in a historically racialized society, perceived chronic racial and especially non-racial discrimination acts independently of demographic factors, other stressors, psychological factors (social desirability, self-esteem and personal mastery), and multiple SES indicators to adversely affect mental health

Race and Psychological Distress: The South African Stress and Health Study

We analyze data from the South African Stress and Health Study, a nationally representative in-person psychiatric epidemiologic survey of 4,351 adults conducted as part of the World Mental Health Survey Initiative between January 2002 and June 2004. All blacks (Africans, Coloreds, and Indians) initially report higher levels of non-specific distress and anger/hostility than whites. Access to socioeconomic resources helps explain differences in non-specific distress between Coloreds and whites and Indians and whites. However, only when social stressors are considered do we find few differences in psychological distress (i.e., non-specific distress and anger/hostility) between Africans and whites. In addition, self-esteem and mastery have independent effects on non-specific distress and anger/hostility, but differences between Coloreds and whites in feelings of anger/hostility are not completely explained by self-esteem and mastery. The findings contribute to the international body of work on social stress theory, challenge underlying assumptions of the minority status perspective, and raise a series of questions regarding mental health disparities among South Africans

Triple Network Resting State Connectivity Predicts Distress Tolerance and Is Associated with Cocaine Use

Distress tolerance (DT), a predictor of substance use treatment retention and post-treatment relapse, is associated with task based neural activation in regions located within the salience (SN), default mode (DMN), and executive control networks (ECN). The impact of network connectivity on DT has yet to be investigated. The aim of the present study was to test within and between network resting-state functional connectivity (rsFC) associations with DT, and the impact of cocaine use on this relationship. Twenty-nine adults reporting regular cocaine use (CU) and 28 matched healthy control individuals (HC), underwent resting-state functional magnetic resonance imaging followed by the completion of two counterbalanced, computerized DT tasks. Dual-regression analysis was used to derive within and between network rsFC of the SN, DMN, and lateralized (left and right) ECN. Cox proportional-hazards survival models were used to test the interactive effect of rsFC and group on DT. The association between cocaine use severity, rsFC, and DT was tested within the CU group. Lower LECN and higher DMN-SN rsFC were associated with DT impairment. Greater amount of cocaine use per using day was associated with greater DMN-SN rsFC. The findings emphasize the role of neural resource allocation within the ECN and between DMN-SN on distress tolerance

Mental health service use among South Africans for mood, anxiety and substance use disorders

Background. Europe and North America have low rates of mental health service use despite high rates of mental disorder. Little is known about mental health service use among South Africans. Design. A nationally representative survey of 4 351 adults. Twelve-month DSM-IV (Diagnostic and Statistical Manual, 4th edition) diagnoses, severity, and service utilisation were determined using the World Health Organization Composite International Diagnostic Interview (CIDI). Twelve-month treatment was categorised by sector and province. South Africans in households and hostel quarters were interviewed between 2002 and 2004 in all nine provinces. Outcome measures. 4 317 respondents 18 years and older were analysed. Bivariate logistic regression models predicted (i) 12-month treatment use of service sectors by gender, and (ii) 12-month treatment use by race by gender. Results. Of respondents with a mental disorder, 25.2% had sought treatment within the previous 12 months; 5.7% had used any formal mental health service. Mental health service use was highest for adults with mood and anxiety disorders, and among those with a mental disorder it varied by province, from 11.4% (Western Cape) to 2.2% (Mpumalanga). More women received treatment, and this was largely attributable to higher rates of treatment in women with mood disorders. Age, income, education and marital status were not significantly associated with mental health service use. Race was associated with the treatment sector accessed in those with a mental disorder. Conclusions. There is a substantial burden of untreated mental disorders in the South African population, across all provinces and even in those with substantial impairment. Greater allocation of resources to mental health services and more community awareness initiatives are needed to address the unmet need

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly

Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells

INTRODUCTION: The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-α) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance. METHODS: MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-α production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-α by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-κB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR). RESULTS: MCF-7 and A2780 cells increased production of sTNF-α in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-α, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-α was NF-κB dependent and correlated with decreased sensitivity to sTNF-α, decreased levels of TNFR1, and increased survival through TNFR2 and NF-κB activation. The NF-κB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene-expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes in the expression of TNF-α-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-κB survival pathways. CONCLUSIONS: We report for the first time that taxanes can promote dose-dependent sTNF-α production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-κB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance

The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance

We show that the mouse macrophage-restricted F4/80 protein is not required for the development and distribution of tissue macrophages but is involved in the generation of antigen-specific efferent regulatory T (T reg) cells that suppress antigen-specific immunity. In the in vivo anterior chamber (a.c.)–associated immune deviation (ACAID) model of peripheral tolerance, a.c. inoculation of antigen into F4/80−/− mice was unable to induce efferent T reg cells and suppress delayed-type hypersensitivity (DTH) responses. Moreover, the use of anti-F4/80 mAb and F4/80−/− APCs in an in vitro ACAID model showed that all APC cells in the culture must be able to express F4/80 protein if efferent T reg cells were to be generated. In a low-dose oral tolerance model, WT but not F4/80−/− mice generated an efferent CD8+ T reg cell population that suppressed an antigen-specific DTH response. Peripheral tolerance was restored in F4/80−/− mice by adoptive transfer of F4/80+ APCs in both peripheral tolerance models, indicating a central role for the F4/80 molecule in the generation of efferent CD8+ T reg cells

What is it about humanity that we can't give away to intelligent machines? A European perspective

One of the most significant recent technological developments concerns the development and implementation of ‘intelligent machines’ that draw on recent advances in artificial intelligence (AI) and robotics. However, there are growing tensions between human freedoms and machine controls. This article reports the findings of a workshop that investigated the application of the principles of human freedom throughout intelligent machine develop- ment and use. Forty IS researchers from ten different countries discussed four contemporary AI and humanity issues and the most relevant IS domain challenges. This article summarizes their experiences and opinions regarding four AI and humanity themes: Crime & conflict, Jobs, Attention, and Wellbeing. The outcomes of the workshop discussions identify three attributes of humanity that need preservation: a critique of the design and application of AI, and the intelligent machines it can create; human involvement in the loop of intelligent ma- chine decision-making processes; and the ability to interpret and explain intelligent machine decision-making processes. The article provides an agenda for future AI and humanity researchpublishedVersio