Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

Background: VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings: Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion: Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first‑line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses

Spray Cooling Of Igbts Under High Heat Flux

In this investigation, high current levels were applied to an IGBT and, using spray cooling, a heat flux of 825W/cm2 at the die was achieved. Current and heat flux levels achieved during this investigation could not have been done using ordinary cooling methods. The techniques used in this investigation clearly demonstrate the superior cooling performance of spray cooling over traditional cooling methods. Copyright © 2005 by ASME

Bubble Behavior And Nucleate Boiling Heat Transfer In Saturated Fc-72 Spray Cooling

Bubble behavior during saturated FC-72 spray cooling was experimentally investigated. A heater previously used for pool boiling was used to allow direct comparison. The results are analyzed to reveal the interaction between bubbles and impinging droplets. The following are presented: (1) the importance of secondary nuclei entrained by impingement droplets, (2) the role of impinging droplets on bubble parameters such as growth, diameter at puncture, lifetime, life cycle and bubble number density, and (3) the relative contribution of nucleation, especially that of secondary nuclei, to the heat transfer. It is concluded that increasing the droplet flux increases the number of secondary nuclei, helps to lower surface temperature for a given heat flux, increases the overall heat transfer coefficient, and increases heat transfer due to both nucleate boiling and enhanced convection. Increasing the droplet flux also shortens the bubble growth time (i.e., resulting in earlier bubble removal) and life cycle. However, increasing the droplet flux (and, therefore, secondary nucleation) for each of the three heat flux values does not affect the percentage of either nucleate or convection heat transfer. This suggests that both the nucleate and convection heat transfer are enhanced, as a result of increased secondary nuclei and turbulent mixing due to the impinging droplets

Bubble Behavior and Nucleate Boiling Heat Transfer in Saturated FC-72 Spray Cooling

Bubble behavior during saturated FC-72 spray cooling was experimentally investigated. A heater previously used for pool boiling was used to allow direct comparison. The results are analyzed to reveal the interaction between bubbles and impinging droplets. The following are presented: (1) the importance of secondary nuclei entrained by impingement droplets, (2) the role of impinging droplets on bubble parameters such as growth, diameter at puncture, lifetime, life cycle and bubble number density, and (3) the relative contribution of nucleation, especially that of secondary nuclei, to the heat transfer. It is concluded that increasing the droplet flux increases the number of secondary nuclei, helps to lower surface temperature for a given heat flux, increases the overall heat transfer coefficient, and increases heat transfer due to both nucleate boiling and enhanced convection. Increasing the droplet flux also shortens the bubble growth time (i.e., resulting in earlier bubble removal) and life cycle. However, increasing the droplet flux (and, therefore, secondary nucleation) for each of the three heat flux values does not affect the percentage of either nucleate or convection heat transfer. This suggests that both the nucleate and convection heat transfer are enhanced, as a result of increased secondary nuclei and turbulent mixing due to the impinging droplets

Bubble Behavior And Heat Transfer Mechanism In Fc-72 Pool Boiling

A transparent heater made of a thin synthetic diamond substrate along with a high-speed camera was used to investigate bubble behavior during pool boiling. The heater design, combined with the selected FC-72 liquid, overcame the difficulty of previous thin-film heater experiments where transparency and adequate heat flux could not be simultaneously achieved. It also resulted in an essentially uniform temperature field over the heater surface. The growth and merging of bubbles were visualized and quantitatively documented. The relative contribution from phase change to the overall heat flux was determined at several heat flux levels. At a heat flux level half of the critical heat flux (CHF), surface bubble nucleation was found to contribute to more than 70% of the heat transfer from the heater surface. At a similar heat flux level, the ratio of dry to wetted area was determined to exceed 1/3, significantly higher than that predicted by a recent hydrodynamic model for CHF (approximately 1/16). This result suggests that modifications are needed for the hydrodynamic model when applied to highly wetting fluid on nearly isothermal surfaces. The merging of bubbles to form vapor blankets over the heater surface was observed, as has been assumed in recent hydrodynamic models

Spray Cooling With Ammonia On Microstructured Surfaces: Performance Enhancement And Hysteresis Effect

Experiments were performed to investigate spray cooling on microstructured surfaces. Surface modification techniques were utilized to obtain microscale indentations and protrusions on the heater surfaces. A smooth surface was also tested to have baseline data for comparison. Tests were conducted in a closed loop system with ammonia using RTI\u27s vapor atomized spray nozzles. Thick film resistors, simulating heat source, were mounted onto 1×2 cm2 heaters, and heat fluxes up to 500 W/cm2 (well below critical heat flux limit) were removed. Two nozzles each spraying 1 cm2 of the heater area used 96 ml/cm2 min (9.7 gal/ in.2 h) liquid and 13.8 ml/cm2 s (11.3 ft3 / in.2 h) vapor flow rate with only 48 kPa (7 psi) pressure drop. Comparison of cooling curves in the form of surface superheat (ΔTsat=Tsurf-Tsat) versus heat flux in the heating-up and coolingdown modes (for increasing and decreasing heat flux conditions) demonstrated substantial performance enhancement for both microstructured surfaces over smooth surface. At 500 W/cm2, the increases in the heat transfer coefficient for microstructured surfaces with protrusions and indentations were 112% and 49% over smooth surface, respectively. Moreover, results showed that smooth surface gives nearly identical cooling curves in the heating-up and cooling-down modes, while microstructured surfaces experience a hysteresis phenomenon depending on the surface roughness level and yields lower surface superheat in the cooling-down mode, compared with the heating-up mode, at a given heat flux. Microstructured surface with protrusions was further tested using two approaches to gain better understanding on hysteresis. Data indicated that microstructured surface helps retain the established three-phase contact lines, the regions where solid, liquid, and vapor phases meet, resulting in consistent cooling curve and hysteresis effect at varying heat flux conditions (as low as 25 W/cm2 for the present work). Data also confirmed a direct connection between hysteresis and thermal history of the heater. Copyright © 2009 by ASME

Hysteresis In Spray Cooling Of Micro-Structured Surfaces

Spray cooling experiments were performed in a closed loop with ammonia using RT1\u27s vapor atomized spray nozzles, Thick film resistors, simulating heat source, were mounted onto 1cm × 2cm heater surfaces and heat fluxes up to 500 W/cm2 (well below critical heat flux (CHF) limit) were removed. Two nozzles each spraying 1 cm2 of heater area utilized 96 mlJcm 2- mm (9.7 gallin2-hr) liquid and 13.8 ml/cm2-s (11.3 ft3/in2-hr) vapor flow rate with only 48 kPa (7 psi) pressure drop. A smooth surface and two types of micro-structured surfaces with indentations and protrusions were used as test surfaces, Comparison of cooling curves in the form of surface superheat (ΔTsat T surf - Tsat) vs. heat flux in the heating-up and cooling- down modes (for increasing and decreasing heat flux conditions) demonstrated substantial performance enhancement for both micro-structured surfaces over a smooth surface, Moreover, results showed that smooth surface gives nearly identical cooling curves while micro-structured surfaces experience a hysteresis phenomenon depending on the surface roughness level and yields lower surface superheat in the cooling-down mode, compared to the heating-up mode, at a given heat flux, Micro-structured surface with protrusions was tested using two approaches to gain better understanding on hysteresis. Data mainly indicated that micro-structured surface helps retain established three-phase contact line, the region where solid, liquid and vapor phases meet, resulting in consistent cooling curve and hysteresis effect at varying heat flux conditions (as low as 25 W/cm2 for the present work), Data furthermore confirmed a direct connection between hysteresis and thermal history of the heater. Copyright © 2008 by ASME