Alicia K. Morgans

Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2

Prior studies have shown that PI3Ks play a necessary but incompletely defined role in platelet activation. One potential effector for PI3K is the serine/threonine kinase, Akt, whose contribution to platelet activation was explored here. Two isoforms of Akt were detected in mouse platelets, with expression of Akt2 being greater than Akt1. Deletion of the gene encoding Akt2 impaired platelet aggregation, fibrinogen binding, and granule secretion, especially in response to low concentrations of agonists that activate the G(q)-coupled receptors for thrombin and thromboxane A(2). Loss of Akt2 also impaired arterial thrombus formation and stability in vivo, despite having little effect on platelet responses to collagen and ADP. In contrast, reducing Akt1 expression had no effect except when Akt2 was also deleted. Activation of Akt by thrombin was abolished by deletion of Galpha(q) but was relatively unaffected by deletion of Galpha(i2), which abolished Akt activation by ADP. From these results we conclude that Akt2 is a necessary component of PI3K-dependent signaling downstream of G(q)-coupled receptors, promoting thrombus growth and stability in part by supporting secretion. The contribution of Akt1 is less evident except in the setting in which Akt2 is absent.

Disparities by race, age, and sex in the improvement of survival for major cancers: Results from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program in the United States, 1990 to 2010

IMPORTANCE Substantial progress has been made in cancer diagnosis and treatment, resulting in a steady improvement in cancer survival. The degree of improvement by age, race, and sex remains unclear. OBJECTIVE To quantify the degree of survival improvement over time by age, race, and sex in the United States. DESIGN, SETTING, AND PARTICIPANTS Longitudinal analyses of cancer follow-up data from 1990 to 2010, from 1.02 million patients who had been diagnosed as having cancer of the colon or rectum, breast, prostate, lung, liver, pancreas, or ovary from 1990 to 2009 and who were included in 1 of 9 population-based registries of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) and 95% CIs for cancer-specific death were estimated for patients diagnosed as having any of these cancers during 1995 to 1999, 2000 to 2004, and 2005 to 2009, compared with those diagnosed in 1990 to 1994. RESULTS Significant improvements in survival were found for cancers of the colon or rectum, breast, prostate, lung, and liver. Improvements were more pronounced for younger patients. For patients aged 50 to 64 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.57 (95% CI, 0.55-0.60), 0.48 (95% CI, 0.45-0.51), 0.61 (95% CI, 0.57-0.69), and 0.32 (95% CI, 0.30-0.36), for cancer of the colon or rectum, breast, liver, and prostate, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. However, the corresponding HRs (95% CIs) for elderly patients (those 75-85 years old) were only 0.88 (95% CI, 0.84-0.92), 0.88 (95% CI, 0.82-0.95), 0.76 (95% CI, 0.69-0.84), and 0.65 (95% CI, 0.61-0.70), for the same 4 cancer sites, respectively. A similar, although weaker, age-related period effect was observed for lung and pancreatic cancers. The adjusted HRs (95% CIs) for lung cancer were 0.75 (95% CI, 0.73-0.77) and 0.84 (95% CI, 0.81-0.86), respectively, for patients aged 50 to 64 years and 75 to 85 years diagnosed between 2005 and 2009, compared with the same age groups of patients diagnosed between 1990 and 1994 (0.73 [95% CI, 0.69-0.77] and 0.90 [95% CI, 0.85-0.95], respectively. Compared with whites or Asians, African Americans experienced greater improvement in prostate cancer survival. From 1990 to 2009, ovarian cancer survival declined among African Americans but improved among whites. No apparent sex difference in the degree of improvement for any non-sex-specific cancer was noted. CONCLUSIONS AND RELEVANCE Younger patients experienced greater benefit from recent oncology advances than elderly patients. African Americans experienced poorer survival than whites for all cancers, and the racial difference decreased for prostate cancer but increased for ovarian cancer. Identifying factors associated with varied improvement in cancer survival can inform future improvements in cancer care for all.

Endothelial cell specific adhesion molecule (ESAM) localizes to platelet–platelet contacts and regulates thrombus formation in vivo

Summary.  Background: In resting platelets, endothelial cell specific adhesion molecule (ESAM) is located in alpha granules, increasing its cell surface expression following platelet activation. However, the function of ESAM on platelets is unknown. Objective: To determine whether ESAM has a role in thrombus formation. Methods and results: We found that following platelet activation ESAM localizes to the junctions between adjacent platelets, suggesting a role for this protein in contact‐dependent events that regulate thrombus formation. To test this hypothesis we examined the effect of ESAM deletion on platelet function. In vivo, ESAM−/− mice achieved more stable hemostasis than wild‐type mice following tail transection, and developed larger thrombi following laser injury of cremaster muscle arterioles. In vitro, ESAM−/− platelets aggregated at lower concentrations of G protein‐dependent agonists than wild‐type platelets, and were more resistant to disaggregation. In contrast, agonist‐induced calcium mobilization, αIIbβ3 activation, alpha‐granule secretion and platelet spreading, were normal in ESAM‐deficient platelets. To understand the molecular mechanism by which ESAM regulates platelet activity, we utilized a PDZ domain array to identify the scaffold protein NHERF‐1 as an ESAM binding protein, and further demonstrated that it associates with ESAM in both resting and activated platelets. Conclusions: These findings support a model in which ESAM localizes to platelet contacts following platelet activation in order to limit thrombus growth and stability so that the optimal hemostatic response occurs following vascular injury.

Using a population-based observational cohort study to address difficult comparative effectiveness research questions: The CEASAR study

BACKGROUND While randomized controlled trials represent the highest level of evidence we can generate in comparative effectiveness research, there are clinical scenarios where this type of study design is not feasible. The Comparative Effectiveness Analyses of Surgery and Radiation in localized prostate cancer (CEASAR) study is an observational study designed to compare the effectiveness and harms of different treatments for localized prostate cancer, a clinical scenario in which randomized controlled trials have been difficult to execute and, when completed, have been difficult to generalize to the population at large. METHODS CEASAR employs a population-based, prospective cohort study design, using tumor registries as cohort inception tools. The primary outcome is quality of life after treatment, measured by validated instruments. Risk adjustment is facilitated by capture of traditional and nontraditional confounders before treatment and by propensity score analysis. RESULTS We have accrued a diverse, representative cohort of 3691 men in the USA with clinically localized prostate cancer. Half of the men invited to participate enrolled, and 86% of patients who enrolled have completed the 6-month survey. CONCLUSION Challenging comparative effectiveness research questions can be addressed using well-designed observational studies. The CEASAR study provides an opportunity to determine what treatments work best, for which patients, and in whose hands.

Prostate cancer survivorship care guideline: American society of clinical oncology clinical practice guideline endorsement

PURPOSE The guideline aims to optimize health and quality of life for the post-treatment prostate cancer survivor by comprehensively addressing components of follow-up care, including health promotion, prostate cancer surveillance, screening for new cancers, long-term and late functional effects of the disease and its treatment, psychosocial issues, and coordination of care between the survivors primary care physician and prostate cancer specialist. METHODS The American Cancer Society (ACS) Prostate Cancer Survivorship Care Guidelines were reviewed for developmental rigor by methodologists. The American Society of Clinical Oncology (ASCO) Endorsement Panel reviewed the content and recommendations, offering modifications and/or qualifying statements when deemed necessary. RESULTS The ASCO Endorsement Panel determined that the recommendations from the 2014 ACS Prostate Cancer Survivorship Care Guidelines are clear, thorough, and relevant, despite the limited availability of high-quality evidence to support many of the recommendations. ASCO endorses the ACS Prostate Cancer Survivorship Care Guidelines, with a number of qualifying statements and modifications. RECOMMENDATIONS Assess information needs related to prostate cancer, prostate cancer treatment, adverse effects, and other health concerns and provide or refer survivors to appropriate resources. Measure prostate-specific antigen (PSA) level every 6 to 12 months for the first 5 years and then annually, considering more frequent evaluation in men at high risk for recurrence and in candidates for salvage therapy. Refer survivors with elevated or increasing PSA levels back to their primary treating physician for evaluation and management. Adhere to ACS guidelines for the early detection of cancer. Assess and manage physical and psychosocial effects of prostate cancer and its treatment. Annually assess for the presence of long-term or late effects of prostate cancer and its treatment.

Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single Referral Center.

Johnson and colleagues performed a retrospective analysis of the medical records of 33 melanoma patients who survived more than 2 years after receiving ipilimumab for metastatic disease or as an adjuvant therapy, and report the long-term health outcomes, chronic side effects, and functional status of these patients. Ipilimumab, a novel immune checkpoint inhibitor, is associated with long-term survival in approximately 20% of patients with advanced melanoma and is also being evaluated in the adjuvant setting. With this growing cohort of survivors, long-term health outcomes, chronic toxicities, and functional outcomes among survivors treated with ipilimumab need to be defined. Using retrospective medical record abstraction, we evaluated disease status, chronic immune- and non–immune-related health events, pharmacologic management of symptoms, and functional status in patients with melanoma, with overall survival ≥2 years following ipilimumab treatment at Vanderbilt University. Ninety patients received ipilimumab for metastatic disease or as adjuvant therapy between January 2006 and September 2012, and 33 patients survived ≥2 years, with a median overall survival of 60.1 months. Of these, 24 patients were alive at the last follow-up (73%), with 14 patients free of disease (42%). Gastrointestinal and dermatologic adverse events were frequent but largely transient. By contrast, patients with hypophysitis universally required ongoing corticosteroids, although largely remained asymptomatic with appropriate hormone replacement. Surviving patients generally had excellent performance status (ECOG 0–1 in 23 of 24). Chronic neurologic toxicities caused substantial morbidity and mortality in 2 patients who received whole-brain radiotherapy >5 years before analysis, and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals were identified. In conclusion, ipilimumab was associated with largely excellent functional outcomes among long-term survivors. Chronic endocrine dysfunction and occasional neurologic toxicity (primarily associated with whole-brain radiation) were observed in a small number of patients. Cancer Immunol Res; 3(5); 464–9. ©2015 AACR.

Contemporary prevalence of pretreatment urinary, sexual, hormonal, and bowel dysfunction: Defining the population at risk for harms of prostate cancer treatment

The authors investigated the prevalence of pretreatment urinary, sexual, hormonal, and bowel dysfunction in a contemporary, population‐based prostate cancer cohort. They also explored the associations between baseline function and age, comorbidity, and timing of baseline survey completion with respect to treatment.

Renal cell cancer histological subtype distribution differs by race and sex

To examine racial differences in the distribution of histological subtypes of renal cell carcinoma (RCC) and associations with established RCC risk factors by subtype.

Development of a Standardized Set of Patient-centered Outcomes for Advanced Prostate Cancer: An International Effort for a Unified Approach

BACKGROUND There are no universally monitored outcomes relevant to men with advanced prostate cancer, making it challenging to compare health outcomes between populations. OBJECTIVE We sought to develop a standard set of outcomes relevant to men with advanced prostate cancer to follow during routine clinical care. DESIGN, SETTING, AND PARTICIPANTS The International Consortium for Health Outcomes Measurement assembled a multidisciplinary working group to develop the set. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We used a modified Delphi method to achieve consensus regarding the outcomes, measures, and case mix factors included. RESULTS AND LIMITATIONS The 25 members of the multidisciplinary international working group represented academic and nonacademic centers, registries, and patients. Recognizing the heterogeneity of men with advanced prostate cancer, the group defined the scope as men with all stages of incurable prostate cancer (metastatic and biochemical recurrence ineligible for further curative therapy). We defined outcomes important to all men, such as overall survival, and measures specific to subgroups, such as time to metastasis. Measures gathered from clinical data include measures of disease control. We also identified patient-reported outcome measures (PROMs), such as degree of urinary, bowel, and erectile dysfunction, mood symptoms, and pain control. CONCLUSIONS The international multidisciplinary group identified clinical data and PROMs that serve as a basis for international health outcome comparisons and quality-of-care assessments. The set will be revised annually. PATIENT SUMMARY Our international group has recommended a standardized set of patient-centered outcomes to be followed during routine care for all men with advanced prostate cancer.

Novel strategies for relapsed and refractory acute myeloid leukemia

Purpose of reviewTreatment for relapsed or refractory acute myeloid leukemia remains a major challenge for the leukemia community. Although several approaches have been tested in phase II study designs, few comparative data exist to guide treatment choices. We searched the recent literature in Medline, EMBASE and BIOSIS, and abstracts from the American Society of Hematology and American Society of Clinical Oncology published between 2005 and 2007. We reviewed each report to identify studies that used a phase II or III design and that included a majority of adults with non-M3 acute myeloid leukemia described as ‘relapsed’ or ‘refractory’. Recent findingsSeveral studies utilized novel cytotoxic chemotherapies, immunotherapies, epigenetic agents, and small molecule inhibitors. It is not possible to identify a single regimen or approach as the standard of care in relapsed and refractory acute myeloid leukemia. New and promising approaches are being explored, however. SummaryOutcomes in patients treated for relapsed or refractory acute myeloid leukemia remain inadequate. Striking a balance between the treatment-related mortality associated with salvage therapies, response rates of salvage regimens, and the likelihood of long-term disease-free survival are critical in planning a treatment approach for the individual patient with relapsed or refractory acute myeloid leukemia.