Working Group Recommendations Research Articles

Optimizing Sediment Diversion Operations: Working Group Recommendations for Integrating Complex Ecological and Social Landscape Interactions

Future conditions of coastal Louisiana are highly uncertain due to the dynamic nature of deltas, climate change, tropical storms, and human reliance on natural resources and ecosystem services. Managing a system in which natural and socio-economic components are highly integrated is inherently difficult. Sediment diversions are a unique restoration tool that would reconnect the Mississippi River to its deltaic plain to build and sustain land. Diversions are innately adaptable as operations can be modified over time. An expert working group was formed to explore how various operational strategies may affect the complex interactions of coastal Louisiana’s ecological and social landscape and provide preliminary recommendations for further consideration and research. For example, initial operations should be gradually increased over 5 to 10 years to facilitate the development of a distributary channel network, reduce flood risk potential to communities, limit erosion of adjacent marshes and reduce stress to vegetation and fish and wildlife species. Diversions should operate over winter peaks to capture the highest sediment concentration, reduce vegetation loss while dormant, and reduce detrimental effects to fish and wildlife. Operations during the spring/summer should occur over shorter periods to capture the highest sediment load during the rising limb of the flood peak and minimize impacts to the ecosystem. Operational strategies should strive to build and sustain as much of the coastal landscape as possible while also balancing the ecosystem and community needs.

NCI Breast Cancer Steering Committee Working Group (WG) report on meaningful and appropriate endpoints for clinical trials (CT) in metastatic breast cancer (MBC).

1073 Background: There is significant heterogeneity in the natural history of MBC. Several recent randomized CT have yielded statistically significant advantages for the experimental arm, but neither led to regulatory approval nor practice change. Formal guidance for industry on CT endpoints provided by the US FDA in 2007 was not disease-specific. Patient-focused drug development is mandated by Prescription Drug User Fee Act V. Our WG sought to create specific consensus on endpoints for MBC CT focusing on subtype and line of therapy, with sensitivity to various stakeholders. Methods: A WG composed of medical oncologists, statisticians, advocates, FDA and NCI liaisons performed a systematic literature review of MBC natural history, CT endpoints by subtype (HR+/HER2-, HR+/HER+, HR-/HER2-, HR-/HER2+), and line of therapy (n = 146 papers). External expertise was obtained on industry perspectives, big data and real world evidence (RWE), and patient reported outcomes (PROs). WG members voted anonymously on statements and positions generated from deliberation. Results: The WG reached consensus on definitions relevant to contemporary CT endpoints. WG recommendations on the appropriate choice of OS or PFS are sensitive to expected post progression survival (PPS), and proportional and absolute gains. Currently, for HR-/HER2- MBC, OS is preferred as the optimal primary endpoint regardless of line of therapy; PFS is preferred in settings where expected PPS is longer. Toxicity can outweigh modest gains in PFS; scant data exist to gauge how patients value PFS gain vs toxicity. Where new agents may prolong PFS without impacting OS, exploring/validating graphic approaches that capture grade and timing of toxicity and PROs is warranted. An overview of WG Consensus Statements will be presented in detail. Conclusions: CT design for MBC should be sensitive to natural history (PPS), availability of other effective agents, PROs and toxicity burden. As unique subtypes (e.g. AR+) and novel therapies (e.g. immunotherapy) emerge, reassessment of relevant benchmarks is indicated. Rigorous big data approaches providing insights from RWE may inform CT endpoints in the future.

The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II)

To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific castration-resistant prostate cancer (CRPC) treatments. The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for metastatic CRPC based on available data and clinical experience. A consensus was developed to address important questions on management of patients with metastatic CRPC. In the absence of large-scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.

The Vitiligo Working Group recommendations for narrowband ultraviolet B light phototherapy treatment of vitiligo

Treatment of vitiligo with narrowband ultraviolet B light (NBUVB) is an important component of the current standard of care. However, there are no consistent guidelines regarding the dosing and administration of NBUVB in vitiligo, reflected by varied treatment practices around the world. To create phototherapy recommendations to facilitate clinical management and identify areas requiring future research. The Vitiligo Working Group (VWG) Phototherapy Committee addressed 19 questions regarding the administration of phototherapy over 3 conference calls. Members of the Photomedicine Society and a group of phototherapy experts were surveyed regarding their phototherapy practices. Based on comparison and analysis of survey results, expert opinion, and discussion held during conference calls, expert recommendations for the administration of NBUVB phototherapy in vitiligo were created. There were several areas that required further research before final recommendations could be made. In addition, no standardized methodology was used during literature review and to assess the strength of evidence during the development of these recommendations. This set of expert recommendations by the VWG is based on the prescribing practices of phototherapy experts from around the world to create a unified, broadly applicable set of recommendations on the use of NBUVB in vitiligo.

Abstract P4-12-15: Triple-negative breast cancers (TNBCs) rich in infiltrating stromal plasma cells have improved disease-free survival and overall survival

Abstract Background Tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic indicator in patients with TNBC. Furthermore, lymphocyte-predominant breast cancer (LPBC), defined as those containing ≥50% stromal TILs has been shown to be associated with better prognosis. While cell-mediated immunity has received much of the credit for anti-tumor responses, the International TILs Working Group recommends that the assessment of stromal density of TILs should incorporate all mononuclear cells including plasma cells. Very little is known about the role of humoral immunity, particularly the role of plasma cells in the anti-tumoral response in breast cancer. We sought to evaluate the prognostic value of plasma cells in the setting of stromal TIL assessment of TNBC. Design Morphologic assessment of TILs was performed on a representative H&E slide of 76 cases of primary TNBC. For each case, the stromal density of TILs was estimated and then classified as LPBC or non-LPBC using a cutoff of ≥50% for the former. Also, the plasma cell intensity defined as the mean percentage of stromal plasma cells of five 40x high power microscopic fields of TILs was recorded at 5% increments. Statistical analyses were performed using disease-free survival (DFS) and overall survival (OS) (range: 16 to 196 months, mean: 110 months) as primary endpoints. Results Plasma cell intensity was dichotomized at 12.5% and predictive of OS [.21, 95% confidence interval (CI) .05-.93, P = 0.0401)]. A positive dose related response trended toward significance for each 5% increase in plasma cell intensity (.97, 95% CI .93-1.01, P = 0.1168). Disease-free survival also trended positively towards significance (.39, 95% CI .13-1.20, P = 0.0991). When comparing LPBC, tumors rich in plasma cells (>12.5% of TILs) trended towards longer DFS (.17, 95% CI .02-1.62, P = 0.1226) when compared to plasma cell poor LPBC. Conclusion In addition to the cell-mediated immune response in TNBC, our findings suggest that humoral immunity may also play a role in predicting recurrence and survival in these patients. Our findings suggest that inclusion of an additional parameter of plasma cell intensity may be prognostically valuable in TIL assessment of TNBC. Citation Format: McIntire PJ, Cui X, Ginter PS, Irshaid L, Chen Z, Shin SJ. Triple-negative breast cancers (TNBCs) rich in infiltrating stromal plasma cells have improved disease-free survival and overall survival [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-15.

PA01.02 The Route to Diagnosis: Impacting Survival by Changing the System

PA01.02 The Route to Diagnosis: Impacting Survival by Changing the System

PC01.02 Invasive Staging and Restaging

PC01.02 Invasive Staging and Restaging

The 2017 International Joint Working Group recommendations of the Indian College of Cardiology, the Academic College of Emergency Experts, and INDUSEM on the management of low-risk chest pain in emergency departments across India.

There have been no published recommendations for the management of low-risk chest pain in emergency departments (EDs) across India. This is despite the fact that chest pain continues to be one of the most common presenting complaints in EDs. Risk stratification of patients utilizing an accelerated diagnostic protocol has been shown to decrease hospitalizations by approximately 40% with a low 30-day risk of major adverse cardiac events. The experts group of academic leaders from the Indian College of Cardiology and Academic College of Emergency Experts in India partnered with academic experts in emergency medicine and cardiology from leading institutions in the UK and USA collaborated to study the scientific evidence and make recommendations to guide emergency physicians working in EDs across India.

Effective Treatment of Severe Chronic Graft Versus Host Disease with a Combination of B-Cell Depletion and Tyrosine Kinase Inhibition

IntroductionChronic Graft Versus Host Disease (cGVHD) has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therapeutic approaches for cGVHD are limited. Affected patients require long-term use of immunosuppressive drugs, mainly corticosteroids combined with a calcineurin inhibitor, which lead to severe side effects. Options for second line therapy are numerous but no consensus on the most favourable choice of agents has been reached. Both monotherapy with rituximab (Cutler, Miklos et al. 2006, Kharfan-Dabaja, Mhaskar et al. 2009, van Dorp, Resemann et al. 2011) and monotherapy with tyrosine kinase inhibition (Magro, Mohty et al. 2009, Olivieri, Locatelli et al. 2009) have shown to be effective in reducing cGVHD symptoms.Materials and MethodsWe performed a prospective study to test whether the sequential therapy of the anti-CD20 antibody rituximab followed by a 6 month treatment period with nilotinib, a tyrosine kinase inhibitor, is a favorable treatment strategy for patients with sclerotic cGVHD (EudraCT nr 2008-004125-42). All patients were evaluated monthly according to NIH cGVHD consensus response criteria working group recommendations from 2005. Serial blood sampling was performed every other month.ResultsWe included 29 patients, 5 patients went offstudy (1 with side effects rituximab, 2 with gastro-intestinal side effects nilotinib, 1 patient had progression of M. Hodgkin, 1 patient due to viral encephalitis with cognitive impairment), 24 are available for analysis. Baseline characteristics are depicted in table 1. We observed a response in 71% (2 patients CR, 15 patients PR). Only 1 patient showed progressive disease (PD) and the remaining 6 patients showed stable disease (SD). Moreover, 2 out of 5 patients who suffered from severe ulcerations at the start of the study had a complete resolution of ulcers at the end of the treatment period. Responding patients show a significant decrease in cGVHD affected body surface area (Figure 1) mostly explained by a significant reduction in nonmoveable sclerosis. Patients with a (partial) response also show a clinically relevant decrease in self attributed severity of cGVHD. On a scale of 10 points their self-attributed cGVHD severity decreased in the PD+SD group with a mean of 0,3 points whilst in the PR+CR group there was a mean decrease of 2,4 points. Fifty percent of responding patients could taper >50% of their daily prednisolone dose at the end of the study period. Other immunosuppressive drugs (ciclosporin, MMF) could also be tapered. Rituximab was well tolerated except for 1 patient who showed a neurological syndrome resembling Guillain Barre after 2 infusions and therefor went offstudy. Nilotinib was dosed 300mg b.i.d. however only 9 patients tolerated this dose without side effects. For the remaining patients the dose was decreased to 200mg b.i.d. which was well tolerated for the majority. Most encountered side effects included fatigue, nausea, pain in extremities and prolonged QT-interval on standard ECG monitoring.ConclusionsThe combination of B-cell depletion and tyrosine kinase inhibition provides a new and interesting alternative treatment option for this difficult and heavily pretreated patient category. Approximately 70% of patients achieve a (partial) response with a decrease of sclerosis, an improved quality of life and a significant reduction in the use of corticosteroids. Two patients reached a complete resolution of all cGVHD related symptoms which is seldom achieved. How to prospectively designate which patients will benefit from this treatment strategy is currently under investigation. [Display omitted] [Display omitted] DisclosuresKuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees.

The political constitution: from Westminster to Waitangi

Drawing on the work of Matike Mai Aotearoa: The Independent Iwi Working Group on Constitutional Transformation (the Working Group), this article argues that there is an evolving New Zealand constitutionalism, one that offers a constitutional understanding grounded in the Māori constitutional system. The article opens with a descriptive analysis of the Māori constitutional system, explains the key features of New Zealand’s existing constitution and concludes with an argument that the existing constitution can evolve – and, through the political process, ought to evolve – according to the constitutional models that the Working Group recommends. This article deploys legal research methods, primarily doctrinal research and applied doctrinal research.1

A Prospective Study of Comparing Multi-Gene Biomarker Chip and Serum Carcinoembryonic Antigen in the Postoperative Surveillance for Patients with Stage I-III Colorectal Cancer.

BackgroundCirculating biomarkers can predict clinical outcomes in colorectal cancer patients. The aim of the study was to evaluate the feasibility of our multigene biomarker chip for detecting circulating tumor cells for postoperative surveillance of stage I–III colorectal cancer patients.Materials and MethodsIn total, 298 stage I–III colorectal cancer patients were analyzed after curative resection between June 2010 and October 2014. During each follow-up, a postoperative surveillance strategy, including ESMO Guidelines Working Group recommendations and the biochip, was used.ResultsAfter a 28.4-month median follow-up, 48 (16.1%) patients had postoperative relapse. Univariate analysis revealed that the postoperative relapse risk factors were rectal tumor, perineural invasion, elevated preoperative and postoperative serum carcinoembryonic antigen levels, and positive biochip results (all P < 0.05). Multivariate analyses revealed that postoperative relapse correlated significantly with elevated postoperative serum carcinoembryonic antigen levels (odds ratio = 4.136, P = 0.008) and positive biochip results (odds ratio = 66.878, P < 0.001). However, the sensitivity (P = 0.003), specificity (P = 0.003), positive (P = 0.002) and negative (P = 0.006) predictive values, and accuracy (P < 0.001) of the biochip for predicting postoperative relapse were significantly higher than those of elevated postoperative serum carcinoembryonic antigen levels. Moreover, the median lead time between positive biochip result and postoperative relapse detection was significantly earlier than that between elevated postoperative serum carcinoembryonic antigen level and postoperative relapse detection (10.7 vs. 2.8 months, P < 0.001). Furthermore, positive biochip results correlated strongly with lower disease-free survival and overall survival of colorectal cancer patients (both P < 0.001).ConclusionCompared with conventional serum carcinoembryonic antigen detection, our multigene chip aided more accurate and earlier prediction of postoperative relapse during stage I–III colorectal cancer patient surveillance. In clinical practice, this biochip may facilitate early postoperative relapse diagnosis in colorectal cancer patients.

Benefits of new immunoglobulin-derived biomarkers for the diagnosis and follow-up of patients with dysglobulinemia.

The diagnostics and follow-up of monoclonal gammopathies such as multiple myeloma require precise analysis of the monoclonal component as well as the other immunoglobulins isotypes, which might be limited by the sensitivity of standard laboratory methods. New serum biomarkers were developed for routine practice in the last decades, such as the free light chain assays and more recently the heavy/light chain assay<strike>s</strike>. Studies have shown that serum free light chain measurement was useful in the identification and follow-up of pauci or nonsecretory myeloma, free light-chain multiple myeloma and AL amyloidosis. It is also an important prognostic marker for monoclonal gammopathy of undetermined significance and AL amyloidosis progression. Hevylite method enables quantitative analysis of heavy/light chain pairs of IgG, IgA and IgM immunoglobulins. This technique has a promising potential to enrich the standard analytic tools as it enables to assess the concentration and ratio of the levels of both tumor and physiological immunoglobulins (heavy/light chain pair suppression), which is not possible with serum protein electrophoresis or global quantitative analysis of immunoglobulin isotypes. This review includes the latest International myeloma working group recommendations and key data presented at the Euromedlab convention in June 2015 Paris regarding serum free light chain and heavy/light chain assays in the biological monitoring of dysglobulinemia.

St Gallen 2015 subtyping of luminal breast cancers: impact of different Ki67-based proliferation assessment methods.

Ki67 has been proposed as prognostic proliferation marker in luminal breast cancer (BC), but little is known on the influence of Ki67 assessment methods on subtyping into luminal A- and B-like tumors. Our aim was to study the influence of different Ki67-labeling index (Ki67-LI) assessment methods on the proportion of BCs classified as luminal A-like. 280 early BCs were subtyped according to the St Gallen 2015 definitions into 71% luminal (HER2 negative), 6% luminal B-like (HER2 positive), 13% triple negative, 1% HER2 positive (nonluminal), and 9% special type. Digitized whole slides were counted manually on the screen. We used nine defined counting methods to assess the Ki67-LI (including the International Ki67 in Breast Cancer Working Group recommendations), and compared the resulting medians and the proportions of cancers classified as luminal A-like according to the formerly used cut-off <20%. Methods assessing hot spots and tumor periphery resulted in significantly higher Ki67-LI medians than those measuring an average proliferation (27.45% vs 16.96%, p <0.0001). Substantially lower median Ki67-LI were found when assessing 1020 compared to counting 100, 200, 300 cells (17.65 vs 33%, vs 28%, vs 24.33%, respectively; p<0.0001), or 510 cells (20.59%, p=0.019). Applying a standard Ki67-LI cut-off <20% to define low proliferation for all methods, the proportion of luminal A-like cancers varied between 13 and 44%. The proportion of BCs classified as luminal A-like is highly influenced by the Ki67-LI assessment method. As a consequence, the selection of a specific Ki67-LI assessment method may have a direct effect on the proportion of patients considered having low-risk disease and thus influence therapeutic decision making. This calls for a standardized assessment method.

The CanPain SCI Clinical Practice Guideline for Rehabilitation Management of Neuropathic Pain after Spinal Cord: recommendations for model systems of care.

Clinical practice guidelines. The project objectives were to develop the first Canadian recommendations on a model of care for the management of at- and below-level neuropathic pain in people with spinal cord injury (SCI). The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. On the basis of a review of the Accreditation Canada standards, the Steering Committee developed questions to guide the CanPainSCI Working Group when developing the recommendations. The Working Group agreed on recommendations through a consensus process. The Working Group developed five recommendations for the organization of neuropathic pain rehabilitation care in people with SCI. The Working Group recommendations for a model of care for at- and below-level neuropathic pain after SCI should be used to inform clinical practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: introduction, methodology and recommendation overview.

Clinical practice guidelines. The objective was to develop the first Canadian clinical practice guidelines for the management of neuropathic pain in people with spinal cord injury (SCI). The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. The guidelines were developed in accordance with the Appraisal of Guidelines for Research and Evaluation II tool. A Steering Committee and Working Group reviewed the relevant evidence on neuropathic pain management (encompassing screening and diagnosis, treatment and models of care) after SCI. The quality of evidence was scored using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A consensus process was followed to achieve agreement on recommendations and clinical considerations. The Working Group developed 12 recommendations for screening and diagnosis, 12 recommendations for treatment and 5 recommendations for models of care. Important clinical considerations accompany each recommendation. The Working Group recommendations for the management of neuropathic pain after SCI should be used to inform practice.

Patient-reported outcome measures in arthroplasty registries

— The International Society of Arthroplasty Registries (ISAR) Patient-Reported Outcome Measures (PROMs) Working Group have evaluated and recommended best practices in the selection, administration, and interpretation of PROMs for hip and knee arthroplasty registries. The 2 generic PROMs in common use are the Short Form health surveys (SF-36 or SF-12) and EuroQol 5-dimension (EQ-5D). The Working Group recommends that registries should choose specific PROMs that have been appropriately developed with good measurement properties for arthroplasty patients. The Working Group recommend the use of a 1-item pain question (“During the past 4 weeks, how would you describe the pain you usually have in your [right/left] [hip/knee]?”; response: none, very mild, mild, moderate, or severe) and a single-item satisfaction outcome (“How satisfied are you with your [right/left] [hip/knee] replacement?”; response: very unsatisfied, dissatisfied, neutral, satisfied, or very satisfied). Survey logistics include patient instructions, paper- and electronic-based data collection, reminders for follow-up, centralized as opposed to hospital-based follow-up, sample size, patient- or joint-specific evaluation, collection intervals, frequency of response, missing values, and factors in establishing a PROMs registry program. The Working Group recommends including age, sex, diagnosis at joint, general health status preoperatively, and joint pain and function score in case-mix adjustment models. Interpretation and statistical analysis should consider the absolute level of pain, function, and general health status as well as improvement, missing data, approaches to analysis and case-mix adjustment, minimal clinically important difference, and minimal detectable change. The Working Group recommends data collection immediately before and 1 year after surgery, a threshold of 60% for acceptable frequency of response, documentation of non-responders, and documentation of incomplete or missing data.

ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis

Malnutrition is both a frequent feature and a comorbidity of cystic fibrosis (CF), with nutritional status strongly associated with pulmonary function and survival. Nutritional management is therefore standard of care in CF patients. ESPEN, ESPGHAN and ECFS recommended guidelines to cover nutritional management of patients with CF. The guidelines were developed by an international multidisciplinary working group in accordance with officially accepted standards. The GRADE system was used for determining grades of evidence and strength of recommendation. Statements were discussed, submitted to Delphi rounds, reviewed by ESPGHAN and ECFS and accepted in an online survey among ESPEN members. The Working Group recommends that initiation of nutritional management should begin as early as possible after diagnosis, with subsequent regular follow up and patient/family education. Exclusive breast feeding is recommended but if not possible a regular formula is to be used. Energy intake should be adapted to achieve normal weight and height for age. When indicated, pancreatic enzyme and fat soluble vitamin treatment should be introduced early and monitored regularly. Pancreatic sufficient patients should have an annual assessment including fecal pancreatic elastase measurement. Sodium supplementation is recommended and a urinary sodium:creatinine ratio should be measured, corresponding to the fractional excretion of sodium. If iron deficiency is suspected, the underlying inflammation should be addressed. Glucose tolerance testing should be introduced at 10 years of age. Bone mineral density examination should be performed from age 8-10 years. Oral nutritional supplements followed by polymeric enteral tube feeding are recommended when growth or nutritional status is impaired. Zinc supplementation may be considered according to the clinical situation. Further studies are required before essential fatty acids, anti-osteoporotic agents, growth hormone, appetite stimulants and probiotics can be recommended. Nutritional care and support should be an integral part of management of CF. Obtaining a normal growth pattern in children and maintaining an adequate nutritional status in adults are major goals of multidisciplinary cystic fibrosis centers.

International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment.

The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma-related renal impairment (RI). Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m(2) to 140 mg/m(2)) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).

Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children.

This article provides recommendations, developed by the Working Group (WG) on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, for the use of probiotics for the prevention of antibiotic-associated diarrhea (AAD) in children based on a systematic review of previously completed systematic reviews and of randomized controlled trials published subsequently to these reviews. The use of probiotics for the treatment of AAD is not covered. The recommendations were formulated only if at least 2 randomized controlled trials that used a given probiotic (with strain specification) were available. The quality of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation guidelines. If the use of probiotics for preventing AAD is considered because of the existence of risk factors such as class of antibiotic(s), duration of antibiotic treatment, age, need for hospitalization, comorbidities, or previous episodes of AAD diarrhea, the WG recommends using Lactobacillus rhamnosus GG (moderate QoE, strong recommendation) or Saccharomyces boulardii (moderate QoE, strong recommendation). If the use of probiotics for preventing Clostridium difficile-associated diarrhea is considered, the WG suggests using S boulardii (low QoE, conditional recommendation). Other strains or combinations of strains have been tested, but sufficient evidence is still lacking.

Abstract C88: Genomics, advocacy, and emerging therapeutics to address triple-negative breast cancer (TNBC) outcome disparities.

Abstract Background: Collaborative team science provides a starting point for comprehensive change, and advocates have a unique and important role developing and engaging in transdisciplinary collaboratives that focus on new questions and new possibilities to advance the science of ethnic and medically underserved health care disparities. Participating in four areas : 1) research and programmatic support, 2) education and outreach, 3) policy and strategy, and 4) representation and advisory, the UCSF Breast Science Advocacy Core (BSAC) Program, a volunteer affiliate of the Breast Oncology Program (BOP), one of ten multidisciplinary research programs under the umbrella of the UCSF Helen Diller Comprehensive Cancer Center promotes a transformative, transdisciplinary, integrated environment to study the biological basis of the diseases that comprise breast cancer; to define the risk of developing or progressing with specific types of breast cancer; to develop novel interventions that work locally and globally to reduce morbidity and mortality from breast cancer and its treatment; and to leverage new collaborative research, education, and mentoring/training opportunities that address cancer outcome disparities. Advocates involved in KOMEN, DOD, PCORI, AND CBCRP funded research and training grants apply four core principles that forge synergy with NCI Advocacy Research Working Group Recommendations: 1)strategic innovation, 2)collaborative execution, 3)evidence based decision-making, and 4) ethical codes of conduct. Embracing transdisciplinary professionalism, researchers and advocates build on their track record as shared value partners committed to furthering the collective impact of science advocacy exchange (SAE). Study Objectives: Genomic analyses of patient tumors have unearthed an overwhelming number of recurrent somatic alterations in genes that have dramatic effects on tumor biology, patient drug responses, and clinical outcomes. In one study, high grade triple negative breast cancer (TNBC) accounts for 34% of breast cancers in African American women versus 21% in white women. A growing body of evidence has shown that African American women have biologically more aggressive disease, independent of social determinants, and suffer the highest mortality rates. While biological breakthroughs of the last decade have greatly advanced our understanding of cancer, in advanced TNBC, a poor prognosis subtype, there is an urgent need to translate this evolving patient genomic data into new therapeutic paradigms. Our study focuses on the intersection of synthetic lethal approaches, MYC driven human cancers, and immunotherapy as an “innovation agenda”. A distinct MYC vision highlights how overexpression is associated with aggressive outcomes and poor patient outcomes, and synthetic lethal strategies to target MYC (CDK inhibitors, PIM2, as well as the PDI immune pathways) have potential for addressing outcome disparities In African American Women with Triple Negative Breast Cancer (TNBC). Key Findings: We have developed a screening technique that can be used to rapidly and accurately identify potential synthetic lethal interactions in TNBC. This platform utilizes an isogenic cell line system that we have developed to model oncogene activation in TNBC. A growing body of evidence has shown that: 1) Quantitative approach maps genotype-specific drug responses in isogenic cells 2) Systematic discovery of biomarkers for cancer drugs under clinical investigation 3) Clinically actionable synthetic lethal interaction between MYC and dasatinib is discovered 4) Mechanism of dasatinib action through inhibition of LYN kinase is described Key Take-Away Message: The inclusion of advocates in convergent science settings remind academic stakeholders that research is there to benefit the patient as they attempt to spark innovation, democratize science, and support smarter interventions that expedite the incredible potential of future investments in bioscience within disparities arenas. Citation Format: Susan Samson, Alicia Y. Zhou, Maria Martins, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John Gordan, Rebecca Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul Clemens, Alykhan Shamji, Stuart Schreiber, Nevan Krogan, Kevan Shokat, Frank McCormick, Sourav Bandyopadhyay, Andrei Goga. Genomics, advocacy, and emerging therapeutics to address triple-negative breast cancer (TNBC) outcome disparities. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C88.