A Systematic Review of Kidney Transplantation Decision Modelling Studies.

BACKGROUND: Genome-based precision medicine strategies promise to minimize premature graft loss after renal transplantation, through precision approaches to immune compatibility matching between kidney donors and recipients. The potential adoption of this technology calls for important changes to clinical management processes and allocation policy. Such potential policy change decisions may be supported by decision models from health economics, comparative effectiveness research and operations management. OBJECTIVE: We used a systematic approach to identify and extract information about models published in the kidney transplantation literature and provide an overview of the status of our collective model-based knowledge about the kidney transplant process. METHODS: Database searches were conducted in MEDLINE, Embase, Web of Science and other sources, for reviews and primary studies. We reviewed all English-language papers that presented a model that could be a tool to support decision making in kidney transplantation. Data were extracted on the clinical context and modelling methods used. RESULTS: A total of 144 studies were included, most of which focused on a single component of the transplantation process, such as immunosuppressive therapy or donor-recipient matching and organ allocation policies. Pre- and post-transplant processes have rarely been modelled together. CONCLUSION: A whole-disease modelling approach is preferred to inform precision medicine policy, given its potential upstream implementation in the treatment pathway. This requires consideration of pre- and post-transplant natural history, risk factors for allograft dysfunction and failure, and other post-transplant outcomes. Our call is for greater collaboration across disciplines and whole-disease modelling approaches to more accurately simulate complex policy decisions about the integration of precision medicine tools in kidney transplantation.

A retrospective analysis of actionable pharmacogenetic/genomic biomarker language in FDA labels.

The primary goal of precision medicine is to maximize the benefit-risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene-drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA-PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug-metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

Patients Desire Personalized, Specific, and Continuous Advice on Weight Management.

OBJECTIVE: To deliver effective care, healthcare systems should understand patients' preferences for weight management across a spectrum of needs. Our objective was to describe patients' perceptions of what helps or hinders weight loss and maintenance. METHODS: Semistructured interviews were conducted with patients who accessed weight management services at a large integrated health system in 2018. The interview guide was developed and iteratively refined through a literature search and by consulting experts. Questions included the respondent's weight history, interactions with the health system, and current health status. The analysis used a grounded theory approach, and each transcript was double-coded in 2019. Codes were sorted into themes. All discrepancies were resolved through team discussion. RESULTS: Fifteen patients were interviewed. The majority of respondents (87%) reported multiple weight loss attempts. Three themes were identified. First, advice should be matched to a patient's knowledge and prior experience (eg, using bariatric deck cards). As patients progressed, clinician advice also needed to advance (eg, explaining how to expand food options instead of defining a healthy diet). Second, respondents had a variety of motivating factors, and understanding where motivation is generated from can inform how to design a weight management approach. Third, patients need continual and long-term advice. Some respondents feared becoming ineligible for services if their weight dropped too much. CONCLUSIONS: Health systems can support patients by developing processes for identifying the extent of a patient's knowledge and giving personalized advice based on the patient's preferences and experiences. Reassessing needs at defined intervals may help patients attain and sustain their goals.

Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group 'Molecular Diagnostics and Therapy'.

Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force 'Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality.

Therapeutic management of neuro-oncologic patients - potential relevance of CSF liquid biopsy.

Background: In the era of precision medicine, cancer treatment is increasingly tailored according to tumor-specific genomic alterations. The analysis of tumor-derived circulating nucleic acids in cerebrospinal fluid (CSF) by next generation sequencing (NGS) may facilitate precision medicine in the field of CNS cancer. We therefore evaluated whether NGS from CSF of neuro-oncologic patients reliably detects tumor-specific genomic alterations and whether this may help to guide the management of patients with CNS cancer in clinical practice. Patient and methods: CSF samples from 27 patients with various primary and secondary CNS malignancies were collected and evaluated by NGS using a targeted, amplicon-based NGS-panel (Oncomine Focus Assay). All cases were discussed within the framework of a molecular tumor board at the Comprehensive Cancer Center Munich. Results: NGS was technically successful in 23/27 patients (85%). Genomic alterations were detectable in 20/27 patients (74%), 11/27 (40%) of which were potentially actionable. After discussion in the MTB, a change of therapeutic management was recommended in 7/27 (26%) of the cases. However, due to rapid clinical progression, only 4/27 (15%) of the patients were treated according to the recommendation. In a subset of patients (6/27, 22%), a high number of mutations of unknown significance suggestive of a high tumor mutational burden (TMB) were detected. Conclusions: NGS from cerebrospinal fluid is feasible in routine clinical practice and yields therapeutically relevant alterations in a large subset of patients. Integration of this approach into a precision cancer medicine program might help to improve therapeutic options for patients with CNS cancer.

Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing.

BACKGROUND: Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. METHODS: NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients' medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. RESULTS: Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). CONCLUSIONS: We found an appropriate "dose-response" relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.

Impact of Genomic Assay Testing and Clinical Factors on Chemotherapy Use After Implementation of Standardized Testing Criteria.

BACKGROUND: For clinically appropriate early-stage breast cancer patients, reflex criteria for Oncotype DX ordering ("the intervention") were implemented at our comprehensive cancer center, which reduced time-to-adjuvant chemotherapy initiation. Our objective was to evaluate Oncotype DX ordering practices and chemotherapy use before and after implementation of the intervention. MATERIALS AND METHODS: We examined medical records for 498 patients who had definitive breast cancer surgery at our center. The post-intervention cohort consisted of 232 consecutive patients who had Oncotype DX testing after reflex criteria implementation. This group was compared to a retrospective cohort of 266 patients who were diagnosed and treated prior to reflex criteria implementation, including patients who did and did not have Oncotype DX ordered. Factors associated with Oncotype DX ordering pre- and post-intervention were examined. We used multivariate logistic regression to evaluate factors associated with chemotherapy receipt among patients with Oncotype DX testing. RESULTS: The distribution of Oncotype DX scores, the proportion of those having Oncotype DX testing (28.9% vs. 34.1%) and those receiving chemotherapy (14.3% vs. 19.4%), did not significantly change between pre- and post-intervention groups. Age ≤65 years, stage II, grade 2, 1-3+ nodes, and tumor size >2 cm were associated with higher odds of Oncotype DX testing. Among patients having Oncotype DX testing, node status and Oncotype DX scores were significantly associated with chemotherapy receipt. CONCLUSION: Our criteria for reflex Oncotype DX ordering appropriately targeted patients for whom Oncotype DX would typically be ordered by providers. No significant change in the rate of Oncotype DX ordering or chemotherapy use was observed after reflex testing implementation. IMPLICATIONS FOR PRACTICE: This study demonstrates that implementing multidisciplinary consensus reflex criteria for Oncotype DX ordering maintains a stable Oncotype DX ordering rate and chemotherapy rate, mirroring what was observed in a specific clinical practice, while decreasing treatment delays due to additional testing. These reflex criteria appropriately capture patients who would likely have had Oncotype DX ordered by their providers and for whom the test results are predicted to influence management. This intervention serves as a potential model for other large integrated, multidisciplinary oncology centers to institute processes targeting patient populations most likely to benefit from genomic assay testing, while mitigating treatment delays.

Common themes and challenges in hemophilia care: a multinational perspective.

OBJECTIVE: To identify ways that provision of hemophilia care can be maximized at the local level, irrespective of available resources or cultural or geographic challenges. METHODS: The SHIELD group used its multinational experience to share examples of local initiatives that have been employed to deliver optimal hemophilia care. RESULTS: The examples were reviewed and categorized into four key themes: guidelines and algorithms for delivery of care; collaboration with patients and allied groups for care and education; registries for the monitoring of treatment and outcomes and health care planning and delivery; and opportunities for personalization of care. These themes were then incorporated into a road map for collaborative care in hemophilia that reflected the contribution of best practice. DISCUSSION: Differing healthcare reimbursement systems, budgetary constraints, and geographical and cultural factors make it difficult for any country to fully deliver ideal care for people with hemophilia. The SHIELD approach for collaborative care provides illustrative examples of how four key themes can be used to optimize hemophilia care in any setting. ABBREVIATIONS: AHCDC: Association of Hemophilia Clinic Directors of Canada; AICE: Italian Association of Hemophilia Centres; ATHN: American Thrombosis and Hemostasis Network; EAHAD: European Association for Haemophilia and Allied Disorders; EHC: European Hemophilia Consortium; FIX: Coagulation Factor IX; FVIII: Coagulation Factor VIII; HAL: Haemophilia Activity List; HJHS: Haemophilia Joint Health Score; HTC: Hemophilia Treatment Centre; HTCCNC: Hemophilia Treatment Centre Collaborative Network of China; MASAC: Medical and Scientific Advisory Council; MDT: Multidisciplinary team; NHD: National Haemophilia Database; NHF: National Hemophilia Foundation; PK: Pharmacokinetics; POCUS: Point of care ultrasound; PWH: People with haemophilia; SHIELD: Supporting Hemophilia through International Education, Learning and Development; WFH: World Federation of Hemophilia.

How Can Law Support Development of Genomics and Precision Medicine to Advance Health Equity and Reduce Disparities?

There is growing recognition that the genomic and precision medicine revolution in health care can deepen health disparities. This has produced urgent calls to prioritize inclusion of historically underrepresented populations in research and to make genomic databases more inclusive. Answering the call to address health care disparities in the delivery of genomic and precision medicine requires a consideration of important, yet understudied, legal issues that have blocked progress. This article introduces a special issue of Ethnicity & Disease which contains a series of articles that grew out of a public conference to investigate these legal issues and propose solutions. This 2018 conference at Meharry Medical College was part of an NIH-funded project on "LawSeqSM" to evaluate and improve the law of genomics in order to support appropriate integration of genomics into clinical care. This conference was composed of presentations and interactive sessions designed to specify the top legal barriers to health equity in precision medicine and stimulate potential solutions. This article synthesizes the results of those discussions. Multiple legal barriers limit broad inclusion in genomic research and the development of precision medicine to advance health equity. Problems include inadequate privacy and anti-discrimination protections for research participants, lack of health coverage and funding for follow-up care, failure to use law to ensure access to genomic medicine, and practices by research sponsors that tolerate and entrench disparities. Analysis of the legal barriers to health equity in precision medicine is essential for progress. Progressive use of law is vital to avoid worsening of health care disparities.

Position of the Academy of Nutrition and Dietetics: Individualized Nutrition Approaches for Older Adults: Long-Term Care, Post-Acute Care, and Other Settings.

It is the position of the Academy of Nutrition and Dietetics that the quality of life and nutritional status of older adults in long-term care, post-acute care, and other settings can be enhanced by individualized nutrition approaches. The Academy advocates that as part of the interprofessional team, registered dietitian nutritionists assess, evaluate, and recommend appropriate nutrition interventions according to each individual's medical condition, desires, and rights to make health care choices. Nutrition and dietetic technicians, registered assist registered dietitian nutritionists in the implementation of individualized nutrition care, including the use of least restrictive diets. Health care practitioners must assess risks vs benefits of therapeutic diets, especially for frail older adults. Food is an essential component of quality of life; an unpalatable or unacceptable diet can lead to poor food and fluid intake, resulting in malnutrition and related negative health effects. Including older individuals in decisions about food can increase the desire to eat and improve quality of life.

Utilizing biomarkers in colorectal cancer: an interview with Ajay Goel.

Ajay Goel speaks to Rachel Jenkins, Commissioning Editor. Ajay Goel, PhD, is a Professor and Director, Center for Gastrointestinal Research, and Director, Center for Translational Genomics and Oncology, at the Baylor Scott & White Research Institute, Baylor University Medical Center in Dallas, Texas. Dr Goel has spent more than 20 years researching cancer and has been the lead author or contributor to over 240 scientific articles published in peer-reviewed international journals and several book chapters. He is also a primary inventor on more than 15 international patents aimed at developing various biomarkers for the diagnosis, prognosis and prediction of gastrointestinal cancers. He is currently using advanced genomic and transcriptomic approaches to develop novel DNA- and miRNA-based biomarkers for the early detection of colorectal cancers. In addition, he is researching the prevention of gastrointestinal cancers using integrative and alternative approaches, including botanical products such as curcumin (from turmeric) and boswellia. Dr Goel is a member of the American Association for Cancer Research (AACR) and the American Gastroenterology Association (AGA) and is on the international editorial boards of several journals including Gastroenterology, Clinical Cancer Research, Carcinogenesis, PLoS ONE, Scientific Reports, Epigenomics, Future Medicine, Alternative Therapies in Heath and Medicine and World Journal of Gastroenterology. He is also actively involved in peer-reviewing activities for more than 100 international scientific journals and various grant review panels of various national and international funding organizations. His research has been actively funded by various private and federal organizations, including funding from the National Cancer Institute (NCI) at the NIH, American Cancer Society (ACS) and other state organizations. He has won more than dozen awards and honors, including the Union of European Gastroenterology Federation's Distinguished Researcher Award, multiple Poster of Distinction Awards from the AGA, and Visiting Professorships from various national and international academic institutions and academic bodies. Some of his key research interests include: Understanding the basic genetics and epigenetic basis of gastrointestinal cancers; Use of epigenetic markers, both DNA and RNA, for the early detection of colorectal, pancreatic and other gastrointestinal cancers; Personalized medicine and treatment of gastrointestinal cancers; Chemoprevention, using complementary and alternative approaches using nutraceuticals such as curcumin, green tea, resveratrol and other botanicals.

Interventional radiology in breast cancer.

Molecular profiling of metastatic disease may greatly influence the systemic therapy recommended by oncologists and chosen by patients, allowing treatment to be more targeted. Comprehensive care of patients with advanced breast cancer now includes percutaneous image-guided biopsy if this has the potential to influence systemic treatment [1]. Interventional radiologists can contribute significantly to the care of patients affected by breast cancer, in diagnostic and supportive procedures and importantly also in treatment. Interventional radiologists carry out image guided percutaneous biopsies not only of the primary tumour but also of metastases. They insert percutaneous ports and tunnelled central venous catheters. They ablate painful bone metastases, and can treat or prevent pathological fractures. Most importantly they can ablate liver metastases in patients with limited or oligometastatic disease. The inhomogeneity and variety of cell populations in metastatic tumours from breast cancer, which is an important consideration in systemic therapy, is not an important consideration in the treatment of metastatic tumours using percutaneous ablative techniques, which are the major focus of this article. The treatment of primary tumours in the breast is also being explored, but is considered in its infancy at this stage.

Towards an optimal therapy strategy for myogenous TMD, physiotherapy compared with occlusal splint therapy in an RCT with therapy-and-patient-specific treatment durations.

BACKGROUND: Temporomandibular Disorders (TMD) may be characterized by pain and restricted jaw movements. In the absence of somatic factors in the temporomandibular joint, mainly myogenous, psychobiological, and psychosocial factors may be involved in the aetiology of myogenous TMD. An occlusal appliance (splint) is commonly used as a basic therapy of the dental practice. Alternatively, a type of physiotherapy which includes, apart from massage of sore muscles, aspects of cognitive-behavioural therapy might be a basic therapy for myogenous TMD. Treatment outcome of physiotherapy (Ph-Tx) was evaluated in comparison to that of splint therapy (Sp-Tx), using the index Treatment Duration Control (TDC) that enabled a randomized controlled trial with, comparable to clinical care, therapy-and-patient-specific treatment durations. METHODS: Seventy-two patients were randomly assigned to either Ph-Tx or Sp-Tx, with an intended treatment duration between 10 and 21 or 12 and 30 weeks respectively. Using TDC, the clinician controlled treatment duration and the number of visits needed. A blinded assessor recorded anamnestic and clinical data to determine TDC-values following treatment and a 1-year follow-up, yielding success rate (SR) and effectiveness (mean TDC) as treatment outcomes. Cohen's d, was determined for pain intensity. Overall SR for stepped-care was assessed in a theoretical model, i.e. a second of the two studied therapies was applied if the first treatment was unsuccessful, and the effect of therapy sequence and difference in success rates was examined. RESULTS: SR and effectiveness were similar for Ph-Tx and Sp-Tx (long-term SR: 51-60%; TDC: -0.512- -0.575). Cohen's d was 0.86 (Ph-Tx) and 1.39 (Sp-Tx). Treatment duration was shorter for Ph-Tx (on average 10.4 weeks less; p < 0.001). Sp-Tx needed 7.1 less visits (p < 0.001). CONCLUSIONS: Physiotherapy may be preferred as initial therapy over occlusal splint therapy in stepped-care of myogenous TMD. With a similar SR and effectiveness, physiotherapy has a shorter duration. Thus patients whose initial physiotherapy is unsuccessful can continue earlier with subsequent treatment. The stepped-care model reinforces the conclusion on therapy preference as the overall SR hardly depends on therapy sequence. TRIAL REGISTRATION: isrctn.com/ISRCTN17469828 . Retrospectively registered: 11/11/2016.

Clinical Considerations for Use of Initial Combination Therapy in Type 2 Diabetes.

Type 2 diabetes is a progressive disorder characterized by increasing hyperglycemia and the need to gradually intensify therapy in order to achieve and maintain glycemic control. Early initiation of combination therapy has been proposed as an approach to achieve glycemic goals earlier and delay the deterioration of glycemic control and with possible better preservation of ß-cell function. We discuss in this article the pros and cons of this approach, focusing on individuals with HbA1c at diagnosis of 7.5-9.0%, where difference of opinion still exists on management. Initial combination therapy is proposed to lead to better and faster achievement of glycemic targets versus monotherapy and to impede clinical inertia and may possibly slow the deterioration of ß-cell function. However, treating patients with sequential therapy is proposed to allow one to fully assess the efficacy and risk-to-benefit ratio of each drug as it is added. Furthermore, there is no evidence to support that rapid addition and titration of medications according to the glycemic profile achieved are inferior to initial combination therapy if glycemic targets are attained in a timely manner. Initial combination therapy is argued to postpone clinical inertia to the next decision point but does not eliminate it. Additionally, it may have been the agents chosen and not the timing of their initiation that led to improved ß-cell function in the studies of initial combination therapy, and there are no data currently comparing use of the same drugs initiated simultaneously or sequentially. Heightened awareness of providers, individualization of therapy and setting, and reaching glycemic targets remain the mainstays of care.

Endorsing good quality assurance practices in molecular pathology: risks and recommendations for diagnostic laboratories and external quality assessment providers.

Quality assurance is an indispensable element in a molecular diagnostic laboratory. The ultimate goal is to warrant patient safety. Several risks that can compromise high quality procedures are at stake, from sample collection to the test performed by the laboratory, the reporting of test results to clinicians, and the organization of effective external quality assessment schemes. Quality assurance should therefore be safeguarded at each level and should imply a holistic multidisciplinary approach. This review aims to provide an overview of good quality assurance practices and discusses certain risks and recommendations to promote and improve quality assurance for both diagnostic laboratories and for external quality assessment providers. The number of molecular targets is continuously rising, and new technologies are evolving. As this poses challenges for clinical implementation and increases the demand for external quality assessment, the formation of an international association for improving quality assurance in molecular pathology is called for.

[PERSONALIZED MEDICINE: ALL BENEFITS FOR THE PATIENT BUT NEW CHALLENGE IN THE PHYSICIAN-PATIENT RELATIONSHIP]. / MÉDECINE PERSONNALISÉE: tout bénéfice pour le patient, mais nouveau challenge pour la relation médecin-malade.

Personalized medicine should lead to major advances for patient care since it contributes to deliver the <>. In curative medicine, this approach should improve the efficacy of medications by initial selection of "good responders", and should reduce adverse events due to poor tolerance or toxicity by a better pharmacological choice and a more appropriate individualized dose adjustment. Over recent years, considerable technical advances have increasingly linked personalized medicine with predictive and preventive medicine. This progress raises hopes for major advancements in medicine, but may also cause some concern among the lay public. The patient should actively be involved in the decisions related to his/her health, in a true model of participatory medicine. Finally, personalized medicine should leave its strict technical nature and become more interested in the person as a whole, within a holistic approach also integrating psychosocial aspects that are so important in the physician-patient relationship.