The Nitrogen Mustards.

The nitrogen mustards are powerful cytotoxic and lymphoablative agents and have been used for more than 60 years. They are employed in the treatment of cancers, sarcomas, and hematologic malignancies. Cyclophosphamide, the most versatile of the nitrogen mustards, also has a place in stem cell transplantation and the therapy of autoimmune diseases. Adverse effects caused by the nitrogen mustards on the central nervous system, kidney, heart, bladder, and gonads remain important issues. Advances in analytical techniques have facilitated the investigation of the pharmacokinetics of the nitrogen mustards, especially the oxazaphosphorines, which are prodrugs requiring metabolic activation. Enzymes involved in the metabolism of cyclophosphamide and ifosfamide are very polymorphic, but a greater understanding of the pharmacogenomic influences on their activity has not yet translated into a personalized medicine approach. In addition to damaging DNA, the nitrogen mustards can act through other mechanisms, such as antiangiogenesis and immunomodulation. The immunomodulatory properties of cyclophosphamide are an area of current exploration. In particular, cyclophosphamide decreases the number and activity of regulatory T cells, and the interaction between cyclophosphamide and the intestinal microbiome is now recognized as an important factor. New derivatives of the nitrogen mustards continue to be assessed. Oxazaphosphorine analogs have been synthesized in attempts to both improve efficacy and reduce toxicity, with varying degrees of success. Combinations of the nitrogen mustards with monoclonal antibodies and small-molecule targeted agents are being evaluated. SIGNIFICANCE STATEMENT: The nitrogen mustards are important, well-established therapeutic agents that are used to treat a variety of diseases. Their role is continuing to evolve.

Harmonizing the Tripartite Mission in Academic Family Medicine: A Longitudinal Case Example.

Academic practices and departments are defined by a tripartite mission of care, education, and research, conceived as being mutually reinforcing. But in practice, academic faculty have often experienced these 3 missions as competing rather than complementary priorities. This siloed approach has interfered with innovation as a learning health system in which the tripartite missions reinforce each other in practical ways. This paper presents a longitudinal case example of harmonizing academic missions in a large family medicine department so that missions and people interact in mutually beneficial ways to create value for patients, learners, and faculty. We describe specific experiences, implementation, and examples of harmonizing missions as a feasible strategy and culture. "Harmonized" means that no one mission subordinates or drives out the others; each mission informs and strengthens the others (quickly in practice) while faculty experience the triparate mission as a coherent whole faculty job. Because an academic department is a complex system of work and relationships, concepts for leading a complex adaptive system were employed: (1) a "good enough" vision, (2) frequent and productive interactions, and (3) a few simple rules. These helped people harmonize their work without telling them exactly what to do, when, and how. Our goal here is to highlight concrete examples of harmonizing missions as a feasible operating method, suggesting ways it builds a foundation for a learning health system and potentially improving faculty well-being.

Team-based care: an expanded medical assistant role - enhanced rooming and visit assistance.

Primary care practices face significant challenges as they pursue the Quadruple Aim. Redistributing care across the interprofessional primary care team by expanding the role of the medical assistant (MA) is a potential strategy to address these challenges. Two sequential, linked processes to expand the role of the MA, called Enhanced Rooming and Visit Assistance, were implemented in four family medicine residency clinics in Minnesota. In Enhanced Rooming, MAs addressed preventive services, obtained a preliminary visit agenda, and completed a warm hand-off to the provider. In Visit Assistance, MAs stayed in the room the entire visit to assist with the visit workflow. Enhanced Rooming and Visit Assistance processes were successfully implemented and sustained for over one year. MAs and providers were satisfied with both processes, and patients accepted the expanded MA roles. Mammogram ordering rates increased from 10% to 25% (p < 0.0001). After Visit Summary (AVS) print rates increased by 12% (p < 0.0001). Visit Turn-Around-Time (TAT) decreased 3.1 minutes per visit (p = 0.0001). Expanding the MA role in a primary care interprofessional team is feasible and a potentially useful tool to address the Quadruple Aim.

Lean Implementation for Graduating Optimally Controlled Stable Type 2 Diabetics from Endocrine Specialty Clinic Back to Primary Care.

INTRODUCTION: Endocrine specialty clinics (SCs) are occupied by a high percentage of stable follow-up patients, limiting access to new patients with greater needs. AIM: Feasibility project to improve access to diabetes SC by reducing the number of stable optimally controlled follow-up type 2 diabetic patients. SETTING: M Health Fairview (MHFV), a hybrid network of University of Minnesota academic and Fairview Health community hospitals and clinics with affiliated providers. PROGRAM DESCRIPTION: A team-based lean methodology quality improvement graduation program including medical assistants, nurses, physicians, and a compact with primary care (PC) was used to identify within the Endocrine clinic population the graduation-eligible optimally controlled stable type 2 diabetic patients, acclimate them to the graduation concept, engage in shared decision-making, and transition them back to PC with a warm hand-off and graduation certificate. PROGRAM EVALUATION: Seventeen percent (58/341) of eligible patients with optimally controlled diabetes graduated by 6 months, ranging between 0 and 83% per week. DISCUSSION: The innovation and feasibility of opening SC access through the use of a team-based graduation program to transfer stable diabetes patients back to their home clinic was demonstrated. This innovation has the potential to support health system triage of new patients to limited access specialty care.

Shared Language for Shared Work in Population Health.

People working on behalf of population health, community health, or public health often experience confusion or ambiguity in the meaning of these and other common terms-the similarities and differences and how they bear on the tasks and division of labor for care delivery and public health. Shared language must be clear enough to help, not hinder people working together as they ultimately come to mutual understanding of roles, responsibilities, and actions in their joint work. Based on an iterative lexicon development process, the authors developed and propose a definitional framework as an aid to navigating among related population and community health terms. These terms are defined, similarities and differences clarified, and then organized into 3 categories that reflect goals, realities, and ways to get the job done. Goals include (a) health as well-being for persons, (b) population health as that goal expressed in measurable terms for groups, and (c) community health as population health for particular communities of interest, geography, or other defining characteristic-groups with shared identity and particular systemic influences on health. Realities are social determinants as influences, health disparities as effects, and health equity as both a goal and a design principle. Ways to get the job done include health care delivery systems for enrollees and public health in population-based civic activities-with a broad zone of collaboration where streams of effort converge in partnership with served communities. This map of terms can enable people to move forward together in a broad zone of collaboration for health with less confusion, ambiguity, and conflict.

Team-based approach to improving medication reconciliation rates in family medicine residency clinics.

OBJECTIVE: The objective of this quality improvement project was to design and implement a systematic team-based care approach to medication reconciliation, with a goal of physician-documented medication reconciliation at 70% of all patient office visits. SETTING: Ambulatory clinics located in urban, underserved communities in Minneapolis and St. Paul, MN. PRACTICE DESCRIPTION: Four family medicine residency clinics, with pharmacists integrated at each site. All clinics use the Epic electronic medical record (Epic Systems Corporation). PRACTICE INNOVATION: A team-based care approach to medication reconciliation was designed and implemented involving medical assistants (MAs), physicians, and pharmacists. The MAs did an initial review with patients, the physicians addressed discrepancies, and difficult situations were escalated to the pharmacist for a detailed assessment. EVALUATION: The percentage of visits with physician-documented medication reconciliation was measured preintervention and then for 18 months postintervention in 6-month intervals involving more than 118,000 patient visits. Satisfaction surveys of team members were done pre- and postintervention. RESULTS: The percentage of visits with physician-documented medication reconciliation improved significantly from 6.5% preintervention to 58.7% (P < 0.001) postintervention, and was sustained and further improved to 70.3% (P < 0.001) 1 year later. The team members had a statistically significant improvement in their ability to articulate the medication reconciliation process. Satisfaction improved significantly for physicians, but MAs did not experience a statistically significant change. CONCLUSION: A team-based care approach to medication reconciliation was successfully implemented and sustained at 4 family medicine clinics. There was significant improvement in physician-documented medication reconciliation. Future studies need to address whether this process improves medication-list discrepancies, completeness, and accuracy.

Palbociclib and endocrine therapy in heavily pretreated hormone receptor-positive HER2-negative advanced breast cancer: the UK Compassionate Access Programme experience.

PURPOSE: Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Programme previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the Programme across ten institutions in the United Kingdom. METHODS: We retrospectively identified HR-positive HER2-negative ABC patients on the Programme between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, χ2 method and Cox regression were used. RESULTS: 118 patients identified had a median age of 59. 82.2% were postmenopausal and 92.4% performance status 0-1. 81.4% had visceral involvement and 6.8% bone-only disease after a median of 5 prior treatments and 3 prior chemotherapies. Clinical benefit rate was 47.5%, overall response rate 15.8%, median PFS 4.5 months and median OS 15.8 months. Longer progression-free survival on prior endocrine therapy was a predictor of longer PFS and OS. 89.7% developed neutropenia (grade ≥ 3 in 56.8%). 5.1% experienced febrile neutropenia. 48.3% had dose reductions and 3.4% discontinued Palbociclib following toxicity. No statistically significant difference in grade ≥ 3 neutropenia was observed according to metastatic sites nor previous treatments. CONCLUSIONS: This is the most extensive analysis of palbociclib in ≥ 4th-line setting. Clinical benefit was confirmed particularly for endocrine-sensitive, predominantly bony disease and in earlier lines of treatment. Safety was similar to PALOMA trials with higher febrile neutropenia rate.

Human genetics in troubled times and places.

The development of human genetics world-wide during the twentieth century, especially across Europe, has occurred against a background of repeated catastrophes, including two world wars and the ideological problems and repression posed by Nazism and Communism. The published scientific literature gives few hints of these problems and there is a danger that they will be forgotten. The First World War was largely indiscriminate in its carnage, but World War 2 and the preceding years of fascism were associated with widespread migration, especially of Jewish workers expelled from Germany, and of their children, a number of whom would become major contributors to the post-war generation of human and medical geneticists in Britain and America. In Germany itself, eminent geneticists were also involved in the abuses carried out in the name of 'eugenics' and 'race biology'. However, geneticists in America, Britain and the rest of Europe were largely responsible for the ideological foundations of these abuses. In the Soviet Union, geneticists and genetics itself became the object of persecution from the 1930s till as late as the mid 1960s, with an almost complete destruction of the field during this time; this extended also to Eastern Europe and China as part of the influence of Russian communism. Most recently, at the end of the twentieth century, China saw a renewal of government sponsored eugenics programmes, now mostly discarded. During the post-world war 2 decades, human genetics research benefited greatly from recognition of the genetic dangers posed by exposure to radiation, following the atomic bomb explosions in Japan, atmospheric testing and successive accidental nuclear disasters in Russia. Documenting and remembering these traumatic events, now largely forgotten among younger workers, is essential if we are to fully understand the history of human genetics and avoid the repetition of similar disasters in the future. The power of modern human genetic and genomic techniques now gives a greater potential for abuse as well as for beneficial use than has ever been seen in the past.

The ß2-adrenoceptor agonist clenbuterol reduces the neuroinflammatory response, neutrophil infiltration and apoptosis following intra-striatal IL-1ß administration to rats.

OBJECTIVES: Clenbuterol is a brain penetrant ß2-adrenoceptor agonist with anti-inflammatory and putative neuroprotective properties. In the present investigation, the effect of clenbuterol was assessed in a rat model of acute brain injury induced by intra-striatal administration of the pro-inflammatory cytokine IL-1ß. METHODS: Clenbuterol (0.5 mg/kg; i.p.) was administered one hour prior to stereotactically delivered IL-1ß (100 ng) into the striatum. Four hours postinjection, rats were anesthetized, blood samples were collected for circulating cytokine and chemokine analysis, and the ipsilateral striatum and liver tissue were harvested for mRNA expression analysis of target genes. RESULTS: Intrastriatal IL-1ß provoked an inflammatory response with increased expression of IL-1ß and the pro-inflammatory cytokine TNF-α. TNF-α expression was also increased in the liver and circulating concentrations of the chemokine cytokine-induced neutrophil chemoattractant 1 (CINC-1) were raised in response to intrastriatal IL-1ß administration. The striatal response was accompanied by NFκB activation and 24 hours postinjection, increased immunoreactivity of the neutrophil marker MBS-2, indicative of cell infiltration and increased TUNEL staining, a cell marker of apoptosis. Treatment with clenbuterol attenuated all IL-1ß-induced changes in the striatum including MBS-2 immunoreactivity and TUNEL + staining. Clenbuterol also attenuated IL-1ß-induced expression of TNF-α in the liver and the increase in circulating CINC-1 concentrations. CONCLUSIONS: The results provide evidence that clenbuterol elicits anti-inflammatory effects, suppresses the peripheral acute phase response and reduces the infiltration of neutrophils and apoptotic response to acute IL-1ß-induced brain injury. Suppression of both the central and peripheral response following clenbuterol administration may contribute to its protective properties following brain injury.

Recorded interviews with human and medical geneticists.

A series of 100 recorded interviews with human and medical geneticists has been carried out and some general results are reported here. Twenty countries across the world are represented, mostly European, with a particular emphasis on the United Kingdom. A priority was given to older workers, many of whom were key founders of human genetics in their own countries and areas of work, and over 20 of whom are now no longer living. The interviews also give valuable information on the previous generation of workers, as teachers and mentors of the interviewees, thus extending the coverage of human genetics back to the 1930s or even earlier. A number of prominent themes emerge from the interview series; notably the beginnings of human cytogenetics from the late 1950s, the development of medical genetics research and its clinical applications in the 1960s and 1970s, and more recently the beginnings and rapid growth of human molecular genetics. The interviews provide vivid personal portraits of those involved, and also show the effects of social and political issues, notably those arising from World War 2 and its aftermath, which affected not only the individuals involved but also broader developments in human genetics, such as research related to risks of irradiation. While this series has made a start in the oral history of this important field, extension and further development of the work is urgently needed to give a fuller picture of how human genetics has developed.

Risk of prostate cancer-specific death in men with baseline metabolic aberrations treated with androgen deprivation therapy for biochemical recurrence.

OBJECTIVES: To investigate the associations of host metabolic factors and metabolic syndrome on prostate cancer-specific death (PCSD) and overall survival (OS) in patients treated with androgen deprivation therapy (ADT) for biochemically recurrent disease. PATIENTS AND METHODS: The analysis included 273 patients with prostate cancer treated with ADT for rising prostate-specific antigen level after surgery or radiotherapy. Patients were assessed for the presence of diabetes, hypertension, dyslipidaemia and obesity before commencing ADT, and Adult Treatment Panel III criteria were used to assess the presence of the composite diagnosis of metabolic syndrome. A competing risks regression model was used to assess associations of time to PCSD with the metabolic conditions, while a multivariable Cox regression model was used to assess associations of OS with metabolic syndrome and metabolic conditions. RESULTS: During a median follow-up of 11.6 years, 157 patients (58%) died, of whom 58 (21%) died from prostate cancer. At the start of ADT the median (range) patient age was 74 (46-92) years and the median PSA level was 3.0 ng/mL. Metabolic syndrome was observed in 31% of patients; hypertension (68%) and dyslipidaemia (47%) were the most common metabolic conditions. No association of PCSD and metabolic syndrome status was observed. Patients with hypertension tended to have a higher cumulative incidence of PCSD than those without hypertension (sub-distribution hazard ratio [HR] 1.59, 95% confidence interval [CI] 0.89, 2.84; P = 0.11) although the difference was not statistically significant. Patients with metabolic syndrome had an increased risk of death from all causes (HR 1.56, 95% CI 1.07, 2.29; P = 0.02) when compared with patients without metabolic syndrome, as did patients with hypertension (HR 1.72, 95% CI 1.18, 2.49; P = 0.004). CONCLUSIONS: No association of PCSD and metabolic syndrome was observed in this cohort of men receiving ADT for biochemically recurrent prostate cancer. Metabolic syndrome was associated with an increased risk of death from all causes and a similar effect was also observed for patients with prostate cancer with hypertension alone.

Decomposition for decarbonisation: evaluation of decarbonisation programmes.

The Kaya Identity has long been used as a simple yet rigorous way to assess options in energy and climate policy. Its shortcoming is that it fails to address the very wide range of non-energy factors. This paper presents a simple extension of the Kaya Identity - the Emissions Quantification Tool or EQT - that incorporates the missing factors while retaining the mathematical transparency of the original. The tool allows national policies to be analysed and compared with international standards for allowable quotas, from which shortfalls or 'carbon debts' can be calculated. It can be used to represent almost any conceivable decarbonisation programme, testing assumptions and revealing necessary rates of change. The paper demonstrates the use of the tool by analysing prevailing UK policy and variant scenarios. The results are often surprising.

Overcoming challenges of prescribing long-term opioid therapy in residency clinics.

OBJECTIVES: To describe the impact of a standardized opioid prescribing intervention when implemented in three family medicine (FM) residency training - clinics-environments that face operational challenges including regular resident turnover. DESIGN: We performed a retrospective cohort study to compare patterns of long-term opioid prescribing between residency and nonresidency clinics. SETTING: This study took place within a large, academic, health system. PATIENTS AND PARTICIPANTS: Three FM residency clinics were compared with three nonresidency FM clinics. INTERVENTIONS: A standardized opioid prescribing process was developed and implemented within the FM residency clinics. Nonresidency clinics used an independent process and were not exposed to the intervention. MAIN OUTCOME MEASURES: Descriptive comparisons were performed for treatment and control clinics' opioid prescribing from 2015 to 2018. The primary outcome was a patient's annual opioid exposure supplied from these select clinics. We also examine coprescribing with high-risk medications that potentiate the overdose risk of opioid prescriptions. Difference-in-difference modeling was used to control for clinic-level variation in practice. RESULTS: Statistically significant decreases were observed in both residency and nonresidency clinics for the mean number of opioid prescriptions and the mean daily morphine milligram equivalent. These decreases were comparable between the residency and nonresidency clinics. CONCLUSIONS: Residency clinics face unique challenges and require innovative solutions to keep up with best practices in opioid prescribing. Our residency clinics' implementation of a standardized intervention, including electronic health record integration, standardized processes, and metric management, suggests steps that may be valuable in achieving outcomes comparable to nonresidency clinics in large health systems.

Bone metastases in germ cell tumours: lessons learnt from a large retrospective study.

OBJECTIVE: To determine the characteristics of patients with germ cell cancer and bone metastases. PATIENTS AND METHODS: The case records of patients with known germ cell tumours (GCTs) within the Anglian Germ Cell Cancer Group database between January 2005 and March 2011 were reviewed retrospectively. Data were collected for histopathology, presence of bone metastases at diagnosis or relapse, site of bone metastases and imaging method used to confirm bone metastases, treatment received, response to treatment and overall survival. We present here the largest unselected cohort of bone metastases in patients with GCTs. RESULTS: In all, 2550 cases of GCTs were reviewed and there was bone involvement in 19 cases. The primary site was either testicular (13/19), mediastinal (1/19) or unknown (5/19). Most cases were non-seminomatous GCTs (11/19, 58%) and only three cases of seminomatous GCTs (3/19, 16%) with five cases in which diagnosis was based on clinical history and significantly raised GCT markers (5/19, 26%). In all of these five cases ß-human chorionic gonadotrophin was raised and in three α-fetoprotein was raised, consistent with non-seminomatous GCT. There were bone metastases at diagnosis (0.51%, 13/2550) or at relapse (0.24%, 6/2550). The sites of bone metastases were the vertebrae (15/19, 79%), pelvis (3/19, 16%), ribs (3/19, 16%) and femur (2/19, 11%). Ten patients (53%) had solitary, and nine patients (47%) had multiple, sites of bone metastases. In patients presenting with bone metastases at diagnosis compared with relapse, the mortality rate was 23% (3/13) and 50% (3/6), respectively. After receiving one line of chemotherapy, nine patients (47%) remained in remission not requiring further treatment, six (32%) required further chemotherapy due to subsequent relapse, three (16%) died after first-line chemotherapy and one was lost to follow-up. At the time of data collection and based on the last clinic follow-up, six patients (32%) had died with a median (interquartile range, IQR) follow-up of 11.5 (4.3, 24.8) months and 10 (53%) remained alive with a median (IQR) follow-up of 26 (13.5, 48) months Three patients were lost to follow-up. Of the known patients alive, eight (42%) remained in remission and two (11%) had recurrent disease requiring further treatment. CONCLUSION: Although bone disease in germ cell cancer is rare, awareness of this condition is important and there is a need for prospective evaluation of patient characteristics, treatment approaches and survival outcome in this group of patients.

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial.

BACKGROUND: Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. METHODS: Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. FINDINGS: The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7-34·4, IQR 2·5-18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7-52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. INTERPRETATION: Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring.

Mary Lyon and the hypothesis of random X chromosome inactivation.

The 50th anniversary of Mary Lyon's 1961 Nature paper, proposing random inactivation in early embryonic life of one of the two X chromosomes in the cells of mammalian females, provides an opportunity to remember and celebrate the work of those involved. While the hypothesis was initially put forward by Lyon based on findings in the mouse, it was founded on earlier studies, notably the work of Susumu Ohno; it was also suggested independently by Beutler and colleagues using experimental evidence from a human X-linked disorder, glucose-6-phosphate dehydrogenase deficiency, and has proved to be of as great importance for human and medical genetics as it has for general mammalian genetics. Alongside the hypothesis itself, previous cytological studies of mouse and human chromosomes, and the observations on X-linked mutants in both species deserve recognition for their essential role in underpinning the hypothesis of random X-inactivation, while subsequent research on the X-inactivation centre and the molecular mechanisms underlying the inactivation process represent some of the most outstanding contributions to human and wider mammalian genetics over the past 50 years.

Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or on haemodialysis.

OBJECTIVE: To further investigate the effect of sunitinib, which is currently a standard of care for the treatment of metastatic renal cell carcinoma (mRCC), in patients with severe renal impairment or those undergoing dialysis. PATIENTS AND METHODS: Clinical databases were used to identify all patients with mRCC treated with sunitinib in seven institutions internationally. Databases were searched to identify only those patients with an estimated glomerular filtration rate of < 30 mL/min/1.73 m² or those who had end-stage renal disease requiring dialysis. Baseline characteristics, adverse event data, response and progression-free survival were recorded. RESULTS: Nineteen patients met the inclusion criteria, 10 of whom were undergoing haemodialysis. Of the nine non-dialysis-dependent patients at drug initiation, the median estimated glomerular filtration rate was 27 mL/min/1.73 m² (range 23-29). Baseline characteristics included a median age of 61 years (range 44-77); 17 patients had a Karnofsky performance status of >80; eight patients had more than two metastatic sites and 17 had undergone prior nephrectomy. The estimated median progression-free survival of this cohort was 43 weeks (range 7 to 158+) and progression has not yet been reached in six patients. Partial response or stable disease was observed as best response in 15 patients. The most common treatment-related adverse events included fatigue, diarrhoea, hand-foot skin reaction (HFSR), nausea and vomiting and rash. Grade three treatment-related adverse events including fatigue (seven patients), HFSR (two patients), diarrhoea (one patient), rash (one patient) and stomatitis (one patient) occurred in a total of 12 patients. Only one patient experienced a grade four adverse event (HFSR). Only diarrhoea (P = 0.0002), HFSR (P < 0.0001) and neutropenia (P = 0.001) were more common in patients undergoing haemodialysis compared with non-dialysis-dependent patients. Four of the non-dialysis dependent patients started at a dose of 50 mg compared with three of the patients undergoing haemodialysis. However five and two of the patients undergoing haemodialysis started at doses of 37.5 mg and 25 mg daily, respectively, compared with four and one of the non-dialysis-dependent patients. All patients took sunitinib for 4 out of every 6 weeks. Dose reductions during treatment were performed in eight patients but only one patient required discontinuation of treatment. CONCLUSION: These data suggest that patients with severe renal impairment or end-stage renal disease on haemodialysis can be safely treated with sunitinib at doses of 25-50 mg daily for 4 weeks followed by a 2-week break. The observed efficacy of therapy is similar to that reported in patients with normal renal function. These preliminary results warrant confirmation in a larger cohort of patients.

The Family Education Diabetes Series (FEDS): community-based participatory research with a midwestern American Indian community.

Indigenous people around the globe tend to struggle with poorer health and well-being than their non-indigenous counterparts. One area that this is especially evident is in the epidemic of diabetes in North America's American Indians (AIs) - who evidence higher prevalence rates and concomitant disease-related complications than any other racial/ethnic group. As researchers and AI communities work together to transcend conventional top-down, service-delivery approaches to care, community-based participatory research is beginning to show promise as a way to partner contemporary biomedical knowledge with the lived-experience, wisdom, and customs of Indigenous people. This study describes the Family Education Diabetes Series (FEDS) as an example of such effort, and highlights pilot findings assessing its value and impact across key diabetes-relevant variables. Following 36 intervention participants across baseline, 3-month, and 6-month time periods, data show significant improvements in weight, blood pressure, and metabolic control (A1c). Strengths and limitations of this investigation are presented, along with suggestions about how to further advance and empirically test the work across other Indigenous communities.