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.

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.

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.

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.

Financial Impact of Universal Precepting in Family Medicine Residency Clinics.

BACKGROUND AND OBJECTIVES: Precepting methods have significant impact on the financial viability of family medicine residency programs. Following an adverse event, four University of Minnesota Family Medicine residency clinics moved from using Medicare's Primary Care Exception (PCE) and licensure precepting (LP) to a "universal precepting" method in which preceptors see every patient face to face. Variation in the implementation of universal precepting created a natural experiment of its financial impact. METHODS: Universal precepting was implemented in October 2013 across four residency programs. Billing codes were measured 1 year before and 2.5 years after implementation by clinic and residency year. RESULTS: There were significant financial differences between clinics based on original precepting method and implementation quality of universal precepting. The clinic moving from PCE to universal precepting with excellent implementation increased higher-level billing (99214) by 8%-10%. Clinics moving from LP demonstrated wide variation ranging from an 18% increase to a 13% decrease, consistent with the implementation quality. CONCLUSIONS: Clinics transitioning from PCE to universal precepting can see a significant increase in 99214 billing. Clinics transitioning from LP to universal precepting are at significant financial risk if poorly implemented, but may see increased 99214 billing with effective implementation. This suggests that both implementation quality and original precepting method impact 99214 billing rates when transitioning to universal precepting.

Transforming medical care: case study of an exemplary, small medical group.

PURPOSE: Most published descriptions of organizations providing or improving quality of care concern large medical groups or systems; however, 90% of the medical care in the United States is provided by groups of no more than 20 physicians. We studied one such group to determine the organizational and cultural attributes that seem related to its achievements in care quality. METHODS: A 15-family physician medical group was identified from comparative public performance scores of 27 medical groups providing most of the primary care in our metropolitan area. Semistructured interviews were conducted with diverse personnel in this group, operations were observed, and written documents were reviewed. Four primary care physician researchers and a consultant then reviewed transcriptions, field notes, and materials during semistructured sessions to identify the main attributes of this group and their probable origins. RESULTS: This medical group ranked first in a composite measure of preventive services and fourth and sixth, respectively, in composite scores for coronary artery disease and diabetes care. Our analysis identified 12 attributes of this group that seemed to be associated with its good care quality, with patient-centeredness being the foundational attribute for most of the others. Historical factors important to most of these attributes included small size, physician ownership, and a high value on practice consistency among the clinicians in the group. CONCLUSIONS: The identified 12 attributes of this medical group seem to be associated with its superior care quality, and most of them might be replicable by other small groups if they choose to work toward that end.

Challenges of change: a qualitative study of chronic care model implementation.

PURPOSE: The Chronic Care Model (CCM) provides a conceptual framework for transforming health care for patients with chronic conditions; however, little is known about how to best design and implement its specifics. One large health care organization that tried to implement the CCM in primary care provided an opportunity to study these issues. METHODS: We conducted a qualitative, comparative case study of 5 of 18 group clinics 18 to 23 months after the implementation began. Built on knowledge of the clinics from a previous study of advanced access implementation, data included in-depth interviews with organizational leaders and varied clinic personnel, observation of clinic care processes, and review of written materials. RESULTS: Relatively small and highly variable care process changes were made during the study period. The change process underwent several marked shifts in strategy when initial efforts failed to achieve much and bore little resemblance to the change process used in the previously successful large-scale implementation of advanced access scheduling. Many barriers were identified, including too many competing priorities, a lack of specificity and agreement about the care process changes desired, and little engagement of physicians. CONCLUSION: These findings highlight specific organizational challenges with health care transformation in the absence of a blueprint more specific than the CCM. Effective models of organizational change and detailed examples of proven, feasible care changes still need to be demonstrated if we are to transform care as called for by the Institute of Medicine.

Sentinel node biopsy: an in depth appraisal.

Sentinel node biopsy (SNB) in primary breast cancer has been taken-up widely to avoid the morbidity attributable to axillary node clearance (ANC). Currently many issues surrounding SNB are undecided. This review summarises why some form of axillary surgery is required and presents data on all aspects of SNB including methodology, clinical results and problems that may delay the introduction of SNB as best practice for all patients with primary breast cancer. There is no long or medium term data relating to the consequences of replacing ANC with SNB, but the mechanisms and probable magnitude of both beneficial and detrimental effects are estimated. A low level of false negative results are inherent to the technique but it is demonstrated that SNB is likely to have an only marginal (0.6%) effect on survival that would be undetectable by clinical trials. Patient sub-groups particularly likely to benefit from SNB are identified.

Quality of life and the treatment of advanced lung cancer.

Lung cancer is the leading cause of cancer deaths worldwide, with the majority of patients presenting with advanced disease. Despite the introduction of newer therapeutic agents and modest survival improvement, the overall prognosis for these patients is poor. The goals of therapy should therefore include improvement in quality of life (QOL), palliation of symptoms, and prolongation of survival. Quality of life has now become recognized as an important outcome measure for cancer therapy. Quality-of-life endpoints are being increasingly incorporated into clinical trials of newer agents to further define meaningful response. The assessment of QOL involves comprehensive measurement tools that address the physical, social, functional, and emotional well-being of the patient. Such measurements should be easy to use, meaningful, and relevant to the patients and clinician. Although these measures assess the longitudinal impact of treatment on QOL, pretreatment QOL scores may also be an important prognostic factor for survival in patients with lung carcinoma. This article reviews QOL measures and the data for QOL benefits from therapy in patients with advanced small-cell and non-small-cell lung cancer.

Gastro-oesophageal complications in patients receiving cancer therapy: the role of proton pump inhibitors.

Chemotherapy and radiotherapy, both alone and in combination, remain important tools in the successful treatment of cancer. Because the oral and gastrointestinal (GI) mucosa is often significantly damaged by cancer therapy, management of these problems is an important challenge for oncologists. Such treatment complications are generally not severe or life threatening, but they can result in both treatment delays and dose reductions in potentially curative regimens. Numerous therapeutic approaches have been evaluated as prophylaxis or treatment for mucosal damage in patients undergoing cancer therapy. The results of large-scale, placebo-controlled, comparative trials demonstrate that administration of a proton pump inhibitor (PPI) can provide both significant symptom relief and prophylaxis against upper GI ulceration in patients receiving cancer chemotherapy. Although no corresponding clinical trial has been conducted in patients undergoing irradiation, PPIs are also likely to be effective in preventing gastro-oesophageal mucosal injury in such individuals. Thus, PPIs may play a crucial role in supportive care for patients undergoing cancer therapy.

Community-based participatory research to decrease smoking prevalence in a high-risk young adult population: an evaluation of the Students Against Nicotine and Tobacco Addiction (SANTA) project.

Students Against Nicotine and Tobacco Addiction is a community-based participatory research project that engages local medical and mental health providers in partnership with students, teachers, and administrators at the Minnesota-based Job Corps. This intervention contains multiple and synchronous elements designed to allay the stress that students attribute to smoking, including physical activities, nonphysical activities, purposeful modifications to the campus's environment and rules/policies, and on-site smoking cessation education and peer support. The intent of the present investigation was to evaluate (a) the types of stress most predictive of smoking behavior and/or nicotine dependence, (b) which activities students are participating in, and (c) which activities are most predictive of behavior change (or readiness to change). Quantitative data were collected through 5 campus-wide surveys. Response rates for each survey exceeded 85%. Stressors most commonly cited included struggles to find a job, financial problems, family conflict, lack of privacy or freedom, missing family or being homesick, dealing with Job Corps rules, and other-unspecified. The most popular activities in which students took part were physically active ones. However, activities most predictive of beneficent change were nonphysical. Approximately one third of respondents were nicotine dependent at baseline. Nearly half intended to quit within 1 month and 74% intended to quit within 6 months. Interventions perceived as most helpful toward reducing smoking were nonphysical in nature. Future efforts with this and comparable populations should engage youth in advancing such activities within a broader range of activity choices, alongside conventional education and support.