The Association Between Oncology Outreach and Timely Treatment for Rural Patients with Breast Cancer: A Claims-Based Approach.

BACKGROUND: Oncology outreach is a common strategy for increasing rural access to cancer care, where traveling oncologists commute across healthcare settings to extend specialized care. Examining the extent to which physician outreach is associated with timely treatment for rural patients is critical for informing outreach strategies. METHODS: We identified a 100% fee-for-service sample of incident breast cancer patients from 2015 to 2020 Medicare claims and apportioned them into surgery and adjuvant therapy cohorts based on treatment history. We defined an outreach visit as the provision of care by a traveling oncologist at a clinic outside of their primary hospital service area. We used hierarchical logistic regression to examine the associations between patient receipt of preoperative care at an outreach visit (preoperative outreach) and > 60-day surgical delay, and patient receipt of postoperative care at an outreach visit (postoperative outreach) and > 60-day adjuvant delay. RESULTS: We identified 30,337 rural-residing patients who received breast cancer surgery, of whom 4071 (13.4%) experienced surgical delay. Among surgical patients, 14,501 received adjuvant therapy, of whom 2943 (20.3%) experienced adjuvant delay. In adjusted analysis, we found that patient receipt of preoperative outreach was associated with reduced odds of surgical delay (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.61-0.91); however, we found no association between patient receipt of postoperative outreach and adjuvant delay (OR 1.04, 95% CI 0.85-1.25). CONCLUSIONS: Our findings indicate that preoperative outreach is protective against surgical delay. The traveling oncologists who enable such outreach may play an integral role in catalyzing the coordination and timeliness of patient-centered care.

Structure and integration of specialty palliative care in three NCI-designated cancer centers: a mixed methods case study.

INTRODUCTION: Early access to specialty palliative care is associated with better quality of life, less intensive end-of-life treatment and improved outcomes for patients with advanced cancer. However, significant variation exists in implementation and integration of palliative care. This study compares the organizational, sociocultural, and clinical factors that support or hinder palliative care integration across three U.S. cancer centers using an in-depth mixed methods case study design and proposes a middle range theory to further characterize specialty palliative care integration. METHODS: Mixed methods data collection included document review, semi-structured interviews, direct clinical observation, and context data related to site characteristics and patient demographics. A mixed inductive and deductive approach and triangulation was used to analyze and compare sites' palliative care delivery models, organizational structures, social norms, and clinician beliefs and practices. RESULTS: Sites included an urban center in the Midwest and two in the Southeast. Data included 62 clinician and 27 leader interviews, observations of 410 inpatient and outpatient encounters and seven non-encounter-based meetings, and multiple documents. Two sites had high levels of "favorable" organizational influences for specialty palliative care integration, including screening, policies, and other structures facilitating integration of specialty palliative care into advanced cancer care. The third site lacked formal organizational policies and structures for specialty palliative care, had a small specialty palliative care team, espoused an organizational identity linked to treatment innovation, and demonstrated strong social norms for oncologist primacy in decision making. This combination led to low levels of specialty palliative care integration and greater reliance on individual clinicians to initiate palliative care. CONCLUSION: Integration of specialty palliative care services in advanced cancer care was associated with a complex interaction of organization-level factors, social norms, and individual clinician orientation. The resulting middle range theory suggests that formal structures and policies for specialty palliative care combined with supportive social norms are associated with greater palliative care integration in advanced cancer care, and less influence of individual clinician preferences or tendencies to continue treatment. These results suggest multi-faceted efforts at different levels, including social norms, may be needed to improve specialty palliative care integration for advanced cancer patients.

Problematic Integration: Racial Discordance in End-of-Life Decision Making.

We describe racially discordant oncology encounters involving EOL decision-making. Fifty-eight provider interviews were content analyzed using the tenets of problematic integration theory. We found EOL discussions between non-Black providers and their Black patients were often complex and anxiety-inducing. That anxiety consisted of (1) ontological uncertainty in which providers characterized the nature of Black patients as distrustful, especially in the context of clinical trials; (2) ontological and epistemological uncertainty in which provider intercultural incompetency and perceived lack of patient health literacy were normalized and intertwined with provider assumptions about patients' religion and support systems; (3) epistemological uncertainty as ambivalence in which providers' feelings conflicted when deciding whether to speak with family members they perceived as lacking health literacy; (4) divergence in which the provider advised palliative care while the family desired surgery or cancer-directed medical treatment; and (5) impossibility when an ontological uncertainty stance of Black distrust was seen as natural by providers and therefore impossible to change. Some communication strategies used were indirect stereotyping, negotiating, asking a series of value questions, blame-guilt framing, and avoidance. We concluded that provider perceptions of Black distrust, religion, and social support influenced their ability to communicate effectively with patients.

Rural-Urban Differences in Breast Cancer Surgical Delays in Medicare Beneficiaries.

BACKGROUND: Delays between breast cancer diagnosis and surgery are associated with worsened survival. Delays are more common in urban-residing patients, although factors specific to surgical delays among rural and urban patients are not well understood. METHODS: We used a 100% sample of fee-for-service Medicare claims during 2007-2014 to identify 238,491 women diagnosed with early-stage breast cancer undergoing initial surgery and assessed whether they experienced biopsy-to-surgery intervals > 90 days. We employed multilevel regression to identify associations between delays and patient, regional, and surgeon characteristics, both in combined analyses and stratified by rurality of patient residence. RESULTS: Delays were more prevalent among urban patients (2.5%) than rural patients (1.9%). Rural patients with medium- or high-volume surgeons had lower odds of delay than patients with low-volume surgeons (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.58-0.88; OR = 0.74, 95% CI = 0.61-0.90). Rural patients whose surgeon operated at ≥ 3 hospitals were more likely to experience delays (OR = 1.29, 95% CI = 1.01-1.64, Ref: 1 hospital). Patient driving times ≥ 1 h were associated with delays among urban patients only. Age, black race, Hispanic ethnicity, multimorbidity, and academic/specialty hospital status were associated with delays. CONCLUSIONS: Sociodemographic, geographic, surgeon, and facility factors have distinct associations with > 90-day delays to initial breast cancer surgery. Interventions to improve timeliness of breast cancer surgery may have disparate impacts on vulnerable populations by rural-urban status.

Uncertainty in lung cancer stage for survival estimation via set-valued classification.

The difficulty in identifying cancer stage in health care claims data has limited oncology quality of care and health outcomes research. We fit prediction algorithms for classifying lung cancer stage into three classes (stages I/II, stage III, and stage IV) using claims data, and then demonstrate a method for incorporating the classification uncertainty in survival estimation. Leveraging set-valued classification and split conformal inference, we show how a fixed algorithm developed in one cohort of data may be deployed in another, while rigorously accounting for uncertainty from the initial classification step. We demonstrate this process using SEER cancer registry data linked with Medicare claims data.

Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants. MATERIALS AND METHODS: We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model. RESULTS: Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%. CONCLUSION: Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death. IMPLICATIONS FOR PRACTICE: The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.

Fever-range hyperthermia promotes cGAS-STING pathway and synergizes DMXAA-induced antiviral immunity.

Background: Fever-range hyperthermia or fever-range temperature (hereafter FRT) improves survival and shortens disease duration in microbial infections. However, the mechanisms of these beneficial effects still remain elusive. We hypothesized that FRT might enhance cell responsiveness to infections by promoting cGAS-STING signaling to cause enhanced production of IFN-ß. Objective: To investigate the effect fever-range hyperthermia on cGAS-STING pathway. Methods: RAW 264.7 and cGAS-/- RAW 264.7 cells, stimulated with 5µg/ml herring testis DNA (htDNA), were heated to 39.5°C and analyzed for the expression of cGAS, STING, IFN-ß, and the synthesis of cGAMP and IRF3 phosphorylation. In vivo, wild type C57BL/6J mice were subjected to whole body hyperthermia (WBH) at 39.5°C. The mice were then challenged with influenza virus and analyzed for antiviral response in term of IFN-ß expression, body weight and survival. Results: We found that 39.5°C FRT upregulated the expression of cGAS and STING, and induced the synthesis of cGAMP and production of IFN-ß in htDNA-transfected RAW 264.7 cells more potently as compared to 37°C. Moreover, FRT+DMXAA-treated cells were better protected from vesicular stomatitis virus (VSV)-induced cytotoxicity in vitro in contrast to the nonprotected control (no FRT and DMXAA) or DMXAA treatment alone. In vivo, FRT at 39.5°C, co-administered with DMXAA, significantly induced the expression of IFN-ß, showed reduced weight loss mice and exhibited 25% more survival over the course of 14 days as compared to DMXAA treated mice 37°C. Conclusion: We conclude that fever-range hyperthermia promotes cGAS-STING pathway to cause increased expression of IFN-ß and mediate its antiviral effects.

Association of Participation in the Oncology Care Model With Medicare Payments, Utilization, Care Delivery, and Quality Outcomes.

IMPORTANCE: In 2016, the US Centers for Medicare & Medicaid Services initiated the Oncology Care Model (OCM), an alternative payment model designed to improve the value of care delivered to Medicare beneficiaries with cancer. OBJECTIVE: To assess the association of the OCM with changes in Medicare spending, utilization, quality, and patient experience during the OCM's first 3 years. DESIGN, SETTING, AND PARTICIPANTS: Exploratory difference-in-differences study comparing care during 6-month chemotherapy episodes in OCM participating practices and propensity-matched comparison practices initiated before (January 2014 through June 2015) and after (July 2016 through December 2018) the start of the OCM. Participants included Medicare fee-for-service beneficiaries with cancer treated at these practices through June 2019. EXPOSURES: OCM participation. MAIN OUTCOMES AND MEASURES: Total episode payments (Medicare spending for Parts A, B, and D, not including monthly payments for enhanced oncology services); utilization and payments for hospitalizations, emergency department (ED) visits, office visits, chemotherapy, supportive care, and imaging; quality (chemotherapy-associated hospitalizations and ED visits, timely chemotherapy, end-of-life care, and survival); and patient experiences. RESULTS: Among Medicare fee-for-service beneficiaries with cancer undergoing chemotherapy, 483 319 beneficiaries (mean age, 73.0 [SD, 8.7] years; 60.1% women; 987 332 episodes) were treated at 201 OCM participating practices, and 557 354 beneficiaries (mean age, 72.9 [SD, 9.0] years; 57.4% women; 1 122 597 episodes) were treated at 534 comparison practices. From the baseline period, total episode payments increased from $28 681 for OCM episodes and $28 421 for comparison episodes to $33 211 for OCM episodes and $33 249 for comparison episodes during the intervention period (difference in differences, -$297; 90% CI, -$504 to -$91), less than the mean $704 Monthly Enhanced Oncology Services payments. Relative decreases in total episode payments were primarily for Part B nonchemotherapy drug payments (difference in differences, -$145; 90% CI, -$218 to -$72), especially supportive care drugs (difference in differences, -$150; 90% CI, -$216 to -$84). The OCM was associated with statistically significant relative reductions in total episode payments among higher-risk episodes (difference in differences, -$503; 90% CI, -$802 to -$204) and statistically significant relative increases in total episode payments among lower-risk episodes (difference in differences, $151; 90% CI, $39-$264). The OCM was not significantly associated with differences in hospitalizations, ED visits, or survival. Of 22 measures of utilization, 10 measures of quality, and 7 measures of care experiences, only 5 were significantly different. CONCLUSIONS AND RELEVANCE: In this exploratory analysis, the OCM was significantly associated with modest payment reductions during 6-month episodes for Medicare beneficiaries receiving chemotherapy for cancer in the first 3 years of the OCM that did not offset the monthly payments for enhanced oncology services. There were no statistically significant differences for most utilization, quality, and patient experience outcomes.

Translation of Patient-Reported Outcomes in Oncology Clinical Trials to Everyday Practice.

PURPOSE: Clinical trials in oncology evaluating the effects of patient-reported outcomes (PRO) collection have found that monitoring of symptoms with PROs is associated with improved clinical care through reduced acute care utilization and decreased patient symptom burden. This educational review will evaluate strategies for systematic PRO integration into everyday oncology clinical practice. METHODS: We outline key considerations for using PROs in clinical practice, highlighting evidence from published studies. We also discuss the benefits and challenges of PRO implementation in oncology. RESULTS: Implementing PRO collection in clinical practice can improve care delivery and facilitate patient-centered clinical research. Considerations for using PROs in clinical practice include choice of instrument, method of delivery, and frequency of query. Challenges with implementing systematic PRO collection include the costs and resources needed for implementation, impact on clinical workflow, and controlling/monitoring physician burnout. CONCLUSIONS: While challenges exist in terms of financial resources and staff participation/burnout, patient-reported outcomes in clinical practice provide a number of benefits, including symptom monitoring, clinical research, and potential real-time personalized clinical-decision support.

Role of norms in variation in cancer centers' end-of-life quality: qualitative case study protocol.

BACKGROUND: A critical barrier to improving the quality of end-of-life (EOL) cancer care is our lack of understanding of the mechanisms underlying variation in EOL treatment intensity. This study aims to fill this gap by identifying 1) organizational and provider practice norms at major US cancer centers, and 2) how these norms influence provider decision making heuristics and patient expectations for EOL care, particularly for minority patients with advanced cancer. METHODS: This is a multi-center, qualitative case study at six National Comprehensive Cancer Network (NCCN) and National Cancer Institute (NCI) Comprehensive Cancer Centers. We will theoretically sample centers based upon National Quality Forum (NQF) endorsed EOL quality metrics and demographics to ensure heterogeneity in EOL intensity and region. A multidisciplinary team of clinician and non-clinician researchers will conduct direct observations, semi-structured interviews, and artifact collection. Participants will include: 1) cancer center and clinical service line administrators; 2) providers from medical, surgical, and radiation oncology; palliative or supportive care; intensive care; hospital medicine; and emergency medicine who see patients with cancer and have high clinical practice volume or high local influence (provider interviews and observations); and 3) adult patients with metastatic solid tumors and whom the provider would not be surprised if they died in the next 12 months and their caregivers (patient and caregiver interviews). Leadership interviews will probe about EOL institutional norms and organization. We will observe inpatient and outpatient care for two weeks. Provider interviews will use vignettes to probe explicit and implicit motivations for treatment choices. Semi-structured interviews with patients near EOL, or their family members and caregivers will explore past, current, and future decisions related to their cancer care. We will import transcribed field notes and interviews into Dedoose software for qualitative data management and analysis, and we will develop and apply a deductive and inductive codebook to the data. DISCUSSION: This study aims to improve our understanding of organizational and provider practice norms pertinent to EOL care in U.S. cancer centers. This research will ultimately be used to inform a provider-oriented intervention to improve EOL care for racial and ethnic minority patients with advanced cancer. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT03780816 ; December 19, 2018.

FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial.

BACKGROUND: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma. METHODS: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort. CONCLUSIONS: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.

Comparison of treatment of early-stage breast cancer among Nurses' Health Study participants and other Medicare beneficiaries.

PURPOSE: Increasingly epidemiological cohorts are being linked to claims data to provide rich data for healthcare research. These cohorts tend to be different than the general United States (US) population. We will analyze healthcare utilization of Nurses' Health Study (NHS) participants to determine if studies of newly diagnosed incident early-stage breast cancer can be generalized to the broader US Medicare population. METHODS: Analytic cohorts of fee-for-service NHS-Medicare-linked participants and a 1:13 propensity-matched SEER-Medicare cohort (SEER) with incident breast cancer in the years 2007-2011 were considered. Screening leading to, treatment-related, and general utilization in the year following early-stage breast cancer diagnosis were determined using Medicare claims data. RESULTS: After propensity matching, NHS and SEER were statistically balanced on all demographics. NHS and SEER had statistically similar rates of treatments including chemotherapy, breast-conserving surgery, mastectomy, and overall radiation use. Rates of general utilization include those related to hospitalizations, total visits, and emergency department visits were also balanced between the two groups. Total spending in the year following diagnosis were statistically equivalent for NHS and SEER ($36,180 vs. $35,399, p = 0.70). CONCLUSIONS: NHS and the general female population had comparable treatment and utilization patterns following diagnosis of early-stage incident breast cancers with the exception of type of radiation therapy received. This study provides support for the larger value of population-based cohorts in research on healthcare costs and utilization in breast cancer.

A Systematic Review of Clinical Decision Support Systems for Clinical Oncology Practice.

BACKGROUND: Electronic health records are central to cancer care delivery. Electronic clinical decision support (CDS) systems can potentially improve cancer care quality and safety. However, little is known regarding the use of CDS systems in clinical oncology and their impact on patient outcomes. METHODS: A systematic review of peer-reviewed studies was performed to evaluate clinically relevant outcomes related to the use of CDS tools for the diagnosis, treatment, and supportive care of patients with cancer. Peer-reviewed studies published from 1995 through 2016 were included if they assessed clinical outcomes, patient-reported outcomes (PROs), costs, or care delivery process measures. RESULTS: Electronic database searches yielded 2,439 potentially eligible papers, with 24 studies included after final review. Most studies used an uncontrolled, pre-post intervention design. A total of 23 studies reported improvement in key study outcomes with use of oncology CDS systems, and 12 studies assessing the systems for computerized chemotherapy order entry demonstrated reductions in prescribing error rates, medication-related safety events, and workflow interruptions. The remaining studies examined oncology clinical pathways, guideline adherence, systems for collection and communication of PROs, and prescriber alerts. CONCLUSIONS: There is a paucity of data evaluating clinically relevant outcomes of CDS system implementation in oncology care. Currently available data suggest that these systems can have a positive impact on the quality of cancer care delivery. However, there is a critical need to rigorously evaluate CDS systems in oncology to better understand how they can be implemented to improve patient outcomes.

Highly-accelerated self-gated free-breathing 3D cardiac cine MRI: validation in assessment of left ventricular function.

OBJECTIVE: This work presents a highly-accelerated, self-gated, free-breathing 3D cardiac cine MRI method for cardiac function assessment. MATERIALS AND METHODS: A golden-ratio profile based variable-density, pseudo-random, Cartesian undersampling scheme was implemented for continuous 3D data acquisition. Respiratory self-gating was achieved by deriving motion signal from the acquired MRI data. A multi-coil compressed sensing technique was employed to reconstruct 4D images (3D+time). 3D cardiac cine imaging with self-gating was compared to bellows gating and the clinical standard breath-held 2D cine imaging for evaluation of self-gating accuracy, image quality, and cardiac function in eight volunteers. Reproducibility of 3D imaging was assessed. RESULTS: Self-gated 3D imaging provided an image quality score of 3.4 ± 0.7 vs 4.0 ± 0 with the 2D method (p = 0.06). It determined left ventricular end-systolic volume as 42.4 ± 11.5 mL, end-diastolic volume as 111.1 ± 24.7 mL, and ejection fraction as 62.0 ± 3.1%, which were comparable to the 2D method, with bias ± 1.96 × SD of -0.8 ± 7.5 mL (p = 0.90), 2.6 ± 3.3 mL (p = 0.84) and 1.4 ± 6.4% (p = 0.45), respectively. CONCLUSION: The proposed 3D cardiac cine imaging method enables reliable respiratory self-gating performance with good reproducibility, and provides comparable image quality and functional measurements to 2D imaging, suggesting that self-gated, free-breathing 3D cardiac cine MRI framework is promising for improved patient comfort and cardiac MRI scan efficiency.

Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.

BACKGROUND: Challenges in the diagnosis and classification of cholangiocarcinoma have made it difficult to quantify the true incidence of this highly aggressive malignancy. METHODS: We analyzed the Surveillance, Epidemiology, and End Results data to assess long-term trends in the age-standardized incidence of intrahepatic and extrahepatic cholangiocarcinoma between 1973 and 2012, correcting for systematic coding errors. Because intrahepatic cholangiocarcinoma (ICC) may frequently be misdiagnosed as cancer of unknown primary (CUP), we also analyzed trends in the incidence of CUP. RESULTS: Between 1973 and 2012, the reported U.S. incidence of ICC increased from 0.44 to 1.18 cases per 100,000, representing an annual percentage change (APC) of 2.30%; this trend has accelerated during the past decade to an APC of 4.36%. The incidence of extrahepatic cholangiocarcinoma increased modestly from 0.95 to 1.02 per 100,000 during the 40-year period (APC, 0.14%). The incidence of CUP with histologic features potentially consistent with cholangiocarcinoma decreased by 51% between 1973 and 2012 (APC, -1.87%), whereas the incidence of CUP with squamous or nonepithelial histologic features increased modestly (APC, 0.42%). CONCLUSION: The recognized incidence of ICC in the U.S. continues to rise, whereas the incidence of ECC is stable. The incidence of CUP has fallen dramatically during the same time period. IMPLICATIONS FOR PRACTICE: Clinical distinctions between cholangiocarcinoma (particularly intrahepatic cholangiocarcinoma [ICC]) and cancer of unknown primary (CUP) can be challenging. Recent discoveries have identified recurrent and potentially targetable genomic abnormalities in ICC, highlighting the importance of improving diagnosis. This study demonstrates that the incidence of ICC is increasing in the U.S., whereas the incidence of extrahepatic cholangiocarcinoma is stable. Concomitantly, the incidence of CUP has declined dramatically, suggesting that improved distinction between ICC and CUP may be a major driver of the increasing recognized incidence of ICC. The increasing incidence of ICC warrants further study of prevention and treatment approaches.

Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.

RATIONALE: Holt-Oram syndrome is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and the role of Tbx5 in mammalian coronary vasculogenesis, remains largely unknown. OBJECTIVE: To evaluate the consequences of altered Tbx5 gene dosage during proepicardial organ and epicardial development in the embryonic chick and mouse. METHODS AND RESULTS: Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick proepicardial organ and proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/)) impaired normal proepicardial organ cell development, inhibited epicardial and coronary blood vessel formation, and altered developmental gene expression. The generation of epicardial-derived cells and their migration into the myocardium were impaired between embryonic day (E) 13.5 to 15.5 in mutant hearts because of delayed epicardial attachment to the myocardium and subepicardial accumulation of epicardial-derived cells. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wild-type hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by hypoxia inducible factor-1α upregulation and increased binding of hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity when compared with wild-type mice. CONCLUSIONS: Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and in mouse coronary vascular formation.

An ED pilot intervention to facilitate outpatient acute care for cancer patients.

INTRODUCTION: Unplanned hospitalizations are common in patients with cancer, and most hospitalizations originate in the emergency department (ED). METHODS: We implemented an ED-based pilot intervention designed to reduce hospitalizations among patients with solid tumors. The intervention, piloted at a single academic medical center, involved a medical oncologist embedded in the ED during evening hours. We used a quasiexperimental preimplementation/postimplementation study design to evaluate the proportion of ED visits that resulted in inpatient hospital admission, before and after pilot implementation. General estimating equations were used to evaluate the association between the intervention and hospital admission. RESULTS: There were 390 ED visits by eligible cancer patients in the preintervention period and 418 visits in the intervention period. During the intervention period, 158 (38%) of 418 ED visits were identified by the embedded oncologist during the evening intervention shift. The proportion of ED visits leading to hospitalization was 70% vs 69% in the preintervention and intervention periods (odds ratio, 0.93 [95% confidence interval, 0.69-1.24]; P= .62). There were no differences between periods in ED length of stay or subsequent use of acute care. Among patients with initial ED presentation during the operating hours of the intervention, the proportion of ED visits leading to hospitalization was 77% vs 67% in the preintervention and intervention periods (odds ratio, 0.62 [0.36-1.08]; P= .08). CONCLUSION: Embedding an oncologist in the ED of an academic medical center did not significantly reduce hospital admissions. Novel approaches are needed to strengthen outpatient acute care for patients with cancer.

National trends in pancreatic cancer outcomes and pattern of care among Medicare beneficiaries, 2000 through 2010.

BACKGROUND: Pancreatic cancer is a major cause of morbidity and mortality in the Medicare population. Whether the health care burden of pancreatic cancer has changed over the last decade is unknown. METHODS: The authors used Medicare data from 2000 to 2010 to identify beneficiaries aged ≥ 65 years who were hospitalized for the management of pancreatic cancer. Annual trends were estimated for the age-sex-race-adjusted initial hospitalization rate, the age-sex-race-comorbidity-adjusted 1-year mortality rate after initial hospitalization, age-sex-race-comorbidity-adjusted procedure rates, 1-year all-cause rehospitalizations after initial pancreatic cancer hospitalization, and mean inflation-adjusted Medicare payment for initial hospitalization. RESULTS: A total of 130,728 patients had ≥ 1 hospitalizations for pancreatic cancer and were identified from 56,642,071 beneficiaries during the study period. The age-sex-race-adjusted rate of initial hospitalization for pancreatic cancer was 50 per 100,000 person-years in 2010, representing a 0.5% annual increase since 2000 (95% confidence interval [95% CI], 0.3%-0.7%). In the same period, the age-sex-race-comorbidity-adjusted 1-year mortality rate decreased by 4.4% (95% CI, 3.9%-4.9%), and the age-sex-race-comorbidity-adjusted surgical resection rate increased by 6.9% (95% CI, 6.4%-7.5%). The mean inflation-adjusted Medicare payment for the initial hospitalization decreased, from $14,118 in 2000 to $13,318 in 2010, and the number of 1-year all-cause rehospitalizations after the initial hospitalization increased from 0.75 per patient in 2000 to 0.82 per patient in 2009 (all P < .001). CONCLUSIONS: For Medicare fee-for-service beneficiaries, initial pancreatic cancer hospitalization, surgical resection, and rehospitalization rates increased, but 1-year mortality rates declined over the last decade.