Do Outcomes in Elective Colon and Rectal Cancer Surgery Differ by Weekday? An Observational Study Using Data From the Dutch ColoRectal Audit.

BACKGROUND: Previous studies showing higher mortality after elective surgery performed on a Friday were based on administrative data, known for insufficient case-mix adjustment. The goal of this study was to investigate the risk of adverse events for patients with colon and rectal cancer by day of elective surgery using clinical data from the Dutch ColoRectal Audit. PATIENTS AND METHODS: Prospectively collected data from the 2012-2015 Dutch ColoRectal Audit (n=36,616) were used to examine differences in mortality, severe complications, and failure to rescue by day of elective surgery (Monday through Friday). Monday was used as a reference, analyses were stratified for colon and rectal cancer, and case-mix adjustments were made for previously identified variables. RESULTS: For both colon and rectal cancer, crude mortality, severe complications, and failure-to-rescue rates varied by day of elective surgery. After case-mix adjustment, lower severe complication risk was found for rectal cancer surgery performed on a Friday (odds ratio, 0.84; 95% CI, 0.72-0.97) versus Monday. No significant differences were found for colon cancer surgery performed on different weekdays. CONCLUSIONS: No weekday effect was found for elective colon and rectal cancer surgery in the Netherlands. Lower severe complication risk for elective rectal cancer surgery performed on a Friday may be caused by patient selection.

Weekend Effect in Emergency Colon and Rectal Cancer Surgery: A Prospective Study Using Data From the Dutch ColoRectal Audit.

Background: It is unclear whether emergency weekend colon and rectal cancer surgery are associated with worse outcomes (ie, weekend effect) because previous studies mostly used administrative data, which may insufficiently adjust for case-mix. Materials and Methods: Prospectively collected data from the 2012-2015 Dutch ColoRectal Audit (n=5,224) was used to examine differences in 30-day mortality and severe complication and failure-to-rescue rates for emergency weekend (Saturday and Sunday) versus Monday surgery, stratified for colon and rectal cancer. Analyses were adjusted for age, sex, body mass index, Charlson comorbidity index, American Society of Anesthesiologists classification score, tumor stage, presence of metastasis, preoperative complication, additional resection for metastasis or locally advanced tumor, location primary colon tumor, type of rectal surgery (lower anterior resection or abdominal perineal resection), and type of neoadjuvant therapy (short-course radiotherapy or chemoradiotherapy). Results: A total of 5,052 patients undergoing colon cancer surgery and 172 undergoing rectal cancer surgery were included. Patients undergoing colon or rectal cancer surgery during weekends had significantly more preoperative tumor complications compared with those undergoing surgery on a weekday. Additionally, differences in year of surgery and location of primary tumor were found for colon cancer surgery. Emergency colon cancer surgery during the weekend was associated with increased 30-day mortality (odds ratio [OR], 1.66; 95% CI, 1.10-2.50) and severe complications (OR, 1.29; 95% CI, 1.03-1.63) compared with surgery on Monday. Estimates for emergency weekend rectal cancer surgery were similar but not statistically significant, likely explained by small numbers. Conclusions: Weekend emergency colon cancer surgery was associated with higher mortality and severe complication rates. More research is needed to understand which factors explain and contribute to these differences.

Multicenter Stratified Comparison of Hospital Costs Between Laparoscopic and Open Colorectal Cancer Resections: Influence of Tumor Location and Operative Risk.

OBJECTIVE: To compare actual 90-day hospital costs between elective open and laparoscopic colon and rectal cancer resection in a daily practice multicenter setting stratified for operative risk. BACKGROUND: Laparoscopic resection has developed as a commonly accepted surgical procedure for colorectal cancer. There are conflicting data on the influence of laparoscopy on hospital costs, without separate analyses based on operative risk. METHODS: Retrospective analyses using a population-based database (Dutch Surgical Colorectal Audit). All elective resections for a T1-3N0-2M0 stage colorectal cancer were included between 2010 and 2012 in 29 Dutch hospitals. Operative risk was stratified for age (<75 years or ≥75 years) and ASA status (I-II/III-IV). Ninety-day hospital costs were measured uniformly in all hospitals based on time-driven activity-based costing. RESULTS: Total 90-day hospital costs ranged from &OV0556;10474 to &OV0556;20865 in the predefined subgroups. For colon cancer surgery (N = 4202), laparoscopic resection was significant less expensive than open resection in all subgroups, savings because of laparoscopy ranged from &OV0556;409 (<75 years ASA I-II) to &OV0556;1932 (≥75 years ASA I-II). In patients ≥75 years and ASA I-II, laparoscopic resection was associated with 46% less mortality (P = 0.05), 41% less severe complications (P < 0.001), 25% less hospital stay (P = 0.013), and 65% less ICU stay (P < 0.001). For rectal cancer surgery (N=2328), all laparoscopic subgroups had significantly higher total hospital costs, ranging from &OV0556;501 (<75 years ASA I-II) to &OV0556;2515 (≥75 years ASA III-IV). CONCLUSIONS: Laparoscopic resection resulted in the largest cost reduction in patients over 75 years with ASA I-II undergoing colonic resection, and the largest cost increase in patients over 75 years with ASA III-IV undergoing rectal resection as compared with an open approach.

Single center cost analysis of single-port and conventional laparoscopic surgical treatment in colorectal malignant diseases.

BACKGROUND AND PURPOSE: Single-port laparoscopy (SPL) is a relatively new technique, used in various procedures. There is limited knowledge about the cost effectiveness and the learning curve of this technique. The primary aim of this study was to compare hospital costs between SPL and conventional laparoscopic resections (CLR) for colorectal cancer; the secondary aim was to identify a learning curve of SPL. METHODS: All elective colorectal cancer SPL and CLR performed in a major teaching hospital between 2011 and 2012 that were registered in the Dutch Surgical Colorectal Audit were included (n = 267). The economic evaluation was conducted from a hospital perspective, and costs were calculated using time-driven activity-based costing methodology up to 90 days after discharge. When looking at SPL only, the introduction year (2011) was compared to the next year (2012). RESULTS: SPL (n = 78) was associated with lower mortality, lower reintervention rates, and more complications as compared to CLR (n = 189); however, none of these differences were statistically significant. A significant shorter operating time was seen in the SPL. Total costs were higher for SPL group as compared to CLR; however, this difference was not statistically significant. For the SPL group, most clinical outcomes improved between 2011 and 2012; moreover, total hospital costs for SPL in 2012 became comparable to CLR. CONCLUSION: No significant differences in financial outcomes between SPL and CLR were identified. After the introduction period, SPL showed similar results as compared to CLR. Conclusions are based on a small single-port group and the conclusions of this manuscript should be an impetus for further research.

Hospital costs of colorectal cancer surgery for the oldest old: A Dutch population-based study.

Background Due to increasing healthcare costs, discussions regarding increased hospital costs when operating on high-risk patients is rising. Therefore, the aim of this study was to analyze if oldest-old colorectal cancer patients have a greater impact on hospital costs than their younger counterparts. METHODS: All colorectal cancer procedures performed in 29 Dutch hospitals between 2010 and 2012 and listed in the Dutch Surgical Colorectal Audit were analyzed. Oldest-old patients (≥85 years) were compared to patients <85 years. Ninety-day hospital costs were measured uniformly in all hospitals based on time-driven activity-based costs. RESULTS: Compared to <85-year-old patients (n = 9130), the oldest old (n = 783) had longer hospital stays (LOS) (11.3 vs. 13.2, P < 0.001), more severe complications (21.8% vs. 29.0%, P < 0.001), more failure to rescue (13.9% vs. 37.0%, P < 0.001) and higher mortality (3.0% vs. 10.7%, P < 0.001). Deceased oldest-old patients had significantly less LOS and less LOS ICU. Total hospital costs were 3% lower for oldest-old patients (€13,168) than for <85-year-old patients (€13,644, P < 0.001). In cases of severe complications or death, hospital costs for the oldest old were 25% and 31% lower than those of <85-year-old patients (both P < 0.001). CONCLUSION: Although frequently assumed to be more expensive, operating on oldest-old patients with colorectal cancer does not increase hospital costs compared to younger patients. This was most likely due to faster deterioration or less aggressive treatment of oldest-old patients when (severe) complications occurred. J. Surg. Oncol. 2016;114:1009-1015. © 2016 Wiley Periodicals, Inc.

Colorectal cancer surgery for obese patients: Financial and clinical outcomes of a Dutch population-based registry.

BACKGROUND AND OBJECTIVES: The objective of this study was to explore the association among adverse events, body mass index (BMI), and hospital costs after colorectal cancer surgery in a country with an intermediate BMI distribution. METHODS: All colorectal cancer procedures in 29 Dutch hospitals listed in a 2010-2012 population-based database and with a BMI > 18.5 were included (n = 8687). Hospital costs were measured uniformly and based on time-driven activity-based costing. The BMI classification of the World Health Organization was used. RESULTS: Patients in obesity classes 1 (23.6% [after risk-adjustment OR 1.245, CI 1.064-1.479, P = 0.007]) and ≥2 (28.1% [after risk-adjustment OR 1.816, CI 1.382-2.388, P < 0.001]) were associated with more severe complications and higher hospital costs (€14,294, +9.6%, after risk-adjustment +7.9%, P < 0.001; and €15,913 +22.0%, after risk-adjustment +21.2%, P < 0.001, respectively) than normal weight patients (20.8% and €13,040, respectively). Pre-obese patients had significantly lower mortality rates (2.7%, after risk-adjustment, OR 0.756, CI 0.577-0.991, P = 0.042) than normal-weight patients (3.9%). CONCLUSIONS: Obese surgical colorectal cancer patients in a country with an intermediate BMI distribution are associated with a significant increase in hospital costs because these patients suffer from more severe complications. This is the first study to provide evidence for the "obesity-paradox" for mortality in colorectal cancer surgery. J. Surg. Oncol. 2016;113:489-495. © 2016 Wiley Periodicals, Inc.

Nationwide Outcomes Measurement in Colorectal Cancer Surgery: Improving Quality and Reducing Costs.

BACKGROUND: Recent literature suggests that focus in health care should shift from reducing costs to improving quality; where quality of health care improves, cost reduction will follow. Our primary aim was to investigate whether improving the quality of surgical colorectal cancer care, by using a national quality improvement initiative, leads to a reduction of hospital costs. STUDY DESIGN: This was a retrospective analysis of clinical and financial outcomes after colorectal cancer surgery in 29 Dutch hospitals (9,913 patients). Detailed clinical data were obtained from the 2010 to 2012 population-based Dutch Surgical Colorectal Audit. Patient-level costs were measured uniformly in all participating hospitals and based on time-driven, activity-based costing. Odds ratios (OR) and relative differences (RD) were risk adjusted for hospitals and differences in patient characteristics. RESULTS: Over 3 consecutive years, severe complications and mortality declined by 20% (risk-adjusted OR 0.739, 95% CI 0.653 to 0.836, p < 0.001), and 29% (risk-adjusted OR 0.757, 95% CI 0.571 to 1.003, p = 0.05), respectively. Simultaneously, costs during primary admission decreased 9% (risk-adjusted RD -7%, 95% CI -10% to -5%, p < 0.001) without an increase in costs within the first 90 days after discharge (RD -2%, 95% CI -10% to 6%, p = 0.65). An inverse relationship (at hospital level) between severe complication rate and hospital costs was identified (R = 0.64). Hospitals with increasing severe complication rates (between 2010 and 2012) were associated with increasing costs; hospitals with declining severe complication rates were associated with cost reduction. CONCLUSIONS: This report presents evidence for simultaneous quality improvement and cost reduction. Participation in a nationwide quality improvement initiative with continuous quality measurement and benchmarked feedback reveals opportunities for targeted improvements, bringing the medical field forward in improving value of health care delivery. The focus of health care should shift to improving quality, which will catalyze costs savings as well.

[A female patient with an unusual swelling in the groin]. / Een patiënte met een ongewone zwelling in de lies.

A swelling in the groin is a highly prevalent complaint. However, surgical exploration can sometimes reveal an unexpected finding, such as in our case of a postmenopausal 52-year-old female patient. After surgical excision, a left groin mass appeared to be a leiomyoma of the round ligament of the uterus.

Timing of bone marrow cell delivery has minimal effects on cell viability and cardiac recovery after myocardial infarction.

BACKGROUND: Despite ongoing clinical trials, the optimal time for delivery of bone marrow mononuclear cells (BMCs) after myocardial infarction is unclear. We compared the viability and effects of transplanted BMCs on cardiac function in the acute and subacute inflammatory phases of myocardial infarction. METHODS AND RESULTS: The time course of acute inflammatory cell infiltration was quantified by FACS analysis of enzymatically digested hearts of FVB mice (n=12) after left anterior descending artery ligation. Mac-1(+)Gr-1(high) neutrophil infiltration peaked at day 4. BMCs were harvested from transgenic FVB mice expressing firefly luciferase (Fluc) and green fluorescent protein (GFP). Afterward, 2.5x10(6) BMCs were injected into the left ventricle of wild-type FVB mice either immediately (acute BMC) or 7 days (subacute BMC) after myocardial infarction, or after a sham procedure (n=8 per group). In vivo bioluminescence imaging showed an early signal increase in both BMC groups at day 7, followed by a nonsignificant trend (P=0.203) toward improved BMC survival in the subacute BMC group that persisted until the bioluminescence imaging signal reached BACKGROUND: <0.01) and 6 weeks (both BMC groups versus saline; P<0.05) but no significant differences between the 2 BMC groups. FACS analysis of BMC-injected hearts at day 7 revealed that GFP(+) BMCs expressed hematopoietic (CD45, Mac-1, Gr-1), minimal progenitor (Sca-1, c-kit), and no endothelial (CD133, Flk-1) or cardiac (Trop-T) cell markers. CONCLUSIONS: Timing of BMC delivery has minimal effects on intramyocardial retention and preservation of cardiac function. In general, there is poor long-term engraftment and BMCs tend to adopt inflammatory cell phenotypes.

Poor functional recovery after transplantation of diabetic bone marrow stem cells in ischemic myocardium.

BACKGROUND: Autologous bone marrow mononuclear cell (BMMC) therapy has shown promise for improving cardiac function after myocardial infarction. The efficiency of such therapy for diabetic patients remains unknown. METHODS: BMMCs were harvested from type 2 diabetic male BKS.Cg-m+/+Lepr(db)/J mice or C57BLKS/J (non-diabetic control) mice and were isolated using Ficoll-based separation. Cell characterization was performed by flow cytometry. Cell viability was determined by apoptosis and proliferation assays. Female BKS.Cg-m+/+Lepr(db)/J mice underwent left anterior descending artery ligation and were randomized into 3 groups receiving 2.5 x 10(6) diabetic BMMCs (n = 8), 2.5 x 10(6) control BMMCs (n = 8), or phosphate-buffered saline (n = 6). At Week 5, cardiac function was assessed with echocardiography and invasive hemodynamic measurements. Post-mortem cell survival was quantified by TaqMan real-time transcription polymerase chain reaction (RT-PCR) for the male Sry gene. RESULTS: BKS.Cg-m+/+Lepr(db)/J BMMCs showed a significantly lower mononuclear fraction and a significantly lower proliferation rate compared with C57BLKS/J BMMCs. Fractional shorting (40.1% +/- 1.2% vs 30.3% +/- 1.9%; p = 0.001) and cardiac output (4,166 +/- 393 vs 2,246 +/- 462 microl/min; p = 0.016) significantly improved for mice treated with control BMMCs injection compared with those treated with diabetic BMMCs, respectively. This difference could not be attributed to difference in cell engraftment because TaqMan RT-PCR showed no significant difference in cell survival in infarcted hearts between the 2 groups. CONCLUSIONS: Diabetic BMMCs are significantly impaired in their ability to improve cardiac function after myocardial infarction compared with control BMMCs. These findings could have significant clinical implication regarding autologous BMMC therapy in diabetic patients.

Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart.

BACKGROUND: Mesenchymal stem cells hold promise for cardiovascular regenerative therapy. Derivation of these cells from the adipose tissue might be easier compared with bone marrow. However, the in vivo fate and function of adipose stromal cells (ASC) in the infarcted heart has never been compared directly to bone marrow-derived mesenchymal cells (MSC). METHODS: ASC and MSC were isolated from transgenic FVB mice with a beta-actin promoter driving firefly luciferase and green fluorescent protein double fusion reporter gene, and they were characterized using flow cytometry, microscopy, bioluminescence imaging and luminometry. FVB mice (n=8 per group) underwent myocardial infarction followed by intramyocardial injection of 5x10(5) ASC, MSC, fibroblasts (Fibro, positive control), or saline (negative control). Cell survival was measured using bioluminescence imaging for 6 weeks and cardiac function was monitored by echocardiography and pressure-volume analysis. Ventricular morphology was assessed using histology. RESULTS: ASC and MSC were CD34(-), CD45(-), c-Kit(-), CD90(+), Sca-1(+), shared similar morphology and had a population doubling time of approximately 2 days. Cells expressed Fluc reporter genes in a number-dependent fashion as confirmed by luminometry. After cardiac transplantation, both cell types showed drastic donor cell death within 4 to 5 weeks. Furthermore, transplantation of either cell type was not capable of preserving ventricular function and dimensions, as confirmed by pressure-volume-loops and histology. CONCLUSION: This is the first study comparing the in vivo behavior of both cell types in the infarcted heart. ASC and MSC do not tolerate well in the cardiac environment, resulting in acute donor cell death and a subsequent loss of cardiac function similar to control groups.

Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts.

Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immunodeficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4(+) T cells to be an important modulator of hESC immune-mediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches.

Novel immunosuppression: R348, a JAK3- and Syk-inhibitor attenuates acute cardiac allograft rejection.

BACKGROUND: Janus kinase (JAK)3 is crucial for signal transduction downstream of various cytokine receptors in immune cells. This is the first report on the novel JAK3 inhibitor R348. METHODS: (1) Detailed pharmacokinetic data were obtained in rats; (2) multiple in vitro enzyme inhibition assays were performed to characterize the drug; (3) prevention of acute rejection was investigated in animals treated with different doses of R348 or rapamycin for 5 days; and (4) cardiac allograft survival after a 10-day treatment period was studied for various regimens of R348, tacrolimus, or rapamycin; combination indices were calculated to evaluate drug interactions. RESULTS: (1) Plasma levels of R348's active metabolite R333 sustained high for 8 hr or more, depending on the dose. (2) In vitro enzyme assays showed potent inhibition of JAK3- and Syk-dependent pathways. (3) R348 40 mg/kg preserved graft function, significantly reduced graft infiltration, and decreased histologic ISHLT rejection scores on postoperative day 5. Results were similar to those of rapamycin 3 mg/kg. Likewise, both drugs significantly reduced the cellular Th1 and Th2 immune responses, as determined by enzyme-linked immunosorbent assays. Intragraft inflammatory cytokine upregulation was similarly suppressed by R348 and rapamycin. R348 10 mg/kg was subtherapeutic. (4) Allograft survival was similar for R348 20 and 40 mg/kg, which was comparable with therapeutically dosed tacrolimus or rapamycin. In combination regimens, R348 demonstrated highly beneficial synergistic interactions with tacrolimus. CONCLUSIONS: R348 is a promising novel JAK3/Syk-inhibitor with favorable pharmacokinetics and biological activity. It effectively diminishes acute cardiac allograft rejection and is suitable for combination regimens with tacrolimus.