An International Collaborative Standardizing a Comprehensive Patient-Centered Outcomes Measurement Set for Colorectal Cancer.

IMPORTANCE: Global health systems are shifting toward value-based care in an effort to drive better outcomes in the setting of rising health care costs. This shift requires a common definition of value, starting with the outcomes that matter most to patients. OBJECTIVE: The International Consortium for Health Outcomes Measurement (ICHOM), a nonprofit initiative, was formed to define standard sets of outcomes by medical condition. In this article, we report the efforts of ICHOM's working group in colorectal cancer. EVIDENCE REVIEW: The working group was composed of multidisciplinary oncology specialists in medicine, surgery, radiation therapy, palliative care, nursing, and pathology, along with patient representatives. Through a modified Delphi process during 8 months (July 8, 2015 to February 29, 2016), ICHOM led the working group to a consensus on a final recommended standard set. The process was supported by a systematic PubMed literature review (1042 randomized clinical trials and guidelines from June 3, 2005, to June 3, 2015), a patient focus group (11 patients with early and metastatic colorectal cancer convened during a teleconference in August 2015), and a patient validation survey (among 276 patients with and survivors of colorectal cancer between October 15, 2015, and November 4, 2015). FINDINGS: After consolidating findings of the literature review and focus group meeting, a list of 40 outcomes was presented to the WG and underwent voting. The final recommendation includes outcomes in the following categories: survival and disease control, disutility of care, degree of health, and quality of death. Selected case-mix factors were recommended to be collected at baseline to facilitate comparison of results across treatments and health care professionals. CONCLUSIONS: A standardized set of patient-centered outcome measures to inform value-based health care in colorectal cancer was developed. Pilot efforts are under way to measure the standard set among members of the working group.

Gender Mainstreaming and Transplant Surgery.

BACKGROUND: Gender differences in medicine are gaining in importance. In transplant surgery, not only the patient's gender but also that of the donor play an important role in the outcome of transplantation due to sociocultural and genetic factors. METHODS: This review article gives an overview of the latest investigations into gender-related influences in the field of visceral transplantation. For this purpose, a systematic review of the literature was performed. RESULTS: In general, women are less often evaluated for and subjected to transplantation worldwide. Significantly poorer outcome can be observed in women with liver transplantation following hepatitis C cirrhosis. Furthermore, female renal grafts are less favorable in terms of outcome and survival. Gender disparities affect transplant medicine due to subtle gender-specific immunological factors. Sociocultural factors also lead to differences in the clinical treatment of men and women, which may influence overall survival. CONCLUSION: For a better understanding of gender-specific differences in transplant medicine and a possible improvement in outcome, further research in this field is necessary.

Gender-Specific Differences in Surgical Site Infections: An Analysis of 438,050 Surgical Procedures from the German National Nosocomial Infections Surveillance System.

BACKGROUND: Surgical site infections (SSI) are among the most frequent healthcare-associated infections. They impose a substantial burden with increased morbidity and exceeding healthcare costs. Risk factors such as age, diabetes, and smoking status are commonly accounted for in the literature, but few studies address gender differences. METHODS: Data from the German Nosocomial Infections Surveillance System (Krankenhaus-Infektions-Surveillance-System (KISS)) from 2005 to 2010 were analysed for cardiac, vascular, visceral, and orthopaedic surgery, with a total of 438,050 surgical procedures and 8,639 SSI. Rates of SSI and isolated pathogens were analysed for gender. RESULTS: Women had a lower rate of SSI (SSI/100 procedures) in abdominal surgery than men (2.92 vs. 4.37; p < 0.001). No gender-specific differences were found in orthopaedic and vascular surgery, while women had a higher risk for SSI in cardiac surgery (5.50 vs. 3.02; p < 0.001). Isolated pathogens showed differences for sensitive Staphylococcus aureus and Pseudomonas aeruginosa, which were more frequent in women (both p = 0.007), while coagulase-negative staphylococci occurred more often in men (18.8 vs. 14.0%; p < 0.001). CONCLUSION: Gender differences in SSI exist and are procedure-specific. The underlying mechanisms need to be further elucidated so that targeted measures for the prevention of SSI can be developed.

Problems of randomization to open or laparoscopic sigmoidectomy for diverticular disease.

PURPOSE: Although complicated sigmoid diverticulitis is the most common reason for laparoscopic sigmoidectomy, the level of evidence for preference of the laparoscopic approach is low. METHODS: A multicenter, randomized clinical trial comparing laparoscopic and open sigmoidectomy for diverticulitis was conducted to evaluate the short- and mid-term outcome after both techniques. Data were assessed from randomized patients and from patients who refused randomization. Results of the here presented interim analysis describe the difficulties in randomization leading to abortion of recruitment. RESULTS: 149 patients were enrolled in the randomized trial within 36 months until the interim analysis. A further 294 nonrandomized patients who preferred one of both surgical approaches were assessed. Several differences between these groups were apparent including simple epidemiological characteristics such as age (65 vs. 60 years, p < 0.001), gender (65% vs. 55% female, p = 0.05), BMI (27 vs. 26 kg/m(2), p = 0.01), and ASA class < III (72% vs. 87%, p < 0.001). CONCLUSION: The majority of eligible patients refused a random allocation. A widespread presumption of the advantages of laparoscopic surgery was probably the main reason for refusal. Patients participating in randomization did not reflect the general population in recruiting hospitals. Future trials comparing minimal invasive procedures should be conducted before presumptions concerning the outcome are widespread in the general population.

The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15.

The Wnt/beta-catenin signalling pathway has important roles in normal cellular proliferation, development and angiogenesis. Many malignant transformations, including sporadic colorectal tumours, are caused by constitutive activation of the Wnt route due to mutations in the tumour suppressor protein adenomatous polyposis coli (APC) or the beta-catenin oncogene, ultimately resulting in reduced beta-catenin degradation by the ubiquitin (Ub) proteasome system (UPS). The COP9 signalosome (CSN) regulates the UPS by controlling cullin-RING Ub ligases (CRLs). We show here that the CSN and the beta-catenin destruction complex cooperate in targeting beta-catenin for degradation by the UPS. Together with the CRL that ubiquitinates beta-catenin, they form a supercomplex responsible for beta-catenin degradation. Wnt3A, glycogen synthase kinase 3beta inhibitors or mutation of CSN-mediated deneddylation induce the disassembly of the supercomplex and the accumulation of beta-catenin. Likewise, downregulation of the CSN in HeLa cells leads to retarded degradation of beta-catenin. Additionally, we found that the knockdown of the CSN causes accelerated proteolysis of APC, an essential component of the beta-catenin destruction complex, which is degraded by the UPS as beta-catenin. We show here that APC is stabilised by the Ub-specific protease 15 (USP15) associated with the CSN. This is demonstrated by over-expression of siRNA oligonucleotides against USP15 or by over-expression of an USP15 mutant, which is unable to degrade poly-Ub chains. Thus, the CSN controls the Wnt/beta-catenin signalling by assisting the assembly of beta-catenin-degrading supercomplexes by deneddylation and, simultaneously, by stabilising APC via CSN-associated USP15. The CSN regulates the balance between beta-catenin and APC. Disturbance of this balance can cause cancer by driving cell transformation, tumour angiogenesis and metastasis. A model is provided that proposes a role of CSN-mediated deneddylation in the formation of the beta-catenin-degrading supercomplex and the protection of complex-bound APC via CSN-associated USP15.

Stress and heart rate variability in surgeons during a 24-hour shift.

OBJECTIVE: To determine the specific effects of working long hours in surgery and potential cardiac stress in the individual surgeon by measuring heart rate variability (HRV). DESIGN, SETTING, AND PARTICIPANTS: This prospective study measured HRV before, during, and after a 24-hour shift in a standardized resting period of 10 minutes. Measurements were repeated over 10 shifts for each participant. Eight surgeons from a high-volume inner-city surgery department took part in the study. MAIN OUTCOME MEASURES: Time and frequency domain parameters of HRV as parameters of cardiac stress and correlations with perceived stress and fatigue on a visual analog scale. RESULTS: Perceived fatigue increased over 24 hours (P < .001), whereas stress levels decreased slightly (P = .06). Time domain parameters of HRV increased from before the shift to after the shift (standard deviation of normal to normal intervals, square root of the mean normal to normal interval, and percentage of adjacent pairs of normal to normal intervals differing by more than 50 milliseconds: all P < .01), denoting more cardiac relaxation. Both the low- and high-frequency components increased (P = .04 and P < .001, respectively), showing a heightened activity of the autonomic nervous system. CONCLUSIONS: Measurements of HRV during a 24-hour surgical shift did not show an increase in cardiac stress concerning time domain parameters despite intense workloads for a median of 20 hours. Frequency components increased in parallel, though, suggesting alterations in sympathovagal balance. Perceived stress levels correlated with HRV, whereas fatigue did not. Further studies on occupational stress and its cardiac effects in surgeons are needed.

Expression of receptor activator of NF-kappaB ligand (RANKL) mRNA in human multiple myeloma cells.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and a result of excessive osteoclast activation. Recently, the receptor activator of NF-kappaB ligand (RANKL) was found to be the critical factor for osteoclastogenesis. Studies showed that myeloma cells induce RANKL expression in bone marrow stromal cells, but it remained a controversy whether myeloma cells directly express RANKL. METHODS: Therefore, we analyzed the expression of RANKL mRNA in freshly isolated CD138 positive plasma cells from patients with multiple myeloma and osteolytic bone lesions, using three different primer pairs against human RANKL. RESULTS: RANKL mRNA could be detected in bone marrow plasma cells from myeloma patients with osteolytic myeloma bone disease. CONCLUSIONS: These findings show that myeloma cells directly express RANKL and indicate that specific blockade of RANKL may be an effective treatment for myeloma bone disease.

Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion.

PURPOSE: In this study, we investigated the effects of cell-permeable proteasome inhibitors MG-132, MG-262, PSI, and lactacystin on multiple myeloma cell lines OPM-2, U266, RPMI 8226-S, freshly isolated plasma cells with or without deletion of chromosome 13 from patients with multiple myeloma and plasma cell leukemia, and CD34+ human hematopoietic stem cells. The effects of proteasome inhibitors on cell cycle progression, cell growth, and apoptosis were determined. METHODS: MTT-assay was used to examine the cytotoxicity, and annexin-V staining to quantify apoptosis. Cell cycle analyses were performed using 7-ADD and Ki-67 staining by flow cytometry. RESULTS: PSI was the most potent proteasome inhibitor among those tested with a half maximal cytotoxicity (IC(50)) of 5.7 nM, followed by MG-262, MG-132, and lactacystin. Growth inhibition occurred irrespective of chromosome 13 status. Cell cycle arrest occurred in a dose- and time-dependent manner. Low, subapoptotic dosages led to a partial loss of Ki-67 antigen, whereas apoptotic dosages led to reduced Ki-67 levels. Apoptosis was partially dependent on activation of caspase-3, since Ac-DEVD-cho, a caspase-3 inhibitor, could reduce apoptosis significantly. The cytotoxicity of the four proteasome inhibitors tested was significantly lower in human hematopoietic stem cells than in myeloma cells. CONCLUSIONS: Our results show that proteasome inhibitors induce time- and dose-dependent cell cycle alterations, growth inhibition, and apoptosis in human myeloma cells irrespective of chromosome 13 deletion.

Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. EXPERIMENTAL DESIGN: Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. RESULTS: The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). CONCLUSIONS: These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.

Bone resorption parameters [carboxy-terminal telopeptide of type-I collagen (ICTP), amino-terminal collagen type-I telopeptide (NTx), and deoxypyridinoline (Dpd)] in MGUS and multiple myeloma.

Skeletal morbidity is a major problem in multiple myeloma. Histomorphometric studies have demonstrated that increased bone resorption can be present even in the absence of radiographic abnormalities. To overcome diagnostic problems in estimating the activity of bone resorption, new laboratory parameters that reflect bone metabolism accurately are urgently needed. We analyzed three parameters of osteoclastic bone destruction, i.e. deoxypyridinoline (Dpd) and amino-terminal collagen type-I telopeptide (NTx) in urine and carboxy-terminal telopeptide of type-I collagen (ICTP) in serum, of 75 patients with multiple myeloma (n = 57) or monoclonal gammopathy of undetermined significance (MGUS, n = 18) by ELISA/RIA techniques. Serum ICTP and urinary Dpd levels increased parallel to the stage of the disease and differed significantly (P < 0.001 for ICTP and P = 0.03 for Dpd) between MGUS, myeloma stage I, and myeloma in stages II and III according to Salmon and Durie. ICTP and Dpd were significantly elevated in patients with multiple myeloma in stage I compared to individuals with MGUS, while no significant difference was found for NTx. In this first study comparing the prognostic relevance of ICTP, NTx, and Dpd in multiple myeloma patients, ICTP was found to be a prognostic factor for overall survival in the Kaplan-Meier analysis (log-rank test: P < 0.03). Urinary NTx showed borderline significance (P = 0.05), and Dpd had no prognostic value in the survival analysis. Our data show that serum ICTP and urinary Dpd levels increase in parallel to advanced disease stages, and gives the first report on a significant difference in the bone resorption parameters ICTP and Dpd between individuals with MGUS and patients with myeloma in stage I. Among the bone resorption parameters studied serum ICTP was found to be the best prognostic factor for survival in multiple myeloma.