Rates of paclitaxel hypersensitivity reactions using a modified Markman's infusion protocol as primary prophylaxis.

PURPOSE: Markman's desensitisation protocol allows successful retreatment of patients who have had significant paclitaxel hypersensitivity reactions. We aimed to reduce the risk and severity of paclitaxel hypersensitivity reactions by introducing this protocol as primary prophylaxis. METHODS: We evaluated all patients with a gynaecological malignancy receiving paclitaxel before (December 2018 to September 2019) and after (October 2019 to July 2020) the implementation of a modified Markman's desensitisation protocol. The pre-implementation group received paclitaxel over a gradually up-titrated rate from 60 to 180 ml/h. The post-implementation group received paclitaxel via 3 fixed-dose infusion bags in the first 2 cycles. Rates and severity of paclitaxel hypersensitivity reactions were compared. RESULTS: A total of 426 paclitaxel infusions were administered to 78 patients. The median age was 64 years (range 34-81), and the most common diagnosis was ovarian, fallopian tube and primary peritoneal cancer (67%, n = 52/78). Paclitaxel hypersensitivity reaction rates were similar in the pre-implementation (8%, n = 16/195) and post-implementation groups (9%, n = 20/231; p = 0.87). Most paclitaxel hypersensitivity reactions occurred within 30 min (pre- vs. post-implementation, 88% [n = 14/16] vs. 75% [n = 15/20]; p = 0.45) and were grade 2 in severity (pre- vs. post-implementation, 81% [n = 13/16] vs. 75% [n = 15/20]; p = 0.37). There was one grade 3 paclitaxel hypersensitivity reaction in the pre-implementation group. All patients were successfully rechallenged in the post-implementation group compared to 81% (n = 13/16) in the pre-implementation group (p = 0.43). CONCLUSION: The modified Markman's desensitisation protocol as primary prophylaxis did not reduce the rate or severity of paclitaxel hypersensitivity reactions, although all patients could be successfully rechallenged.

Progress in the Treatment of Small Intestine Cancer.

OPINION STATEMENT: Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.

Taxonomy of fibroblasts and progenitors in the synovial joint at single-cell resolution.

OBJECTIVES: Fibroblasts in synovium include fibroblast-like synoviocytes (FLS) in the lining and Thy1+ connective-tissue fibroblasts in the sublining. We aimed to investigate their developmental origin and relationship with adult progenitors. METHODS: To discriminate between Gdf5-lineage cells deriving from the embryonic joint interzone and other Pdgfrα-expressing fibroblasts and progenitors, adult Gdf5-Cre;Tom;Pdgfrα-H2BGFP mice were used and cartilage injury was induced to activate progenitors. Cells were isolated from knees, fibroblasts and progenitors were sorted by fluorescence-activated cell-sorting based on developmental origin, and analysed by single-cell RNA-sequencing. Flow cytometry and immunohistochemistry were used for validation. Clonal-lineage mapping was performed using Gdf5-Cre;Confetti mice. RESULTS: In steady state, Thy1+ sublining fibroblasts were of mixed ontogeny. In contrast, Thy1-Prg4+ lining fibroblasts predominantly derived from the embryonic joint interzone and included Prg4-expressing progenitors distinct from molecularly defined FLS. Clonal-lineage tracing revealed compartmentalisation of Gdf5-lineage fibroblasts between lining and sublining. Following injury, lining hyperplasia resulted from proliferation and differentiation of Prg4-expressing progenitors, with additional recruitment of non-Gdf5-lineage cells, into FLS. Consistent with this, a second population of proliferating cells, enriched near blood vessels in the sublining, supplied activated multipotent cells predicted to give rise to Thy1+ fibroblasts, and to feed into the FLS differentiation trajectory. Transcriptional programmes regulating fibroblast differentiation trajectories were uncovered, identifying Sox5 and Foxo1 as key FLS transcription factors in mice and humans. CONCLUSIONS: Our findings blueprint a cell atlas of mouse synovial fibroblasts and progenitors in healthy and injured knees, and provide novel insights into the cellular and molecular principles governing the organisation and maintenance of adult synovial joints.

Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis.

OBJECTIVE: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction. METHODS: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap-Tead reporter cells and Yap-Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells. RESULTS: Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen-), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1ß, Jak-dependently activated Yap and induced Yap-Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA. CONCLUSIONS: Our findings uncover the IL-6-Yap-Snail signalling axis in pathogenic SF in inflammatory arthritis.

Communication Training, Adverse Events, and Quality Measures: 2 Retrospective Database Analyses in Washington State Hospitals.

OBJECTIVE: Washington State's HealthPact program was launched in 2011 as part of AHRQ's Patient Safety and Medical Liability Reform initiative. HealthPact delivered interdisciplinary communication training to health-care professionals with the goal of enhancing safety. We conducted 2 exploratory, retrospective database analyses to investigate training impact on the frequency of adverse events (AEs) and select quality measures across 3 time frames: pretraining (2009-2011), transition (2012), and posttraining (2013). METHODS: Using administrative data from Washington State's Comprehensive Hospital Abstract Reporting System (CHARS) and clinical registry data from the Surgical Care and Outcomes Assessment Program (SCOAP), we compared proportions of AEs and quality measures between HealthPact (n = 4) and non-HealthPact (n = 93-CHARS; n = 48-SCOAP) participating hospitals. Risk ratios enabled comparisons between the 2 groups. Multivariable logistic regression enabled investigation of the association between training and the frequency of AEs. RESULTS: Approximately 9.4% (CHARS) and 7.7% (SCOAP) of unique patients experienced 1 AE or greater. In CHARS, the odds of a patient experiencing an AE in a HealthPact hospital were initially (pretraining) higher than in a non-HealthPact hospital (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.10-1.17), lower in transition (OR, 0.80; 95% CI, 0.76-0.83) and posttraining (OR, 0.72; 95% CI, 0.69-0.75) periods. In SCOAP, ORs were consistently lower in HealthPact hospitals: pretraining (OR, 0.87; 95% CI, 0.80-0.95), transition (OR, 0.75; 95% CI, 0.70-0.81), and posttraining (OR, 0.63; 95% CI, 0.58-0.68). The proportion of at-risk patients that experienced each individual AE was low (<1%) throughout. Adherence to quality measures was high. CONCLUSIONS: Interprofessional communication training is an area of intense activity nationwide. A broad-based training initiative may play a role in mitigating AEs.

Decision-making in Orthopaedic Oncology: Does Cognitive Bias Affect a Virtual Patient's Choice Between Limb Salvage and Amputation?

BACKGROUND: The local treatment of extremity sarcomas usually is predicated on a decision between limb salvage and amputation. The manner in which surgical options are presented in the context of shared decision-making may influence this decision. In a population of "simulated" patients-survey respondents presented with a mock clinical vignette and then asked to choose between treatments-we assessed cognitive bias by deliberate alteration of the subjective presentation of the same objective information. QUESTIONS/PURPOSES: (1) Will the manner in which information is presented to a simulated patient, in the setting of treatment for a bone sarcoma, bias their decision regarding pursuing amputation versus limb salvage? (2) At the time of decision-making, will a simulated patient's personal background, demographics, or mood affect their ultimate decision? METHODS: Survey respondents (Amazon MTurk platform) were presented with mock clinical vignettes simulating a sarcoma diagnosis and were asked to choose between amputation and limb salvage. Specific iterations were designed to assess several described types of cognitive bias. These scenarios were distributed, using anonymous online surveys, to potential participants aged 18 years or older. Recruitment was geographically restricted to individuals in the United States. Overall, 404 respondents completed the survey. The average age of respondents was 33 years (SD 1.2 years), 60% were male and 40% were female. In all, 12% of respondents worked in healthcare. Each respondent also completed questions regarding his or her demographics and his or her current mood. Associations between the type of bias presented and the respondent's choice of limb salvage versus amputation were examined. Independent sample t-tests were used to compare means. Statistical significance was defined as p < 0.05. RESULTS: When amputation was presented as an option to mitigate functional loss (framing bias), more patients chose it than when limb salvage was presented as means for increased functional gains (23% [23 of 100] versus 10% [12 of 118], odds ratio [OR], 2.26; p = 0.010). Older simulated patients were more likely to choose limb salvage when exposed to framing bias versus younger patients (mean age 33 years versus 30 years, p = 0.02). Respondents who were employed in healthcare more commonly chose amputation versus limb salvage when exposed to framing bias (24% [eight of 35] versus 9% [17 of 183]; OR, 2.46; p = 0.02). Those who chose amputation were more likely to score higher on scales that measured depression or negative affect. CONCLUSIONS: Shared decision-making in orthopaedic oncology represents a unique circumstance in which several variables may influence a patient's decision between limb salvage and amputation. Invoking cognitive bias in simulated patients appeared to affect treatment decisions. We cannot be sure that these findings translate to the experience of actual sarcoma patients; however, we can conclude that important treatment decisions may be affected by cognitive bias and that patient characteristics (in this study, age, healthcare profession, and mood) may be associated with an individual's susceptibility to cognitive bias. We hope these observations will assist providers in the thoughtful delivery of highly charged information to patients facing difficult decisions, and promote further study of this important concept. LEVEL OF EVIDENCE: Level III, economic and decision analyses.

Stress Urinary Incontinence Surgery in Washington State Before and After Introduction of the Mesh Midurethral Sling.

OBJECTIVES: Mesh midurethral slings (MUSs) are safe, effective treatments for female stress urinary incontinence (SUI), but many companies have ceased production because of controversies surrounding transvaginal mesh. To determine if introduction of MUS has increased the complication rate associated with SUI surgery, we compared women undergoing SUI surgery in the MUS era to those who had surgery prior its introduction. METHODS: This was a retrospective cohort study of a statewide hospital discharge database. Stress urinary incontinence surgeries from 1987 to 1996 and 2007 to 2013 were identified using International Classification of Diseases, Ninth Revision codes. RESULTS: A total of 30,723 SUI surgeries were performed during the study periods. After 2006, slings accounted for 91.8% of SUI surgeries. Patients were older (54.5 vs 53.0 years, P < 0.001) and sicker (22.6% vs 9.7% had ≥1 comorbid condition, P < 0.0001). Blood transfusion was more common in the MUS era (1.2% vs 0.4%, P < 0.001) however, other complications were either similar between groups or less common in the MUS era including 30-day readmission (2.5% vs 2.4%, P = 0.543), reoperation for urinary retention (0.1% vs 0.2%, P < 0.0375), and wound infection (0.1% vs 0.5%, P < 0.001), despite more concomitant prolapse surgeries (69.0 vs 26.9%, P < 0.001) and hysterectomies (53.0 vs 35.4%, P < 0.001) in the MUS era. Hospital stays were shorter after 2006 (1.0 vs 3.0 days, P < 0.001), and fewer women required reoperation for SUI within 2 years (0.5% vs 1.8%, P < 0.001). CONCLUSIONS: Following introduction of MUS, women who underwent SUI surgery were slightly older with more medical comorbidities yet did not appear to experience increased surgical complications. Fewer women underwent reoperation for recurrent SUI, and hospital stays were shorter, suggesting an improvement in care. This study supports the continued availability and use of MUSs.

Automating Electronic Clinical Data Capture for Quality Improvement and Research: The CERTAIN Validation Project of Real World Evidence.

BACKGROUND: The availability of high fidelity electronic health record (EHR) data is a hallmark of the learning health care system. Washington State's Surgical Care Outcomes and Assessment Program (SCOAP) is a network of hospitals participating in quality improvement (QI) registries wherein data are manually abstracted from EHRs. To create the Comparative Effectiveness Research and Translation Network (CERTAIN), we semi-automated SCOAP data abstraction using a centralized federated data model, created a central data repository (CDR), and assessed whether these data could be used as real world evidence for QI and research. OBJECTIVES: Describe the validation processes and complexities involved and lessons learned. METHODS: Investigators installed a commercial CDR to retrieve and store data from disparate EHRs. Manual and automated abstraction systems were conducted in parallel (10/2012-7/2013) and validated in three phases using the EHR as the gold standard: 1) ingestion, 2) standardization, and 3) concordance of automated versus manually abstracted cases. Information retrieval statistics were calculated. RESULTS: Four unaffiliated health systems provided data. Between 6 and 15 percent of data elements were abstracted: 51 to 86 percent from structured data; the remainder using natural language processing (NLP). In phase 1, data ingestion from 12 out of 20 feeds reached 95 percent accuracy. In phase 2, 55 percent of structured data elements performed with 96 to 100 percent accuracy; NLP with 89 to 91 percent accuracy. In phase 3, concordance ranged from 69 to 89 percent. Information retrieval statistics were consistently above 90 percent. CONCLUSIONS: Semi-automated data abstraction may be useful, although raw data collected as a byproduct of health care delivery is not immediately available for use as real world evidence. New approaches to gathering and analyzing extant data are required.

Effectiveness of a Medical vs Revascularization Intervention for Intermittent Leg Claudication Based on Patient-Reported Outcomes.

Importance: Intermittent claudication (IC) is the most common presentation of infrainguinal peripheral artery disease. Both medical and revascularization interventions for IC aim to increase walking comfort and distance, but there is inconclusive evidence of the comparative benefit of revascularization given the possible risk of limb loss. Objective: To compare the effectiveness of a medical (walking program, smoking cessation counseling, and medications) vs revascularization (endovascular or surgical) intervention for IC in the community, focusing on outcomes of greatest importance to patients. Design, Setting, and Participants: Longitudinal (12-month follow-up) prospective observational cohort study conducted between July 3, 2011, and November 5, 2014, at 15 clinics associated with 11 hospitals in Washington State. Participants were 21 years or older with newly diagnosed or established IC. Interventions: Medical or revascularization interventions. Main Outcomes and Measures: Primary end points were 12-month change scores on the distance, speed, and stair-climb domains of the Walking Impairment Questionnaire (score range, 0-100). Secondary outcomes were change scores on the Walking Impairment Questionnaire pain domain (score range, 0-100), Vascular Quality of Life Questionnaire (VascuQol) (score range, 1-7), European Quality of Life-5 Dimension Questionnaire (EQ-5D) (score range, 0-1), and Claudication Symptom Instrument (CSI) (score range, 0-4). Results: A total of 323 adults were enrolled, with 282 (87.3%) in the medical cohort. At baseline, the mean duration of disease was longer for participants in the medical cohort, while those in the revascularization cohort reported more severe disease. Other characteristics were well balanced. At 12 months, change scores in the medical cohort reached significance for the following 3 outcomes: speed (5.9; 95% CI, 0.5-11.3; P = .03), VascuQol (0.28; 95% CI, 0.08-0.49; P = .008), and EQ-5D (0.038; 95% CI, 0.011-0.066; P = .006). In the revascularization cohort, there were significant improvements in the following 7 outcomes: distance (19.5; 95% CI, 7.9-31.0; P = .001), speed (12.1; 95% CI, 1.4-22.8; P = .03), stair climb (11.4; 95% CI, 1.3-21.5; P = .03), pain (20.7; 95% CI, 11.0-30.4; P < .001), VascuQol (1.10; 95% CI, 0.80-1.41; P < .001), EQ-5D (0.113; 95% CI, 0.067-0.159; P < .001), and CSI (-0.63; 95% CI, -0.96 to -0.31; P < .001). Relative improvements (percentage changes) at 12 months in the revascularization cohort over the medical cohort were observed as follows: distance (39.1%), speed (15.6%), stair climb (9.7%), pain (116.9%), VascuQol (41%), EQ-5D (18%), and CSI (13.5%). Conclusions and Relevance: Among patients with IC, those in the revascularization cohort had significantly improved function (Walking Impairment Questionnaire), better health-related quality of life (VascuQol and EQ-5D), and fewer symptoms (CSI) at 12 months compared with those in the medical cohort, providing important information to inform treatment strategies in the community.

Outpatient Rehabilitation for Medicaid-Insured Children Hospitalized With Traumatic Brain Injury.

OBJECTIVES: To describe the prevalence of postdischarge outpatient rehabilitation among Medicaid-insured children hospitalized with a traumatic brain injury (TBI) and to identify factors associated with receipt of services. METHODS: Retrospective cohort of children <21 years, hospitalized for a TBI between 2007 and 2012, from a national Medicaid claims database. Outcome measures were receipt of outpatient rehabilitation (physical, occupational, or speech therapies or physician visits to a rehabilitation provider) 1 and 3 years after discharge. Multivariable regression analyses determined the association of demographic variables, injury severity, and receipt of inpatient services with receipt of outpatient rehabilitation at 1 and 3 years. The mean number of services was compared between racial/ethnic groups. RESULTS: Among 9361 children, only 29% received any type of outpatient rehabilitation therapy during the first year after injury, although 62% sustained a moderate to severe TBI. The proportion of children receiving outpatient therapies declined to 12% in the second and third years. The most important predictor of receipt of outpatient rehabilitation was receipt of inpatient therapies or consultation with a rehabilitation physician during acute care. Compared with children of other racial/ethnic groups, Hispanic children had lower rates of receipt of outpatient speech therapy. CONCLUSIONS: Hospitalized children who received inpatient assessment of rehabilitation needs were more likely to continue outpatient rehabilitation care. Hispanic children with TBI were less likely than non-Hispanics to receive speech therapy. Interventions to increase inpatient rehabilitation during acute care might increase outpatient rehabilitation and improve outcomes for all children.

Hyaluronan expression in primary and secondary brain tumors.

BACKGROUND: Collectively, primary and secondary brain tumors represent a major public health challenge. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with a dismal 5-year survival of only 10%. Breast cancer causes secondary tumors; it occurs in 200,000 patients yearly and 30% of these individuals develop brain metastases which also lead to a very poor prognosis. GBM and primary breast tumors are known to express hyaluronan (HA) which may serve as a therapeutic target. METHODS: For the present study we had two aims: (I) to identify suitable preclinical models for HA in GBM by examining HA expression in human GBM cell lines implanted orthotopically in mice; and (II) to determine whether breast cancer brain metastases in human patients express HA similar to the primary tumor. Forty human surgical samples of primary breast tumors and breast cancer brain metastases were processed and stained for HA. Athymic nu/nu mice were orthotopically implanted with one of 15 GBM lines and after tumors were established, quantitative immunohistochemistry determined whether. RESULTS: HA was expressed. All GBM cell lines and patient-derived orthotopic tumors did express HA, with 3 primary human lines expressing the highest staining intensity, above that of normal brain. All 40 human primary breast tumors and brain metastases examined also contained HA, though staining intensity was highly variable. CONCLUSIONS: Our data support the use of specific patient-derived GBM cell lines in nu/nu mice for preclinical studies on HA-targeting therapies. Additionally, our research provides a basis for the assessment of HA expression and HA-targeting therapeutic agents for the treatment of breast cancer brain metastases.

Perioperative hyperglycemia and risk of adverse events among patients with and without diabetes.

OBJECTIVE: To study the association between diabetes status, perioperative hyperglycemia, and adverse events in a statewide surgical cohort. BACKGROUND: Perioperative hyperglycemia may increase the risk of adverse events more significantly in patients without diabetes (NDM) than in those with diabetes (DM). METHODS: Using data from the Surgical Care and Outcomes Assessment Program, a cohort study (2010-2012) evaluated diabetes status, perioperative hyperglycemia, and composite adverse events in abdominal, vascular, and spine surgery at 53 hospitals in Washington State. RESULTS: Among 40,836 patients (mean age, 54 years; 53.6% women), 19% had diabetes; 47% underwent a perioperative blood glucose (BG) test, and of those, 18% had BG ≥180 mg/dL. DM patients had a higher rate of adverse events (12% vs 9%, P < 0.001) than NDM patients. After adjustment, among NDM patients, those with hyperglycemia had an increased risk of adverse events compared with those with normal BG. Among NDM patients, there was a dose-response relationship between the level of BG and composite adverse events [odds ratio (OR), 1.3 for BG 125-180 (95% confidence interval (CI), 1.1-1.5); OR, 1.6 for BG ≥180 (95% CI, 1.3-2.1)]. Conversely, hyperglycemic DM patients did not have an increased risk of adverse events, including those with a BG 180 or more (OR, 0.8; 95% CI, 0.6-1.0). NDM patients were less likely to receive insulin at each BG level. CONCLUSIONS: For NDM patients, but not DM patients, the risk of adverse events was linked to hyperglycemia. Underlying this paradoxical effect may be the underuse of insulin, but also that hyperglycemia indicates higher levels of stress in NDM patients than in DM patients.

Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy.

Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA(high)) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2(3+) primary breast tumors and approximately 40% of EGFR(+) head and neck squamous cell carcinomas are HA(high), and hypothesized that HA(high) tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA(high) tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA(high) tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA(high) tumors, resulting in enhanced trastuzumab- and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA(high) matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA(high) tumors.

Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment.

Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic ß-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and ß-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.

Enteral contrast in the computed tomography diagnosis of appendicitis: comparative effectiveness in a prospective surgical cohort.

OBJECTIVE: Our goal was to perform a comparative effectiveness study of intravenous (IV)-only versus IV + enteral contrast in computed tomographic (CT) scans performed for patients undergoing appendectomy across a diverse group of hospitals. BACKGROUND: Small randomized trials from tertiary centers suggest that enteral contrast does not improve diagnostic performance of CT for suspected appendicitis, but generalizability has not been demonstrated. Eliminating enteral contrast may improve efficiency, patient comfort, and safety. METHODS: We analyzed data for adult patients who underwent nonelective appendectomy at 56 hospitals over a 2-year period. Data were obtained directly from patient charts by trained abstractors. Multivariate logistic regression was utilized to adjust for potential confounding. The main outcome measure was concordance between final radiology interpretation and final pathology report. RESULTS: A total of 9047 adults underwent appendectomy and 8089 (89.4%) underwent CT, 54.1% of these with IV contrast only and 28.5% with IV + enteral contrast. Pathology findings correlated with radiographic findings in 90.0% of patients who received IV + enteral contrast and 90.4% of patients scanned with IV contrast alone. Hospitals were categorized as rural or urban and by their teaching status. Regardless of hospital type, there was no difference in concordance between IV-only and IV + enteral contrast. After adjusting for age, sex, comorbid conditions, weight, hospital type, and perforation, odds ratio of concordance for IV + enteral contrast versus IV contrast alone was 0.95 (95% CI: 0.72-1.25). CONCLUSIONS: Enteral contrast does not improve CT evaluation of appendicitis in patients undergoing appendectomy. These broadly generalizable results from a diverse group of hospitals suggest that enteral contrast can be eliminated in CT scans for suspected appendicitis.

Peripheral venous and arterial blood gas analysis in adults: are they comparable? A systematic review and meta-analysis.

Peripheral venous blood gas (PVBG) analysis is increasingly being used as a substitute for arterial blood sampling; however, comparability has not been clearly established. To determine if the pH, PCO2 and PO2 obtained from PVBG analysis is comparable with arterial blood gas (ABG) analysis. A search was conducted of electronic databases as well as hand-searching of journals and reference lists through December 2012 to identify studies comparing PVBG with ABG analysis in adult subjects. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A meta-analysis using a random effects model was used to calculate the average difference (bias) and the limits of agreement for the venous and arterial pH, PCO2 and PO2 . A total of 18 studies comprising 1768 subjects were included in the meta-analysis. There was considerable heterogeneity between studies with I(2) approaching 100%. There was little difference between the pH obtained from the PVBG and the ABG, with the arterial pH typically 0.03 higher than the venous pH (95% confidence interval 0.029-0.038). The venous and arterial PCO2 were not comparable because the 95% prediction interval of the bias for venous PCO2 was unacceptably wide, extending from -10.7 mm Hg to +2.4 mm Hg. The PO2 values compared poorly, the arterial PO2 typically 36.9 mm Hg greater than the venous with significant variability (95% confidence interval from 27.2 to 46.6 mm Hg). PVBG analysis compares well with ABG analysis for pH estimations in adults but not to the PCO2 or PO2 . These differences are sufficiently large to be of clinical significance.

Evaluating the association of preoperative functional status and postoperative functional decline in older patients undergoing major surgery.

This prospective cohort study sought to identify predictors of functional decline in patients aged 65 years or older who underwent major, nonemergent abdominal or thoracic surgery in our tertiary hospital from 2006 to 2008. We used the Stanford Health Assessment Questionnaire-Disability Index (HAQ-DI) to evaluate functional decline; a 0.1 or greater increase was used to indicate a clinically significant decline. The preoperative Duke Activity Status Index (DASI) and a physical function score (PFS), assessing gait speed, grip strength, balance, and standing speed, were evaluated as predictors of decline. We enrolled 215 patients (71.2 ± 5.2 years; 56.7% female); 204 completed follow-up HAQ assessments (71.1 ± 5.3 years; 57.8% female). A significant number of patients had functional decline out to 1 year. Postoperative HAQ-DI increases of 0.1 or greater occurred in 45.3 per cent at 1 month, 30.1 per cent at 3 months, and 28.3 per cent at 1 year. Preoperative DASI and PFS scores were not predictors of functional decline. Male sex at 1 month (odds ratio [OR], 3.05; 95% confidence interval [CI], 1.41 to 6.85); American Society of Anesthesiologists class (OR, 3.41; 95% CI, 1.31 to 8.86), smoking (OR, 3.15; 95% CI, 1.27 to 7.85), and length of stay (OR, 1.09; 95% CI, 1.01 to 1.16) at 3 months; and cancer diagnosis at 1 year (OR, 2.6; 95% CI, 1.14 to 5.96) were associated with functional decline.

Routine leak testing in colorectal surgery in the Surgical Care and Outcomes Assessment Program.

OBJECTIVE: To evaluate the effect of routine anastomotic leak testing (performed to screen for leaks) vs selective testing (performed to evaluate for a suspected leak in a higher-risk or technically difficult anastomosis) on outcomes in colorectal surgery because the value of provocative testing of colorectal anastomoses as a quality improvement metric has yet to be determined. DESIGN: Observational, prospectively designed cohort study. SETTING: Data from Washington state's Surgical Care and Outcomes Assessment Program (SCOAP). PATIENTS: Patients undergoing elective left-sided colon or rectal resections at 40 SCOAP hospitals from October 1, 2005, to December 31, 2009. INTERVENTIONS: Use of leak testing, distinguishing procedures that were performed at hospitals where leak testing was selective (<90% use) or routine (≥ 90% use) in a given calendar quarter. MAIN OUTCOME MEASURE: Adjusted odds ratio of a composite adverse event (CAE) (unplanned postoperative intervention and/or in-hospital death) at routine testing hospitals. RESULTS: Among 3449 patients (mean [SD] age, 58.8 [14.8] years; 55.0% women), the CAE rate was 5.5%. Provocative leak testing increased (from 56% in the starting quarter to 76% in quarter 16) and overall rates of CAE decreased (from 7.0% in the starting quarter to 4.6% in quarter 16; both P ≤ .01) over time. Among patients at hospitals that performed routine leak testing, we found a reduction of more than 75% in the adjusted risk of CAEs (odds ratio, 0.23; 95% CI, 0.05-0.99). CONCLUSION: Routine leak testing of left-sided colorectal anastomoses appears to be associated with a reduced rate of CAEs within the SCOAP network and meets many of the criteria of a worthwhile quality improvement metric.