Development of CancerLinQ, a Health Information Learning Platform From Multiple Electronic Health Record Systems to Support Improved Quality of Care.

PURPOSE: ASCO, through its wholly owned subsidiary, CancerLinQ LLC, developed CancerLinQ, a learning health system for oncology. A learning health system is important for oncology patients because less than 5% of patients with cancer enroll in clinical trials, leaving evidence gaps for patient populations not enrolled in trials. In addition, clinical trial populations often differ from the overall cancer population with respect to age, race, performance status, and other clinical parameters. MATERIALS AND METHODS: Working with subscribing practices, CancerLinQ accepts data from electronic health records and transforms the local representation of a patient's care into a standardized representation on the basis of the Quality Data Model from the National Quality Forum. CancerLinQ provides this information back to the subscribing practice through a series of tools that support quality improvement. CancerLinQ also creates de-identified data sets for secondary research use. RESULTS: As of March 2020, CancerLinQ includes data from 63 organizations across the United States that use nine different electronic health records. The database includes 1,426,015 patients with a primary cancer diagnosis, of which 238,680 have had additional information abstracted from unstructured content. CONCLUSION: As CancerLinQ continues to onboard subscribing practices, the breadth of potential applications for a learning health care system widen. Future practice-facing tools could include real-world data visualization, recommendations for treatment of patients with actionable genetic variations, and identification of patients who may be eligible for clinical trials. Feeding these insights back into oncology practice ensures that we learn how to treat patients with cancer not just on the basis of the selective experience of the 5% that enroll in clinical trials, but from the real-world experience of the entire spectrum of patients with cancer in the United States.

Building a Rapid Learning Health Care System for Oncology: Why CancerLinQ Collects Identifiable Health Information to Achieve Its Vision.

The ever-increasing volume of scientific discoveries, clinical knowledge, novel diagnostic tools, and treatment options juxtaposed with rising costs in health care challenge physicians to identify, prioritize, and use new information rapidly to deliver efficient and high-quality care to a growing and aging patient population. CancerLinQ, a rapid learning health care system in oncology, is an initiative of the American Society of Clinical Oncology and its Institute for Quality that addresses these challenges by collecting information from the electronic health records of large numbers of patients with cancer. CancerLinQ is first and foremost a quality measurement and reporting system through which oncologists can harness the depth and power of their patients' clinical records and other data to assess, monitor, and improve the care they deliver. However, in light of privacy and security concerns with regard to collection, use, and disclosure of patient information, this article addresses the need to collect protected health information as defined under the Health Insurance Portability and Accountability Act of 1996 to drive rapid learning through CancerLinQ.

Variation in hospital mortality rates with inpatient cancer surgery.

OBJECTIVE: To elucidate clinical mechanisms underlying variation in hospital mortality after cancer surgery BACKGROUND: : Thousands of Americans die every year undergoing elective cancer surgery. Wide variation in hospital mortality rates suggest opportunities for improvement, but these efforts are limited by uncertainty about why some hospitals have poorer outcomes than others. METHODS: Using data from the 2006-2007 National Cancer Data Base, we ranked 1279 hospitals according to a composite measure of perioperative mortality after operations for bladder, esophagus, colon, lung, pancreas, and stomach cancers. We then conducted detailed medical record review of 5632 patients at 1 of 19 hospitals with low mortality rates (2.1%) or 30 hospitals with high mortality rates (9.1%). Hierarchical logistic regression analyses were used to compare risk-adjusted complication incidence and case-fatality rates among patients experiencing serious complications. RESULTS: The 7.0% absolute mortality difference between the 2 hospital groups could be attributed to higher mortality from surgical site, pulmonary, thromboembolic, and other complications. The overall incidence of complications was not different between hospital groups [21.2% vs 17.8%; adjusted odds ratio (OR) = 1.34, 95% confidence interval (CI): 0.93-1.94]. In contrast, case-fatality after complications was more than threefold higher at high mortality hospitals than at low mortality hospitals (25.9% vs 13.6%; adjusted OR = 3.23, 95% CI: 1.56-6.69). CONCLUSIONS: Low mortality and high mortality hospitals are distinguished less by their complication rates than by how frequently patients die after a complication. Strategies for ensuring the timely recognition and effective management of postoperative complications will be essential in reducing mortality after cancer surgery.

Cancer recurrence: an important but missing variable in national cancer registries.

BACKGROUND: Cancer recurrence is a critically important outcome to patients and providers. However, no publicly available cancer registry data contain recurrence information. The National Cancer Data Base (NCDB) collects recurrence data; however, this information is not provided to researchers because of completeness and accuracy concerns. Our objective was to examine completeness of cancer recurrence information in the NCDB. METHODS: Stage I-III thyroid/colon/melanoma/pancreas/breast cancers diagnosed in 2002-2005 were identified. Recurrence status, recurrence type, and recurrence date were evaluated for data completeness. Patient, tumor, and hospital factors were examined using generalized linear mixed models. Pseudo-R (2) statistics estimated the relative contribution of patient and hospital factors. RESULTS: Of 702,144 patients with thyroid/colon/melanoma/pancreas/breast cancers treated in 1405 hospitals, recurrence information was incomplete in 21.5/24.0/20.2/34.8/18.2 % of patients, respectively. On average, hospitals had incomplete recurrence information on 56.7-66.7 % of their patients. Patients with incomplete information had more comorbidities, a higher cancer stage, non-private insurance, and lived farther from the hospital. Hospitals with the poorest collection were larger tertiary hospitals serving higher-income patients. However, these patients and hospital factors explained less than 3 %, while unexplained hospital variation accounted for the largest part of the observed variation (%ΔR (2) = 84 %). CONCLUSIONS: The majority of hospitals report incomplete recurrence information for more than half of their patients. The presence of incomplete recurrence information was largely dependent on undefined hospital factors, rather than patient or tumor characteristics. Attempts to improve cancer recurrence information should focus on hospital operational and process factors surrounding how the hospital tumor registries collect recurrence data.

Effect of postoperative complications on adjuvant chemotherapy use for stage III colon cancer.

OBJECTIVE: The National Quality Forum has endorsed a quality metric concerning the use of adjuvant chemotherapy administration in stage III colon cancer, yet a substantial treatment gap exists. Our objective was to evaluate the association of postoperative complications on the use of adjuvant therapy after colectomy for cancer. PATIENTS AND METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program and National Cancer Data Base were linked to augment cancer registry information with robust clinical data on comorbidities and postoperative complications (2006-2008). The association of complications on adjuvant chemotherapy use was assessed using hierarchical multivariable regression models. RESULTS: From 126 hospitals, 2368 patients underwent resection for stage III colon adenocarcinoma. Overall utilization of adjuvant chemotherapy was 63.2% (1497/2368). Of the 871 patients who did not receive chemotherapy, 652 met National Quality Forum exclusion criteria: death, severe comorbidity, refusal of care, advanced age (≥80 years), or prior malignancy. Of the remaining 219 patients, 19.1% (42/219) had 1 or more serious postoperative complications (eg, pneumonia, pulmonary failure). After accounting for the aforementioned potential explanations, the utilization rate was 87.2% (1497/1716). The strongest predictors of adjuvant chemotherapy omission were prolonged postoperative ventilation, renal failure, reintubation, and pneumonia (all Ps < 0.05). Superficial surgical site infection did not decrease adjuvant therapy receipt but delayed the time to its use by 3-fold. Serious complications increased time to chemotherapy by 65%. Abscess/anastomotic leak increased time to adjuvant chemotherapy by more than 5-fold. CONCLUSIONS: Serious postoperative complications explained nearly 20% of the adjuvant chemotherapy treatment gap for patients with stage III colon cancer. The use of clinical data remains important when judging provider performance.

The relationship between extent of thyroid cancer surgery and use of radioactive iodine.

UNLABELLED: By linking surgeon surveys to the National Cancer Database, we found that surgeons' tendency to perform more extensive thyroid resection is associated with greater use of radioactive iodine for stage I thyroid cancer. OBJECTIVE: To determine the relationships between surgeon recommendations for extent of resection and radioactive iodine use in low-risk thyroid cancer. BACKGROUND: There has been an increase in thyroid cancer treatment intensity; the relationship between extent of resection and medical treatment with radioactive iodine remains unknown. METHODS: We randomly surveyed thyroid surgeons affiliated with 368 hospitals with Commission on Cancer-accredited cancer programs. Survey responses were linked to the National Cancer Database. The relationship between extent of resection and the proportion of the American Joint Committee on Cancer stage I well-differentiated thyroid cancer patients treated with radioactive iodine after total thyroidectomy was assessed with multivariable weighted regression, controlling for hospital and surgeon characteristics. RESULTS: The survey response rate was 70% (560/804). Surgeons who recommend total thyroidectomy over lobectomy for subcentimeter unifocal thyroid cancer were significantly more likely to recommend prophylactic central lymph node dissection for thyroid cancer regardless of tumor size (P < 0.001). They were also more likely to favor radioactive iodine in patients with intrathyroidal unifocal cancer ≤1 cm (P = 0.001), 1.1-2 cm (P = 0.004), as well as intrathyroidal multifocal cancer ≤1 cm (P = 0.004). In multivariable analysis, high hospital case volume, fewer surgeon years of experience, general surgery specialty, and preference for more extensive resection were independently associated with greater hospital-level use of radioactive iodine for stage I disease. CONCLUSIONS: In addition to surgeon experience and specialty, surgeons' tendency to perform more extensive thyroid resection is associated with greater use of radioactive iodine for stage I thyroid cancer.

Comparison of cases captured in the national cancer data base with those in population-based central cancer registries.

BACKGROUND: The National Cancer Data Base (NCDB) is a large, geographically diverse hospital-based cancer registry that has been used to study factors related to cancer diagnosis, treatment, and survival. The primary purpose of this study was to compare the case counts and characteristics of patients in NCDB with population-based registries reported in the United States Cancer Statistics (USCS). METHODS: Cancer case counts from NCDB were compared to case counts from USCS to measure NCDB's case coverage, or the percentage of cases captured. Case coverage was examined by a variety of characteristics, including state of residence, race/ethnicity, age, and primary cancer site. RESULTS: The overall NCDB case coverage was 67.4 %, ranging from a high of 88.7 % for Delaware to a low of 27.1 % for Arizona. Case coverage for white, black, and Asian/Pacific Islander cases was high (64.7 % to 67.4 %), but it was much lower for American Indians/Alaskan Natives (32.8 %) and those of Hispanic ethnicity (51.1 %). Among the elderly (aged 65 + years), case coverage is much lower compared to persons younger than 65 (63.0 % and 73.0 %, respectively). Case coverage also varied widely by site, with the highest being cervix (77.9 %) and the lowest being melanoma (50.6 %). CONCLUSIONS: This study highlights the geographic- and site-specific variation in NCDB case coverage, primarily as a result of NCDB facility presence and data collection and processing protocols. These findings illustrate the strengths and limitations of NCDB as a resource for nationwide data on cancer diagnosis, treatment, and survival.

MUC1* ligand, NM23-H1, is a novel growth factor that maintains human stem cells in a more naïve state.

We report that a single growth factor, NM23-H1, enables serial passaging of both human ES and iPS cells in the absence of feeder cells, their conditioned media or bFGF in a fully defined xeno-free media on a novel defined, xeno-free surface. Stem cells cultured in this system show a gene expression pattern indicative of a more "naïve" state than stem cells grown in bFGF-based media. NM23-H1 and MUC1* growth factor receptor cooperate to control stem cell self-replication. By manipulating the multimerization state of NM23-H1, we override the stem cell's inherent programming that turns off pluripotency and trick the cells into continuously replicating as pluripotent stem cells. Dimeric NM23-H1 binds to and dimerizes the extra cellular domain of the MUC1* transmembrane receptor which stimulates growth and promotes pluripotency. Inhibition of the NM23-H1/MUC1* interaction accelerates differentiation and causes a spike in miR-145 expression which signals a cell's exit from pluripotency.

Referral patterns for patients with high-risk thyroid cancer.

OBJECTIVE: Knowledge of referral patterns for specialty cancer care is sparse. Information on both the need and reasons for referral of high-risk, well-differentiated thyroid cancer patients should provide a foundation for eliminating obstacles to appropriate patient referrals and improving patient care. METHODS: We surveyed 370 endocrinologists involved in thyroid cancer management. From information in a clinical vignette, respondents were asked to identify the reasons they would need to refer a high-risk patient to a more specialized facility for care. We performed multivariable analysis controlling for hospital and physician characteristics. RESULTS: Thirty-two percent of respondents reported never referring thyroid cancer patients to another facility. Of those that would refer a high-risk patient to another facility, the opportunity for a patient to enter a clinical trial was the most common reason reported (44%), followed by high-dose radioactive iodine (RAI) with or without dosimetry (33%), lateral neck dissection (24%), and external beam radiation (15%). In multivariable analysis, endocrinologists with a higher percentage of their practice devoted to thyroid cancer care were significantly less likely to refer patients to another facility (P = .003). CONCLUSION: The majority of endocrinologists treating thyroid cancer patients report referring a high-risk patient to another facility for some or all of their care. Knowledge of the patterns of physician referrals and the likelihood of need for referral are key to understanding discrepancies in referral rates and obstacles in the referral process.

Variation in the management of thyroid cancer.

CONTEXT: Little is known about practice patterns in thyroid cancer, a cancer that is increasing in incidence. OBJECTIVE: We sought to identify aspects of thyroid cancer management that have the greatest variation. DESIGN/SETTING/PARTICIPANTS: We surveyed 944 physicians involved in thyroid cancer care from 251 hospitals affiliated with the US National Cancer Database. Physicians were asked questions in the following four domains: thyroid surgery, radioactive iodine use, thyroid hormone replacement postsurgery, and long-term thyroid cancer management. We calculated the ratio of observed variation to hypothetical maximum variation under the assumed distribution of the response. Ratios closer to 1 indicate greater variation. RESULTS: We had a 66% response rate. We found variation in multiple aspects of thyroid cancer management, including the role of central lymph node dissections (variation, 0.99; 95% confidence interval [CI], 0.98-1.00), the role of pretreatment scans before radioactive iodine treatment (variation, 1.00; 95% CI, 0.98-1.00), and all aspects of long-term thyroid cancer management, including applications of ultrasound (variation, 0.97; 95% CI, 0.93-0.99) and radioactive iodine scans (variation, 0.99; 95% CI, 0.97-1.00). For the management of small thyroid cancers, variation exists in all domains, including optimal extent of surgery (variation, 0.91; 95% CI, 0.88-0.94) and the role of both radioactive iodine treatment (variation, 0.91; 95% CI, 0.89-0.93) and suppressive doses of thyroid hormone replacement (variation, 1.00; 95% CI, 0.99-1.00). CONCLUSION: We identified areas of variation in thyroid cancer management. To reduce the variation and improve the management of thyroid cancer, there is a need for more research and more research dissemination.

Completeness of American Cancer Registry Treatment Data: implications for quality of care research.

BACKGROUND: Evaluating and improving the quality of cancer care requires complete information on cancer stage and treatment. Hospital-based registries are a key tool in this effort, but reports in the 1990s showed that they fail to identify a major fraction of outpatient-administered treatment, including chemotherapy, endocrine therapy, and radiation. This can limit their value for evaluating patterns and quality of care. To determine the completeness of registry data in more recent years, we linked administrative claims from 2 private payers in Ohio to the National Cancer Data Base and Ohio Cancer Incidence and Surveillance System. METHODS: Incident breast and colorectal cancers among Ohio residents diagnosed in 2004-2006 were identified from linkage of the National Cancer Data Base, Ohio Cancer Incidence and Surveillance System, and payer insurance claims using ICD-9 and CPT procedure codes, and ICD-9 diagnosis codes. Linkage was accomplished using patient demographics, surgery dates, and hospital facility. Treatment found in claims and registry data were compared and assessed using the κ statistic. RESULTS: The analytic cohort included 2,552 breast and 822 colorectal cases. Results showed high agreement for breast surgery type, and moderately high agreement for colorectal surgery type. For breast cases, the registries captured 87% of chemotherapy, 86% of radiation, and 64% of endocrine treatment in claims. For colorectal cases, the registry captured 83% of chemotherapy and 84% of radiation in claims. CONCLUSIONS: Hospital-based registries for breast and colon cancer diagnosed in 2004-2006 captured about 85% of radiation and chemotherapy data compared with claims data, a higher percentage than earlier reports. These findings provide direction and a cautionary note to those using registry data for study of patterns and quality of systemic and radiation therapy care.

SLC4A2-mediated Cl-/HCO3- exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts.

Bone remodeling requires osteoclasts to generate and maintain an acidified resorption compartment between the apical membrane and the bone surface to solubilize hydroxyapatite crystals within the bone matrix. This acidification process requires (i) apical proton secretion by a vacuolar H(+)-ATPase, (ii) actin cytoskeleton reorganization into a podosome belt that forms a gasket to restrict lacunar acid leakage, and (iii) basolateral chloride uptake and bicarbonate extrusion by an anion exchanger to provide Cl(-) permissive for apical acid secretion while preventing cytoplasmic alkalinization. Here we show that osteoclast-targeted deletion in mice of solute carrier family 4 anion exchanger member 2 (Slc4a2) results in osteopetrosis. We further demonstrate a previously unrecognized consequence of SLC4A2 loss of function in the osteoclast: dysregulation of calpain-dependent podosome disassembly, leading to abnormal actin belt formation, cell spreading, and migration. Rescue of SLC4A2-deficient osteoclasts with functionally defined mutants of SLC4A2 indicates regulation of actin cytoskeletal reorganization by anion-exchange activity and intracellular pH, independent of SLC4A2's long N-terminal cytoplasmic domain. These data suggest that maintenance of intracellular pH in osteoclasts through anion exchange regulates the actin superstructures required for bone resorption.

Effect of including cancer-specific variables on risk-adjusted hospital surgical quality comparisons.

BACKGROUND: Quality initiatives are increasingly focusing on the quality of oncologic surgery. However, there is concern that a lack of cancer-specific variables may make risk-adjusted hospital quality comparisons inadequate. Our objective was to assess whether hospital quality rankings for cancer surgery are influenced by the addition of cancer-specific variables to the risk-adjusted models. METHODS: Patients from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and National Cancer Data Base (NCDB) who underwent colon or rectal resection for cancer were linked (2006-2008). Hierarchical models were developed predicting ACS NSQIP outcomes based on ACS NSQIP only vs a model using NSQIP and NCDB-derived cancer variables (e.g., stage and neoadjuvant therapy). Changes in hospital quality rankings were compared. RESULTS: A total of 11,405 patients underwent colon (n = 9,678, 146 hospitals) or rectal (n = 1,727, 135 hospitals) resection for cancer (2006-2008). Hospital-level complication rates (and standard deviation) after colon surgery were 2.2 % (±2.7 %) for mortality and 17.2 % (±8.7 %) for serious morbidity. After rectal cancer resection, complication rates were 0.9 % (±3.8 %) for mortality and 22.3 % (±20.4 %) for serious morbidity. When cancer-specific variables were included in risk-adjustment, outlier agreement was very good (kappa >0.85), and hospital odds ratio correlations were nearly identical (R > 0.98) for all outcomes assessed. Median changes in hospital rankings with the addition of the cancer-specific variables ranged from 1 to 2 after colon resection to 2-4 after rectal resection. CONCLUSIONS: Addition of the available cancer-specific variables to risk-adjustment models did not affect hospital quality rankings for cancer surgery. Existing ACS NSQIP risk-adjustment variables appears to be sufficient for accurate comparisons of hospital quality.

Substitution of transmembrane domain Cys residues alters pH(o)-sensitive anion transport by AE2/SLC4A2 anion exchanger.

AE2/SLC4A2 is the most widely expressed of the Na(+)-independent SLC4 Cl(-)/HCO3 (-) exchangers and is essential for postnatal survival, but its structure remains unknown. We have generated and expressed a mouse AE2 construct devoid of transmembrane domain cysteine (Cys) residues, mAE2Cys-less, to enhance the utility of Cys-substitution mutagenesis for structural and structure-function studies of mAE2. mAE2Cys-less expressed in Xenopus oocytes exhibited partial reduction of stilbene disulfonate-sensitive anion exchange activity. This activity was independent of the mAE2 N-terminal cytosolic domain and was accompanied by near-normal surface expression, without change in K 1/2 for extracellular Cl(-). mAE2Cys-less exhibited wildtype activation of anion exchange by hypertonicity and by NH4Cl, and wildtype inhibition of anion exchange by acidic intracellular pH (pHi) in the absence of NH4 (+). However, inhibition of anion exchange by extracellular pH (pHo) exhibited an alkaline shifted pHo(50) value of at least 0.6-0.7 pH units. Although SO4 (2-) transport by mAE2Cys-less resembled wildtype mAE2 in its stimulation by acidic pHo, the absence of transmembrane domain Cys residues abrogated activation of oxalate transport by acidic pHo. The contrasting enhancement of SO4 (2-) transport by alkaline pHo in the mAE1 anion translocation pathway mutant E699Q (Am J Physiol Cell Physiol 295: C302) was phenocopied by the corresponding mutant E1007Q in both AE2 and AE2Cys-less. However, the absence of transmembrane domain Cys residues exacerbated the reduced basal anion transport function exhibited by this and other missense substitutions at AE2 residue E1007. AE2Cys-less will be a valuable experimental tool for structure-function studies of the SLC4 gene family, but its utility for studies of AE2 regulation by extracellular pH must be evaluated in the context of its alkaline-shifted pHo sensitivity, resembling that of AE2 gastric parietal cell variant AE2c1.

The role of clinicians in determining radioactive iodine use for low-risk thyroid cancer.

BACKGROUND: There is controversy regarding the optimal management of thyroid cancer. The proportion of patients with low-risk thyroid cancer who received radioactive iodine (RAI) treatment increased over the last 20 years, and little is known about the role played by clinicians in hospital-level RAI use for low-risk disease. METHODS: Thyroid surgeons affiliated with 368 hospitals that had Commission on Cancer-accredited cancer programs were surveyed. Survey data were linked to data reported to the National Cancer Database. A multivariable analysis was used to assess the relation between clinician decision makers and hospital-level RAI use after total thyroidectomy in patients with stage I, well differentiated thyroid cancer. RESULTS: The survey response rate was 70% (560 of 804 surgeons). The surgeon was identified as the primary decision maker by 16% of the surgeons; the endocrinologist was identified as the primary decision maker by 69%, and a nuclear medicine, radiologist, or other physician was identified as the primary decision maker by 15%. In a multivariable analysis controlling for hospital case volume and hospital type, when the primary decision maker was in a specialty other than endocrinology or surgery, there was greater use of RAI at the hospital (P < .001). A greater number of providers at the hospital where RAI was administered and having access to a tumor board also were associated with increased use of RAI (P < .001 and P = .006, respectively). CONCLUSIONS: The specialty of the primary decision maker, the number of providers administering RAI, and having access to a tumor board were associated significantly with the use of RAI for stage I thyroid cancer. The findings have implications for addressing nonclinical variation between hospitals, with a marked heterogeneity in decision making suggesting that standardization of care will be challenging.

Surgeon training and use of radioactive iodine in stage I thyroid cancer patients.

BACKGROUND: The majority of thyroid cancer diagnoses in the United States are stage I well-differentiated cancer. The use of radioactive iodine (RAI) in these low-risk patients has increased over time. The role of surgeon training in decision making regarding treatment with RAI is unknown. METHODS: Thyroid surgeons affiliated with 368 hospitals associated with the US National Cancer Database (NCDB) were surveyed. Survey data were linked to the NCDB data. A multivariable weighted analysis controlling for surgeon and hospital characteristics was conducted to examine the relationship between surgeon training, continuing education and hospital-level RAI use for stage I well-differentiated thyroid cancer. RESULTS: The response rate was 70% (560 of 804). In both univariate and multivariable analysis controlling for hospital case volume, practice setting and surgeon specialty, training with a thyroid surgeon was associated with less RAI use for stage I thyroid cancer (P = 0.022 and 0.028, respectively). Attending one or more professional society meetings a year was associated with a lower rate of hospital-level RAI use in univariate analysis (P = 0.044) but not multivariable analysis. CONCLUSIONS: Training with a surgeon or group of surgeons who focus on thyroid surgery was associated with a lower proportion of stage I thyroid cancer patients receiving RAI after total thyroidectomy. This study emphasizes the importance of surgeon training in hospital practice patterns.

Effect of including cancer-specific variables on models examining short-term outcomes.

BACKGROUND: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) generally has not collected cancer-specific variables. Because increasing numbers of studies are using ACS NSQIP data to study cancer surgery, the objectives of the current study were 1) to examine differences between existing ACS NSQIP variables and cancer registry variables, and 2) to determine whether the addition of cancer-specific variables improves modeling of short-term outcomes. METHODS: Data from patients in the ACS NSQIP and National Cancer Data Base (NCDB) who underwent colorectal resection for cancer were linked (2006-2008). By using regression methods, the relative importance of cancer staging and neoadjuvant therapy variables were assessed along with their effects on morbidity, serious morbidity, and mortality. RESULTS: From 146 hospitals, 11,405 patients were identified who underwent surgery for colorectal cancer (colon, 85%; rectum, 15%). The NCDB metastatic cancer variable and the ACS NSQIP disseminated cancer variables agreed marginally (Cohen kappa coefficient, 0.454). For mortality, only the ACS NSQIP disseminated cancer variable and the NCDB stage IV variable were identified as important predictors; whereas the variables stage I through III, tumor (T)-classification, and lymph node (N)-classification were not selected. Cancer stage variables were inconsistently important for serious morbidity (stage IV, T-classification), superficial surgical site infection (N-classification), venous thromboembolism (metastatic cancer), and pneumonia (T-classification). With respect to neoadjuvant therapy, ACS NSQIP and NCDB variables agreed moderately (kappa, 0.570) and predicted superficial surgical site infection, serious morbidity, and organ space surgical site infection. The model fit was similar regardless of the inclusion of stage and neoadjuvant therapy variables. CONCLUSIONS: Although advanced disease stage and neoadjuvant therapy variables were predictors of short-term outcomes, their inclusion did not improve the models.

Loss of Slc4a1b chloride/bicarbonate exchanger function protects mechanosensory hair cells from aminoglycoside damage in the zebrafish mutant persephone.

Mechanosensory hair cell death is a leading cause of hearing and balance disorders in the human population. Hair cells are remarkably sensitive to environmental insults such as excessive noise and exposure to some otherwise therapeutic drugs. However, individual responses to damaging agents can vary, in part due to genetic differences. We previously carried out a forward genetic screen using the zebrafish lateral line system to identify mutations that alter the response of larval hair cells to the antibiotic neomycin, one of a class of aminoglycoside compounds that cause hair cell death in humans. The persephone mutation confers resistance to aminoglycosides. 5 dpf homozygous persephone mutants are indistinguishable from wild-type siblings, but differ in their retention of lateral line hair cells upon exposure to neomycin. The mutation in persephone maps to the chloride/bicarbonate exchanger slc4a1b and introduces a single Ser-to-Phe substitution in zSlc4a1b. This mutation prevents delivery of the exchanger to the cell surface and abolishes the ability of the protein to import chloride across the plasma membrane. Loss of function of zSlc4a1b reduces hair cell death caused by exposure to the aminoglycosides neomycin, kanamycin, and gentamicin, and the chemotherapeutic drug cisplatin. Pharmacological block of anion transport with the disulfonic stilbene derivatives DIDS and SITS, or exposure to exogenous bicarbonate, also protects hair cells against damage. Both persephone mutant and DIDS-treated wild-type larvae show reduced uptake of labeled aminoglycosides. persephone mutants also show reduced FM1-43 uptake, indicating a potential impact on mechanotransduction-coupled activity in the mutant. We propose that tight regulation of the ionic environment of sensory hair cells, mediated by zSlc4a1b activity, is critical for their sensitivity to aminoglycoside antibiotics.

Deletion of Slc26a6 alters the stoichiometry of apical Cl-/HCO-3 exchange in mouse pancreatic duct.

To define the stoichiometry and molecular identity of the Cl(-)/HCO(3)(-) exchanger in the apical membrane of pancreatic duct cells, changes in luminal pH and volume were measured simultaneously in interlobular pancreatic ducts isolated from wild-type and Slc26a6-null mice. Transepithelial fluxes of HCO(3)(-) and Cl(-) were measured in the presence of anion gradients favoring rapid exchange of intracellular HCO(3)(-) with luminal Cl(-) in cAMP-stimulated ducts. The flux ratio of Cl(-) absorption/HCO(3)(-) secretion was ∼0.7 in wild-type ducts and ∼1.4 in Slc26a6(-/-) ducts where a different Cl(-)/HCO(3)(-) exchanger, most likely SLC26A3, was found to be active. Interactions between Cl(-)/HCO(3)(-) exchange and cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated ducts were examined by measuring the recovery of intracellular pH after alkali-loading by acetate prepulse. Hyperpolarization induced by luminal application of CFTRinh-172 enhanced HCO(3)(-) efflux across the apical membrane via SLC26A6 in wild-type ducts but significantly reduced HCO(3)(-) efflux in Slc26a6(-/-) ducts. In microperfused wild-type ducts, removal of luminal Cl(-), or luminal application of dihydro-4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid to inhibit SLC26A6, caused membrane hyperpolarization, which was abolished in Slc26a6(-/-) ducts. In conclusion, we have demonstrated that deletion of Slc26a6 alters the apparent stoichiometry of apical Cl(-)/HCO(3)(-) exchange in native pancreatic duct. Our results are consistent with SLC26A6 mediating 1:2 Cl(-)/HCO(3)(-) exchange, and the exchanger upregulated in its absence, most probably SLC26A3, mediating 2:1 exchange.