Sex differences in the survival benefit of kidney transplantation: a retrospective cohort study using target trial emulation.

BACKGROUND: Kidney transplantation is the preferred treatment for eligible patients with kidney failure who need renal replacement therapy. However, it remains unclear whether the anticipated survival benefit from kidney transplantation is different for women and men. METHODS: We included all dialysis patients recorded in the Austrian Dialysis and Transplant Registry who were waitlisted for their first kidney transplant between 2000 and 2018. In order to estimate the causal effect of kidney transplantation on 10-year restricted mean survival time, we mimicked a series of controlled clinical trials and applied inverse probability of treatment and censoring weighted sequential Cox models. RESULTS: This study included 4408 patients (33% female) with a mean age of 52 years. Glomerulonephritis was the most common primary renal disease both in women (27%) and men (28%). Kidney transplantation led to a gain of 2.22 years (95% CI 1.88 to 2.49) compared with dialysis over a 10-year follow-up. The effect was smaller in women (1.95 years, 95% CI 1.38 to 2.41) than in men (2.35 years, 95% CI 1.92 to 2.70) due to a better survival on dialysis. Across ages the survival benefit of transplantation over a follow-up of 10 years was smaller in younger women and men and increased with age, showing a peak for both women and men aged about 60 years. CONCLUSIONS: There were few differences in survival benefit by transplantation between females and males. Females had better survival than males on the waitlist receiving dialysis and similar survival to males after transplantation.

Leave-one-out cross-validation, penalization, and differential bias of some prediction model performance measures-a simulation study.

BACKGROUND: The performance of models for binary outcomes can be described by measures such as the concordance statistic (c-statistic, area under the curve), the discrimination slope, or the Brier score. At internal validation, data resampling techniques, e.g., cross-validation, are frequently employed to correct for optimism in these model performance criteria. Especially with small samples or rare events, leave-one-out cross-validation is a popular choice. METHODS: Using simulations and a real data example, we compared the effect of different resampling techniques on the estimation of c-statistics, discrimination slopes, and Brier scores for three estimators of logistic regression models, including the maximum likelihood and two maximum penalized likelihood estimators. RESULTS: Our simulation study confirms earlier studies reporting that leave-one-out cross-validated c-statistics can be strongly biased towards zero. In addition, our study reveals that this bias is even more pronounced for model estimators shrinking estimated probabilities towards the observed event fraction, such as ridge regression. Leave-one-out cross-validation also provided pessimistic estimates of the discrimination slope but nearly unbiased estimates of the Brier score. CONCLUSIONS: We recommend to use leave-pair-out cross-validation, fivefold cross-validation with repetitions, the enhanced or the .632+ bootstrap to estimate c-statistics, and leave-pair-out or fivefold cross-validation to estimate discrimination slopes.

Intraoperative Hypotension Is Associated with Postoperative Nausea and Vomiting in the PACU: A Retrospective Database Analysis.

Multiple risk factors for postoperative nausea and vomiting (PONV)-a very distressing and outcome-related complication-have been identified, including female sex, absence of a history of smoking, history of PONV, and postoperative opioid use. Evidence of association of intraoperative hypotension with PONV is contradictory. A retrospective analysis of the perioperative documentation of 38,577 surgeries was conducted. The associations between different characterizations of intraoperative hypotension and PONV in the postoperative care unit (PACU) were investigated. First, the relationship between different characterizations of intraoperative hypotension with regard to PONV in the PACU was investigated. Secondly, the performance of the optimal characterization was assessed in an independent dataset derived via random split. The vast majority of characterizations showed an association of hypotension with the incidence of PONV in the PACU. In a multivariable regression, time with a MAP under 50 mmHg showed the strongest association with PONV in terms of the cross-validated Brier score. The adjusted odds for PONV in the PACU were estimated to be 1.34 times higher (95% CI: 1.33-1.35) when a MAP was under 50 mmHg for at least 1.8 min than when a MAP remained above 50 mmHg. The finding indicates that intraoperative hypotension may yet be another risk factor for PONV and therefore emphasizes the importance of intraoperative blood pressure management not only in patients at risk for cardiovascular complications but also in young and healthy patients at risk of PONV.

The value of intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism and varying baseline parathyroid hormone levels.

BACKGROUND: When applying intraoperative parathyroid hormone monitoring (IOPTH) to patients with primary hyperparathyroidism (PHPT), there are established criteria predicting biochemical cure in patients with basal parathyroid hormone (PTH) levels in the medium range (100-400 pg/ml); however, there is a challenge concerning patients with low (less than 100 pg/ml) or high (more than 400 pg/ml) basal PTH levels. The aim of this study was to investigate the value of the 'Vienna criterion' applied during IOPTH in patients with PHPT and various basal PTH concentrations. METHODS: Consecutive patients between 1999-2009 with a biochemical diagnosis of PHPT who underwent surgical parathyroidectomy were included. Based on preoperative PTH levels they were divided into three groups: group 1 (low) (<100 pg/ml), group 2 (medium) (100-400 pg/ml) and group 3 (high) (>400 pg/ml) basal PTH. PTH was measured at the start of the operation, when the gland was excised and then at 5, 10 and 15 min after. Calcium and PTH levels were measured at 7 days and 12 months postoperatively. Sensitivity, specificity, positive and negative predictive value, as well as accuracy of IOPTH were calculated for the different groups postoperatively. RESULTS: 675 patients with PHPT were analysed. Sensitivity and specificity were 83.7 per cent and 66.7 per cent in group 1 (n = 187), 90.7 per cent and 69.2 per cent in group 2 (n = 433), and 94.4 per cent and 100 per cent in group 3 (n = 55) to predict cure. Preoperative creatinine (p = 0.002) showed significant statistical difference between the groups but was not related to intraoperative PTH decline. At 12 months follow-up normocalcaemia was documented in 98.9 per cent in group 1, 99.0 per cent group 2, and 98.0 per cent of group 3 patients. CONCLUSION: Normocalcaemia was predicted intraoperatively by applying the 'Vienna criterion' in 98 to 100 per cent and was confirmed after 12 months follow-up in up to 99.0 per cent of patients. Low specificity and a high false-negative rate in patients with low basal PTH show that other criteria might be better suited for this group.

Survival Benefit of First Single-Organ Deceased Donor Kidney Transplantation Compared With Long-term Dialysis Across Ages in Transplant-Eligible Patients With Kidney Failure.

Importance: Kidney transplant is considered beneficial in terms of survival compared with continued dialysis for patients with kidney failure. However, randomized clinical trials are infeasible, and available evidence from cohort studies is at high risk of bias. Objective: To compare restricted mean survival times (RMSTs) between patients who underwent transplant and patients continuing dialysis across transplant candidate ages and depending on waiting time, applying target trial emulation methods. Design, Setting, and Participants: In this retrospective cohort study, patients aged 18 years or older appearing on the wait list for their first single-organ deceased donor kidney transplant between January 1, 2000, and December 31, 2018, in Austria were evaluated. Available data were obtained from the Austrian Dialysis and Transplant Registry and Eurotransplant and included repeated updates on wait-listing status and relevant covariates. Data were analyzed between August 1, 2019, and December 23, 2021. Exposures: A target trial was emulated in which patients were randomized to either receive the transplant immediately (treatment group) or to continue dialysis and never receive a transplant (control group) at each time an organ became available. Main Outcomes and Measures: The primary outcome was time from transplant allocation to death. Effect sizes in terms of RMSTs were obtained using a sequential Cox approach. Results: Among the 4445 included patients (2974 men [66.9%]; mean [SD] age, 52.2 [13.2] years), transplant was associated with increased survival time across all considered ages compared with continuing dialysis and remaining on the wait list within a 10-year follow-up. The estimated RMST differences were 0.57 years (95% CI, -0.14 to 1.84 years) at age 20 years, 3.01 years (95% CI, 2.50 to 3.54 years) at age 60 years, and 2.48 years (95% CI, 1.88 to 3.04 years) at age 70 years. The survival benefit for patients who underwent transplant across ages was independent of waiting time. Conclusions and Relevance: The findings of this study suggest that kidney transplant prolongs the survival time of persons with kidney failure across all candidate ages and waiting times.

An investigation of penalization and data augmentation to improve convergence of generalized estimating equations for clustered binary outcomes.

BACKGROUND: In binary logistic regression data are 'separable' if there exists a linear combination of explanatory variables which perfectly predicts the observed outcome, leading to non-existence of some of the maximum likelihood coefficient estimates. A popular solution to obtain finite estimates even with separable data is Firth's logistic regression (FL), which was originally proposed to reduce the bias in coefficient estimates. The question of convergence becomes more involved when analyzing clustered data as frequently encountered in clinical research, e.g. data collected in several study centers or when individuals contribute multiple observations, using marginal logistic regression models fitted by generalized estimating equations (GEE). From our experience we suspect that separable data are a sufficient, but not a necessary condition for non-convergence of GEE. Thus, we expect that generalizations of approaches that can handle separable uncorrelated data may reduce but not fully remove the non-convergence issues of GEE. METHODS: We investigate one recently proposed and two new extensions of FL to GEE. With 'penalized GEE' the GEE are treated as score equations, i.e. as derivatives of a log-likelihood set to zero, which are then modified as in FL. We introduce two approaches motivated by the equivalence of FL and maximum likelihood estimation with iteratively augmented data. Specifically, we consider fully iterated and single-step versions of this 'augmented GEE' approach. We compare the three approaches with respect to convergence behavior, practical applicability and performance using simulated data and a real data example. RESULTS: Our simulations indicate that all three extensions of FL to GEE substantially improve convergence compared to ordinary GEE, while showing a similar or even better performance in terms of accuracy of coefficient estimates and predictions. Penalized GEE often slightly outperforms the augmented GEE approaches, but this comes at the cost of a higher burden of implementation. CONCLUSIONS: When fitting marginal logistic regression models using GEE on sparse data we recommend to apply penalized GEE if one has access to a suitable software implementation and single-step augmented GEE otherwise.

Retrospective, Multicenter Analysis Comparing Conventional with Oncoplastic Breast Conserving Surgery: Oncological and Surgical Outcomes in Women with High-Risk Breast Cancer from the OPBC-01/iTOP2 Study.

INTRODUCTION: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4). METHODS: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. RESULTS: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. CONCLUSIONS: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.

Solutions to problems of nonexistence of parameter estimates and sparse data bias in Poisson regression.

Poisson regression can be challenging with sparse data, in particular with certain data constellations where maximum likelihood estimates of regression coefficients do not exist. This paper provides a comprehensive evaluation of methods that give finite regression coefficients when maximum likelihood estimates do not exist, including Firth's general approach to bias reduction, exact conditional Poisson regression, and a Bayesian estimator using weakly informative priors that can be obtained via data augmentation. Furthermore, we include in our evaluation a new proposal for a modification of Firth's approach, improving its performance for predictions without compromising its attractive bias-correcting properties for regression coefficients. We illustrate the issue of the nonexistence of maximum likelihood estimates with a dataset arising from the recent outbreak of COVID-19 and an example from implant dentistry. All methods are evaluated in a comprehensive simulation study under a variety of realistic scenarios, evaluating their performance for prediction and estimation. To conclude, while exact conditional Poisson regression may be confined to small data sets only, both the modification of Firth's approach and the Bayesian estimator are universally applicable solutions with attractive properties for prediction and estimation. While the Bayesian method needs specification of prior variances for the regression coefficients, the modified Firth approach does not require any user input.

To tune or not to tune, a case study of ridge logistic regression in small or sparse datasets.

BACKGROUND: For finite samples with binary outcomes penalized logistic regression such as ridge logistic regression has the potential of achieving smaller mean squared errors (MSE) of coefficients and predictions than maximum likelihood estimation. There is evidence, however, that ridge logistic regression can result in highly variable calibration slopes in small or sparse data situations. METHODS: In this paper, we elaborate this issue further by performing a comprehensive simulation study, investigating the performance of ridge logistic regression in terms of coefficients and predictions and comparing it to Firth's correction that has been shown to perform well in low-dimensional settings. In addition to tuned ridge regression where the penalty strength is estimated from the data by minimizing some measure of the out-of-sample prediction error or information criterion, we also considered ridge regression with pre-specified degree of shrinkage. We included 'oracle' models in the simulation study in which the complexity parameter was chosen based on the true event probabilities (prediction oracle) or regression coefficients (explanation oracle) to demonstrate the capability of ridge regression if truth was known. RESULTS: Performance of ridge regression strongly depends on the choice of complexity parameter. As shown in our simulation and illustrated by a data example, values optimized in small or sparse datasets are negatively correlated with optimal values and suffer from substantial variability which translates into large MSE of coefficients and large variability of calibration slopes. In contrast, in our simulations pre-specifying the degree of shrinkage prior to fitting led to accurate coefficients and predictions even in non-ideal settings such as encountered in the context of rare outcomes or sparse predictors. CONCLUSIONS: Applying tuned ridge regression in small or sparse datasets is problematic as it results in unstable coefficients and predictions. In contrast, determining the degree of shrinkage according to some meaningful prior assumptions about true effects has the potential to reduce bias and stabilize the estimates.

Steroid pretreatment of deceased donors and liver allograft function - Ten years follow-up of a blinded randomized placebo controlled trial.

BACKGROUND: Within the last decade numerous attempts have been reported in order to expand the donor pool and alleviate organ shortage in the setting of liver transplantation. Aim of this blinded randomized controlled trial was to evaluate the effect of donor steroid pretreatment on outcomes after liver transplantation. METHODS: We performed an international, multi-center double-blinded randomized placebo controlled trial. Donors received 1000 mg methylprednisone or placebo before organ procurement. Primary endpoint were patient and graft survival. Secondary end points were rate of BPAR and liver functions trajectories after transplantation. Follow up was 10 years. RESULTS: There was no effect of steroid pretreatment vs. placebo on overall patient survival (50% vs. 46%, p = n.s.) as well as graft survival (47% vs. 51%, p= n.s.). Further donor steroid pretreatment did not alter the rate of biopsy proven acute rejections (34% steroid group vs. 36% placebo, p = n.s.). Evaluating short term and long term graft function, steroid pretreatment had minor effect on immediate liver function trajectories within the first 2 weeks after transplantation. This was not seen in long-term follow up. CONCLUSION: In conclusion we found no evidence that donor steroid pretreatment translates in improved outcomes after liver transplantation.

The spectrum of skin diseases in four different types of organ-transplant recipients: a comparative single-centre cohort study.

BACKGROUND: Organ transplant recipients (OTR) are at marked increased risk of skin cancer and skin infections compared to the general population. OBJECTIVES: The purpose of this study was to acquire long-term incidence data on commonly occurring skin diseases in four different transplant groups. MATERIALS & METHODS: This retrospective single-centre cohort study included 621 OTR. By counting defined malignant, inflammatory, infectious or drug-related skin conditions per patient and visit, incidence rates (IR) for the different groups of OTR were calculated as cases per 1000-patient years and cumulative incidences of non-melanoma skin cancer (NMSC), respectively. RESULTS: Overall, 2,309 non-malignant skin conditions and 340 NMSC were registered. Skin infections were most common (51.4%), followed by inflammatory skin conditions (35.6%) and sun-induced skin damage (32.9%). Kidney transplant recipients (KTR) had a 4.7-fold (95% CI: 2.7-8.0; p < 0.0001), 2.6-fold (95% CI: 1.2-5.3; p = 0.0098) and 5.4-fold (95% CI: 2.8-10.3; - < 0.0001) higher IR for oral candidiasis, oral aphthosis and herpes simplex virus infections, respectively, compared to the other OTR. Pruritus was most commonly reported in liver transplant recipients (95% CI: 1.3-5.3; p = 0.0047). KTR and lung transplant recipients (LuTR) had a 10.7-fold (95% CI:3.6-43.2; p < 0.0001) higher IR of steroid induced acne. KTR had a 1.6-fold (95% CI: 1.1-2.3; p = 0.0096) higher IR of squamous cell carcinoma compared to the other groups. The incidence of basal cell carcinoma was 2.5-fold higher (95% CI: 1.7-3.6; p < 0.0001) in LuTR, compared to the other OTR. CONCLUSION: This study provides additional organ-specific incidence data on non-malignant skin diseases and skin cancer in OTR.

Bring More Data!-A Good Advice? Removing Separation in Logistic Regression by Increasing Sample Size.

The parameters of logistic regression models are usually obtained by the method of maximum likelihood (ML). However, in analyses of small data sets or data sets with unbalanced outcomes or exposures, ML parameter estimates may not exist. This situation has been termed 'separation' as the two outcome groups are separated by the values of a covariate or a linear combination of covariates. To overcome the problem of non-existing ML parameter estimates, applying Firth's correction (FC) was proposed. In practice, however, a principal investigator might be advised to 'bring more data' in order to solve a separation issue. We illustrate the problem by means of examples from colorectal cancer screening and ornithology. It is unclear if such an increasing sample size (ISS) strategy that keeps sampling new observations until separation is removed improves estimation compared to applying FC to the original data set. We performed an extensive simulation study where the main focus was to estimate the cost-adjusted relative efficiency of ML combined with ISS compared to FC. FC yielded reasonably small root mean squared errors and proved to be the more efficient estimator. Given our findings, we propose not to adapt the sample size when separation is encountered but to use FC as the default method of analysis whenever the number of observations or outcome events is critically low.

Applicability of a shortened interpretation model for intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism in an endemic goiter region.

BACKGROUND: In primary hyperparathyroidism (pHPT), quick intraoperative parathyroid hormone monitoring (IOPTH) is performed to predict complete excision of hyperfunctioning tissue and therefore cure. In recent years, efforts have been made to make this prediction more accurate and to shorten the duration of the test, respectively, and therefore reduce waiting and total operating time. The aim of this study was to evaluate the practicability and safety of a time-reduced criterion (decline ≥ 35% after 5 min) in a large cohort of patients. METHODS: In an 11-year period, all patients operated for pHPT were analyzed. After preoperative localization studies, hyperfunctioning parathyroid tissue was removed and IOPTH monitoring was performed. Intraoperatively, a decline of ≥50% from baseline 10 min after excision of the gland predicted cure. The performance of an interpretation model, using an earlier PTH level was analyzed retrospectively (decline ≥ 35% from baseline 5 min after excision). Differences in sensitivity, specificity, positive/negative predictive value and accuracy were calculated. RESULTS: According to the inclusion criteria, 1018 patients were analyzed. IOPTH predicted cure in 854 patients (83.9%) 10 min after gland excision with a false positive decline in 13 patients (1.5%). Applying the modified criterion (≥35% decline within 5 min), 814 patients (80%) showed an appropriate decline (false positive in 18 [2.2%]). Overall, multiple gland disease would have been missed in 7 patients. McNemar's test showed a significantly lower sensitivity, specificity and accuracy applying the "35%" criterion. CONCLUSIONS: In an endemic goiter region, a criterion, demanding a ≥ 35% decline 5 min after excision can not be recommended for IOPTH monitoring in patients with pHPT.

Mortality and continuity of care - Definitions matter! A cohort study in diabetics.

OBJECTIVE: To demonstrate that when investigating the relevance of continuity of care for patient outcomes, different definitions can lead to contradicting results. METHODS: We used claims data from the regional public health insurer of Lower Austria covering the period from 2008 to 2011. The study sample included subjects with repeated dispensings of anti-diabetic drugs. The continuity of care index was calculated firstly based on a patient's contacts with general practitioners (primary COCI) and secondly based on contacts at all medical disciplines (total COCI). The association of the two continuity of care measures with mortality was assessed in separate univariable and multivariable Cox regression models. RESULTS: Our study sample consisted of 51,717 patients with a median observation time of 3.65 years. The data showed that a high total COCI was associated with increased mortality, while there was no association between primary COCI and mortality. CONCLUSIONS: Measures of continuity of care are highly sensitive to the type of medical disciplines taken into account. The continuity of care index calculated from contacts at all medical disciplines might measure diversity rather than continuity of care.

Primary hyperparathyroidism: Dynamic postoperative metabolic changes.

OBJECTIVE: Little is known about the natural changes in parathyroid function after successful parathyroid surgery for primary hyperparathyroidism. The association of intact parathyroid hormone (iPTH) and calcium (Ca) with "temporary hypoparathyroidism" and "hungry bone syndrome" (HBS) was evaluated. DESIGN: Potential risk factors for temporary hypoparathyroidism and HBS were evaluated by taking blood samples before surgery, intra-operatively, at postoperative day (POD) 1, at POD 5 to 7, in postoperative week (POW) 8 and in postoperative month (POM) 6. PATIENTS: Of 425 patients, 43 (10.1%) had temporary hypoparathyroidism and 36 (8.5%) had HBS. MEASUREMENTS: The discriminative ability of iPTH and Ca on POD 1 for temporary hypoparathyroidism and HBS. RESULTS: Intact parathyroid hormone (IPTH) on POD 1 showed the highest discriminative ability for temporary hypoparathyroidism (C-index = 0.952), but not for HBS. IPTH was helpful in diagnosing HBS between POD 5 and 7 (C-index = 0.708). Extending the model by including Ca resulted in little improvement of the discriminative ability for temporary hypoparathyroidism (C-index = 0.964) and a decreased discriminative ability for HBS (C-index = 0.705). Normal parathyroid metabolism was documented in 139 (32.7%) patients on POD 1 and in 423 (99.5%) 6 months postoperatively, while 2 (0.5%) patients had persistent hyperparathyroidism, one diagnosed between POD 5 and 7 and another at POW 8. No patients suffered from permanent hypoparathyroidism. CONCLUSIONS: The necessity for Ca and vitamin D3 substitution cannot be predicted with certainty before POD 5 to 7 without serial laboratory measurements. Based on the results, a routine 8-week course of Ca and vitamin D3 treatment seems reasonable and its necessity should be evaluated in a follow-up study.

Separation in Logistic Regression: Causes, Consequences, and Control.

Separation is encountered in regression models with a discrete outcome (such as logistic regression) where the covariates perfectly predict the outcome. It is most frequent under the same conditions that lead to small-sample and sparse-data bias, such as presence of a rare outcome, rare exposures, highly correlated covariates, or covariates with strong effects. In theory, separation will produce infinite estimates for some coefficients. In practice, however, separation may be unnoticed or mishandled because of software limits in recognizing and handling the problem and in notifying the user. We discuss causes of separation in logistic regression and describe how common software packages deal with it. We then describe methods that remove separation, focusing on the same penalized-likelihood techniques used to address more general sparse-data problems. These methods improve accuracy, avoid software problems, and allow interpretation as Bayesian analyses with weakly informative priors. We discuss likelihood penalties, including some that can be implemented easily with any software package, and their relative advantages and disadvantages. We provide an illustration of ideas and methods using data from a case-control study of contraceptive practices and urinary tract infection.

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer.

Purpose: Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC.Experimental Design: Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC.Results: Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens, CEACAM21, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones.Conclusions: The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications. Clin Cancer Res; 23(24); 7621-32. ©2017 AACR.

Disease Monitoring Related Adherence and Its Association with Mortality in Lower Austrian Diabetes Patients.

BACKGROUND: Patient adherence is an important component of an efficient therapy. For diabetes patients it may contribute to controlled glucose values and reduction of adverse outcomes. OBJECTIVES: We aim to examine a potential association of Lower Austrian diabetes patients' adherence concerning their disease monitoring and mortality. METHODS: Using a retrospective cohort study design, claims data of 55,873 diabetes patients were examined for regular HbA1c lab tests that served as a proxy for monitoring related adherence. The cumulative incidence of mortality was estimated in the total study population and separately for different levels of adherence using the product-limit method. Mortality was compared between the different levels of adherence by the log-rank test. RESULTS: The cumulative incidence of mortality after one and two years was 4.2% and 8.7%. Patients with low adherence had a significantly higher risk of mortality than patients with high adherence (p < 0.001). Further results of a multivariable analysis will be presented at the conference. CONCLUSION: According to our preliminary univariate analysis, monitoring related adherence seems to be substantially beneficial for diabetes patients in Lower Austria.

Factors influencing pre-operative urinary calcium excretion in primary hyperparathyroidism.

OBJECTIVE: Normal or elevated 24-hour urinary calcium (Ca) excretion is a diagnostic marker in primary hyperparathyroidism (PHPT). It is used to distinguish familial hypocalciuric hypercalcaemia (FHH) from PHPT by calculating the Ca/creatinine clearance ratio (CCCR). The variance of CCCR in patients with PHPT is considerable. The aim of this study was to analyse the parameters affecting CCCR in patients with PHPT. DESIGN: The data were collected prospectively. Patients with sporadic PHPT undergoing successful surgery were included in a retrospective analysis. PATIENTS: The analysis covered 381 patients with pre-operative workup 2 days before removal of a solitary parathyroid adenoma. MEASUREMENTS: The impact of serum Ca and 25-hydroxyvitamin D3 (25-OH D3) on CCCR. RESULTS: The coefficient of determination (R2 ) in the multivariable model for CCCR consisting of age, Ca, 25-OH D3, 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), testosterone (separately for males and females), intact parathyroid hormone (iPTH) and osteocalcin was 25.8%. The only significant parameters in the multivariable analysis were 1,25-(OH)2 D3 and osteocalcin with a drop in R2 of 15.4% (P<.001) and 2.4% (P=.006), respectively. Bone mineral densities at the lumbar spine, distal radius and left femoral neck were not associated with CCCR (r=-.08, r=-.10 and r=-0.09). CONCLUSIONS: In multivariable analysis, 1,25-(OH)2 D3 and osteocalcin were the only factors correlating with CCCR. Vitamin D3 replacement may therefore impair the diagnostic value of CCCR and increase the importance of close monitoring of urinary Ca excretion during treatment.