Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study ...was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor.
Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions.
Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes.
These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs.
The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment ...effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.
The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor.
Blood loss, ...one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations.
The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS.
For model design, 1924 patients were included of whom 12% developed POPF. Three predictors were strongly associated with POPF: soft pancreatic texture odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80-3.69, small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61-0.76), and high body mass index (BMI) (per kg/m increase, OR: 1.07, 95% CI: 1.04-1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71-0.78) after internal validation, and 0.78 (0.74-0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05).
The a-FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. The online calculator is available at www.pancreascalculator.com.
A mixture risk assessment (MRA) for four metals relevant to chronic kidney disease (CKD) was performed. Dietary exposure to cadmium or lead alone exceeded the respective reference values in the ...majority of the 10 European countries included in our study. When the dietary exposure to those metals and inorganic mercury and inorganic arsenic was combined following a classical or personalised modified reference point index (mRPI) approach, not only high exposure (95th percentile) estimates but also the mean exceeded the tolerable intake of the mixture in all countries studied. Cadmium and lead contributed most to the combined exposure, followed by inorganic arsenic and inorganic mercury. The use of conversion factors for inorganic arsenic and inorganic mercury from total arsenic and total mercury concentration data was a source of uncertainty. Other uncertainties were related to the use of different principles to derive reference points. Yet, MRA at the target organ level, as performed in our study, could be used as a way to efficiently prioritise assessment groups for higher-tier MRA. Since the combined exposure to the four metals exceeded the tolerable intake, we recommend a refined MRA based on a common, specific nephrotoxic effect and relative potency factors (RPFs) based on a similar effect size.
Recent evidence suggests that there is often substantial variation in the benefits and harms across a trial population. We aimed to identify regression modeling approaches that assess heterogeneity ...of treatment effect within a randomized clinical trial.
We performed a literature review using a broad search strategy, complemented by suggestions of a technical expert panel.
The approaches are classified into 3 categories: 1) Risk-based methods (11 papers) use only prognostic factors to define patient subgroups, relying on the mathematical dependency of the absolute risk difference on baseline risk; 2) Treatment effect modeling methods (9 papers) use both prognostic factors and treatment effect modifiers to explore characteristics that interact with the effects of therapy on a relative scale. These methods couple data-driven subgroup identification with approaches to prevent overfitting, such as penalization or use of separate data sets for subgroup identification and effect estimation. 3) Optimal treatment regime methods (12 papers) focus primarily on treatment effect modifiers to classify the trial population into those who benefit from treatment and those who do not. Finally, we also identified papers which describe model evaluation methods (4 papers).
Three classes of approaches were identified to assess heterogeneity of treatment effect. Methodological research, including both simulations and empirical evaluations, is required to compare the available methods in different settings and to derive well-informed guidance for their application in RCT analysis.
Several less-invasive staging procedures have been proposed to replace axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) in patients with initially clinically node-positive ...(cN+) breast cancer, but these procedures may fail to detect residual disease. Owing to the lack of high-level evidence, it is not yet clear which procedure is most optimal to replace ALND.
To determine the diagnostic accuracy of radioactive iodine seed placement in the axilla with sentinel lymph node biopsy (RISAS), a targeted axillary dissection procedure.
This was a prospective, multicenter, noninferiority, diagnostic accuracy trial conducted from March 1, 2017, to December 31, 2019. Patients were included within 14 institutions (general, teaching, and academic) throughout the Netherlands. Patients with breast cancer clinical tumor categories 1 through 4 (cT1-4; tumor diameter <2 cm and up to >5 cm or extension to the chest wall or skin) and pathologically proven positive axillary lymph nodes (ie, clinical node categories cN1, metastases to movable ipsilateral level I and/or level II axillary nodes; cN2, metastases to fixed or matted ipsilateral level I and/or level II axillary nodes; cN3b, metastases to ipsilateral level I and/or level II axillary nodes with metastases to internal mammary nodes) who were treated with NAC were eligible for inclusion. Data were analyzed from July 2020 to December 2021.
Pre-NAC, the marking of a pathologically confirmed positive axillary lymph node with radioactive iodine seed (MARI) procedure, was performed and after NAC, sentinel lymph node biopsy (SLNB) combined with excision of the marked lymph node (ie, RISAS procedure) was performed, followed by ALND.
The identification rate, false-negative rate (FNR), and negative predictive value (NPV) were calculated for all 3 procedures: RISAS, SLNB, and MARI. The noninferiority margin of the observed FNR was 6.25% for the RISAS procedure.
A total of 212 patients (median range age, 52 22-77 years) who had cN+ breast cancer underwent the RISAS procedure and ALND. The identification rate of the RISAS procedure was 98.2% (223 of 227). The identification rates of SLNB and MARI were 86.4% (197 of 228) and 94.1% (224 of 238), respectively. FNR of the RISAS procedure was 3.5% (5 of 144; 90% CI, 1.38-7.16), and NPV was 92.8% (64 of 69; 90% CI, 85.37-97.10), compared with an FNR of 17.9% (22 of 123; 90% CI, 12.4%-24.5%) and NPV of 72.8% (59 of 81; 90% CI, 63.5%-80.8%) for SLNB and an FNR of 7.0% (10 of 143; 90% CI, 3.8%-11.6%) and NPV of 86.3% (63 of 73; 90% CI, 77.9%-92.4%) for the MARI procedure. In a subgroup of 174 patients in whom SLNB and the MARI procedure were successful and ALND was performed, FNR of the RISAS procedure was 2.5% (3 of 118; 90% CI, 0.7%-6.4%), compared with 18.6% (22 of 118; 90% CI, 13.0%-25.5%) for SLNB (P < .001) and 6.8% (8 of 118; 90% CI, 3.4%-11.9%) for the MARI procedure (P = .03).
Results of this diagnostic study suggest that the RISAS procedure was the most feasible and accurate less-invasive procedure for axillary staging after NAC in patients with cN+ breast cancer.
The interest in holistic considerations in the area of food safety is increasing. Risk managers may face the problem that reducing the risk of one compound may increase the risk of another compound. ...An example is the potential increase in mycotoxin levels due to a reduced use of fungicides in crop production. The Integrated Probabilistic Risk Assessment (IPRA) model was used to compare the estimated health impacts on humans caused by crops contaminated with the fungicides spiroxamine (SPI) and tebuconazole (TEB) or with the mycotoxins deoxynivalenol (DON) and zearalenone (ZEA). The IPRA model integrates a distribution characterising the exposure of individuals with a distribution characterising the susceptibility of individuals towards toxic effects. Its outcome, a distribution of Individual Margins of Exposure (IMoE), served as basis to perform comparisons of compounds, effects, countries, and population groups. Based on the available data and the assumptions made, none of the four compounds was found to have impact on human health in the addressed scenarios. The IMoE distributions were located as follows: DON
<
TEB
=
ZEA
<
SPI, showing DON to be the compound with the highest potential for negative health impacts. The presented approach can help risk managers to prioritise risk-reduction measures.
Objectives
To report the clinical presentation, complications, and long‐term outcomes of cats treated for perineal hernia with modified internal obturator muscle transposition.
Methods
The medical ...records of cats surgically treated for perineal hernia between 2013 and 2019 were reviewed and an owner questionnaire was conducted to determine long‐term outcome.
Results
Thirty‐six cats were included in the study: 34 had bilateral and two unilateral hernias. Of these 36, 24 (67%) were male neutered with a median age of 10 (range: 1 to 18) years. The complication rate was low, however, one cat experienced a major postoperative complication: rectal prolapse requiring revision surgery 48 hours postsurgery. Short‐term outcomes were available for 32 of 36 (89%) cats. Of the 32, 23 were examined 6 weeks postoperatively, and a telephonic consultation was performed for an additional nine of 32. Of the 23 cats examined directly, none had recurrence. Overall 12 of 32 experienced short‐term postoperative tenesmus which resolved in nine of 12 (75%). Long‐term outcomes were available for 31 of 36 cats (86%), with a median of 18.5 (6 to 89) months follow‐up. A good outcome was achieved in 23 of 31 (74%) whereas three of 31 (10%) had fair outcomes and five of 31 (16%) had a poor outcome. Of the five cats with a poor outcome, two required subtotal colectomy to manage clinical signs related to megacolon, two were euthanised following a return of clinical signs, and one developed unilateral recurrence.
Clinical Significance
Perineal hernia should be considered in cats presenting with tenesmus or recurrent obstipation. Surgical treatment of perineal hernias in cats can result in good owner‐assessed long‐term outcome.
Targeting low-dose computed tomography (LDCT) for lung cancer screening to persons at highest risk for lung cancer mortality has been suggested to improve screening efficiency.
To quantify the value ...of risk-targeted selection for lung cancer screening compared with National Lung Screening Trial (NLST) eligibility criteria.
Cost-effectiveness analysis using a multistate prediction model.
NLST.
Current and former smokers eligible for lung cancer screening.
Lifetime.
Health care sector.
Risk-targeted versus NLST-based screening.
Incremental 7-year mortality, life expectancy, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of screening with LDCT versus chest radiography at each decile of lung cancer mortality risk.
Participants at greater risk for lung cancer mortality were older and had more comorbid conditions and higher screening-related costs. The incremental lung cancer mortality benefits during the first 7 years ranged from 1.2 to 9.5 lung cancer deaths prevented per 10 000 person-years for the lowest to highest risk deciles, respectively (extreme decile ratio, 7.9). The gradient of benefits across risk groups, however, was attenuated in terms of life-years (extreme decile ratio, 3.6) and QALYs (extreme decile ratio, 2.4). The incremental cost-effectiveness ratios (ICERs) were similar across risk deciles ($75 000 per QALY in the lowest risk decile to $53 000 per QALY in the highest risk decile). Payers willing to pay $100 000 per QALY would pay for LDCT screening for all decile groups.
Alternative assumptions did not substantially alter our findings.
Our model did not account for all correlated differences between lung cancer mortality risk and quality of life.
Although risk targeting may improve screening efficiency in terms of early lung cancer mortality per person screened, the gains in efficiency are attenuated and modest in terms of life-years, QALYs, and cost-effectiveness.
National Institutes of Health (U01NS086294).
Abstract Background In 1 of 3 patients with initial lymph node-positive (cN+ ) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax-pCR). This urges ...the need for a less-invasive axillary staging method. Recently introduced less-invasive procedures have been insufficient in accurately identifying ax-pCR. Therefore, we propose a novel less-invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB). Patients and Methods In the present open single-arm multicenter validation study, 225 cN+ (biopsy-proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine-125 seed before NAC. After NAC completion, this iodine-125 seed-marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false-negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported. Conclusion The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN+ patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax-pCR confirmed using the RISAS procedure.
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