Identification and recombinant expression of a cutinase from Papiliotrema laurentii that hydrolyzes natural and synthetic polyesters.

Given the multitude of extracellular enzymes at their disposal, many of which are designed to degrade nature's polymers (lignin, cutin, cellulose, etc.), fungi are adept at targeting synthetic polyesters with similar chemical composition. Microbial-influenced deterioration of xenobiotic polymeric surfaces is an area of interest for material scientists as these are important for the conservation of the underlying structural materials. Here, we describe the isolation and characterization of the Papiliotrema laurentii 5307AH (P. laurentii) cutinase, Plcut1. P. laurentii is basidiomycete yeast with the ability to disperse Impranil-DLN (Impranil), a colloidal polyester polyurethane, in agar plates. To test whether the fungal factor involved in this clearing was a secreted enzyme, we screened the ability of P. laurentii culture supernatants to disperse Impranil. Using size exclusion chromatography (SEC), we isolated fractions that contained Impranil-clearing activity. These fractions harbored a single ~22 kD band, which was excised and subjected to peptide sequencing. Homology searches using the peptide sequences identified, revealed that the protein Papla1 543643 (Plcut1) displays similarities to serine esterase and cutinase family of proteins. Biochemical assays using recombinant Plcut1 confirmed that this enzyme has the capability to hydrolyze Impranil, soluble esterase substrates, and apple cutin. Finally, we confirmed the presence of the Plcut1 in culture supernatants using a custom antibody that specifically recognizes this protein. The work shown here supports a major role for the Plcut1 in the fungal degradation of natural polyesters and xenobiotic polymer surfaces.IMPORTANCEFungi play a vital role in the execution of a broad range of biological processes that drive ecosystem function through production of a diverse arsenal of enzymes. However, the universal reactivity of these enzymes is a current problem for the built environment and the undesired degradation of polymeric materials in protective coatings. Here, we report the identification and characterization of a hydrolase from Papiliotrema laurentii 5307AH, an aircraft-derived fungal isolate found colonizing a biodeteriorated polymer-coated surface. We show that P. laurentii secretes a cutinase capable of hydrolyzing soluble esters as well as ester-based compounds forming solid surface coatings. These findings indicate that this fungus plays a significant role in biodeterioration through the production of a cutinase adept at degrading ester-based polymers, some of which form the backbone of protective surface coatings. The work shown here provides insights into the mechanisms employed by fungi to degrade xenobiotic polymers.

Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.

BACKGROUND: The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. PATIENTS AND METHODS: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. RESULTS: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. CONCLUSIONS: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. GOV IDENTIFIERS: NCT01958021, NCT02422615, NCT02278120.

Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2- advanced breast cancer receiving first-line ribociclib plus fulvestrant.

BACKGROUND: The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2- ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. METHODS: Postmenopausal patients with HR+/HER2- ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). RESULTS: At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50-0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. CONCLUSIONS: This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2- ABC.

Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

The effectiveness of mRNA-1273 vaccine against COVID-19 caused by Delta variant: A systematic review and meta-analysis.

We aimed to perform meta-analyses to summarize the overall effectiveness of the mRNA-1273 vaccine against COVID-19 caused by the Delta variant from real-world studies. A systematic literature search with no language restriction was performed in electronic databases to identify eligible observational studies that reported the effectiveness of the mRNA-1273 vaccine to prevent reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19 caused by Delta variant of SARS-CoV-2 (B.1.617.2). A random-effects meta-analysis model was used to estimate the pooled odds ratio (OR) at a 95% confidence interval (CI), and the vaccine effectiveness was indicated as (pooled OR - 1)/OR. Five studies were included for this systematic review and meta-analysis. The meta-analysis revealed that the administration of mRNA-1273 vaccine protected against RT-PCR confirmed COVID-19 caused by Delta variant ≥21 days post first dose, with pooled vaccine effectiveness of 66% (95% CI: 65%-67%), as well as ≥14 days after the second dose, with pooled vaccine effectiveness of 91% (95% CI: 84%-95%). In conclusion, the mRNA-1273 vaccine offers a substantial protection rate against RT-PCR confirmed COVID-19 caused by the Delta variant upon full vaccination, although with slightly reduced effectiveness relative to other strains of SARS-CoV-2.

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.

BACKGROUND: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months). PATIENTS AND METHODS: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling). RESULTS: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed. CONCLUSIONS: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.

Impact of sequence order of anthracyclines and taxanes in neoadjuvant chemotherapy on pathologic complete response rate in HER2-negative breast cancer patients.

PURPOSE: Data exploring optimal sequencing of anthracyclines and taxanes as neoadjuvant chemotherapy (NACT) for breast cancer are limited and inconsistent. The objective of this study was to assess the real-world impact of sequence order on pathologic complete response (pCR) and clinical outcomes from NACT. METHODS: Patients with HER2-negative breast cancer treated with NACT from May 2012 to April 2020 were identified from a prospectively collected institutional database. The primary endpoint was to compare rates of pCR (ypT0/isN0) between patients who received anthracyclines followed by taxanes (AC-T) to those who received taxanes followed by anthracyclines (T-AC). Additional endpoints of interest included clinical complete response, downstaging, Neo-Bioscore, conversion to breast-conserving surgery eligibility, relapse-free survival, and overall survival between groups. RESULTS: Of the 283 patients who met eligibility criteria, 187 (66%) received AC-T and 96 (34%) received T-AC. Sequence order did not influence the primary endpoint of pCR rate (19% for AC-T vs. 21% for T-AC, p = 0.752). There were also no significant differences in secondary NACT efficacy outcomes between groups. In the overall cohort, pCR rate was higher in patients with triple-negative breast cancer (TNBC) (32% vs. 13% in hormone-positive cancer, p < 0.001) and grade 3 tumors (31% vs. 12% for grade 1-2 tumors, p < 0.001). CONCLUSIONS: In this real-world analysis of HER2-negative breast cancer patients, there was no differential impact on pCR rate or clinical outcomes from NACT with sequence order of anthracyclines and taxanes. This supports the current variation in prescribing practice.

Does the time from diagnostic biopsy to neoadjuvant chemotherapy affect the rate of pathologic complete response in stages I-III breast cancer?

Background: Studies in the adjuvant setting suggest that the timing of breast cancer diagnosis, surgery, and chemotherapy might affect outcomes. In the neoadjuvant setting, data exploring whether expeditious neoadjuvant chemotherapy (nac) after diagnosis improves the rate of pathologic complete response (pcr) in breast cancer are limited. Methods: Patients who received nac and completed treatment between May 2012 and December 2018 were identified from a prospectively collected database at BC Cancer. Time from diagnosis to start of nac was calculated. Patients were grouped into those who did and did not experience a pcr, and those who started nac within 28 days or after 28 days [time to nac (ttn)]. The association between pcr and ttn was tested using logistic regression. Results: In the time period studied, 482 patients who received nac were identified. After exclusions, 421 patients met the eligibility criteria. Median time from biopsy to chemotherapy was 33 days (range: 7-140 days). In 149 patients (35.4%), nac was received within 28 days of diagnosis (range: 7-28 days); in 272 patients (64.6%), it was received after more than 28 days (range: 29-140 days). The overall pcr rate was 31.8%. A trend toward a higher pcr rate, although not statistically significant, was observed in the group that initiated chemotherapy within 28 days (34.2% vs. 30.5%, p = 0.43). In the logistic regression model, rates of pcr were associated with receptor status, but not age, stage, or ttn. Conclusions: In the neoadjuvant setting, we observed no difference in the rate of pcr in patients who started nac within 28 days or after 28 days.

Patient-reported Outcome Measures of Revision Total Hip Arthroplasty for Prosthetic Joint Infection is not Inferior to Aseptic Revision Total Hip Arthroplasty.

INTRODUCTION: This study aims to investigate whether patients undergoing two-stage revision total hip arthroplasty (THA) for prosthetic joint infection (PJI) and one-stage revision THA for aseptic reasons have similar clinical outcomes and patient satisfaction during their post-operative follow-up. We hypothesise that the two-stage revision THA for PJI is associated with poorer outcomes as compared to aseptic revision THA. MATERIALS AND METHODS: We reviewed prospectively collected data in our tertiary hospital arthroplasty registry and identified patients who underwent revision THA between 2001 and 2014, with a minimum of two years follow-up. The study group (two-stage revision THA for PJI) consists of 23 patients and the control group (one-stage revision THA for aseptic reasons) consists of 231 patients. Patient demographics, Western Ontario and McMaster Universities Arthritis Index (WOMAC), Oxford Hip Score (OHS), Short Form-36 (SF-36) scores and patient reported satisfaction were evaluated. Student's t-test was used to compare continuous variables between the two groups. Statistical significance was defined as p <0.05. RESULTS: The pre-operative demographics and clinical scores were relatively similar between the two groups of patients. At two years, patients who underwent revision THA for PJI reported a better WOMAC Pain Score and OHS as compared to aseptic revision THA. A similar proportion of patients were satisfied with their results of surgery in both groups (p=0.093). CONCLUSIONS: Although patients who underwent revision THA for PJI had poorer pre-operative functional scores (WOMAC function and SF-36 PF), at two years follow-up, these two groups of patients have comparable post-operative outcomes. Interestingly, patients who had revision THA for PJI reported a better clinical outcome in terms of OHS and WOMAC Pain score as compared to the aseptic group. We conclude that the revision THA for PJI is not inferior to aseptic revision THA in terms of patient satisfaction and clinical outcomes.

Impact of pathologic complete response on survival after neoadjuvant chemotherapy in early-stage breast cancer: a population-based analysis.

BACKGROUND: Achieving a pathologic complete response (pCR) has been associated with improved long-term outcomes in clinical trials. However, the benefit of achieving pCR across subtypes and its prognostic effect on real-world outcomes has not been well described. METHODS: A retrospective analysis of the Breast Cancer Outcomes Unit database was undertaken to identify patients with stage I-III breast cancer treated with neoadjuvant chemotherapy from 2005 to 2010 in British Columbia. Patients were separated into two groups: those with pCR and those with residual invasive disease in the breast/axillary lymph nodes (RD). The primary endpoint was relapse-free survival (RFS). Key secondary endpoints included breast cancer-specific survival (BCSS) and overall survival (OS). RESULTS: Of 267 patients identified, 74 patients (28%) achieved pCR and 193 patients (72%) had RD. Median follow-up was 7.5 years. The 5-year RFS was higher in the pCR group compared to the RD group (84% vs 70%; HR 0.45, p = 0.011). The 5-year BCSS was also higher in the pCR group than in the RD group (90% vs 77%; HR 0.39, p = 0.014). In multivariable analyses, pCR was associated with improved RFS (HR 0.39, p = 0.0077) and BCSS (HR 0.35, p = 0.015), whereas traditional pathological prognostic factors were not. Patients with TNBC who achieved pCR had improved RFS and BCSS compared to those with RD (HR 0.26, p = 0.020 and HR 0.35, p = 0.090, respectively). A similar but non-statistically significant trend was seen in the HER-2-positive and ER + subtypes. CONCLUSIONS: Achieving pCR after neoadjuvant chemotherapy was associated with clinically meaningful improvements in survival parameters in a real-world setting. The cumulative data support pCR as a valid surrogate endpoint in both clinical trials and population-based settings.

The influence of obesity on clinical outcomes of fixed-bearing unicompartmental knee arthroplasty: a ten-year follow-up study.

AIMS: The aim of this study was to assess the influence of obesity on the clinical outcomes and survivorship ten years postoperatively in patients who underwent a fixed-bearing unicompartmental knee arthroplasty (UKA). PATIENTS AND METHODS: We prospectively followed 184 patients who underwent UKA between 2003 and 2007 for a minimum of ten years. A total of 142 patients with preoperative body mass index (BMI) of < 30 kg/m2 were in the control group (32 male, 110 female) and 42 patients with BMI of ≥ 30 kg/m2 were in the obese group (five male, 37 female). Pre- and postoperative range of movement (ROM), Knee Society Score (KSS), Oxford Knee Score (OKS), 36-Item Short-Form Health Survey (SF-36), and survivorship were analyzed. RESULTS: Patients in the obese group underwent UKA at a significantly younger mean age (56.5 years (sd 6.4)) than those in the control group (62.4 years (sd 7.8); p < 0.001). There was no significant difference in preoperative functional scores. However, those in the obese group had a significantly lower ROM (116° (sd 15°) vs 123° (sd 17°); p = 0.003). Both groups achieved significant improvement in outcome scores regardless of BMI, ten years postoperatively. All patients achieved the minimal clinically important difference (MCID) for OKS and KSS. Both groups also had high rates of satisfaction (96.3% in the control group and 97.5% in the obese group) and the fulfilment of expectations (94.9% in the control group and 95.0% in the obese group). Multiple linear regression showed a clear association between obesity and a lower OKS two years postoperatively and Knee Society Function Score (KSFS) ten years postoperatively. After applying propensity matching, obese patients had a significantly lower KSFS, OKS, and physical component score (PCS) ten years postoperatively. Seven patients underwent revision to total knee arthroplasty (TKA), two in the control group and five in the obese group, resulting in a mean rate of survival at ten years of 98.6% and 88.1%, respectively (p = 0.012). CONCLUSION: Both groups had significant improvements in functional and quality-of-life scores postoperatively. However, obesity was a significant predictor of poorer improvement in clinical outcome and an increased rate of revision ten years postoperatively.

Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Evaluation of anesthesia informed consent in pediatric practice - An observation cohort study.

BACKGROUND AND AIMS: An informed consent requires active participation by both physicians and patients. It is the responsibility of the physician to give the complete disclosure of information in easy language for the parent to understand. An informed consent process can be a challenge especially for the anesthetists when time is a limiting factor for patient-anesthetist interaction especially in same day admission and day surgery. The aim of this study was to subjectively evaluate the understanding and recall of the informed consent by the parents. MATERIAL AND METHODS: The validated survey was conducted over 10 weeks and was limited to one parent per child and to the parent who was directly involved in the consent process. RESULTS: Majority of parents rated positively for adequate disclosure of all items of information. Consent process done on day of surgery was found to be associated with lower parental rating in adequacy of disclosure of pain relief options. Seniority of anesthetists was associated with higher parental rating of adequacy of information regarding post operative plan, specific risk of child and overall consent process. Consent for minor surgeries, on day of surgery, did not significantly affect the parental performance in their recall of disclosed information but was associated with significant lower rating of adequacy of postoperative plan. Postoperative pain is among the areas for improvement especially in day surgery cases. CONCLUSION: Consent taken on day of surgery was found to be associated with lower parental rating. Postoperative plan for pain required improvement especially in day surgery cases.

A systematic review of factors affecting medication adherence among patients with osteoporosis.

The aim of this review was to identify factors that influence patients' adherence to anti-osteoporotic therapy. Factors identified that were associated with poorer medication adherence included polypharmacy, older age, and misconceptions about osteoporosis. Physicians need to be aware of these factors so as to optimize therapeutic outcomes for patients. INTRODUCTION: To identify factors that influence patients' adherence to anti-osteoporotic therapy. METHODS: A systematic review of literature was performed for articles published up till January 2018 using PubMed®, PsychINFO®, Embase®, and CINAHL®. Peer-reviewed articles which examined factors associated with anti-osteoporotic medication adherence were included. Classes of anti-osteoporotic therapy included bisphosphonates, parathyroid hormone-related analogue, denosumab, selective estrogen receptor modulators, estrogen/progestin therapy, calcitonin, and strontium ranelate. Meta-analyses, case reports/series, and other systematic reviews were excluded. Identified factors were classified using the World Health Organization's five dimensions of medication adherence (condition, patient, therapy, health-system, and socio-economic domains). RESULTS: Of 2404 articles reviewed, 124 relevant articles were identified. The prevalence of medication adherence ranged from 12.9 to 95.4%. Twenty-four factors with 139 sub-factors were identified. Bisphosphonates were the most well-studied class of medication (n = 59, 48%). Condition-related factors that were associated with poorer medication adherence included polypharmacy, and history of falls was associated with higher medication adherence. Patient-related factors which were associated with poorer medication adherence included older age and misconceptions about osteoporosis while therapy-related factors included higher dosing frequency and medication side effects. Health system-based factors associated with poorer medication adherence included care under different medical specialties and lack of patient education. Socio-economic-related factors associated with poorer medication adherence included current smoker and lack of medical insurance coverage. CONCLUSION: This review identified factors associated with poor medication adherence among osteoporotic patients. To optimize therapeutic outcomes for patients, clinicians need to be aware of the complexity of factors affecting medication adherence.