Enzyme replacement therapy for late-onset Pompe disease.

BACKGROUND: Pompe disease is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). People with infantile-onset disease have either a complete or a near-complete enzyme deficiency; people with late-onset Pompe disease (LOPD) retain some residual enzyme activity. GAA deficiency is treated with an intravenous infusion of recombinant human acid alglucosidase alfa, an enzyme replacement therapy (ERT). Alglucosidase alfa and avalglucosidase alfa are approved treatments, but cipaglucosidase alfa with miglustat is not yet approved. OBJECTIVES: To assess the effects of enzyme replacement therapies in people with late-onset Pompe disease. SEARCH METHODS: We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched MEDLINE OvidSP, clinical trial registries, and the reference lists of relevant articles and reviews. Date of last search: 21 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of ERT in people with LOPD of any age. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias and the certainty of the evidence (using GRADE). We resolved disagreements through discussion and by consulting a third author. MAIN RESULTS: We included six trials (358 randomised participants) lasting from 12 to 78 weeks. A single trial reported on each comparison listed below. None of the included trials assessed two of our secondary outcomes: need for respiratory support and use of a walking aid or wheelchair. Certainty of evidence was most commonly downgraded for selective reporting bias. Alglucosidase alfa versus placebo (90 participants) After 78 weeks, alglucosidase alfa probably improves the six-minute walk test (6MWT) distance compared to placebo (mean difference (MD) 30.95 metres, 95% confidence interval (CI) 7.98 to 53.92; moderate-certainty evidence) and probably improves respiratory function, measured as the change in per cent (%) predicted forced vital capacity (FVC) (MD 3.55, 95% CI 1.46 to 5.64; moderate-certainty evidence). There may be little or no difference between the groups in occurrence of infusion reactions (risk ratio (RR) 1.21, 95% CI 0.57 to 2.61; low-certainty evidence), quality of life physical component score (MD -1.36 points, 95% CI -5.59 to 2.87; low-certainty evidence), or adverse events (RR 0.94, 95% CI 0.64 to 1.39; low-certainty evidence). Alglucosidase alfa plus clenbuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus clenbuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 34.55 metres, 95% CI-10.11 to 79.21; very low-certainty evidence) and change in % predicted FVC (MD -13.51%, 95% CI -32.44 to 5.41; very low-certainty evidence). This study did not measure infusion reactions, quality of life, and adverse events. Alglucosidase alfa plus albuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus albuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 30.00 metres, 95% CI 0.55 to 59.45; very low-certainty evidence), change in % predicted FVC (MD -4.30%, 95% CI -14.87 to 6.27; very low-certainty evidence), and risk of adverse events (RR 0.67, 95% CI 0.38 to 1.18; very low-certainty evidence). This study did not measure infusion reactions and quality of life. VAL-1221 versus alglucosidase alfa (12 participants) Insufficient information was available about this trial to generate effect estimates measured at one year or later. Compared to alglucosidase alfa, VAL-1221 may increase or reduce infusion-associated reactions at three months, but the evidence is very uncertain (RR 2.80, 95% CI 0.18 to 42.80). This study did not measure quality of life and adverse events. Cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo (125 participants) Compared to alglucosidase alfa plus placebo, cipaglucosidase alfa plus miglustat may make little or no difference to: 6MWT distance at 52 weeks (MD 13.60 metres, 95% CI -2.26 to 29.46); infusion reactions (RR 0.94, 95% CI 0.49 to 1.80); quality of life scores for physical function (MD 1.70, 95% CI -2.13 to 5.53) and fatigue (MD -0.30, 95% CI -2.76 to 2.16); and adverse effects potentially related to treatment (RR 0.83, 95% CI 0.49 to 1.40) (all low-certainty evidence). Cipaglucosidase alfa plus miglustat probably improves % predicted FVC compared to alglucosidase alfa plus placebo (MD 3.10%, 95% CI 1.04 to 5.16; moderate-certainty evidence); however, it may make little or no change in % predicted sniff nasal inspiratory pressure (MD -0.06%, 95% CI -8.91 to 7.71; low-certainty evidence). Avalglucosidase alfa versus alglucosidase alfa (100 participants) After 49 weeks, avalglucosidase alfa probably improves 6MWT compared to alglucosidase alfa (MD 30.02 metres, 95% CI 1.84 to 58.20; moderate-certainty evidence). Avalglucosidase alfa probably makes little or no difference to % predicted FVC compared to alglucosidase alfa (MD 2.43%, 95% CI -0.08 to 4.94; moderate-certainty evidence). Avalglucosidase alfa may make little or no difference to infusion reactions (RR 0.78, 95% CI 0.42 to 1.45), quality of life (MD 0.77, 95% CI -2.09 to 3.63), or treatment-related adverse events (RR 0.92, 95% CI 0.61 to 1.40), all low-certainty evidence. AUTHORS' CONCLUSIONS: One trial compared the effect of ERT to placebo in LOPD, showing that alglucosidase alfa probably improves 6MWT and respiratory function (both moderate-certainty evidence). Avalglucosidase alfa probably improves 6MWT compared with alglucosidase alfa (moderate-certainty evidence). Cipaglucosidase plus miglustat probably improves FVC compared to alglucosidase alfa plus placebo (moderate-certainty evidence). Other trials studied the adjunct effect of clenbuterol and albuterol along with alglucosidase alfa, with little to no evidence of benefit. No significant rise in adverse events was noted with all ERTs. The impact of ERT on some outcomes remains unclear, and longer RCTs are needed to generate relevant information due to the progressive nature of LOPD. Alternative resources, such as post-marketing registries, could capture some of this information.

Meta-analysis of the effect of sarcopenia in predicting postoperative mortality in emergency and elective abdominal surgery.

OBJECTIVES: To investigate the effect of sarcopenia on postoperative mortality in patients undergoing emergency abdominal procedures and to compare postoperative mortality in patients with sarcopenia undergoing emergency abdominal procedures with those undergoing elective abdominal procedures. METHODS: A search of electronic information sources was conducted to identify all observational studies comparing sarcopenia with no sarcopenia in a) emergency abdominal surgery and b) elective abdominal surgery. We also identified the available cohort of patients in the literature with sarcopenia undergoing abdominal procedures and divided the entire cohort into two groups based on exposure to emergency surgery or elective surgery. The primary outcome measure of this study was postoperative 30-day mortality. RESULTS: Overall, 4 studies, enrolling a total of 734 patients, were eligible for the comparison in emergency setting and 16 studies, enrolling a total of 4590 patients, were eligible for the comparison in elective setting. Sarcopenia is associated with significantly higher risk of 30-day mortality (RR: 2.15, P < 0.0001), 1-year mortality (RR:1.97, P < 0.0001), total complications (RR:2.07, P = 0.0008), and need for ICU admission (RR:1.38, P = 0.003) and significantly longer length of ICU stay (MD:2.26, P = 0.006) and length of hospital stay (MD:2.46, P < 0.00001) compared to no sarcopenia in patients undergoing emergency abdominal procedures. Sarcopenia was also associated with significantly higher risk of 30-day mortality in patients undergoing elective abdominal procedures (RR:2.15, P = 0.002). Emergency abdominal surgery in patients with sarcopenia was associated with significantly higher risk of 30-day mortality compared to elective surgery (OR:12.00, P < 0.00001). CONCLUSIONS: Sarcopenia is an independent predictor of postoperative mortality in emergency abdominal surgery.

Cohort study investigating evolution and factors associated with dyspnoea after anatomic lung resection.

Background: Dyspnoea is common following surgical resection for non-small cell lung cancer (NSCLC). The effects range from reduced quality of life to impact on adjuvant therapy outcomes. Currently, dyspnoea beyond the immediate postoperative phase and risk factors are not well characterised. We hope to assess the evolution of patient-reported dyspnoea after anatomic lung resection and associated factors. Methods: Single-centre cohort study with analysis on data collected longitudinally of 131 patients undergoing anatomic lung resections for NSCLC between September 2014 and December 2018. The European Organization for Research and Treatment Lung Cancer-specific Quality of Life Questionnaire Dyspnoea Scale was used to measure dyspnoea before and after surgery. Multivariable regression analysis was used to identify factors associated with clinically meaningful perioperative changes in dyspnoea at 6-12 months. Results: Mean Dyspnoea Scale scores preoperatively and 6-12 months after resection were 12.6 (standard deviation 17.4) and 17.9 (standard deviation 20.5), respectively. Of all patients 31% experienced a clinically meaningful increase in dyspnoea, defined as >10 points between Dyspnoea Scale scores preoperatively and at 6-12 months. Comparatively, 71% of patients without preoperative symptoms of dyspnoea developed a clinically meaningful increase of dyspnoea postoperatively. After adjusting the analysis for baseline factors and preoperative Dyspnoea Scale score, female sex remained the only patient factor associated with increased postoperative dyspnoea at 6-12 months after surgery (P=0.046). A total of 34% of patients reported increased dyspnoea after lobectomies and 9% after segmentectomies (P=0.014). Segmentectomy (as opposed to larger resections) was the only surgical factor associated with lower risk of increased dyspnoea (P=0.057). Conclusions: A clinically meaningful increase in dyspnoea is frequent after lung resection. Postoperative evolution of dyspnoea is non-predictable using objective baseline factors highlighting the importance of patient reported symptoms and involvement in clinical consultation.

Patient-reported Physical Function Is Associated With Survival After Lung Resection for Non-Small Cell Lung Cancer.

BACKGROUND: We investigated the association between preoperative quality of life and long-term survival in patients undergoing surgical resection for non-small cell lung cancer. METHODS: Retrospective analysis was conducted on 388 consecutive patients who completed the quality of life assessment through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and lung cancer specific module (LC13), before anatomic lung resection for non-small cell lung cancer (2014-2018). Survival distribution was estimated by the Kaplan-Meier method. Cox proportional hazards regression and competing risk regression analyses were used to assess the independent association of preoperative patient-reported outcomes with overall and cancer-specific survival. RESULTS: Higher score in patient-reported physical functioning was significantly associated with longer overall survival. Factors significantly associated with poorer overall survival remained older age (P = .005), low body mass index (P = .007), male sex (P < .001), and nodal involvement (P = .007). Competing regression analysis found that worse baseline lung cancer-specific dyspnea (P = .03), low body mass index (P = .01), worse performance status (P = .03), and lymph node involvement (P = .01) were significantly associated with poorer cancer-specific survival. CONCLUSIONS: Higher patient-reported physical function score was associated with longer overall survival after resection. Our study highlights the significance of routinely collecting quality of life data to aid preoperative decision making in non-small cell lung cancer.

Shared Decision Making in Early-Stage Non-small Cell Lung Cancer: A Systematic Review.

BACKGROUND: The United Kingdom National Institute for Health and Care Excellence guidelines recommend that patients and professionals make shared decisions between surgery and stereotactic ablative radiotherapy (SABR) when treating early-stage non-small cell lung cancer (NSCLC). Variation by center suggests treatment decisions may be disproportionately influenced by clinician judgment and treatment availability rather than by patient preference. This systematic review critically evaluates studies of patient and clinician preferences for treatment of early-stage NSCLC. METHODS: Primary empirical research up to April 30, 2020, was identified from searches of MEDLINE, Embase, PsycInfo, and Web of Science databases. Data extracted included study characteristics and methods, preferences for NSCLC treatment, and involvement in decision making and risk of bias using the Mixed Methods Appraisal Tool. Findings were synthesized using descriptive data and narrative synthesis. RESULTS: Included in the review were 23 studies, of which 18 measured patient preferences, 4 clinician preferences, and 1 both clinician and patient preferences. Patients and clinicians were both most likely to prefer a collaborative role in treatment decisions. Most patients did not recall there being a choice between surgery or SABR options and thus experienced minimal decisional conflict. CONCLUSIONS: For professionals to support patients in making informed, value-based decisions about NSCLC treatments, better quality evidence is needed of the clinical and quality of life trade-offs for both surgery and SABR.

Factors influencing patient satisfaction after treatments for early-stage non-small cell lung cancer.

PURPOSE: Patient-reported outcome measures, including satisfaction with treatment decisions, provide important information in addition to clinical outcomes, survival and decision-making in lung cancer surgery. We investigated associations between preoperative clinical and socio-demographic factors and patient-reported satisfaction 6 weeks after radical treatment for early-stage non-small cell lung cancer (NSCLC). METHODS: We conducted a sub-group analysis of the prospective observational longitudinal study of 225 participants in two treatment groups-surgical (VATS) and radiotherapy (SABR). The Patient Satisfaction Questionnaire-18 (PSQ-18) was used to measure patient satisfaction 6 weeks after treatment. Clinical variables, Index of Multiple Deprivation decile and Decision self-efficacy scores were used in regression analysis. Variables with a p level < 0.1 were used as independent predictors in generalised linear logistic regression analyses. RESULTS: As expected, the two groups differed in pre-treatment clinical features. The SABR group experienced more grade 1-2 complications than the VATS group. No differences were found between the groups in any subscale of the PSQ-18 questionnaire. Patients experiencing complications or living in more deprived areas were more satisfied with care. Properative factors independently associated with patient satisfaction were the efficacy in decision-making and age. CONCLUSION: We showed that efficacy in treatment decision-making and age was the sole predictor of patient satisfaction with their care after radical treatment for early-stage NSCLC. Patients from more deprived areas and patients who suffered complications reported greater subsequent satisfaction. Involving patients in their care may improve satisfaction after treatment for early-stage NSCLC.