Plain language summary: 5-year results from the CROWN study of lorlatinib vs crizotinib in non-small-cell lung cancer.

WHAT IS THIS STUDY ABOUT?: This is a summary of the results of an ongoing study called CROWN. In the CROWN study, researchers looked at the effects of two medicines called lorlatinib (Lorbrena) and crizotinib (Xalkori) for people with advanced non-small cell lung cancer (NSCLC) who had not been treated yet. Everyone in the study had changes in a gene called anaplastic lymphoma kinase, or ALK, in their cancer cells. The changes in the ALK gene can make cancer grow. This analysis looked at how well lorlatinib and crizotinib worked and their side effects in people with advanced ALK-positive NSCLC after 5 years. WHAT DID THIS STUDY FIND?: After observing people for an average of 5 years, researchers found that more people who took lorlatinib were still alive without their cancer getting worse than the people who took crizotinib. At 5 years, the probability of being alive without their cancer getting worse was 60% in people who took lorlatinib compared with 8% in people who took crizotinib. Fewer people who took lorlatinib had their cancer spread within or to the brain than the people who took crizotinib. In more than half of the people who took lorlatinib, tumors that had spread to the brain did not get worse, and no new tumors spread to the brain after 5 years. In contrast, in about half of the people who took crizotinib, tumors that had spread to the brain got worse or new tumors spread to the brain after 16.4 months. More people who took lorlatinib (115 out of 149, or 77%) had severe or life-threatening side effects than people who took crizotinib (81 out of 142, or 57%). These side effects were like the ones reported in the earlier 3-year analysis. WHAT DO THE FINDINGS OF THE STUDY MEAN?: The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK-positive NSCLC has never been seen before.Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).

Reasons influencing the nurses' prioritization process while preventing and managing delirium: findings from a qualitative study.

BACKGROUND: Nurses play an important role in the prevention and management of delirium episodes. However, some studies have reported that not all interventions recommended are applied due to time and resource constraints, resulting in patients receiving less care than required because other patients and/or interventions are prioritised. The concept of prioritization is part of the broader concept of decision-making as the ability to choose between two or more alternatives to ensure patient safety. Understanding the reasons influencing the prioritization process in patients at risk or with delirium may inform interventions to prevent and/or minimise the unfinished nursing care. AIM: The purpose of this study was to explore the reasons that inform the prioritisation process among nurses when they are challenged to make decisions for patients at risk and with delirium. METHODS: A descriptive qualitative study performed according to the COnsolidated criteria for Reporting guidelines, in 2021. An intentional sample of nurses working full-time with older patients in medical, geriatric, and post-acute care facilities affiliated with the National Health System was involved. Semi-structured interviews were conducted and narratives thematic analysed. RESULTS: A total of 56 nurses (55.4% in internal medicine, 26.8% in geriatrics and 17.8% in post-acute/intermediate care) participated with an average age of 31.6 years. The reasons informing the prioritisation process while providing preventive or managerial interventions towards a patient at risk of or with delirium are set at three levels: (1) unit level, as reasons belong to the inadequacy of the 'Environment', the 'Human Resources', and the 'Organisation and Work Processes', (2) nurse's level, as issues in 'Competencies' and 'Attitudes' possessed, and (3) patient level, due to the 'Multidimensional Frailty'. CONCLUSION: Nurses caring for patients at risk of and with delirium face several challenges in providing care. To prioritise preventive and managerial interventions, it is essential to implement multilevel and multifaced organizational and educational strategies.

Nurses prioritization processes to prevent delirium in patients at risk: Findings from a Q-Methodology study.

BACKGROUND: This study aimed at (a) exploring how nurses prioritise interventions to prevent delirium among patients identified at risk and (b) describing the underlying prioritisation patterns according to nurses' individual characteristics. METHODS: There was used the Q-methodology a research process following specific steps: (a) identifying the concourse, (b) the Q-sample, and (c) the population (P-set); (d) collecting data using the Q-sort table; (e) entering the data and performing the factor analysis; and (f) interpreting the factors identified. RESULTS: There were involved 56 nurses working in medical, geriatric and log-term facilities (46; 82.2 %). The preventive intervention receiving the highest priority was 'Monitoring the vital parameters (heart rate, blood pressure, oxygen saturation)' (2.96 out of 4 as the highest priority; CI 95 %: 2.57, 3.36). Two priority patterns emerged among nurses (explained variance 44.78 %), one 'Clinical-oriented' (36.19 %) and one 'Family/caregiver-oriented' (8.60 %) representing 53 nurses out 56. CONCLUSION: Alongside the overall tendency to prioritise some preventive interventions instead of others, the priorities are polarised in two main patterns expressing two main individual characteristics of nurses. Knowing the existence of individual patterns and their aggregation informs how to shape educational interventions.

Plain language summary of the updated results from the CROWN study comparing lorlatinib with crizotinib in people with advanced non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase, or ALK. This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years. WHAT DID THIS STUDY FIND?: After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib. WHAT DO THE RESULTS OF THE STUDY MEAN?: The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.

Applicability of the interventions recommended for patients at risk or with delirium in medical and post-acute settings: a systematic review and a Nominal Group Technique study.

BACKGROUND: Delirium is a common condition during hospitalisation that should be prevented and treated. Several recommendations have been established to date, whereas few studies have investigated their applicability in daily practice for medical and post-acute settings. AIM: The aim of this research exercise was to emerge the applicability of the interventions recommended by studies in the daily care of patients at risk or with delirium cared in medical and post-acute settings. METHODS: The study was organised in three phases. A systematic literature review according to Centre for Reviews and Dissemination was conducted (January-February 2021). Cochrane Library, Pubmed, Scopus, Cumulative Index to Nursing and Allied Health Literature, Psychological Information Database, and the Joanna Briggs Institute databases were searched. Primary and secondary studies were evaluated in their methodological quality with the Standard Quality Assessment Criteria, the Critical Appraisal Skills Programme, and the Appraisal of Guidelines for Research & Evaluation. Then, the interventions identified were assessed in their applicability using the Nominal Group Technique who ranked their judgement on a four-point Likert scale from 1 (totally inapplicable) to 4 (totally applicable). Qualitative feedbacks were also considered, and a validation of the final list was performed by the Nominal Group. RESULTS: A total of 12 studies were included producing a list of 96 interventions categorised into four macro-areas (prevention, non-pharmacological, communication and pharmacological management). The Nominal Group identified 51 interventions (average score > 3.5) as applicable in medical and post-acute settings. Then, through a process of re-reading, and revising according to the comments provided by the Nominal Group, a list of 35 interventions out of the initial 96 were judged as applicable. CONCLUSION: Applicability should be assessed with experts in the field to understand the involved factors. One-third of interventions have been judged as applicable in the Italian context; the nurses' expertise, the work environment features, and the time required for each intervention in a high workload setting may prevent the full applicability of the interventions recommended by the literature.

Assessing self-efficacy in type 2 diabetes management: validation of the Italian version of the Diabetes Management Self-Efficacy Scale (IT-DMSES).

BACKGROUND: Being highly self-efficacious is a key factor in successful chronic disease self-management. In the context of measuring self-efficacy in type 2 diabetes management, the Diabetes Management Self-Efficacy Scale (DMSES) is the most widely used scale. The aim of this study was to adapt the English version of the scale to Italian and to evaluate the psychometric properties of the Italian version of DMSES in type 2 diabetes (IT-DMSES). METHODS: We conducted a cross-sectional study of people with type 2 diabetes attending the Endocrine-Metabolic Disease Care Unit of the Internal Medicine Department of San Marino State Hospital between October 2016 and February 2017. Patients completed a socio-demographic and clinical data form, the IT-DMSES and 3 self-report questionnaires measuring diabetes distress (PAID-5), psychological well-being (WHO-5) and depression (PHQ-9). Psychometric testing included construct validity (principal component analysis), internal consistency (Cronbach's α coefficient) and convergent/discriminant validity (Spearman's correlation coefficient). Decision tree analysis was performed to classify patients into homogeneous subgroups of self-efficacy based on their demographic and clinical characteristics. RESULTS: Participants were 110 males and 55 females, mean age of 65.2 years (SD ± 9), 56.9% had been diagnosed for 1-15 years, 63% had HbA1c level > 53 mmol/mol. Two main factors underlain the construct of self-efficacy in diabetes management: 'Disease Management' and "Lifestyles Management". Disease Management had a good reliability (α = .849) and Lifestyle Management had an excellent reliability (α = .902) indicating that the instrument is internally consistent. A negative and weak correlation was found between Lifestyle management, PAID-5 (r = - 0.258, p = < 0.01) and PHQ-9 (r = - 0.274, p = < 0.01) and a positive one with WHO-5 (r = 0.325, p < 0.01) supporting convergent validity. Disease management was uncorrelated with PAID-5 (r = - 0.142, p = 0.083), PHQ-9 (r = - 0.145, p = 0.076) and weekly correlated with WHO-5 (r = 0.170, p = 0.037) confirming discriminant validity. Higher levels of self-efficacy in lifestyle management were found in patients diagnosed for at least 1 year up to 15 years and aged > 65 years and the poorest self-efficacy was found in males < 65 years. CONCLUSIONS: Results support the validity and reliability of IT-DMSES. The scale can be used in research and clinical practice to monitor type 2 diabetes self-management over time.

Clinical Health Psychology Perspectives in Diabetes Care: A Retrospective Cohort Study Examining the Role of Depression in Adherence to Visits and Examinations in Type 2 Diabetes Management.

BACKGROUND: Depression in type 2 diabetes mellitus (T2DM) impacts glycemic control and complications. This study examines the influence of depression on compliance with recommended annual diabetes assessments in patients within the Local Healthcare Authority of Romagna. From a clinical health psychology perspective, understanding how depression influences patients' engagement in managing their conditions is crucial. This insight can help improve healthcare services by ensuring they address mental health needs and thereby enhance treatment effectiveness and overall patient outcomes. METHODS: This retrospective cohort study included residents of Romagna with incident T2DM from 2015 to 2017, followed from 1 January 2018 to 31 December 2022. Depression was identified via hospital discharge records or antidepressant prescriptions. Adherence to diabetes care guidelines was measured using the Guideline Composite Indicator (GCI). RESULTS: The study included 13,285 patients, with a mean age of 61.1 years. Prevalence of post-diabetes depression increased from 3.0% in 2018 to 8.9% in 2022. Initial analyses showed higher GCI rates among patients with depression. However, propensity-score adjustment revealed that by 2021-2022, patients with pre-diabetes depression had 5% lower compliance rates (p-value ≤ 0.05). Older adults with depression had reduced adherence, while younger adults with post-diabetes depression had higher adherence rates. CONCLUSIONS: Depression significantly affects adherence to diabetes care guidelines in T2DM patients, particularly among older adults. Integrated care models addressing both diabetes and depression are crucial for improving health outcomes.

The Reasons for Unfinished Nursing Care during the COVID-19 Pandemic: An Integrative Review.

Background: The concept of unfinished nursing care (UNC) describes nursing interventions required by patients and families that nurses postpone or omit. UNC reasons have been documented; however, no studies have summarised the underlying factors triggering the UNC during the pandemic. Therefore, the aim was to synthesise the available studies exploring factors affecting UNC during a pandemic. Methods: We conducted an integrative review following Whittemore and Knafl's framework according to the Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Scopus databases were searched for primary studies that collected data from 1 January 2020 to 1 May 2023. Both qualitative and quantitative studies assessing the reasons for UNC were eligible and evaluated in their quality using the Critical Appraisal Skills Programme and the Mixed Methods Appraisal Tool. Results: Four studies were included-three qualitative and one cross-sectional. The reasons for UNC have been documented at the following levels: (a) system (e.g., new healthcare system priorities); (b) unit (e.g., ineffective work processes); (c) nurse management (e.g., inadequate nurse manager's leadership); (d) nurse (e.g., nurses' attitudes, competences, performances); and (e) patient (increased demand for care). Conclusion: The reasons for UNC during the COVID-19 pandemic are different to those documented in the pre-pandemic times and reflect a pre-existing frailty of the National Health Service towards nursing care.

Coordinated Care Experiences Among Middle-Aged and Older Adults With Multiple Chronic Conditions: Characteristics, Correlates, and Consequences for Health and Healthcare Utilization.

BACKGROUND AND OBJECTIVES: Although coordinated care (CC) seeks to improve patient experiences and ultimately health outcomes, evidence from empirical research on the impacts of CC is mixed. This study examined the relationship between CC and healthcare outcomes over a 4-year period among older adults with multiple chronic conditions. RESEARCH DESIGN AND METHODS: This observational cohort study is based on data from the 2016-2020 Health and Retirement Study. Analysis is limited to respondents with 2+ chronic conditions who completed an experimental module on CC in 2016 (n = 906). Three domains of CC were assessed: perceptions, informal (family/friends) and formal (healthcare staff) tangible support, and technical support (using a "patient portal"). The longitudinal relationship between CC and health (e.g., pain, functioning, and self-rated health [SRH]) and healthcare (e.g., doctor visits, hospitalization, and care satisfaction) outcomes was investigated using mixed-effects models. RESULTS: Better perceptions of CC were associated with lower odds of ADL limitations (Odds ratio [OR] = 0.91; 95% CI = 0.84-0.99) and greater satisfaction with care (B = 0.04, 95% CI = 0.02-0.06). Receipt of more informal tangible support was associated with 1.34 higher odds of ADL limitations (95% CI = 1.19-1.51) and 1.74 higher odds of hospitalization (95% CI = 1.07-1.21). Use of technical support was associated with better SRH and greater satisfaction with care. DISCUSSION AND IMPLICATIONS: The longitudinal relationship between CC and health is multifaceted. Although positive perceptions and more technical support have beneficial effects on health outcomes, higher utilization of tangible support may reflect a higher demand among older adults with more complex healthcare needs.

Age of type 2 diabetes onset as a risk factor for dementia: A 13-year retrospective cohort study.

AIMS: To examine whether age at type 2 diabetes onset is an independent predictor of dementia risk. METHODS: Retrospective cohort drawn from healthcare administrative records of all inhabitants within Romagna's catchment area, Italy, with an estimated onset of type 2 diabetes in 2008-2017 and aged ≥ 55, with follow-up until 2020. Time to dementia or censoring was estimated with the Kaplan-Meier method, using diabetes onset as the time origin. Age groups were compared with the log-rank test. Multivariable competing-risks analysis was used to assess predictors of dementia. RESULTS: In patients aged ≥ 75 years, dementia-free survival (DFS) declined to below 90 % within five years and linearly decreased to 68.8 % until the end of follow-up. In contrast, DFS for those aged 55-64 years showed a marginal decrease, reaching 97.4 % after 13 years. Competing-risks regression showed that individuals aged ≥ 75 and 65-74 had a significantly higher risk of dementia compared to those aged 55-64 years. Having more comorbidities at diabetes onset and initial treatment with ≥ 2 antidiabetics were clinical predictors. CONCLUSIONS: Later age at onset of diabetes is strongly associated with dementia. A better understanding of the diabetes-dementia relationship is needed to inform strategies for promoting specific healthcare pathways.

A multi-state analysis of disease trajectories and mental health transitions in patients with type 2 diabetes: A population-based retrospective cohort study utilizing health administrative data.

AIMS: To investigate the risk of major depression and dementia in patients with type 2 diabetes, including dementia resulting from depression, and their impact on diabetes-related complications and mortality. METHODS: We conducted a population-based retrospective cohort study including 11,441 incident cases of diabetes in 2015-2017, with follow-up until 2022. A multi-state survival analysis was performed on a seven-state model with 15 transitions to capture disease progression and onset of mental disorders. RESULTS: Eight-year probabilities of depression, dementia, diabetes-related complications, and death were 9.7% (95% CI 8.7-10.7), 0.9% (95% CI 0.5-1.3), 10.4% (95% CI 9.5-11.4), and 14.8% (95% CI 13.9-15.7), respectively. Depression increased the risk of dementia up to 3.7% (95% CI 2.0-5.4), and up to 10.3% (95% CI 0.3-20.4) if coupled with diabetes complications. Eight-year mortality was 37.5% (95% CI 33.1-42.0) after depression, 74.1% (95% CI 63.7-84.5) after depression plus complications, 76.4% (95% CI 68.8-83.9) after dementia, and 98.6% (95% CI 96.1-100.0) after dementia plus complications. CONCLUSIONS: The interconnections observed across depression, dementia, complications, and mortality underscore the necessity for comprehensive and integrated approaches in managing diabetes. Early screening for depression, followed by timely and targeted interventions, may mitigate the risk of dementia and improve diabetes prognosis.

Long-Term Efficacy and Safety of Lorlatinib in Japanese Patients With ALK-Positive Advanced NSCLC-A Brief Report From the CROWN Study.

Introduction: Lorlatinib was found to have improved efficacy versus crizotinib in the global phase 3 CROWN study (NCT03052608). Similar results were revealed for the Japanese population as for the overall population. We present results from the unplanned 3-year follow-up from the CROWN study in Japanese patients. Methods: Patients were randomized to either lorlatinib 100 mg once daily (n = 25) or crizotinib 250 mg twice daily (n = 23). The primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial responses assessed by blinded independent central review and safety. Results: At the data cutoff of September 20, 2021, median progression-free survival was not reached with lorlatinib and 11.1 months with crizotinib (hazard ratio = 0.36). Objective response rate was 72.0% with lorlatinib and 52.2% with crizotinib. For patients with baseline brain metastases, intracranial response rate was 100.0% versus 28.6% with lorlatinib versus crizotinib. Nine patients in the lorlatinib group received more than or equal to 1 subsequent anticancer systemic therapy, with ALK tyrosine kinase inhibitor as the most common first subsequent therapy. The safety profile was consistent with that reported previously, with no new safety signals. Conclusions: This updated analysis in the Japanese population revealed prolonged benefits of lorlatinib over crizotinib in patients with treatment-naive advanced ALK-positive NSCLC with and those without brain metastases.

Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study.

PURPOSE: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up. METHODS: Two hundred ninety-six patients with ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses. RESULTS: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment. CONCLUSION: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.

Application of the COM-B Framework to Understand Facilitators and Barriers for Practising Physical Activity among Pregnant Women and Midwives Participating in the WELL-DONE! Study.

Regular physical activity (PA) is protective and reduces disease burden but remains a challenge for pregnant women (PW). According to the World Health Organization (WHO) guidelines, PW without contraindications should practice 150 min of moderate PA per week. Nonetheless, PA levels are concerningly low among PW. The aim of this study was to investigate PW's and midwives' perceptions regarding PA and recommended guidelines, and use this information to inform future health promotion strategies. We recruited 10 PW and 10 midwives to participate in online focus groups conducted between July 2020 and April 2021. Focus group probes and data analysis were guided by the COM-B (capability, opportunity, motivation-behaviour) framework. The majority of the sample had already practised PA, recognized the importance of PA during pregnancy, and considered the WHO guidelines reasonable. Notwithstanding, PW wanted more specific instruction on PA and desired opportunities to practice. Additional barriers reported by PW included low self-efficacy and lack of motivation. Midwives considered the lack of specific knowledge and confidence in managing PA as the main obstacles. The current findings suggest that PW and midwives need specific training in PA to overcome both psychological and physical barriers. Midwives play a vital role in educating and encouraging PA among PW.

Assessing attitudes towards insulin pump therapy in adults with type 1 diabetes: Italian validation of the Insulin Pump Attitudes Questionnaire (IT-IPA questionnaire).

AIMS: The aim of the study was to adapt the German version of the insulin pump therapy (IPA) questionnaire to Italian (IT-IPA) and to evaluate its psychometric properties in adults with type 1 diabetes. METHODS: We conducted a cross-sectional study, data were collected through an online survey. In addition to IT-IPA, questionnaires evaluating depression, anxiety, diabetes distress, self-efficacy, and treatment satisfaction were administered. The six factors identified in the IPA German version were assessed using confirmatory factor analysis; psychometric testing included construct validity and internal consistency. RESULTS: The online survey was compiled by 182 individuals with type 1 diabetes: 45.6% continuous subcutaneous insulin infusion (CSII) users and 54.4% multiple daily insulin injection users. The six-factor model had a very good fit in our sample. The internal consistency was acceptable (Cronbach's α = 0.75; 95% IC [0.65-0.81]). Diabetes treatment satisfaction was positively correlated with a positive attitude towards CSII therapy (Spearman's rho = 0.31; p < 0.01), less Technology Dependency, higher Ease of Use, and less Impaired Body Image. Furthermore, less Technology Dependency was associated with lower diabetes distress and depressive symptoms. CONCLUSIONS: The IT-IPA is a valid and reliable questionnaire evaluating attitudes towards insulin pump therapy. The questionnaire can be used for clinical practice during consultations for shared decision-making to CSII therapy.

Factors Associated With Developing Neurocognitive Adverse Events in Patients Receiving Lorlatinib After Progression on Other Targeted Therapies.

INTRODUCTION: The safety profile of lorlatinib includes neurocognitive adverse events (NAEs). Baseline factors associated with developing NAEs remain poorly characterized. METHODS: Records from patients who received lorlatinib through prospective studies at Massachusetts General Hospital (MGH, n = 124) or the phase 1/2 B7461001 (NCT01970865; n = 248) study were reviewed to identify potential associations between comorbidities, baseline medications, and NAEs. RESULTS: Most patients experienced a NAE (MGH: 60%, B7461001: 49%). Cognitive effects occurred in 40% and 29% of patients in the MGH and B7461001 cohorts, respectively. Brain metastases (p = 0.008), brain radiation (p = 0.033), psychiatric illness (p = 0.008), psychiatric medications (p < 0.001), antiepileptics (p < 0.001), and stimulants (p = 0.026) were associated with developing cognitive effects in B7461001. Mood effects occurred in 36% and 23% of patients in the MGH and B7461001 cohorts, respectively. In the MGH cohort, psychiatric illness (p = 0.02) and stimulants (p = 0.01) were associated with developing mood effects whereas brain surgery (p = 0.020), psychiatric medications (p < 0.001), benzodiazepines (p = 0.002), and sedatives (p = 0.034) were associated with developing mood effects in B7461001. Psychotic effects were infrequent (MGH: 3%, B7461001: 9%) and were associated with brain surgery in the MGH cohort (p = 0.001) and age in B7461001 (p = 0.014). Speech effects were observed in 23% and 11% of patients in the MGH and B7461001 cohorts, respectively. Brain radiation (p = 0.012) and antiepileptics (p < 0.001) were associated with speech effects in B7461001. Dose reductions were implemented for 52% and 18% of patients with NAEs in MGH and B7461001 cohorts, respectively, with mitigating effect. CONCLUSIONS: Neurocognitive effects from lorlatinib are common. Lorlatinib-related NAEs may be influenced by multiple factors, including brain metastases, brain radiation, psychiatric illness, and use of neurotropic medications.

Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study.

BACKGROUND: After a median follow-up of 18·3 months, the third-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, lorlatinib, improved progression-free survival in patients with treatment-naive, ALK-positive non-small-cell lung cancer in the phase 3 CROWN study. Here we report updated efficacy data, including intracranial activity, from an unplanned analysis after 3 years of follow-up. METHODS: CROWN is an ongoing, international, randomised, open-label phase 3 trial done in 104 centres in 23 countries worldwide. Eligible participants were aged 18 years and older or aged 20 years and older (depending on local regulations) with advanced, ALK-positive non-small-cell lung cancer, had received no previous systemic treatment for metastatic disease, had at least one extracranial measurable target lesion (according to the Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1), and had an Eastern Cooperative Oncology Group performance status score of 0-2. Patients were randomly assigned (1:1) to oral lorlatinib 100 mg daily or oral crizotinib 250 mg twice daily in 28-day cycles. Randomisation was stratified by the presence or absence of brain metastasis, and by ethnicity. Since the primary endpoint of the study had been met at the planned interim analysis, no further formal analysis of progression-free survival was planned, per protocol. The current unplanned analysis was done to further characterise tumour-related endpoints with a longer follow-up and is presented descriptively. For the planned study, the primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, intracranial duration of response, and safety. Efficacy endpoints were also assessed by the presence or absence of baseline brain metastases. This study is registered with ClinicalTrials.gov, NCT03052608. FINDINGS: Between May 11, 2017, and Feb 28, 2019, 425 patients were screened for eligibility, of whom 296 were enrolled and randomly assigned to the lorlatinib (n=149) or crizotinib (n=147) group. At data cutoff for this unplanned analysis (Sept 20, 2021), median duration of follow-up for progression-free survival was 36·7 months (IQR 31·3-41·9) for lorlatinib and 29·3 months (10·8-35·0) for crizotinib. Median progression-free survival by blinded independent central review was not reached (95% CI not reached-not reached) for lorlatinib and was 9·3 months (7·6-11·1) for crizotinib (hazard ratio [HR] 0·27 [95% CI 0·18-0·39]). 3-year progression-free survival was 64% (95% CI 55-71) in the lorlatinib group and 19% (12-27) in the crizotinib group. Progression-free survival (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and duration of response were improved with lorlatinib versus crizotinib. In patients with baseline brain metastases (n=37 lorlatinib; n=39 crizotinib), the HR for time to intracranial progression for lorlatinib versus crizotinib was 0·10 (95% CI 0·04-0·27); in patients without baseline brain metastases (n=112 lorlatinib; n=108 crizotinib), the HR was 0·02 (95% CI 0·002-0·14). In patients without brain metastases, one (1%) in the lorlatinib group and 25 (23%) in the crizotinib group had intracranial progression. Grade 3-4 adverse events occurred in 113 (76%) of 149 patients (most commonly due to altered lipid levels) with lorlatinib and in 81 (57%) of 142 patients with crizotinib. Adverse events led to treatment discontinuation in 11 (7%) patients in the lorlatinib group and 14 (10%) patients in the crizotinib group. There were no new safety signals. INTERPRETATION: These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases. FUNDING: Pfizer.

Tackling diabetes as a team: co-designing healthcare interventions to engage couples living with type 1 diabetes.

AIMS: Couples living with Type 1 diabetes: co-designing interventions to support them. METHODS: This is a qualitative study comprising two phases. Phase I represents the exploratory phase, consisting of semi-structured interviews with persons with Type 1 diabetes (N = 16) and partners (N = 6). In the second phase, co-design principles guided workshops with healthcare professionals, persons with Type 1 diabetes, and partners (N = 7) to facilitate discussion of the key themes identified and solutions to engage couples living with Type 1 diabetes in diabetes care. RESULT: The key themes identified from phase I as priorities to target in future interventions were: (i) Emotional impact of diabetes and (ii) Partners' involvement. Priority (i) captures the impact the emotional burden of diabetes management produces within couples' relationship. Priority (ii) captures the request from partners to be more involved in diabetes management. Characteristics of the interventions suggested during the co-design phase II focused on engaging patients and partners via a counseling point in healthcare settings and tailored help for couples' psychological support needs. CONCLUSIONS: Couples value pro-active intervention and support from their diabetes team or primary care for both the partners to live well with Type 1 diabetes.

Is it time to consider depression as a major complication of type 2 diabetes? Evidence from a large population-based cohort study.

AIMS: Depression in type 2 diabetes may heavily affect the course of the disease. In this study, we investigated, among new cases with type 2 diabetes, the incidence and clinical predictors of depression and determined the extent to which depression constitutes a risk factor for acute and long-term diabetes complications and mortality. METHODS: In this population-based retrospective cohort study, incident cases of type 2 diabetes without a prior history of depression were identified from the administrative databases of the Emilia-Romagna Region, Italy, between 2008 and 2017 and followed up until 2020. Logistic regression models were used to identify the predictors of depression. Cox regression models were used to estimate the risk of acute complications over three years, and the risk of long-term complications and mortality over ten years. RESULTS: Incident cases with type 2 diabetes were 30,815, of whom 5146 (16.7%) developed depression. The predictors of depression onset were as follows: female sex, age > 65 years, living in rural areas and comorbid diseases. Depression in type 2 diabetes was associated with a 2.3-fold risk of developing acute complications, 1.6-fold risk of developing long-term complications and 2.8-fold mortality risk. CONCLUSIONS: Our findings highlight that depression is associated with an increased risk for complications in type 2 diabetes and mortality and should not be neglected. Therefore, it is important to promote screening activities and introduce targeted and personalized treatment for depression in order to reduce the risk of poor short- and long-term outcomes of diabetes.