Treatment Patterns and Use of Immune Checkpoint Inhibitors Among Patients with Metastatic Bladder Cancer in a Dutch Nationwide Cohort.

Since 2017, two immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of metastatic urothelial carcinoma in Europe: pembrolizumab as second-line therapy and avelumab as maintenance therapy. Our aim was to describe the use of ICIs as first and later lines of treatment in patients with metastatic bladder cancer (mBC) in the Netherlands. We identified all patients diagnosed with primary mBC between 2018 and 2021 in the Netherlands from the Netherlands Cancer Registry (NCR). NCR data were supplemented with data from the Dutch nationwide Prospective Bladder Cancer Infrastructure (ProBCI) collected from medical files, with follow-up until death or end of data collection on January 1, 2023. A total of 1525 patients were diagnosed with primary mBC between 2018 and 2021 in the Netherlands. Of these, 34.7% received at least one line of systemic treatment with chemotherapy or ICI. After first-line platinum-based chemotherapy, 34.1% received second-line ICI and 3.9% received maintenance ICI. Among patients who completed or discontinued first-line cisplatin- or carboplatin-based chemotherapy after approval of maintenance ICI in the Netherlands, 40.7% and 19.7% received second-line ICI, and 9.3% and 14.1% received maintenance ICI, respectively. ICI use for mBC treatment has not increased considerably since their introduction in 2017. Future research should assess whether the introduction of maintenance avelumab (available since April 2021 in the Netherlands) has led to increases in the proportion of patients with mBC patients receiving systemic treatment and the proportion receiving ICI. Patient summary: We assessed the rate of immunotherapy use for patients with metastatic bladder cancer in the Netherlands. Since its introduction, immunotherapy has been used in a minority of patients, mostly as second-line treatment after platinum-based chemotherapy.

Chiral Aminoalcohol-Derived δ-Lactams Provide Easy Access to Piperidines and Acyclic Five-Carbon Building Blocks Bearing a Tertiary and a Quaternary Stereocenter.

A procedure for the synthesis of enantiopure piperidines and acyclic building blocks (5-aminopentanols, O-protected 5-hydroxypentanenitriles) containing a tertiary and a quaternary stereocenter has been developed. Starting from a phenylglycinol- or aminoindanol-derived δ-lactam bearing an alkyl substituent at the α-position of the N,O-acetal carbon, easily accessible by a cyclocondensation reaction, the stereoselective dialkylation at the carbonyl α-position generates the quaternary stereocenter and the subsequent two-step reductive removal of the chiral inductor provides enantiopure 3,3,5-trisubstituted piperidines. Alternatively, the simultaneous reductive opening of the oxazolidine and piperidone rings of the dialkylated lactams followed by reductive or oxidative cleavage of the chiral inductor opens access to chiral 2,2,4-trisubstituted 5-amino-1-pentanols or 2,4,4-trisubstituted 5-hydroxypentanenitriles.

Correlation between Power Elbow Flexion and Physical Performance Test: A Potential Predictor for Assessing Physical Performance in Older Adults.

BACKGROUND: With the increasing number of older adults and their declining motor and cognitive function, it is crucial to find alternative methods for assessing physical functionality. The Short Physical Performance Battery (SPPB), the Time Up and Go (TUG) test, the 4 Meter Walk Test and the Barthel Index (BI) have been used to evaluate mobility and fragility and predict falls. But some of these functional test tasks could be difficult to perform for frail older adults or bedridden patients that cannot ambulate. This study aimed to evaluate the relationship between these functional tests and the power elbow flexion (PEF test). MATERIAL AND METHODS: A correlation study was designed with 41 older adults over 65 years of age. The upper limb muscle power was measured using a linear encoder (VITRUBE VBT) with the flexion of the elbow. RESULTS: Strong correlations were found between the PEF test and the 4mWT (rho = 0.715, p = 0.001) and TUG (rho= -0.768, p = 0.001), indicating that the greater the upper limb muscle power is, the greater physical performance will be. Moderate correlations were also found between the PEF and Barthel Index (rho = 0.495, p = 0.001) and SPPB (rho = 0.650, p < 0.001). CONCLUSIONS: There is a strong correlation between PEF and the functional tests, proving that older adults that have greater upper limb muscle power have better physical performance. Upper limb muscle power and PEF could be an interesting tool for the assessment of physical performance in bedridden older adults.

Correlation between Physical Performance and Tensiomyographic and Myotonometric Parameters in Older Adults.

BACKGROUND: To examine the correlation between physical performance and muscle strength and the variables obtained from tensiomyography and myotonometry. METHODS: Fifty-two older adults able to complete functional tests participated in this observational study. Variables of maximal radial muscle displacement (Dm) and contraction time (Tc) (using tensiomyography) and muscle stiffness (using myotonometry) of the rectus femoris and vastus lateralis muscles were assessed. Physical performance (Short Physical Performance Battery, Timed Up and Go, Five Times Sit to Stand, and walking speed), isometric knee extension strength, and grip strength were assessed. A correlation analysis was performed between all the variables. RESULTS: A significant correlation between the Short Physical Performance Battery and the rectus femoris (rho = 0.491) and vastus lateralis Dm (rho = 0.329) was found. Significant correlations between the Five Times Sit to Stand Test and the Dm values of the rectus femoris (rho = -0.340) and Dm (rho = -0.304), and stiffness (rho = -0.345) in the vastus lateralis, were also found. No significant correlations were found between tensiomyography and myotonometry, the Timed Up and Go, and walking speed, nor between tensiomyography and myotonometry and grip strength or isometric knee extension strength. CONCLUSIONS: Functional tests should be prioritized in the assessment of older adults, but further research into muscle quality using technology is advisable.

Effectiveness of multicomponent training on physical performance in older adults: A systematic review and meta-analysis.

Multicomponent training (MCT) is characterized by the combination of at least 3 types of training. The purpose of this meta-analysis was to assess the effectiveness of MCT programs for improving physical performance in healthy older adults. A systematic review and meta-analysis of randomized control trials (RCTs) was conducted. The systematic search was performed in the Web of Sciences, PubMed (MEDLINE), and Cochrane Library databases. Articles were included if participants were healthy and 65 years or older, and the control group did not perform any type of training. Studies were excluded if the interventions lasted less than 8 weeks. PEDro scale and Risk of Bias tool (RoB) were used in order to assess the quality of the articles. The search strategy found a total of 388 studies. After inclusion and exclusion criteria, 19 studies were included for the qualitative analysis. Finally, 13 articles were included in the meta-analysis, with a total of 808 healthy older adults analyzed. The main results of the meta-analysis showed that MCT improves physical performance significantly more than no training (SMD: 0.78; 95% CI: 0.55, 1.00; Z = 6.84, p < 0.01; I2 = 54%). In addition, the MCT also seems to significantly increase in upper and lower limb strength, walking speed and aerobic capacity. MCT improves general functionality, strength in upper and lower extremities, walking speed and aerobic capacity. Implementation of MCT programs should be encouraged as an effective strategy in the prevention of adverse conditions in the older adult.

Effects of Adding an Online Exercise Program on Physical Function in Individuals Hospitalized by COVID-19: A Randomized Controlled Trial.

The worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has impacted all healthcare systems. One potential sequela experienced by hospitalized coronavirus disease 2019 (COVID-19) survivors includes muscle weakness with a reduction in strength and, consequently, a possible increase in frailty. The aim of this clinical trial was to evaluate the efficacy of adding an online therapeutic exercise program for 8 weeks to the medical prescriptions on functional variables in patients hospitalized due to COVID-19. A randomized controlled trial including 70 previously hospitalized COVID-19 survivors was conducted. Patients were randomly allocated to an experimental (n = 35) or control (n = 35) group. Both groups received regular prescriptions provided by their medical doctors. The experimental group also received a live online therapeutic exercise program for 8 weeks (3 sessions/week). Handgrip strength, gait speed, lower-extremity strength, balance, and frailty were assessed at baseline, at the end of the program, and one month after the end of the intervention. The repeated measures analysis of variance revealed significant Group*Time interactions for all the outcomes: (handgrip dominant: F = 17.395, p < 0.001, η2 = 0.24; handgrip non-dominant: F = 33.197, p < 0.001, η2 = 0.33; 4 m walk test (4WT): F = 13.039, p = 0.001, η2 = 0.16; short physical performance battery (SPPB): F = 26.421, p < 0.001, η2 = 0.28; the five chair-raise test (5CRT): F = 5.628, p = 0.004, η2 = 0.08; FRAIL scale: F = 11.249, p = 0.001, η2 = 0.14): patients in the experimental group experienced greater improvements in all outcomes than those assigned to the control group. This study revealed that the addition of an online exercise program for 8 weeks obtained greater improvements in handgrip strength, gait speed, lower-extremity strength, balance, and frailty in a sample of previously hospitalized COVID-19 survivors than application of just usual medical prescription.

Effect of goal-directed haemodynamic therapy guided by non-invasive monitoring on perioperative complications in elderly hip fracture patients within an enhanced recovery pathway.

BACKGROUND: Goal-directed haemodynamic therapy (GDHT) has been shown to reduce morbidity and mortality in high-risk surgical patients. However, there is little evidence of its efficacy in patients undergoing hip fracture surgery. This study aims to evaluate the effect of GDHT guided by non-invasive haemodynamic monitoring on perioperative complications in patients undergoing hip fracture surgery. METHODS: Patients > 64 years undergoing hip fracture surgery within an enhanced recovery pathway (ERP) were enrolled in this single-centre, non-randomized, intervention study with a historical control group and 12-month follow-up. Exclusion criteria were patients with pathological fractures, traffic-related fractures and refractures. Control group (CG) patients received standard care treatment. Intervention group (IG) patients received a GDHT protocol based on achieving an optimal stroke volume, in addition to a systolic blood pressure > 90 mmHg and an individualized cardiac index. No changes were made between groups in the ERP during the study period. Primary outcome was percentage of patients who developed intraoperative haemodynamic instability. Secondary outcomes were intraoperative arrhythmias, postoperative complications (cardiovascular, respiratory, infectious and renal complications), administered fluids, vasopressor requirements, perioperative transfusion, length of hospital stay, readmission and 1-year survival. RESULTS: In total, 551 patients (CG=272; IG=279) were included. Intraoperative haemodynamic instability was lower in the IG (37.5% vs 28.0%; p=0.017). GDHT patients had fewer postoperative cardiovascular (18.8% vs 7.2%; p < 0.001), respiratory (15.1% vs 3.6%; p<0.001) and infectious complications (21% vs 3.9%; p<0.001) but not renal (12.1% vs 33.7%; p<0.001). IG patients had less vasopressor requirements (25.5% vs 39.7%; p<0.001) and received less fluids [2.600 ml (IQR 1700 to 2700) vs 850 ml (IQR 750 to 1050); p=0.001] than control group. Fewer patients required transfusion in GDHT group (73.5% vs 44.4%; p<0.001). For IG patients, median length of hospital stay was shorter [11 days (IQR 8 to 16) vs 8 days; (IQR 6 to 11) p < 0.001] and 1-year survival higher [73.4% (95%CI 67.7 to 78.3 vs 83.8% (95%CI 78.8 to 87.7) p<0.003]. CONCLUSIONS: The use of GDHT decreases intraoperative complications and postoperative cardiovascular, respiratory and infectious but not postoperative renal complications. This strategy was associated with a shorter hospital stay and increased 1-year survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT02479321 .

Association Between Geriatric Assessment and Post-Chemotherapy Functional Status in Older Patients with Cancer.

BACKGROUND: Maintaining functional status is among the most important patient-centered outcomes for older adults with cancer. This study investigated the association between comprehensive geriatric assessment (CGA) and progressive disease or decline of IADL-independence 1 year after chemotherapy, overall survival (OS), and premature termination of chemotherapy. CGA-based functional status and quality of life (QOL) 1 year after chemotherapy are also described. METHODS: This prospective cohort study involved patients aged ≥65 years treated with chemotherapy for any cancer type. CGA and the G8-screening tool were performed before and after the completion of chemotherapy. Analyses were adjusted for tumor type and treatment intent: (a) indolent hematological malignancies, (b) aggressive hematological malignancies, c) solid malignancies treated with curative intent, and (d) solid malignancies treated with palliative intent. RESULTS: All 291 included patients lived in The Netherlands; 193 (67.4%) lived fully independent prior to chemotherapy. The median age was 72 years; 164 (56.4%) were male. IADL independence, CGA-based functional status, and QOL were maintained in half of the patients 1 year after chemotherapy. An abnormal G8-score before chemotherapy was a higher risk for progressive disease or a decline of IADL-independence (OR 3.60, 95% CI, 1.98-6.54, P < .0001), prematurely terminated chemotherapy (OR 2.12, 95% CI, 1.24-3.65, P = .006), and shorter median OS (HR 1.71, 95% CI, 1.16-2.52, P = .007). The impact of an abnormal G8-score differed across tumor type (oncological or hematological) and treatment indication (adjuvant or palliative). CONCLUSION: An abnormal G8 score before chemotherapy is associated with progressive disease and functional decline after chemotherapy and shorter median OS, especially in patients with solid malignancies.

Total Synthesis of (-)-Cylindricine H.

Starting from (R)-phenylglycinol-derived tricyclic lactam 1, the enantioselective synthesis of (-)-cylindricine H is reported. From the stereochemical standpoint, the key steps are the stereoselective generation of the quaternary C10 stereocenter, the stereoselective introduction of the C4 acetoxy and C2 butyl substituents taking advantage of the lactam carbonyl functionality, and the assembly of the pyrrolidine ring with the required functionalized one-carbon chain at C13 by intramolecular opening of an epoxide.

Intraoperative haemodynamic optimisation using the Hypotension Prediction Index and its impact on tissular perfusion: a protocol for a randomised controlled trial.

INTRODUCTION: Intraoperative arterial hypotension is associated with poor postoperative outcomes. The Hypotension Prediction Index (HPI) developed using machine learning techniques, allows the prediction of arterial hypotension analysing the arterial pressure waveform. The use of this index may reduce the duration and severity of intraoperative hypotension in adults undergoing non-cardiac surgery. This study aims to determine whether a treatment protocol based on the prevention of arterial hypotension using the HPI algorithm reduces the duration and severity of intraoperative hypotension compared with the recommended goal-directed fluid therapy strategy and may improve tissue oxygenation and organ perfusion. METHODS AND ANALYSIS: We will conduct a multicentre, randomised, controlled trial (N=80) in high-risk surgical patients scheduled for elective major abdominal surgery. All participants will be randomly assigned to a control or intervention group. Haemodynamic management in the control group will be based on standard haemodynamic parameters. Haemodynamic management of patients in the intervention group will be based on functional haemodynamic parameters provided by the HemoSphere platform (Edwards Lifesciences), including dynamic arterial elastance, dP/dtmax and the HPI. Tissue oxygen saturation will be recorded non-invasively and continuously by using near-infrared spectroscopy technology. Biomarkers of acute kidney stress (cTIMP2 and IGFBP7) will be obtained before and after surgery. The primary outcome will be the intraoperative time-weighted average of a mean arterial pressure <65 mm Hg. ETHICS AND DISSEMINATION: Ethics committee approval was obtained from the Ethics Committee of Hospital Gregorio Marañón (Meeting of 27 July 2020, minutes 18/2020, Madrid, Spain). Findings will be widely disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04301102.

Effectiveness of a Multicomponent Training Program on Physical Performance and Muscle Quality in Older Adults: A Quasi-Experimental Study.

Aging is associated with a decrease in functional capacity, manifested by a loss of strength, physical performance and muscle quality. Multicomponent training (MCT), characterized by the combination of at least three types of training, could be a good strategy to counteract these changes. To date there are no studies evaluating the effectiveness of MCT in improving both physical performance and muscle quality simultaneously. The aim of this study is to evaluate the changes produced by an MCT program on both physical performance and muscle quality in a population of healthy older adults. Sixteen healthy older adults were recruited to perform a 15-session multicomponent training intervention. Physical performance was assessed by different functional tests, and muscle quality was assessed by tensiomyography and myotonometry. The main results of this study show some improvement in functional tests, but not in muscle quality parameters, except for vastus lateralis stiffness. MCT is able to generate improvements in the physical performance of older adults, but these improvements are not reflected in muscle quality parameters measured by tensiomyography and myotonometry.

High-Intensity Care in the End-of-Life Phase of Castration-Resistant Prostate Cancer Patients: Results from the Dutch CAPRI-Registry.

Background: Intensive end-of-life care (i.e., the overuse of treatments and hospital resources in the last months of life), is undesirable since it has a minimal clinical benefit with a substantial financial burden. The aim was to investigate the care in the last three months of life (end-of-life [EOL]) in castration-resistant prostate cancer (CRPC). Methods: Castration-resistant prostate cancer registry (CAPRI) is an investigator-initiated, observational multicenter cohort study in 20 hospitals retrospectively including patients diagnosed with CRPC between 2010 and 2016. High-intensity care was defined as the initiation of life-prolonging drugs (LPDs) in the last month, continuation of LPD in last 14 days, >1 admission, admission duration ≥14 days, and/or intensive care admission in last three months of life. Descriptive and binary logistic regression analyses were performed. Results: High-intensity care was experienced by 41% of 2429 patients in the EOL period. Multivariable analysis showed that age (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.97-0.99), performance status (OR 0.57, 95% CI 0.33-0.97), time from CRPC to EOL (OR 0.98, 95% CI 0.97-0.98), referral to a medical oncologist (OR 1.99, 95% CI 1.55-2.55), prior LPD treatment (>1 line OR 1.72, 95% CI 1.31-2.28), and opioid use (OR 1.45, 95% CI 1.08-1.95) were significantly associated with high-intensity care. Conclusions: High-intensity care in EOL is not easily justifiable due to high economic cost and little effect on life span, but further research is awaited to give insight in the effect on patients' and their caregivers' quality of life.

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3'-oxindole] Alkaloids.

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3'-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.

Real-world outcomes of radium-223 dichloride for metastatic castration resistant prostate cancer.

Aim: Timing of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to alternative options and short window of opportunity. Methods: Ra-223 treated patients in the CAPRI-registry were included. Outcomes were evaluated based on treatment line of Ra-223. Results: Out of 285 patients, 49% received Ra-223 in line ≥3. 51% completed six Ra-223 injections and 34% had a symptomatic skeletal event after first Ra-223 without differences between subgroups. After correction of known prognostic factors Ra-223 in line ≥3 (HR: 3.267; 95% CI: 1.689-6.317; p < 0.01) remained associated with worse OS. Conclusion: In the Netherlands, Ra-223 was mainly started as second or third mCRPC-treatment in 2014-2018. Later timing of Ra-223 did affect OS, but not treatment completion and occurrence of symptomatic skeletal events.

Enantioselective formal synthesis of the marine macrolide (-)-callyspongiolide.

A short enantioselective synthesis of the macrocyclic core 19 of callyspongiolide, involving a homocrotylboration of aldehyde 4, a Still-Genari olefination, an esterification with alcohol 17, and a ring-closing metathesis, is reported.

Access to Enantiopure Advanced Intermediates en Route to Madangamines.

The synthesis of enantiopure ABCE and ABCD tetracyclic advanced intermediates en route to madangamine alkaloids and studies for the construction of the triunsaturated 15-membered D ring of madangamine B and the saturated 13-membered D ring of madangamine E are reported.

Second-Line Cabazitaxel Treatment in Castration-Resistant Prostate Cancer Clinical Trials Compared to Standard of Care in CAPRI: Observational Study in the Netherlands.

BACKGROUND: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC). PATIENTS AND METHODS: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response. RESULTS: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS. CONCLUSION: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes.

Enantioselective formal synthesis of (+)-madangamine A.

An enantioselective formal synthesis of the marine alkaloid madangamine A using phenylglycinol-derived lactam 1 as the starting enantiomeric scaffold is reported. The synthesis involves the construction of the C-9 substituted diazatricyclic ABC core and the final closure of D and E rings from the polyunsaturated skipped intermediate 19.