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.

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.

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.

Enantioselective Synthesis of the Ethyl Analog of the Marine Alkaloid Haliclorensin C.

The enantioselective synthesis (3.7% overall yield in nine steps from 2) and biological screening of the ethyl analog of the macrocyclic marine alkaloid haliclorensin C (compound 5) are reported. Amino alcohol 3, generated by a LiNH2BH3-promoted reductive ring-opening/debenzylation sequence from phenylglycinol-derived lactam 2, was used as the starting chiral linear building block. Incorporation of the undecene chain via the nosyl derivative 12, methylenation of the pentanol moiety, and a ring-closing metathesis are the key steps of the synthesis.

A Straightforward Synthesis of Functionalized cis-Perhydroisoquinolin-1-ones.

Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type reagents are reported. The effect of the solvent polarity and the concentration of the reagents is studied. The process involves two successive Michael additions and stereoselectively provides functionalized cis-perhydroisoquinolin-1-ones.

Studies on the Synthesis of Phlegmarine-Type Lycopodium Alkaloids: Enantioselective Synthesis of (-)-Cermizine B, (+)-Serratezomine E, and (+)-Luciduline.

The synthesis of the Lycopodium alkaloids, (-)-cermizine B, (+)-serratezomine E, and (+)-luciduline using phenylglycinol-derived tricyclic lactams as chiral scaffolds, is reported. The requisite lactams are prepared by a cyclocondensation reaction between ( R)- or ( S)-phenylglycinol and the substituted δ-keto ester 11, easily accessible from ( R)-pulegone. The factors governing the stereoselectivity of these cyclocondensation reactions are discussed. Key steps of the synthesis from the stereochemical standpoint are the stereoselective elaboration of the allyl substituent to the ( S)-2-(piperidyl)methyl moiety and the stereoselective removal of the chiral inductor to give a cis-decahydroquinoline.

Evaluation of two strategies for the interpretation of tumour markers in pleural effusions.

BACKGROUND: Pleural effusions present a diagnostic challenge. Approximately 20% are associated with cancer and some 50% require invasive procedures to perform diagnosis. Determination of tumour markers may help to identify patients with malignant effusions. Two strategies are used to obtain high specificity in the differential diagnosis of malignant pleural effusions: a) high cut-off, and b) fluid/serum (F/S) ratio and low cut-off. The aim of this study is to compare these two strategies and to establish whether the identification of possible false positives using benign biomarkers - ADA, CRP and % of polymorphonuclear cells - improves diagnostic accuracy. METHODS: We studied 402 pleural effusions, 122 of them malignant. Benign biomarkers were determined in pleural fluid, and CEA, CA72-4, CA19-9 and CA15-3 in pleural fluid and serum. RESULTS: Establishing a cut-off value for each TM for a specificity of 100%, a joint sensitivity of 66.5% was obtained. With the F/S strategy and low cut-off points, sensitivity was 77% and specificity 98.2%, Subclassifying cases with negative benign biomarkers, both strategies achieved a specificity of 100%; sensitivity was 69.9% for single determination and 80.6% for F/S ratio. CONCLUSIONS: The best interpretation of TM in the differential diagnosis of malignant pleural effusions is obtained using the F/S ratio in the group with negative benign biomarkers.

Enantioselective synthesis of lepadins A-D from a phenylglycinol-derived hydroquinolone lactam.

The marine alkaloids (-)-lepadins A-C and (+)-lepadin D, belonging to two diastereoisomeric series, were synthesized from an (R)-phenylglycinol-derived tricyclic lactam via a common cis-decahydroquinoline intermediate. Crucial aspects of the synthesis are the stereochemical control in the assembly of the cis-decahydroquinoline platform, in the introduction of the C2 methyl and C3 hydroxy substituents, and in the generation of the C5 stereocenter.

Stereocontrolled Annulations of Indolo[2,3-a]quinolizidine-Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine-Type Derivatives.

The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 has been studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind -unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert-butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov-derived adducts is demonstrated by their conversion into allo and epiallo yohimbine-type targets.

Access to enantiopure 4-substituted 1,5-aminoalcohols from phenylglycinol-derived δ-lactams: synthesis of Haliclona alkaloids.

LiNH2BH3-promoted reductive opening of 8-substituted phenylglycinol-derived oxazolopiperidone lactams leads to enantiopure 4-substituted-5-aminopentanols, which are used as starting building blocks in the synthesis of the Haliclona alkaloids haliclorensin C, haliclorensin, and halitulin (formal). The starting lactams are easily accessible by a cyclocondensation reaction of (R)-phenylglycinol with racemic γ-subtituted δ-oxoesters, in a process that involves a dynamic kinetic resolution.

Stereoselective total synthesis of the putative structure of nitraraine.

After the structure originally proposed for nitraraine was shown to be incorrect by total synthesis, the alternative structure 5 was recently suggested for the alkaloid on biosynthetic grounds and by comparison with the (1)H NMR data of tangutorine. The unambiguous synthesis of 5 is reported from tryptophanol and ketodiester 6, via oxazoloquinolone lactam 7. However, the melting point and (1)H NMR data of 5 did not match those reported for the natural product.

Total synthesis of (+)-madangamine D.

Madangamines are a group of bioactive marine sponge alkaloids, embodying an unprecedented diazapentacyclic skeletal type. The enantioselective total synthesis of madangamine D has been accomplished, and represents the first total synthesis of an alkaloid of the madangamine group. It involves the stereoselective construction of the diazatricyclic ABC core using a phenylglycinol-derived lactam as the starting enantiomeric scaffold and the subsequent assembly of the peripheral macrocyclic rings. The synthesis provides, for the first time, a pure sample of madangamine D and confirms the absolute configuration of this alkaloid family.

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.

Enantio- and diastereoconvergent cyclocondensation reactions: synthesis of enantiopure cis-decahydroquinolines.

Up to four stereocenters with a well-defined configuration are generated in a single synthetic step by the cyclocondensation of (R)-phenylglycinol or (1S,2R)-1-amino-2-indanol with stereoisomeric mixtures (racemates, meso forms, diastereoisomers) of cyclohexanone-based δ-keto-acid and δ-keto-diacid derivatives in enantio- and diastereoconvergent processes that involve dynamic kinetic resolution and/or desymmetrization of enantiotopic groups. A detailed analysis of the stereochemical outcome of this process is presented. This method provides easy access to enantiopure 8- and 6,8-substituted cis-decahydroquinolines, including alkaloids of the myrioxazine family.

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 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.

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.

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.