The impact of multidisciplinary geriatric follow-up on quality of life in older, non-surgical prefrail and frail patients with cancer A randomized controlled trial.

INTRODUCTION: Cancer management in older frail patients can be complex, given the high decline in functional status, comorbidity, and limited life expectancy affecting this group of patients. Therefore, this study aimed to investigate whether oncological treatment combined with comprehensive geriatric assessment (CGA) and tailored follow-up interventions improved or maintained quality of life (QoL) in older prefrail and frail patients with cancer. MATERIALS AND METHODS: A single-center randomized controlled trial included participants aged 70 or older with head, neck, lung, upper gastrointestinal tract, colon, or rectum cancer referred to non-surgical treatment. All participants underwent CGA conducted by a multidisciplinary geriatric team in an outpatient oncological clinic. The team consisted of a geriatrician and a specialized nurse who provided tailored follow-up visits and phone calls within 90 days after randomization. Exclusion criteria were fit patients, referral for specialized palliative care, or participating in another geriatric research program. In patients with well-functioning cognition, QoL was assessed using the EORTC QLQ-C30 and QlQ-ELD-14 questionnaires before and after the intervention. In patients with cognitive impairment, the Overall QoL-Depression List was used. Changes in QoL were dichotomized into improved/unchanged or worsened and analyzed in a logistic regression model. RESULTS: In total, 363 participants were included with a mean age of 76 years (SD 4.6) and 45 % were female. Sixty percent in the intervention group had improved or unchanged QoL compared to 66 % in the control group (odds ratio: 0.75 [95 % confidence interval(CI): 0.45-1.23]). Overall, clinically important changes were found in fatigue and reduced worries about the future. The intervention showed improvements in insomnia symptoms and reported decreased role functioning. Discrepancies were found in the burden of illness without a clinically important difference, where the intervention group experienced an increased burden while the control group had a decreased burden (coefficient: 9.02 [95 % CI, 0.49-17.5]). DISCUSSION: Multidisciplinary geriatric follow-up did not universally improve QoL in older frail patients with cancer. However, positive changes in specific aspects of QoL revealed nuanced impacts, warranting further exploration and larger studies to validate these observations. Tailored interventions targeting fatigue, insomnia, and emotional well-being are crucial for improving QoL in this population. TRIAL REGISTRATION: Registered in January 2016 at ClinicalTrials.gov (ID: NCT02837679).

A versatile microbial platform as a tunable whole-cell chemical sensor.

Biosensors are used to detect and quantify chemicals produced in industrial microbiology with high specificity, sensitivity, and portability. Most biosensors, however, are limited by the need for transcription factors engineered to recognize specific molecules. In this study, we overcome the limitations typically associated with traditional biosensors by engineering Pseudomonas putida for whole-cell sensing of a variety of chemicals. Our approach integrates fluorescent reporters with synthetic auxotrophies within central metabolism that can be complemented by target analytes in growth-coupled setups. This platform enables the detection of a wide array of structurally diverse chemicals under various conditions, including co-cultures of producer cell factories and sensor strains. We also demonstrate the applicability of this versatile biosensor platform for monitoring complex biochemical processes, including plastic degradation by either purified hydrolytic enzymes or engineered bacteria. This microbial system provides a rapid, sensitive, and readily adaptable tool for monitoring cell factory performance and for environmental analyzes.

Benefit of range uncertainty reduction in robust optimisation for proton therapy of brain, head-and-neck and breast cancer patients.

Background and Purpose: The primary cause of range uncertainty in proton therapy is inaccuracy in estimating the stopping-power ratio from computed tomography. This study examined the impact on dose-volume metrics by reducing range uncertainty in robust optimisation for a diverse patient cohort and determined the level of range uncertainty that resulted in a relevant reduction in doses to organs-at-risk (OARs). Materials and Methods: The effect of reducing range uncertainty on OAR doses was evaluated by robustly optimising six proton plans with varying range uncertainty levels (ranging from 3.5% in the original plan to 1.0%), keeping setup uncertainty fixed. All plans used the initial clinical treatment plan's beam directions and optimisation objectives and were optimised until a clinically acceptable plan was achieved across all setup and range scenarios. The effect of reduced range uncertainty on dose-volume metrics for OARs near the target was evaluated. This study included 30 brain cancer patients, as well as five head-and-neck and five breast cancer patients, investigating the relevance of reducing range uncertainty when different setup uncertainties were used. Results: Lowering range uncertainty slightly reduced the nominal dose to surrounding tissue. For body volume receiving 80% of the prescribed dose, reducing range uncertainty from 3.5% to 2.0% resulted in a median decrease of 4 cm3 for the brain, 17 cm3 for head-and-neck, and 27 cm3 for breast cancer patients. Conclusions: Reducing range uncertainty in robust optimisation showed a reduction in dose to OARs. The clinical relevance depends on the affected organs and the clinical dose constraints.

Physician barriers and dilemmas in the execution of clinical trials impacting decision-making in the DAHANCA 35 proton therapy trial for head and neck cancer.

Background: Physicians manage multiple obligations, providing best-practice treatment and patient- centred care in the standard treatment pathway while contributing to clinical trials simultaneously. These multifaceted responsibilities may introduce barriers and dilemmas to clinical trial execution, potentially impacting the clinical trial decision- making process. This study explores physicians' barriers and dilemmas in executing clinical trials and the impact on clinical trial decision-making. Method: Qualitative semi-structured interviews were conducted with experienced oncologists. Moreover, participant observations were performed during clinical encounters involving discussions about clinical trials. The analysis followed a structured approach: (1) transcription of data, (2) inductive text coding, (3) exploration of patterns, and (4) interpretation, leading to the results. The results were discussed and validated by the study participants. Results: The results comprise (1) a description of the clinical practice, which presents the setting of clinical trial execution; (2) results regarding physicians' barriers and dilemmas in executing clinical trials, leading to (3) the impact on clinical trial decision- making. The results involve barriers to time constraints for clinical trial tasks, dilemmas emerging from trial requirements or deviations from standard guidelines, and challenges with providing sufficient trial communication and adequate decision-making support, balancing between a paternalistic approach and respecting patient autonomy. Conclusion: The demanding obligations of clinical practice constitute a complex setting for executing clinical trials, resulting in numerous barriers and dilemmas that impact the decision-making process in clinical trials. The study emphasises the need for tailored clinical trial decision-making interventions to facilitate supportive, informed, and non-directive clinical trial decision-making.

Radiation therapy in older patients with cancer.

The general population is aging, which expectedly will lead to a future increase in older patients with cancer. This review summarises the recent advances in radiotherapy. Technological advances have led radiotherapy to be an efficient and well-tolerated treatment option in older patient with cancer. Studies show no difference in toxicity and disease control rates compared with the ones in younger patients with cancer. MR-guided radiotherapy, proton therapy, and integration of artificial intelligence in treatment planning represent the latest advances in the field of radiotherapy and hold potential to further improve the treatment of older patients with cancer.

Relationships of crystallinity and reaction rates for enzymatic degradation of poly (ethylene terephthalate), PET.

Biocatalytic degradation of plastic waste is anticipated to play an important role in future recycling systems. However, enzymatic degradation of crystalline poly (ethylene terephthalate) (PET) remains consistently poor. Herein, we employed functional assays to elucidate the molecular underpinnings of this limitation. This included utilizing complementary activity assays to monitor the degradation of PET disks with varying crystallinity (XC), as well as determining enzymatic kinetic parameters for soluble PET fragments. The results indicate that an efficient PET-hydrolase, LCCICCG, operates through an endolytic mode of action, and that its activity is limited by conformational constraints in the PET polymer. Such constraints become more pronounced at high XC values, and this limits the density of productive sites on the PET surface. Endolytic chain-scissions are the dominant reaction type in the initial stage, and this means that little or no soluble organic product are released. However, endolytic cuts gradually and locally promote chain mobility and hence the density of attack sites on the surface. This leads to an upward concave progress curve; a behavior sometimes termed lag-phase kinetics.

Exploring patient-reported barriers to participating in proton therapy clinical trials.

Introduction: Clinical trials lead the progress in healthcare. To ensure reliable research conclusions, it is essential to enroll diverse patient groups. Identifying and understanding patient-reported barriers to clinical trials may help enhance recruitment among diverse patient groups.The clinical potential of proton therapy (PT) to reduce late effects is being investigated in clinical trials worldwide. Thus, for some patients, PT is only accessible by participating in clinical trials.Individuals with smoking-related head and neck cancer (HNC) are sometimes socioeconomically deprived, leading to barriers to trial participation. This study aims to identify barriers to their participation in a randomised controlled trial (RCT) involving PT. Method: Interviews were conducted with 14 HNC patients declining participation in an RCT involving PT. The interviews were transcribed and systematically analysed using an inductive approach identifying categories and themes. Results: The identified barriers to RCT-participation are: (1) existential distress, which influenced participants' mental and cognitive capacities, (2) insufficient RCT-related knowledge arising from information overload during clinical consultations, (3) the wish for safety and familiarity during the treatment trajectory, particularly for participants needing accommodation during  radiotherapy, and (4) the motivation for study participation was impacted by uncertainty due to randomisation and clinical equipoise. Existential distress is identified as an overarching theme because it influences and amplifies the other three themes. Conclusion: Existential distress is a central theme that influences and amplifies other participation barriers in PT RCTs. It affects participants' comprehension of trial information, their preference for familiar environments, and their motivation to participate in clinical trials.

Evaluation of decentralised model-based selection of head and neck cancer patients for a proton treatment study. DAHANCA 35.

INTRODUCTION: Proton treatment can potentially spare patients with H&N cancer for substantial treatment-related toxicities. The current study investigated the reproducibility of a decentralised model-based selection of patients for a proton treatment study when the selection plans were compared to the clinical treatment plans performed at the proton centre. METHODS: Sixty-three patients were selected for proton treatment in the six Danish Head and Neck Cancer (DAHANCA) centres. The patients were selected based on normal tissue complication probability (NTCP) estimated from local photon and proton treatment plans, which showed a ΔNTCP greater than 5%-point for either grade 2 + dysphagia or grade 2 + xerostomia at six months. The selection plans were compared to the clinical treatment plans performed at the proton centre. RESULTS: Of the 63 patients, 49 and 25 were selected based on an estimated benefit in risk of dysphagia and xerostomia, respectively. Eleven patients had a potential gain in both toxicities. The mean ΔNTCP changed from the local selection plan comparison to the clinical comparison from 6.9 to 5.3 %-points (p = 0.01) and 7.3 to 4.9 %-points (p = 0.03) for dysphagia and xerostomia, respectively. Volume differences in both CTV and OAR could add to the loss in ΔNTCP. 61 of the 63 clinical plans had a positive ΔNTCP, and 38 had a ΔNTCP of 5%-points for at least one of the two endpoints. CONCLUSION: A local treatment plan comparison can be used to select candidates for proton treatment. The local comparative proton plan overestimates the potential benefit of the clinical proton plan. Continuous quality assurance of the delineation procedures and planning is crucial in the subsequent randomised clinical trial setting.

Dose planning study of proton versus photon radiotherapy for head and neck squamous cell carcinoma of unknown primary in the primary and recurrent setting.

BACKGROUND: Patients with head and neck squamous cell carcinoma of unknown primary (HNCUP) are often treated with extensive radiotherapy (RT). Frequently, the bilateral nodal clinical target volume (nCTV) and the volumes of suspected mucosal primary sites (mCTV) of the pharynx and larynx is irradiated. This treatment is effective but toxic. New data suggest that omission of the contralateral nCTV and mCTV, results in few recurrences. The present study explores photon versus proton therapy, in the primary and recurrent setting. MATERIAL AND METHODS: An analysis of twelve patients previously treated for HNCUP was performed. A fictitious recurrence was defined in patients treated for unilateral disease. Independently a volumetric arc photon plan and an intensity-modulated proton plan was made for all cases and scenarios. RESULTS: Compared to the standard bilateral treatment this study shows that limiting the target to unilateral nCTV leads to a significant decrease in dysphagia of 18% and 17% and xerostomia of 4.0% and 5% for photon and protons, respectively. Comparing photon RT directly to proton RT shows a small and often insignificant gain, using protons for both bilateral and unilateral targets. Focusing on re-irradiation, benefits from using protons in both the primary setting and at re-irradiation were limited. However, using protons for re-irradiation only leads to a decrease in the tissue volume receiving a specific dose outside the target overlapping region, e.g., V90Gymean was 31, 25, and 22 cm3 for photons-photons, photons-protons, and protons-protons, respectively. For V100Gy of the ipsilateral carotid artery, no differences were observed. CONCLUSION: Omitting contralateral nCTV irradiation and mCTV irradiation will significantly reduce toxicity. The accumulated high dose volumes can be minimised using protons for re-irradiation. However, the use of protons for primary treatment provides limited benefit in most patients.

Consistency in contouring of organs at risk by artificial intelligence vs oncologists in head and neck cancer patients.

BACKGROUND: In the Danish Head and Neck Cancer Group (DAHANCA) 35 trial, patients are selected for proton treatment based on simulated reductions of Normal Tissue Complication Probability (NTCP) for proton compared to photon treatment at the referring departments. After inclusion in the trial, immobilization, scanning, contouring and planning are repeated at the national proton centre. The new contours could result in reduced expected NTCP gain of the proton plan, resulting in a loss of validity in the selection process. The present study evaluates if contour consistency can be improved by having access to AI (Artificial Intelligence) based contours. MATERIALS AND METHODS: The 63 patients in the DAHANCA 35 pilot trial had a CT from the local DAHANCA centre and one from the proton centre. A nationally validated convolutional neural network, based on nnU-Net, was used to contour OARs on both scans for each patient. Using deformable image registration, local AI and oncologist contours were transferred to the proton centre scans for comparison. Consistency was calculated with the Dice Similarity Coefficient (DSC) and Mean Surface Distance (MSD), comparing contours from AI to AI and oncologist to oncologist, respectively. Two NTCP models were applied to calculate NTCP for xerostomia and dysphagia. RESULTS: The AI contours showed significantly better consistency than the contours by oncologists. The median and interquartile range of DSC was 0.85 [0.78 - 0.90] and 0.68 [0.51 - 0.80] for AI and oncologist contours, respectively. The median and interquartile range of MSD was 0.9 mm [0.7 - 1.1] mm and 1.9 mm [1.5 - 2.6] mm for AI and oncologist contours, respectively. There was no significant difference in ΔNTCP. CONCLUSIONS: The study showed that OAR contours made by the AI algorithm were more consistent than those made by oncologists. No significant impact on the ΔNTCP calculations could be discerned.

Purification and biochemical characterization of SM14est, a PET-hydrolyzing enzyme from the marine sponge-derived Streptomyces sp. SM14.

The successful enzymatic degradation of polyester substrates has fueled worldwide investigation into the treatment of plastic waste using bio-based processes. Within this realm, marine-associated microorganisms have emerged as a promising source of polyester-degrading enzymes. In this work, we describe the hydrolysis of the synthetic polymer PET by SM14est, a polyesterase which was previously identified from Streptomyces sp. SM14, an isolate of the marine sponge Haliclona simulans. The PET hydrolase activity of purified SM14est was assessed using a suspension-based assay and subsequent analysis of reaction products by UV-spectrophotometry and RP-HPLC. SM14est displayed a preference for high salt conditions, with activity significantly increasing at sodium chloride concentrations from 100 mM up to 1,000 mM. The initial rate of PET hydrolysis by SM14est was determined to be 0.004 s-1 at 45°C, which was increased by 5-fold to 0.02 s-1 upon addition of 500 mM sodium chloride. Sequence alignment and structural comparison with known PET hydrolases, including the marine halophile PET6, and the highly efficient, thermophilic PHL7, revealed conserved features of interest. Based on this work, SM14est emerges as a useful enzyme that is more similar to key players in the area of PET hydrolysis, like PHL7 and IsPETase, than it is to its marine counterparts. Salt-tolerant polyesterases such as SM14est are potentially valuable in the biological degradation of plastic particles that readily contaminate marine ecosystems and industrial wastewaters.

Rate Response of Poly(Ethylene Terephthalate)-Hydrolases to Substrate Crystallinity: Basis for Understanding the Lag Phase.

The rate response of poly(ethylene terephthalate) (PET)-hydrolases to increased substrate crystallinity (XC ) of PET manifests as a rate-lowering effect that varies significantly for different enzymes. Herein, we report the influence of XC on the product release rate of six thermostable PET-hydrolases. All enzyme reactions displayed a distinctive lag phase until measurable product formation occurred. The duration of the lag phase increased with XC . The recently discovered PET-hydrolase PHL7 worked efficiently on "amorphous" PET disks (XC ≈10 %), but this enzyme was extremely sensitive to increased XC , whereas the enzymes LCCICCG , LCC, and DuraPETase had higher tolerance to increases in XC and had activity on PET disks having XC of 24.4 %. Microscopy revealed that the XC -tolerant hydrolases generated smooth and more uniform substrate surface erosion than PHL7 during reaction. Structural and molecular dynamics analysis of the PET-hydrolyzing enzymes disclosed that surface electrostatics and enzyme flexibility may account for the observed differences.

Structural and functional characterization of a multi-domain GH92 α-1,2-mannosidase from Neobacillus novalis.

Many secreted eukaryotic proteins are N-glycosylated with oligosaccharides composed of a high-mannose N-glycan core and, in the specific case of yeast cell-wall proteins, an extended α-1,6-mannan backbone carrying a number of α-1,2- and α-1,3-mannose substituents of varying lengths. α-Mannosidases from CAZy family GH92 release terminal mannose residues from these N-glycans, providing access for the α-endomannanases, which then degrade the α-mannan backbone. Most characterized GH92 α-mannosidases consist of a single catalytic domain, while a few have extra domains including putative carbohydrate-binding modules (CBMs). To date, neither the function nor the structure of a multi-domain GH92 α-mannosidase CBM has been characterized. Here, the biochemical investigation and crystal structure of the full-length five-domain GH92 α-1,2-mannosidase from Neobacillus novalis (NnGH92) with mannoimidazole bound in the active site and an additional mannoimidazole bound to the N-terminal CBM32 are reported. The structure of the catalytic domain is very similar to that reported for the GH92 α-mannosidase Bt3990 from Bacteroides thetaiotaomicron, with the substrate-binding site being highly conserved. The function of the CBM32s and other NnGH92 domains was investigated by their sequential deletion and suggested that whilst their binding to the catalytic domain was crucial for the overall structural integrity of the enzyme, they appear to have little impact on the binding affinity to the yeast α-mannan substrate. These new findings provide a better understanding of how to select and optimize other multi-domain bacterial GH92 α-mannosidases for the degradation of yeast α-mannan or mannose-rich glycans.

Complete Genome Sequence of Sphingopyxis sp. Strain PET50, a Potential Polyethylene Terephthalate (PET)-Degrading Bacterium Isolated from Compost.

We report the complete genome sequence of a potential polyethylene terephthalate (PET)-degrading bacterium, Sphingopyxis sp. strain PET50, isolated from compost.

Reaction Pathways for the Enzymatic Degradation of Poly(Ethylene Terephthalate): What Characterizes an Efficient PET-Hydrolase?

Bioprocessing of polyester waste has emerged as a promising tool in the quest for a cyclic plastic economy. One key step is the enzymatic breakdown of the polymer, and this entails a complicated pathway with substrates, intermediates, and products of variable size and solubility. We have elucidated this pathway for poly(ethylene terephthalate) (PET) and four enzymes. Specifically, we combined different kinetic measurements and a novel stochastic model and found that the ability to hydrolyze internal bonds in the polymer (endo-lytic activity) was a key parameter for overall enzyme performance. Endo-lytic activity promoted the release of soluble PET fragments with two or three aromatic rings, which, in turn, were broken down with remarkable efficiency (kcat /KM values of about 105  M-1 s-1 ) in the aqueous bulk. This meant that approximatly 70 % of the final, monoaromatic products were formed via soluble di- or tri-aromatic intermediates.

The Relationship Between Interaural Insertion-Depth Differences, Scalar Location, and Interaural Time-Difference Processing in Adult Bilateral Cochlear-Implant Listeners.

Sensitivity to interaural time differences (ITDs) in acoustic hearing involves comparison of interaurally frequency-matched inputs. Bilateral cochlear-implant arrays are, however, only approximately aligned in angular insertion depth and scalar location across the cochleae. Interaural place-of-stimulation mismatch therefore has the potential to impact binaural perception. ITD left-right discrimination thresholds were examined in 23 postlingually-deafened adult bilateral cochlear-implant listeners, using low-rate constant-amplitude pulse trains presented via direct stimulation to single electrodes in each ear. Angular insertion depth and scalar location measured from computed-tomography (CT) scans were used to quantify interaural mismatch, and their association with binaural performance was assessed. Number-matched electrodes displayed a median interaural insertion-depth mismatch of 18° and generally yielded best or near-best ITD discrimination thresholds. Two listeners whose discrimination thresholds did not show this pattern were confirmed via CT to have atypical array placement. Listeners with more number-matched electrode pairs located in the scala tympani displayed better thresholds than listeners with fewer such pairs. ITD tuning curves as a function of interaural electrode separation were broad; bandwidths at twice the threshold minimum averaged 10.5 electrodes (equivalent to 5.9 mm for a Cochlear-brand pre-curved array). Larger angular insertion-depth differences were associated with wider bandwidths. Wide ITD tuning curve bandwidths appear to be a product of both monopolar stimulation and angular insertion-depth mismatch. Cases of good ITD sensitivity with very wide bandwidths suggest that precise matching of insertion depth is not critical for discrimination thresholds. Further prioritizing scala tympani location at implantation should, however, benefit ITD sensitivity.

Identification of fungal lignocellulose-degrading biocatalysts secreted by Phanerochaete chrysosporium via activity-based protein profiling.

Activity-based protein profiling (ABPP) has emerged as a versatile biochemical method for studying enzyme activity under various physiological conditions, with applications so far mainly in biomedicine. Here, we show the potential of ABPP in the discovery of biocatalysts from the thermophilic and lignocellulose-degrading white rot fungus Phanerochaete chrysosporium. By employing a comparative ABPP-based functional screen, including a direct profiling of wood substrate-bound enzymes, we identify those lignocellulose-degrading carbohydrate esterase (CE1 and CE15) and glycoside hydrolase (GH3, GH5, GH16, GH17, GH18, GH25, GH30, GH74 and GH79) enzymes specifically active in presence of the substrate. As expression of fungal enzymes remains challenging, our ABPP-mediated approach represents a preselection procedure for focusing experimental efforts on the most promising biocatalysts. Furthermore, this approach may also allow the functional annotation of domains-of-unknown functions (DUFs). The ABPP-based biocatalyst screening described here may thus allow the identification of active enzymes in a process of interest and the elucidation of novel biocatalysts that share no sequence similarity to known counterparts.