Early Astrocytic Dysfunction Is Associated with Mistuned Synapses as well as Anxiety and Depressive-Like Behavior in the AppNL-F Mouse Model of Alzheimer's Disease.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of AD. Objective: We aimed to characterize early synaptic impairments in the AppNL-F knock-in mouse model of AD, especially to understand the contribution of astrocytes to early brain dysfunctions. Methods: The AppNL-F mouse model carries two disease-causing mutations inserted in the amyloid precursor protein gene. This strain does not start to develop amyloid-ß plaques until 9 months of age. Thanks to electrophysiology, we investigated synaptic function, at both neuronal and astrocytic levels, in 6-month-old animals and correlate the synaptic activity with emotional behavior. Results: Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B blocker deprenyl or the fast-acting antidepressant ketamine (5 mg/kg). Conclusions: We propose that reactive astrocytes can induce synaptic mistuning early in AD, before plaques deposition, and that these changes are associated with emotional symptoms.

Ultrahypofractionated Radiation Therapy for Prostate Cancer Including Seminal Vesicles in the Target Volume: A Treatment-planning Study Based on the HYPO-RT-PC Fractionation Schedule.

Purpose: Ultrahypofractionated (UHF) radiation therapy (RT) has become a treatment alternative for patients with localized prostate cancer. In more advanced cases, seminal vesicles (SVs) are routinely included in the target volume. The Scandinavian HYPO-RT-PC trial, which compared 42.7 Gy in 7 fractions (fr) to conventional fractionation (CF), did not include SVs in the clinical target volume. The primary objective of the present work was to implement a ultrahypofractionated-simultaneous integrated boost (UHF-SIB) for prostate cancer RT, incorporating SVs into the target volume based on this fractionation schedule. A secondary objective was to analyze the unintentional dose coverage of SVs from state-of-the-art volumetric modulated arc therapy treatments to the prostate gland only. Methods and Materials: Two different equieffective UHF-SIB treatment schedules to SVs were derived based on the CF clinical schedule (50.0 Gy/25 fr to elective SVs and 70.0 Gy/35 fr to verified SV-invasion (SVI)) using the linear quadric model with α/ß = 2 Gy and 3 Gy. The dose to the prostate was 42.7 Gy/7 fr in both schedules, with 31.2 Gy/37.8 Gy (α/ß = 2 Gy) and 32.7 Gy/40.1 Gy (α/ß = 3 Gy) to elective SV/verified SVI. Volumetric modulated arc therapy plans to the proximal 10 mm and 20 mm were optimized, and dose-volume metrics for target volumes and organs at risk were evaluated. Results: Dose metrics were overall lower for UHF-SIB compared with CF. QUANTEC-based volume criteria were 2% to 7% lower for the rectum and 2% to 4% lower for the bladder in the UHF-SIB. The D98% to elective SV was 7 to 12 Gy3 lower with UHF-SIB, and the corresponding data for verified SVI were approximately 2 to 3 Gy3. The SV(10 mm) V90%/(29.5 Gy) for prostate-only treatments (42.7 Gy) were as follows: median (IQR), 99% (87-100) and 78% (58-99) for the clinical target volume and planning target volume, respectively. Conclusions: UHF RT based on the HYPO-RT-PC fractionation schedule, with a SIB technique, to the prostate and the base of the SV can be planned with lower doses (EQD2) to organs at risk, compared with CF. The unintentional dose to the proximal parts of SVs in prostate-only treatment can be substantial.

Secondary cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent colorectal peritoneal metastases.

Background: Secondary treatment of recurrent colorectal peritoneal metastases after previous cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is poorly investigated. Objectives: To evaluate the overall survival outcome of secondary (repeat) CRS + HIPEC compared to palliative treatment in recurrent peritoneal disease. Methods: Patients with colorectal peritoneal metastases treated with an index CRS + HIPEC and subsequently having recurrent peritoneal disease were identified from the prospective Swedish national HIPEC registry. Patients were divided into interventional group (secondary CRS + HIPEC) or palliative group. Multivariable logistic regression, propensity-score matching, and survival outcomes were calculated. Results: Among 575 patients who underwent complete CRS between 2010 and 2021, 208 (36 %) were diagnosed with a subsequent recurrent peritoneal disease. Forty-two patients (20 %) were offered secondary CRS + HIPEC. Propensity-score matching of secondary interventional cases with palliative cases succeeded in 88 % (n = 37) in which female sex, lower peritoneal cancer index at index surgery, longer disease-free interval, and absence of extra-peritoneal metastases were identified as the most relevant matching covariates. Median OS from date of recurrence was 38 months (95%CI 30-58) in the interventional group and 19 months (95%CI: 15-24) in the palliative group (HR 0.35 95%CI: 0.20-0.63, p = 0.0004). Sensitivity analyses confirmed the results. As reference, the median OS from index CRS + HIPEC in the whole colorectal registry (n = 575) was 41 months (95%CI: 38-45). Conclusion: After matching for relevant factors, the hazard ratio for death was significantly reduced in patients who were offered a secondary CRS + HIPEC procedure for recurrent peritoneal disease. Selection bias is inherent, but survival outcomes were comparable to those achieved after the initial procedure.

Patient reported long-term side effects from treatment on urinary and sexual function in anal cancer survivors - 3- and 6-year results from the Swedish national ANCA study.

AIM: The standard treatment for anal cancer is chemoradiotherapy. Most patients survive anal cancer but remain living with long-term side effects related to the treatment received. The aim of this study was to assess the occurrence of long-term impairment of urinary and sexual function at 3 and 6 years after diagnosis and to investigate the additive effect from chemotherapy in combined chemoradiotherapy on urinary incontinence, compared to radiotherapy alone. METHOD: The ANal CAncer study (ANCA) is based on a national Swedish cohort of patients diagnosed with anal cancer between 2011 and 2013. All identified patients within the study were invited to respond to a study-specific questionnaire at 3 and 6 years. Descriptive analyses for the primary endpoint were performed. To investigate a possible additional effect from chemotherapy logistic regression was used. RESULTS: A total of 388 patients were included in the study. At 3 years 264 patients were alive and invited to respond to an anal cancer specific questionnaire. The 3- and 6 year response rates were 195 (74%) and 155 patients (67%), respectively. The patient reported urinary function impairment at 3 years were urgency (63%), incomplete bladder emptying (47%), and incontinence (46%) and there was an absolute increase of the prevalence of urinary dysfunction in about 10% at 6 years. Three years after diagnosis, 77% reported that intercourse was not part of their sex life; this percentage increased at 6 years to 83%. We found no negative effect of chemotherapy in combined chemoradiotherapy versus radiotherapy alone on patient reported urinary incontinence. CONCLUSION: For anal cancer survivors, urinary function was impaired after 3 years and continued to deteriorate as measured at 6 years after diagnosis. Anal cancer and its treatment negatively affected sexual function for both men and women. This may explain why patients reported that sexual activity and frequency of intercourse was not of importance in their life.

Neoadjuvant treatment of colorectal cancer: comprehensive review.

BACKGROUND: Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery. METHODS: A narrative review of the most recent relevant literature was conducted. RESULTS: Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients. CONCLUSION: Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.

Defining Benchmarks for Pelvic Exenteration Surgery: A Multicentre Analysis of Patients with Locally Advanced and Recurrent Rectal Cancer.

OBJECTIVE: To establish globally applicable benchmark outcomes for pelvic exenteration (PE) in patients with locally advanced primary (LARC) and recurrent rectal cancer (LRRC), using outcomes achieved at highly specialised centres. BACKGROUND DATA: PE is established as the standard of care for selected patients with LARC and LRRC. There are currently no available benchmarks against which surgical performance in PE can be compared for audit and quality improvement. METHODS: This international multicentre retrospective cohort study included patients undergoing PE for LARC or LRRC at 16 highly experienced centres between 2018 and 2023. Ten outcome benchmarks were established in a lower-risk subgroup. Benchmarks were defined by the 75th percentile of the results achieved at the individual centres. RESULTS: 763 patients underwent PE, of which 464 patients (61%) had LARC and 299 (39%) had LRRC. 544 patients (71%) who met predefined lower risk criteria formed the benchmark cohort. For LARC patients, the calculated benchmark threshold for major complication rate was ≤44%; comprehensive complication index (CCI): ≤30.2; 30-day mortality rate: 0%; 90-day mortality rate: ≤4.3%; R0 resection rate: ≥79%. For LRRC patients, the calculated benchmark threshold for major complication rate was ≤53%; CCI: ≤34.1; 30-day mortality rate: 0%; 90-day mortality rate: ≤6%; R0 resection rate: ≥77%. CONCLUSIONS: The reported benchmarks for PE in patients with LARC and LRRC represent the best available care for this patient group globally and can be used for rigorous assessment of surgical quality and to facilitate quality improvement initiatives at international exenteration centres.

The Inflammatory Response Induced by Aspergillus fumigatus Conidia Is Dependent on Complement Activation: Insight from a Whole Blood Model.

INTRODUCTION: We aimed to elucidate the inflammatory response of Aspergillus fumigatus conidia in a whole-blood model of innate immune activation and to compare it with the well-characterized inflammatory reaction to Escherichia coli. METHODS: Employing a human lepirudin whole-blood model, we analyzed complement and leukocyte activation by measuring the sC5b-9 complex and assessing CD11b expression. A 27-multiplex system was used for quantification of cytokines. Selective cell removal from whole blood and inhibition of C3, C5, and CD14 were also applied. RESULTS: Our findings demonstrated a marked elevation in sC5b-9 and CD11b post-A. fumigatus incubation. Thirteen cytokines (TNF, IL-1ß, IL-1ra, IL-4, IL-6, IL-8, IL-17, IFNγ, MCP-1, MIP-1α, MIP-1ß, FGF-basic, and G-CSF) showed increased levels. A generally lower level of cytokine release and CD11b expression was observed with A. fumigatus conidia than with E. coli. Notably, monocytes were instrumental in releasing all cytokines except MCP-1. IL-1ra was found to be both monocyte and granulocyte-dependent. Pre-inhibiting with C3 and CD14 inhibitors resulted in decreased release patterns for six cytokines (TNF, IL-1ß, IL-6, IL-8, MIP-1α, and MIP-1ß), with minimal effects by C5-inhibition. CONCLUSION: A. fumigatus conidia induced complement activation comparable to E. coli, whereas CD11b expression and cytokine release were lower, underscoring distinct inflammatory responses between these pathogens. Complement C3 inhibition attenuated cytokine release indicating a C3-level role of complement in A. fumigatus immunity.

Surgical Outcomes after Radiotherapy in Rectal Cancer.

Over the past decade, the treatment of rectal cancer has changed considerably. The implementation of TME surgery has, in addition to decreasing the number of local recurrences, improved surgical morbidity and mortality. At the same time, the optimisation of radiotherapy in the preoperative setting has improved oncological outcomes even further, although higher perineal infection rates have been reported. Radiotherapy regimens have evolved through the adjustment of radiotherapy techniques and fields, increased waiting intervals, and, for more advanced tumours, adding chemotherapy. Concurrently, imaging techniques have significantly improved staging accuracy, facilitating more precise selection of advanced tumours. Although chemoradiotherapy does lead to the downsizing and -staging of these tumours, a very clear effect on sphincter-preserving surgery and the negative resection margin has not been proven. Aiming to decrease distant metastasis and improve overall survival for locally advanced rectal cancer, systemic chemotherapy can be added to radiotherapy, known as total neoadjuvant treatment (TNT). High complete response rates, both pathological (pCR) and clinical (cCR), are reported after TNT. Patients who follow a Watch & Wait program after a cCR can potentially avoid surgical morbidity and colostomy. For both early and more advanced tumours, trials are now investigating optimal regimens in an attempt to offer organ preservation as much as possible. Multidisciplinary deliberation should include patient preference, treatment toxicity, and likelihood of end colostomy, but also the burden of intensive surveillance in a W&W program.

DEAD Box Helicase 24 Is Increased in the Brain in Alzheimer's Disease and AppN-LF Mice and Influences Presymptomatic Pathology.

At the time of diagnosis, Alzheimer's disease (AD) patients already suffer from significant neuronal loss. The identification of proteins that influence disease progression before the onset of symptoms is thus an essential part of the development of new effective drugs and biomarkers. Here, we used an unbiased 18O labelling proteomics approach to identify proteins showing altered levels in the AD brain. We studied the relationship between the protein with the highest increase in hippocampus, DEAD box Helicase 24 (DDX24), and AD pathology. We visualised DDX24 in the human brain and in a mouse model for Aß42-induced AD pathology-AppNL-F-and studied the interaction between Aß and DDX24 in primary neurons. Immunohistochemistry in the AD brain confirmed the increased levels and indicated an altered subcellular distribution of DDX24. Immunohistochemical studies in AppNL-F mice showed that the increase of DDX24 starts before amyloid pathology or memory impairment is observed. Immunocytochemistry in AppNL-F primary hippocampal neurons showed increased DDX24 intensity in the soma, nucleus and nucleolus. Furthermore, siRNA targeting of DDX24 in neurons decreased APP and Aß42 levels, and the addition of Aß42 to the medium reduced DDX24. In conclusion, we have identified DDX24 as a protein with a potential role in Aß-induced AD pathology.

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing.

Alzheimer's disease (AD) pathology is characterized by amyloid beta (Aß) plaques and dysfunctional autophagy. Aß is generated by sequential proteolytic cleavage of amyloid precursor protein (APP), and the site of intracellular APP processing is highly debated, which may include autophagosomes. Here, we investigated the involvement of autophagy, including the role of ATG9 in APP intracellular trafficking and processing by applying the RUSH system, which allows studying the transport of fluorescently labeled mCherry-APP-EGFP in a systematic way, starting from the endoplasmic reticulum. HeLa cells, expressing the RUSH mCherry-APP-EGFP system, were investigated by live cell imaging, immunofluorescence, and Western blot. We found that mCherry-APP-EGFP passed through the Golgi faster in ATG9 knockout cells. Furthermore, ATG9 deletion shifted mCherry-APP-EGFP from early endosomes and lysosomes toward the plasma membrane concomitant with reduced endocytosis. Importantly, this alteration in mCherry-APP-EGFP transport resulted in increased secreted mCherry-soluble APP and C-terminal fragment-EGFP. These effects were also phenocopied by pharmacological inhibition of ULK1, indicating that autophagy is regulating the intracellular trafficking and processing of APP. These findings contribute to the understanding of the role of autophagy in APP metabolism and could potentially have implications for new therapeutic approaches for AD.

Dynamic microglia alterations associate with hippocampal network impairments: A turning point in amyloid pathology progression.

Alzheimer's disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer's disease onset and progression. Characterizing the initial phase of Alzheimer's disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer's disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis- and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network's functionality. These results suggest that the early alteration of microglia dynamics could be a pivotal event in the progression of Alzheimer's disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

Divergent Age-Dependent Conformational Rearrangement within Aß Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice.

Amyloid plaques composed of fibrils of misfolded Aß peptides are pathological hallmarks of Alzheimer's disease (AD). Aß fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aß fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aß fibril structures in situ differ in Aß plaque of different mouse models expressing familial mutations in the AßPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aß-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures within Aß-amyloid plaques depending on the AßPP-processing genotype. Co-staining with Aß-specific antibodies showed that individual plaques from APP23 mice expressing AßPP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aß40 fibrils, and the corona region is dominated by diffusely packed Aß40 fibrils. Conversely, the AßPP knock-in mouse AppNL-F, expressing the AßPP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aß42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by Aß40 and was hence minuscule in AppNL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.

Oncological outcomes after a pathological complete response following total neoadjuvant therapy or chemoradiotherapy for high-risk locally advanced rectal cancer in the RAPIDO trial.

BACKGROUND: A pathological complete response (pCR) following chemoradiation (CRT) or short-course radiotherapy (scRT) leads to a favourable prognosis in patients with rectal cancer. Total neo-adjuvant therapy (TNT) doubles the pCR rate, but it is unknown whether oncological outcomes remain favourable and whether the same characteristics are associated with pCR as after CRT. METHODS: Comparison between patients with pCR in the RAPIDO trial in the experimental [EXP] (scRT, chemotherapy, surgery, as TNT) and standard-of-care treatment [STD] (CRT, surgery, postoperative chemotherapy depending on hospital policy) groups. Primary and secondary outcomes were time-to-recurrence (TTR), overall survival (OS) and association between patient, tumour, and treatment characteristics and pCR. RESULTS: Among patients with a resection within six months after preoperative treatment, 120/423 (28%) [EXP] and 57/398 (14%) [STD] achieved a pCR. Following pCR, 5-year cumulative TTR and OS rates in the EXP and STD arms were 8% vs. 7% (hazard ratio 1.04, 95%CI 0.32-3.38) and 94% vs. 93% (hazard ratio 1.41, 95%CI 0.51-3.92), respectively. Besides the EXP treatment (odds ratio 2.70, 95%CI 1.83-3.97), pre-treatment carcinoembryonic antigen (CEA) <5, pre-treatment tumour size <40 mm and cT2 were associated with pCR. Distance from the anal verge was the only characteristic with a statistically significant difference in association with pCR between the EXP and STD treatment (Pinteraction=0.042). pCR rates did not increase with prolonged treatment time. CONCLUSIONS: The doubled pCR rate of TNT compared to CRT results in similar oncological outcomes. Characteristics associated with pCR are the EXP treatment, normal CEA, and small tumour size.

Efficacy of hyperthermic intraperitoneal chemotherapy in colorectal cancer: A phase I and III open label randomized controlled registry-based clinical trial protocol.

Standard treatment for patient with peritoneal metastases from colorectal cancer is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In recent years, the efficacy of oxaliplatin-based HIPEC has been challenged. An intensified HIPEC (oxaliplatin+irinotecan) in combination with early postoperative intraperitoneal chemotherapy (EPIC) has shown increased recurrence-free survival in retrospective studies. The aim of this trial is to develop a new HIPEC/EPIC regimen and evaluate its effect on morbidity, oncological outcome, and quality-of-life (QoL). This study is designed as a combined phase I/III multicenter randomized trial (RCT) of patients with peritoneal metastases from colorectal cancer eligible for CRS-HIPEC. An initial phase I dose escalation study, designed as a 3+3 stepwise escalation, will determine the maximum tolerable dose of 5-Fluorouracil (5-FU) as 1-day EPIC, enrolling a total of 15-30 patients in 5 dose levels. In the phase III efficacy study, patients are randomly assigned intraoperatively to either the standard treatment with oxaliplatin HIPEC (control arm) or oxaliplatin/irinotecan-HIPEC in combination with single dose of 1-day 5-FU EPIC (experimental arm). 5-FU is administered intraoperatively after CRS-HIPEC and closure of the abdomen. The primary endpoint is 12-month recurrence-free survival. Secondary endpoints include 5-year overall survival, 5-year recurrence-free survival (registry based), postoperative complications, and QoL up to 3 years after study treatment. This phase I/III trial aims to identify a more effective treatment of colorectal peritoneal metastases by combination of HIPEC and EPIC.

Risk of Venous Thromboembolic Events After Surgery for Cancer.

Importance: The risks and benefits of thromboprophylaxis therapy after cancer surgery are debated. Studies that determine thrombosis risk after cancer surgery with high accuracy are needed. Objectives: To evaluate 1-year risk of venous thromboembolic events after major cancer surgery and how these events vary over time. Design, Setting, and Participants: This register-based retrospective observational matched cohort study included data on the full population of Sweden between 1998 and 2016. All patients who underwent major surgery for cancer of the bladder, breast, colon or rectum, gynecologic organs, kidney and upper urothelial tract, lung, prostate, or gastroesophageal tract were matched in a 1:10 ratio with cancer-free members of the general population on year of birth, sex, and county of residence. Data were analyzed from February 13 to December 5, 2023. Exposure: Major surgery for cancer. Main Outcomes and Measures: The main outcome was incidence of venous thromboembolic events within 1 year after the surgery. Crude absolute risks and risk differences of events within 1 year and adjusted time-dependent cause-specific hazard ratios (HRs) of postdischarge events were calculated. Results: A total of 432 218 patients with cancer (median age, 67 years [IQR, 58-75 years]; 68.7% women) and 4 009 343 cancer-free comparators (median age, 66 years [IQR, 57-74 years]; 69.3% women) were included in the study. The crude 1-year cumulative risk of pulmonary embolism was higher among the cancer surgery population for all cancers, with the following absolute risk differences: for bladder cancer, 2.69 percentage points (95% CI, 2.33-3.05 percentage points); for breast cancer, 0.59 percentage points (95% CI 0.55-0.63 percentage points); for colorectal cancer, 1.57 percentage points (95% CI, 1.50-1.65 percentage points); for gynecologic organ cancer, 1.32 percentage points (95% CI, 1.22-1.41 percentage points); for kidney and upper urinary tract cancer, 1.38 percentage points (95% CI, 1.21-1.55 percentage points); for lung cancer, 2.61 percentage points (95% CI, 2.34-2.89 percentage points); for gastroesophageal cancer, 2.13 percentage points (95% CI, 1.89-2.38 percentage points); and for prostate cancer, 0.57 percentage points (95% CI, 0.49-0.66 percentage points). The cause-specific HR of pulmonary embolism comparing patients who underwent cancer surgery with matched comparators peaked just after discharge and generally plateaued 60 to 90 days later. At 30 days after surgery, the HR was 10 to 30 times higher than in the comparison cohort for all cancers except breast cancer (colorectal cancer: HR, 9.18 [95% CI, 8.03-10.50]; lung cancer: HR, 25.66 [95% CI, 17.41-37.84]; breast cancer: HR, 5.18 [95% CI, 4.45-6.05]). The hazards subsided but never reached the level of the comparison cohort except for prostate cancer. Similar results were observed for deep vein thrombosis. Conclusions and Relevance: This cohort study found an increased rate of venous thromboembolism associated with cancer surgery. The risk persisted for about 2 to 4 months postoperatively but varied between cancer types. The increased rate is likely explained by the underlying cancer disease and adjuvant treatments. The results highlight the need for individualized venous thromboembolism risk evaluation and prophylaxis regimens for patients undergoing different surgery for different cancers.

Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aß-dependent expression in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid ß-peptide (Aß) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aß cascade. Exogenous Aß42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aß production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aß-induced upregulation of SPPL2b may enhance Aß production in a vicious cycle, further aggravating Aß pathology. Therefore, SPPL2b emerges as a potential anti-Aß drug target.

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Dose-volume relationships of planned versus estimated delivered radiation doses to pelvic organs at risk and side effects in patients treated with salvage radiotherapy for recurrent prostate cancer.

Purpose: To investigate estimated delivered dose distributions using weekly cone-beam computed tomography (CBCT) scans for pelvic organs at risk (OARs) in salvage radiotherapy (SRT) after radical prostatectomy. Furthermore, to compare them with the originally planned dose distributions and analyse associations with gastrointestinal (GI) and genitourinary (GU) side effects. Methods: This study is part of a phase II trial involving SRT for recurrent prostate cancer. Treatment was personalised based on PSA response during SRT, classifying patients as PSA responders or non-responders. Estimated radiation dose distributions were obtained using deformable image registration from weekly CBCT scans. GI and GU toxicities were assessed using the RTOG toxicity scale, while patient-reported symptoms were monitored through self-assessment questionnaires. Results: The study included 100 patients, with similar treatment-related side effects observed in both responders and non-responders. Differences in dose-volume metrics between the planned and estimated delivered doses for the examined OARs were mostly modest, although generally statistically significant. We identified statistically significant associations between QUANTEC-recommended dose-volume constraints and acute bowel toxicity, as well as late urinary patient-reported symptoms, for both the estimated delivered and planned dose distributions. Conclusion: We found small but statistically significant differences between estimated delivered and planned doses to OARs. These differences showed trends toward improved associations for estimated delivered dose distributions with side effects. Enhanced registration methods and imaging techniques could potentially further enhance the assessment of truly delivered doses and yield more reliable dose-volume constraints for future therapies.

Storage of Transfusion Platelet Concentrates Is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor.

Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 °C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA2R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69-72% (p < 0.05) for TXA2R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA2R activation.