Optimal Time Research Articles

Abstract PR003: Multi-drug adaptive therapy protocol in vitro: An exercise in optimization for neuroblastoma

Abstract From initiation, invasion, dissemination to local and distant progression, relapse, recurrence to metastasis – clinico-pathological development of cancer follows the ecological processes of a multi-species niche construction. Ecological interactions result in adaptive changes that are driven by Darwinian evolution. This can be observed in the heterogeneity of tumor cells and their differential response to therapy. Some tumor cells are sensitive to treatment and can be eliminated by therapy, while others are resistant and can survive and proliferate under therapy. Adaptive therapy is a novel approach that leverages the competitive dynamics between sensitive and resistant cells, by dynamically adjusting the therapy dose and schedule based on biomarkers of tumor burden. In this study, we propose a multi-drug adaptive therapy protocol that uses two drugs with orthogonal mechanisms of action, meaning that they target different pathways or processes in the cancer cells. We investigate how to optimize the switching time between the two drugs, based on the personalized response to therapy and the evolutionary trade-offs between resistance and fitness and describe a corresponding real-time in vitro protocol. We performed experiments using two human neuroblastoma cell lines, sknbe2c and lan1, which exhibit distinct resistance profiles to different therapies, have different genetic profiles and show different growth patterns. We chose the combination of cisplatin and vincristine as the drugs of interest, since they are part of the Rapid COJEC protocol, which is a standard multidrug regimen for treating high-risk neuroblastomas in children. We monitored the drug treatment effects using noninvasive real-time microscopy based on cellular holography, which allows us to capture the morphological and behavioral changes of the cells. We fitted the treatment response curves with a stochastic diffusion equation that incorporates evolutionary mechanisms such as speciation, cost-dependent predator-prey interaction and drift, to model the dynamics of drug resistance and sensitivity. Unlike conventional therapy, which follows a fixed schedule and dose, adaptive therapy uses biomarkers of tumor burden, such as imaging or circulating tumor cells, to guide the timing and intensity of treatment. We propose a stochastic model that predicts the optimal switching time between two drugs based on the personalized response to therapy, which is inferred from Bayesian updating of the model parameters. This results in a patient-specific response model that accounts for the uncertainty and variability in the data. Assuming that a reliable and sensitive measure of tumor burden is available, we demonstrate how our model can be used to design a customized multi-drug adaptive therapy protocol for each patient. We are currently testing the efficacy of our protocol over other conventional protocols, and we plan to translate it to patient derived xenograft mouse models of neuroblastoma in the future. Citation Format: Subhayan Chattopadhyay, Jenny Karlsson, David Gisselsson. Multi-drug adaptive therapy protocol in vitro: An exercise in optimization for neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR003.

Development and design of intelligent lubricating equipment for feed systems

Recently, the lubricating devices for the feed systems of computer numerical control (CNC) machine tools supply oil periodically because programmable logic controller and macro are adopted for designing oil supply for the present CNC machine tools, causing lack or overdose lubrication. This study attempts to discuss and design the optimum lubrication cycle timing for the feed system under the experimental conditions of different loads and feed rates. The parameters of the servomotor are monitored by utilizing an intelligent module, the changes in the current and torque of the servomotor are obtained, and then a lubrication module is created with the Stribeck friction model, a modeling that utilizes response surface methodology. The increase in feed rate will cause increasing current and torque, and the current and torque for the load 35 kg were 11 and 13%, respectively. Finally, different loads and feed rates are imported to determine optimal lubrication timing. According to a long-term validation, the oil supply frequency is improved by over 80% without influencing the feed system accuracy, and the traditional lubrication module is compared with the lubrication module. Long time test is 8 h, and the rate of improvement is 87.5%, the cost of lubricating oil is reduced, and green manufacturing is met. An appropriate oil supply system is provided for the circle.

Theta burst stimulation: what role does it play in stroke rehabilitation? A systematic review of the existing evidence

Various post-stroke dysfunctions often result in poor long-term outcomes for stroke survivors, but the effect of conventional treatments is limited. In recent years, lots of studies have confirmed the effect of repetitive transcranial magnetic stimulation (rTMS) in stroke rehabilitation. As a new pattern of rTMS, theta burst stimulation (TBS) was proved recently to yield more pronounced and long-lasting after-effects than the conventional pattern at a shorter stimulation duration. To explore the role of TBS in stroke rehabilitation, this review summarizes the existing evidence from all the randomized controlled trials (RCTs) so far on the efficacy of TBS applied to different post-stroke dysfunctions, including cognitive impairment, visuospatial neglect, aphasia, dysphagia, spasticity, and motor dysfunction. Overall, TBS promotes the progress of stroke rehabilitation and may serve as a preferable alternative to traditional rTMS. However, it’s hard to recommend a specific paradigm of TBS due to the limited number of current studies and their heterogeneity. Further high-quality clinical RCTs are needed to determine the optimal technical settings and intervention time in stroke survivors.

Abstract 66: Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation: Primary Results of the START Trial

Introduction: Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke due to atrial fibrillation (AF). It is unknown whether there is an optimal day within that 14-day period that balances the risks of recurrent embolic vs serious hemorrhagic events. Methodology: The Lone Start Stroke START trial is a pragmatic, prospective, multi-center, response-adaptive randomized Phase 2 study of 200 patients prescribed a direct oral anticoagulant (DOAC) for secondary prevention of stroke due to AF. Patients were randomized into one of 4 Arms: Day 3-4 from stroke onset, Day 6, Day 10, or Day 14. The primary outcome was an ischemic (stroke or systemic embolus) or hemorrhagic (ICH or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities that each arm was the best were calculated at predefined intervals and randomization allocations were adjusted to favor the Arms with higher probabilities. Results: The median age was 75 (IQR 65-81), median NIHSS at presentation was 7 (IQR 4-14), median lesion diameter was 3.1 cm (IQR 2.0-4.4) at the time of randomization. The sample was 50% female, 17.5% non-white, and 16.5% Hispanic. Apixaban was the prescribed DOAC in 89% of the patients. No ischemic events were observed for Arm 1, and no hemorrhage events were observed for Arm 4. Arm 1 (3-4 days) had a posterior 41.1% probability of being the best among the four, with probabilities of 26.4%, 17.1%, and 15.4 % respectively, for the other arms. Response adapted randomization was feasible and favored the earlier two arms. Expected event rates for each arm are presented in the Table. The timing and severity of the outcome events will be presented at the conference. Conclusion: Although the START trial did not identify a clearly superior day to initiate DOAC for secondary stroke prevention in AF, the evidence suggests that initiating DOAC early is better than at later times within the first 2 weeks after stroke onset.

Screening of Antagonistic Bacillus against Brown Rot in Dendrocalamus latiflorus and Preparation of Applying Bacterial Suspension.

The aim of this study was to isolate biocontrol bacteria that could antagonize brown rot of Dendrocalamus latiflorus, optimize the culture conditions, and develop an effective biocontrol preparation for brown rot of D. latiflorus. This study isolated a bacterium with an antagonistic effect on bamboo brown rot from healthy D. latiflorus rhizosphere soil. Morphology, molecular biology, and physiological biochemistry methods identified it as Bacillus siamensis. The following culturing media and conditions improved the inhibition effect of B. siamensis: the best culturing media were 2% sucrose, 1.5% yeast extract, and 0.7% potassium chloride; the optimal culturing time, temperature, pH, and inoculation amount were 48 h, 30℃, 6, and 20%. The optimum formula of the applying bacterial suspension was 14% sodium dodecyl benzene sulfonate emulsifier, 4% Na2HPO4·2H2O, 0.3% hydroxypropyl methylcellulose thickener, and 20% B. siamensis. The pot experiment results showed the control effect of applying bacterial suspension, diluted 1,000 times is still better than that of 24% fenbuconazole suspension. The applying bacterial suspension enables reliable control of brown rot in D. latiflorus.

Flipping Tradition on Its Head: A Single-Institution Study on United States Medical Licensing Examination Step Order.

Given the recent change in Step 1 grading, medical students are faced with decisions surrounding the optimal Step examination order and timing. There is a current lack of guidance outside commonly used United States Medical Licensing Examination study blogs. The aim of this study was to characterize current practices in Step examination order and understand the factors influencing student examination preference. To gather data, we used a 24-item survey and electronically distributed it through three separate email requests to medical students. Participants included medical students (MS1-4) attending a single institution, interested in a surgical residency. In total, 56 students responded to the survey (response rate of 20%). Most students (63.6%) opted to take Step 2 before Step 1. Justifications included the perceived importance of Step 2 for residency applications (33.3%), the change to pass/fail grading (27.0%), the relevance of Step 2 after rotations (27.0%), and a desire to obtain a Step 2 score earlier (7.9%). Step examination order did not lead to differences in Step 2 score (P = 0.459), time used to prepare for Step 1 (P = 0.396), or time used to prepare for Step 2 (P = 0.078). Due to the perceived importance of Step 2, most medical students at our institution who are interested in pursuing a surgical residency are reversing the traditional Step examination order. As this may represent a national trend, additional work needs to be done to provide guidance to medical students and identify the optimal step examination testing strategy.

Role of PCSK9 inhibition during the inflammatory stage of SARS-COV-2: an updated review

The potential role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in the management of COVID-19 and other medical conditions has emerged as an intriguing area of research. PCSK9 is primarily known for its impact on cholesterol metabolism, but recent studies have unveiled its involvement in various physiological processes, including inflammation, immune regulation, and thrombosis. In this abstract, the authors review the rationale and potential implications of PCSK9 inhibition during the inflammatory stage of SARS-CoV-2 infection. Severe cases of COVID-19 are characterized by an uncontrolled inflammatory response, often referred to as the cytokine storm, which can lead to widespread tissue damage and organ failure. Preclinical studies suggest that PCSK9 inhibition could dampen this inflammatory cascade by reducing the production of pro-inflammatory cytokines. Additionally, PCSK9 inhibition may protect against acute respiratory distress syndrome (ARDS) through its effects on lung injury and inflammation. COVID-19 has been linked to an increased risk of cardiovascular complications, especially in patients with pre-existing cardiovascular conditions or dyslipidemia. PCSK9 inhibitors are known for their ability to lower low-density lipoprotein (LDL) cholesterol levels by enhancing the recycling of LDL receptors in the liver. By reducing LDL cholesterol, PCSK9 inhibition might protect blood vessels from further damage and lower the risk of atherosclerotic plaque formation. Moreover, PCSK9 inhibitors have shown potential antithrombotic effects in preclinical studies, making them a potential avenue to mitigate the increased risk of coagulation disorders and thrombotic events observed in COVID-19. While the potential implications of PCSK9 inhibition are promising, safety considerations and possible risks need careful evaluation. Hypocholesterolemia, drug interactions, and long-term safety are some of the key concerns that should be addressed. Clinical trials are needed to establish the efficacy and safety of PCSK9 inhibitors in COVID-19 patients and to determine the optimal timing and dosing for treatment. Future research opportunities encompass investigating the immune response, evaluating long-term safety, exploring combination therapy possibilities, and advancing personalized medicine approaches. Collaborative efforts from researchers, clinicians, and policymakers are essential to fully harness the therapeutic potential of PCSK9 inhibition and translate these findings into meaningful clinical outcomes.

Tenfold sensitivity increase in streak camera detection by propagation synchronous integration without compromising time resolution.

For many applications that involve measuring ultrafast optical phenomena, the streak camera is the device of choice because of its excellent time resolution, its high sensitivity, the possibility to simultaneously measure lifetimes and spectra, and because it can capture the temporal dynamics in a single shot. Nevertheless, to obtain a good time resolution, often narrow slits have to be employed that restrict the image source area and, therefore, limit the light collection efficiency in the experiment. For some applications, it is therefore challenging to find an acceptable balance between the time resolution and signal-to-noise ratio. To overcome this limitation, we have devised the propagation synchronous integration principle for the streak camera, in which an effective spatio-dependent time-shift in the excitation of a sample is introduced and counteracted by the streak sweep, thereby effectively allowing for an increased image source area while maintaining the optimal time resolution. Using the Optronis streak camera with tunable streak sweep and large (1mm) photocathode width, we could achieve a sevenfold increase in light collection efficiency without affecting the time resolution. Furthermore, we were also able to achieve an 11-fold increase in light collection at the cost of a 26% decrease in the time resolution.

What is the optimal timing to initiate strategic control of Rhipicephalus microplus in taurine cattle in a tropical region?

Cattle tick control poses a significant challenge for livestock in tropical and subtropical regions. The objective of this study was to determine the most suitable timing to initiate a strategic tick control program and to identify the ideal number of acaricide treatments for adult taurine cattle (Bos taurus taurus) in a tropical region throughout the year. Three groups with 10 bovines each were performed: T01 (strategic treatment in late autumn/winter/late spring, every 28 days), T02 (strategic treatment to act in the "first tick generation" - early spring/summer/early autumn, every 28 days) and T03 (control). Tick counts (females 4-8mm) were conducted every 14 days. If the tick burden in any group reached 30 or more during these counts, we applied an additional treatment. Over the course of a year, T02 required significantly fewer (p < 0.05) acaricide treatments than T01, with nine treatments for T02 and eleven for T01. Furthermore, during the tick counts, animals in T02 showed a lower tick burden compared to those in T01. Initiating the strategic tick control program in early spring, corresponding to the first tick generation, proved more effective than starting in autumn. This approach not only required fewer acaricide treatments but also resulted in a reduced tick burden. These benefits are particularly valuable in terms of animal welfare and managing acaricide resistance issues.

General and Complete Synchronization of Mutual Coupling System of Quantum Dot Semiconductor Lasers With Optical Feedback

Abstract The study examines an extensive and complete synchronization of optimal feedback with quantum dot semiconductor laser mutual coupling system. This has been achieved by resolving the transmitter and receiver equations of the quantum dot lasers. Numerous crisis areas have been observed at the time of investigating the relationship between photon density and time. The authors have selected an optimal time delay for the optical feedback so as to render an appropriate situation for intermittent dynamics. The study analyses the impact created by a long external cavity of QDSL upon the synchronization process in this mutual coupling system, in the presence of the enhancement factor of (α =3).

Comparison of Different Osteobiologics in Terms of Imaging Modalities and Time Frames for Fusion Assessment in Anterior Cervical Discectomy and Fusion: A Systematic Review.

Systematic review. The study's primary objective was to determine how osteobiologic choice affects fusion rates in patients undergoing anterior cervical discectomy and fusion (ACDF). The study's secondary objectives were to 1) determine the optimal timing of fusion assessment following ACDF and 2) determine if osteobiologic type affects the timing and optimal modality of fusion assessment. A systematic search of PubMed/MEDLINE was conducted for literature published from 2000 through October 2020 comparing anterior fusion in the cervical spine with various osteobiologics. Both comparative studies and case series of ≥10 patients were included. A total of 74 studies met the inclusion criteria. Seventeen studies evaluated the efficacy of autograft on fusion outcomes, and 23 studies assessed the efficacy of allograft on fusion outcomes. 3 studies evaluated the efficacy of demineralized bone matrix, and seven assessed the efficacy of rhBMP-2 on fusion outcomes. Other limited studies evaluated the efficacy of ceramics and bioactive glasses on fusion outcomes, and 4 assessed the efficacy of stem cell products. Most studies utilized dynamic radiographs for the assessment of fusion. Overall, there was a general lack of supportive data to determine the optimal timing of fusion assessment meaningfully or if osteobiologic type influenced fusion timing. Achieving fusion following ACDF appears to remain an intricate interplay between host biology and various surgical factors, including the selection of osteobiologics. While alternative osteobiologics to autograft exist and may produce acceptable fusion rates, limitations in study methodology prevent any definitive conclusions from existing literature.

Accumulation of Iron Oxide-Based Contrast Agents in Rabbit Atherosclerotic Plaques in Relation to Plaque Age and Vulnerability Features.

In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI). The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats. Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg. Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.

Watch and Wait for Rectal Cancer

About one third of all colorectal carcinomas (CRC) are localised in the rectum. As part of a multimodal therapy concept, neoadjuvant therapy achieves downstaging of the tumour in 50-60% of cases and a so-called complete clinical response (cCR), defined as clinically (and radiologically) undetectable residual tumour after completion of neoadjuvant therapy, in 10-30% of cases.In view of the perioperative morbidity and mortality associated with radical rectal resection, including the occurrence of a symptom complex known as low anterior resection syndrome (LARS) and the need for deviation, at least temporarily, the question of the risk-benefit balance of organ resection in the presence of cCR has been raised. In this context, the therapeutic concept of a "watch-and-wait" approach with omission of immediate organ resection and inclusion in a structured surveillance regime, has emerged.For a safe, oncological implementation of this option, it is necessary to develop standards in the definition of a suitable patient clientele and the implementation of the concept. In addition to the initial correct selection of the patient group that is suitable for a primarily non-surgical procedure, the inherent goal is the early and sufficient detection of tumour recurrence (so-called local regrowth) during the "watch-and-wait" phase (surveillance).In this context, in this paper we address the questions of: 1. the optimal timing of initial re-staging, 2. the criteria for assessing the clinical response and selecting the appropriate patient clientele, 3. the rhythm and design of the surveillance protocol.

Pretreatment with platelet-rich plasma protects against ischemia–reperfusion induced flap injury by deactivating the JAK/STAT pathway in mice

BackgroundIschemia–reperfusion (I/R) injury is a major cause of surgical skin flap compromise and organ dysfunction. Platelet-rich plasma (PRP) is an autologous product rich in growth factors, with tissue regenerative potential. PRP has shown promise in multiple I/R-induced tissue injuries, but its effects on skin flap injury remain unexplored.MethodsWe evaluated the effects of PRP on I/R-injured skin flaps, optimal timing of PRP administration, and the involved mechanisms.ResultsPRP protected against I/R-induced skin flap injury by improving flap survival, promoting blood perfusion and angiogenesis, suppressing oxidative stress and inflammatory response, and reducing apoptosis, at least partly via deactivating Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signalling pathway. PRP given before ischemia displayed overall advantages over that given before reperfusion or during reperfusion. In addition, PRP pretreatment had a stronger ability to reverse I/R-induced JAK/STAT activation and apoptosis than AG490, a specific inhibitor of JAK/STAT signalling.ConclusionsThis study firstly demonstrates the protective role of PRP against I/R-injured skin flaps through negative regulation of JAK/STAT activation, with PRP pretreatment showing optimal therapeutic effects.

Prostate Biopsy May Not Be Indicated Early after Bacillus Calmette Guérin Treatment.

Bacillus Calmette-Guérin (BCG) treatment for non-muscle-invasive bladder cancer frequently causes an intraprostatic BCG granuloma. We investigated the optimal timing for a prostate biopsy after BCG treatment by retrospectively analyzing the cases of 22 patients with non-muscle-invasive bladder cancer who underwent a prostate biopsy after BCG treatment at our institute (2013-2017). Biopsies were indicated for a rising prostate-specific antigen (PSA) level, positive digital rectal examination findings, or the appearance of de novo low apparent diffusion coefficient lesions on MRI. The control group was comprised of 28 age- and PSA-matched patients. The relationships among the cancer detection rate and the patients' PSA levels and MRI findings were analyzed. Prostate cancer was detected by biopsy in only 13.9% (3/22) of the patients in the BCG group but in 78.5% (22/28) of the control patients (p=0.0001). The three patients in the BCG group in whom prostate cancer was detected had all undergone the biopsy > 1 year after their BCG treatment. The remaining biopsies were performed within 1 year after BCG treatment and resulted in no diagnoses of prostate cancer. We suggest that performing a prostate biopsy early after BCG treatment is not informative or useful.

Optimization method of refracturing timing for old shale gas wells

Based on the elastic theory of porous media, embedded discrete fracture model and finite volume method, and considering the micro-seepage mechanism of shale gas, a fully coupled seepage-geomechanical model suitable for fractured shale gas reservoirs is established, the optimization method of refracturing timing is proposed, and the influencing factors of refracturing timing are analyzed based on the data from shale gas well in Fuling of Sichuan Basin. The results show that due to the depletion of formation pressure, the percentage of the maximum horizontal principal stress reversal area in the total area increases and then decreases with time. The closer the area is to the hydraulic fracture, the shorter the time for the peak of the stress reversal area percentage curve to appear, and the shorter the time for the final zero return (to the initial state). The optimum time of refracturing is affected by matrix permeability, initial stress difference and natural fracture approach angle. The larger the matrix permeability and initial stress difference is, the shorter the time for stress reversal area percentage curve to reach peak and return to the initial state, and the earlier the time to take refracturing measures. The larger the natural fracture approach angle is, the more difficult it is for stress reversal to occur near the fracture, and the earlier the optimum refracturing time is. The more likely the stress reversal occurs at the far end of the artificial fracture, the later the optimal time of refracturing is. Reservoirs with low matrix permeability have a rapid decrease in single well productivity. To ensure economic efficiency, measures such as shut-in or gas injection can be taken to restore the stress, and refracturing can be implemented in advance.

Optimal timing of delayed cytoreductive nephrectomy in metastatic renal cell carcinoma during the immunotherapy era.

403 Background: The CARMENA study found no survival benefit from cytoreductive nephrectomy (CN) in poor-risk metastatic renal cell cancer (mRCC) patients treated with first line Sunitinib. Although retrospective studies have reported survival benefits with CN following immunotherapy (IO)-based therapy, the timing remains unclear. We aimed to investigate the ideal timing of CN following IO using the National Cancer Database. Methods: 783 patients with de novo mRCC were diagnosed between 2016 and 2020 who received upfront systemic therapy and underwent CN, 343 patients met our criteria. Patients were categorized into four groups based on the timing of nephrectomy: CN ≤3 months (Group A), 4 to 6 months (Group B), 7 to 9 months (Group C) and ≥ 10 months (Group D) following the initiation of IO-based therapy. Descriptive analysis was performed to examine the demographic and clinical characteristics. Follow up time was measured from the date of surgery to reduce bias. Kaplan-Meier plots were used to analyze survival curves, and a multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 343 patients who received upfront IO -based therapy were divided into four groups: 104 (30%) in A, 114 (33%) in B, 74 (22%) in C and 51 (15%) in D. 71%were male, white (90%), age 40 – 64 (62%), comorbidity index 0 (70%), clear cell histology (69%), sarcomatoid (14%). 54% were treated in academia, 57% had bone metastasis, 50% had lung, 11% had liver, and 7% had brain metastases. 66% received only IO, and 34% received IO + TKI. No significant association between CN timing and survival observed in multivariate cox regression model. (HR 0.87, 95% CI: 0.5- 1.7, p = 0.84). Compared to group A, the HR were 0.96 (95% CI, 0.73 to 1.27; p=0.78), 0.77 (95% CI, 0.53 to 1.13; p=0.19), and 0.66 (95% CI, 0.37 to 1.20; p=0.17) respectively for groups B, C and D. Conclusions: Our study did not find significant survival improvement with an optimal timing of CN following IO-based therapy, while HRs were reduced after 6 months of delay, though insignificant. This could be due to the small sample size or other confounders.

Structural Myelopathies.

This article illustrates the clinical importance, diagnosis, and management of degenerative and nondegenerative structural myelopathies. It also aims to create a diagnostic approach for the evaluation of patients with suspected degenerative myelopathies. There is considerable interest in developing diagnostic methods that can assist in deciding if surgery is indicated in patients with structural myelopathy and the optimal timing for surgery. Diffusion tensor imaging has emerged as a promising imaging modality although it is not used routinely in clinical practice. Neuroprotective medications and interventions are being studied in patients with degenerative myelopathies. Structural myelopathies and particularly degenerative myelopathies are common disorders that are routinely encountered in clinical practice, with symptoms that frequently overlap with other neurologic disorders. The prompt diagnosis and treatment of patients are essential in achieving good functional outcomes.

Integrating Systemic Therapies into the Multimodality Therapy of Patients with Craniopharyngioma.

The integration of targeted therapy into the multimodal management of craniopharyngiomas represents a significant advancement in the field of neuro-oncology. Historically, the management of these tumors has been challenging due to their proximity to vital brain structures, necessitating a delicate balance between tumor control and the preservation of neurological function. Traditional treatment modalities, such as surgical resection and radiation, while effective, carry their own set of risks, including potential damage to surrounding healthy tissues and the potential for long-term side effects. Recent insights into the molecular biology of craniopharyngiomas, particularly the discovery of the BRAF V600E mutation in nearly all papillary craniopharyngiomas, have paved the way for a targeted systemic treatment approach. However, advances have been limited for adamantinomatous craniopharyngiomas. The success of BRAF/MEK inhibitors in clinical trials underscores the potential of these targeted therapies not only to control tumor growth but also to reduce the need for more invasive treatments, potentially minimizing treatment-related complications. However, the introduction of these novel therapies also brings forth new challenges, such as determining the optimal timing, sequencing, and duration of targeted treatments. Furthermore, there are open questions regarding which specific BRAF/MEK inhibitors to use, the potential need for combination therapy, and the strategies for managing intolerable adverse events. Finally, ensuring equitable access to these therapies, especially in healthcare systems with limited resources, is crucial to prevent widening healthcare disparities. In conclusion, targeted therapy with BRAF/MEK inhibitors holds great promise for improving outcomes and quality of life for patients with BRAF-mutated craniopharyngiomas. However, additional research is needed to address the questions that remain about its optimal use and integration into comprehensive treatment plans.

Safety and efficacy of early versus late removal of LAMS for pancreatic fluid collections.

Background and study aims Optimal timing for removal of lumen-apposing metal stents (LAMS) for effective drainage of pancreatic fluid collections (PFC) while minimizing adverse events (AE) is unknown. Outcomes of early (≤ 4 weeks) or delayed (> 4 weeks) LAMS removal on both clinical efficacy and the incidence of AE were assessed. Patients and methods This was a retrospective analysis of a prospectively maintained registry of PFC drainage between November 2016 and September 2021. Clinical success was defined as a 75% decrease in fluid collection volume with no need for reintervention at 6 months. AE were defined using the American Society for Gastrointestinal Endoscopy lexicon. Multiple logistic regression analysis was performed to determine variables associated with clinical success and AE. Results A total of 108 consecutive PFCs were included. LAMS deployment was technically successful in 103 of 108 cases (95.4%). Failure was associated with collection diameter ≤ 4 cm (odds ratio [OR] 24.0, P = 0.005) and presence of more than 50% necrotic material (OR 20.1, P = 0.01). Stents were left in place for a median of 48 days. Patients with early stent removal (< 4 weeks) had clinical success in 70.0% of cases, which was significantly less than in the group with delayed stent removal (96.4%, P = 0.03). On multiple regression analysis, clinical failure was associated with early stent removal (OR 25.5, P = 0.003). AEs occurred in 8.7% of cases (9/103). There were no predictors of AE. Notably, delayed stent removal did not predict the occurrence of AE. Conclusions Early LAMS removal (< 4 weeks) did not prevent AEs but did lead to increased clinical failure.