Virtual reality for postsurgical pain management: An explorative randomized controlled study.

BACKGROUND: Virtual reality (VR) is a promising tool in a multimodal analgesic approach; however, evidence regarding virtual reality for postsurgical pain is limited. This study investigates the initial effectiveness and feasibility of self-administered virtual reality in postsurgical pain management. METHODS: Patients reporting a postsurgical pain score ≥4 were randomized for control or VR, stratified for 3 interventions with varying levels of immersion and interaction. Subjects were instructed to use virtual reality as add-on treatment at least 3 times a day for 10 minutes on days 2 till 4 postoperatively. Primary outcome was the mean daily pain intensity. Results of pain scores were related to patient and intervention characteristics, to explore which characteristics interact with virtual reality effects. Secondary outcomes were analgesic use, anxiety, stress, and feasibility. RESULTS: One hundred patients were included in the analyses: 37 in the control group and 63 for VR. VR did not demonstrate a significant effect on self-reported pain scores (P = .43), nor were specific patient or intervention characteristics associated with greater VR effects. Analgesic usage did not differ between groups. However, there was a trend toward greater cumulative percentages of patients achieving a 30% pain reduction, and significantly lower daily experienced stress (P = .01) and anxiety (P = .03) levels in VR intervention groups. VR was used less than prescribed, mainly because of illness and pain. Adverse events included disorientation, nausea, and fatigue. CONCLUSIONS: This explorative study did not demonstrate initial effectiveness of VR as add-on pain treatment regarding pain and analgesic use; however, VR positively affected stress and anxiety. VR is safe and suitable for a wide target audience, and feasibility differed between interventions. Personalizing and improving VR technology may enhance its effectiveness.

Lessons learned from the experiences of patients with chronic pelvic pain syndrome (CPP syndrome) with a multidisciplinary consultation: a qualitative study.

INTRODUCTION: Chronic pelvic pain syndrome is a complex multifactorial condition with an increasing prevalence probably due to a rising awareness. Chronic pelvic pain syndrome is pain in the pelvic area and often accompanied with complaints in other organ systems of the lesser pelvis. Patients with chronic pelvic pain syndrome who present at our center are evaluated in a standardized care pathway with an integrated multidisciplinary consultation. The team works in a single center and consists of gynecologists, pain specialists, urologists, a pelvic floor physiotherapist and a psychologist. The aim of this interview study is to evaluate the value of the multidisciplinary consultation from the patient's perspectives. METHODS: In a qualitative study, we evaluated the experiences and perspectives of patients with chronic pelvic pain syndrome concerning the multidisciplinary consultation at the Radboud University Medical Center. Semistructured interviews were conducted with patients with chronic pelvic pain syndrome who attended a multidisciplinary consultation between 2019 and 2022. All interviews were transcribed verbatim, coded and analyzed via ATLAS.ti with the conventional content analysis. RESULTS: Data saturation was reached after seven interviews, followed by three confirmative interviews. In total, 10 patients (22-76 years) participated in the study. Three relevant themes were identified in the interviews: the deleterious effects of pain on overall health, the importance of the design of the multidisciplinary consultation, and the performance of healthcare professionals (knowledge, skills and interaction with patients and colleagues). Participants suggested that although the consultation did not improve their pain experience, there was value in having a comprehensive assessment of their disease. Patients preferred the consultation to occur at the beginning of the care. Additionally, they acknowledged the performance of healthcare providers and having their complaints recognized. However, some participants suggested the need for additional attention to mental health issues during the multidisciplinary consultation. DISCUSSION: Even though patients did not perceive the multidisciplinary consultation to improve their pain experience, they appreciated the sense of recognition by this team. CONCLUSION: A multidisciplinary consultation is of value from the patients' perspective. A suggestion for improvement emerged where the multidisciplinary consultation should occur at the beginning of the patient journey.

Targeting a lineage-specific PI3KÉ£-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.

Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers.

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.

PitViper: a software for comparative meta-analysis and annotation of functional screening data.

Recent advancements in shRNA and Cas protein technologies have enabled functional screening methods targeting genes or non-coding regions using single or pooled shRNA and sgRNA. CRISPR-based systems have also been developed for modulating DNA accessibility, resulting in CRISPR-mediated interference (CRISPRi) or activation (CRISPRa) of targeted genes or genomic DNA elements. However, there is still a lack of software tools for integrating diverse array of functional genomics screening outputs that could offer a cohesive framework for comprehensive data integration. Here, we developed PitViper, a flexible and interactive open-source software designed to fill this gap, providing reliable results for the type of elements being screened. It is an end-to-end automated and reproducible bioinformatics pipeline integrating gold-standard methods for functional screening analysis. Our sensitivity analyses demonstrate that PitViper is a useful tool for identifying potential super-enhancer liabilities in a leukemia cell line through genome-wide CRISPRi-based screening. It offers a robust, flexible, and interactive solution for integrating data analysis and reanalysis from functional screening methods, making it a valuable resource for researchers in the field.

Clinical Patient-Relevant Outcome Domains for Persistent Spinal Pain Syndrome-A Scoping Review and Expert Panels.

Large variation exists in the monitoring of clinical outcome domains in patients with persistent spinal pain syndrome (PSPS). Furthermore, it is unclear which outcome domains are important from the PSPS patient's perspective. The study objectives were to identify patient-relevant outcome domains for PSPS and to establish a PSPS outcomes framework. PubMed, CINAHL, Cochrane, and EMBASE were searched to identify studies reporting views or preferences of PSPS patients on outcome domains. The Arksey and O'Malley framework was followed to identify outcome domains. An expert panel rated the domains based on the importance for PSPS patients they have treated. A framework of relevant outcome domains was established using the selected outcome domains by the expert panel. No studies were found for PSPS type 1. Five studies with 77 PSPS type 2 patients were included for further analysis. Fourteen outcome domains were identified. An expert panel, including 27 clinical experts, reached consensus on the domains pain, daily activities, perspective of life, social participation, mobility, mood, self-reliance, and sleep. Eleven domains were included in the PSPS type 2 outcomes framework. This framework is illustrative of a more holistic perspective and should be used to improve the evaluation of care for PSPS type 2 patients. Further research is needed on the prioritization of relevant outcome domains.

A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.

A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiotherapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. In addition, in cells lacking BRCA1/2 XRD-0394 shows single-agent activity and synergy in combination with PARP inhibitors. A phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.

Are specialist-provided end-of-life scenarios key to initiation of advance care planning in primary care? A mixed-methods study.

OBJECTIVES: Specialist-provided end-of-life scenarios (SP-EOLS) may improve advance care planning (ACP) implementation in primary care by helping overcome barriers such as uncertain prognosis and poor interprofessional collaboration. We aimed to explore the current use and potential impact of SP-EOLS on ACP in Dutch primary care. METHODS: We performed a mixed-methods study. From patients discussed in a hospital-based academic palliative care multidisciplinary team meeting between 2016 and 2019 and died, we collected primary care electronic medical records data on SP-EOLS, actual EOLS, and ACP initiation and applied descriptive and comparative analyses. Subsequently, we interviewed general practitioners (GPs) and thematically analyzed the transcripts. RESULTS: In 69.7% of 66 reviewed patient files, SP-EOLS were found. In patients whose GP had received SP-EOLS, ACP conversations were more often reported (92.0 vs. 61.0%, p = 0.006). From 11 GP interviews, we identified 4 themes: (1) SP-EOLS guide GPs, patients, and relatives when dealing with an uncertain future perspective; (2) SP-EOLS provide continuity of care between primary and secondary/tertiary care; (3) SP-EOLS should be tailored to the individual patient; and (4) SP-EOLS need to be personalized and uniformly transferred to GPs. SIGNIFICANCE OF RESULTS: SP-EOLS may facilitate ACP conversations by GPs. They have the potential to help overcome existing barriers to ACP implementation by providing guidance and supporting interprofessional collaboration. Future research should focus on improving SP-EOLS and tailor them to the needs of all end users, focusing on improving their effect on ACP conversations.

Factors Predicting Clinically Relevant Pain Relief After Spinal Cord Stimulation for Patients With Chronic Low Back and/or Leg Pain: A Systematic Review With Meta-Analysis and Meta-Regression.

RATIONALE: To optimize results with spinal cord stimulation (SCS) for chronic low back pain (CLBP) and/or leg pain, including persistent spinal pain syndrome (PSPS), careful patient selection based on proved predictive factors is essential. Unfortunately, the necessary selection process required to optimize outcomes of SCS remains challenging. OBJECTIVE: This review aimed to evaluate predictive factors of clinically relevant pain relief after SCS for patients with CLBP and/or radicular leg pain, including PSPS. MATERIALS AND METHODS: In August 2023, PubMed, Cinahl, Cochrane, and EMBASE were searched to identify studies published between January 2010 and August 2023. Studies reporting the percentage of patients with ≥50% pain relief after SCS in patients with CLBP and leg pain, including PSPS at 12 or 24 months, were included. Meta-analysis was conducted to pool results for back, leg, and general pain relief. Predictive factors for pain relief after 12 months were examined using univariable and multivariable meta-regression. RESULTS: A total of 27 studies (2220 patients) were included for further analysis. The mean percentages of patients with substantial pain relief were 68% for leg pain, 63% for back pain, and 73% for general pain at 12 months follow-up, and 63% for leg pain, 59% for back pain, and 71% for general pain at 24 months follow-up assessment. The implantation method and baseline Oswestry Disability Index made the multivariable meta-regression model for ≥50% back pain relief. Sex and pain duration made the final model for ≥50% leg pain relief. Variable stimulation and implantation method made the final model for general pain relief. CONCLUSIONS: This review supports SCS as an effective pain-relieving treatment for CLBP and/or leg pain, and models were developed to predict substantial back and leg pain relief. To provide high-grade evidence for predictive factors, SCS studies of high quality are needed in which standardized factors predictive of SCS success, based on in-patient improvements, are monitored and reported.

Sublethal engagement of apoptotic pathways in residual cancer.

Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical, regulated step in this apoptotic pathway. The residual cancer cells that survive treatment serve as the seeds of eventual relapse and are often functionally characterized by their transient tolerance of multiple therapeutic treatments. New studies suggest that, in these cells, a sublethal degree of MOMP, reflective of incomplete apoptotic commitment, is widely observed. Here, we review recent evidence that this sublethal MOMP drives the aggressive features of residual cancer cells while templating a host of unique vulnerabilities, highlighting how failed apoptosis may counterintuitively enable new therapeutic strategies to target residual disease (RD).

Perioperative pain management models in four European countries: A narrative review of differences, similarities and future directions.

There is general agreement that acute pain management is an important component of perioperative medicine. However, there is no consensus on the best model of care for perioperative pain management, mainly because evidence is missing in many aspects. Comparing the similarities and differences between countries might reveal some insights into different organisational models and how they work. Here, we performed a narrative review to describe and compare the structures, processes and outcomes of perioperative pain management in the healthcare systems of four European countries using Donabedian's framework as a guide. Our comparison revealed many similarities, differences and gaps. Different structures of acute pain services in the four countries with no common definition and standards of care were found. Protocols have been implemented in all countries and guidelines in some. If outcome is assessed, it is mainly pain intensity, and many patients experiencing more intense pain than others have common risk factors (e.g. preoperative pain, preoperative opioid intake, female sex and young age). Outcome assessment beyond pain intensity (such as pain-related physical function, which is important for early rehabilitation and recovery) is currently not well implemented. Developing common quality indicators, a European guideline for perioperative pain management (e.g. for patients at high risk for experiencing severe pain and other outcome parameters) and common criteria for acute pain services might pave the way forward for improving acute pain management in Europe. Finally, the education of general and specialist staff should be aligned in Europe, for example, by using the curricula of the European Pain Federation (EFIC).

Drug dependence in cancer is exploitable by optimally constructed treatment holidays.

Cancers with acquired resistance to targeted therapy can become simultaneously dependent on the presence of the targeted therapy drug for survival, suggesting that intermittent therapy may slow resistance. However, relatively little is known about which tumours are likely to become dependent and how to schedule intermittent therapy optimally. Here we characterized drug dependence across a panel of over 75 MAPK-inhibitor-resistant BRAFV600E mutant melanoma models at the population and single-clone levels. Melanocytic differentiated models exhibited a much greater tendency to give rise to drug-dependent progeny than their dedifferentiated counterparts. Mechanistically, acquired loss of microphthalmia-associated transcription factor in differentiated melanoma models drives ERK-JunB-p21 signalling to enforce drug dependence. We identified the optimal scheduling of 'drug holidays' using simple mathematical models that we validated across short and long timescales. Without detailed knowledge of tumour characteristics, we found that a simple adaptive therapy protocol can produce near-optimal outcomes using only measurements of total population size. Finally, a spatial agent-based model showed that optimal schedules derived from exponentially growing cells in culture remain nearly optimal in the context of tumour cell turnover and limited environmental carrying capacity. These findings may guide the implementation of improved evolution-inspired treatment strategies for drug-dependent cancers.

The Predicted Outcome of Spinal Cord Stimulation in Patients With a Psychopathological Disorder and Persistent Spinal Pain Syndrome Type 2: A Systematic Review From 2009 to 2021.

OBJECTIVES: Psychologic screening is often included as a mandatory component of evaluation of the impact of psychopathology disorders on the predicted outcome of spinal cord stimulation (SCS) for patients with chronic pain due to persistent spinal pain syndrome type 2 (PSPS type 2). The conclusion of such screenings can influence the decision to offer SCS therapy to a patient. However, evidence on the impact of psychopathology on SCS outcomes is still scarce. MATERIALS AND METHODS: To address this knowledge gap, we systematically reviewed the literature from 2009 to 2021 to explore the correlation between the presence of a psychopathological disorder and the predicted outcome of SCS in patients with PSPS type 2. The literature search was conducted using various online data bases with "failed back surgery syndrome," "psychopathology," and "spinal cord stimulation" used as essential keywords. The identified studies were organized in a Rayyan AI data base, and the quality was analyzed with the Critical Appraisal Skills Program tool. RESULTS: Our search generated the identification of 468 original articles, of which two prospective and four retrospective studies met our inclusion criteria. These studies reported pain relief, a reduction of symptoms of anxiety and depression, and an improvement in rumination on the Pain Catastrophizing Scale in patients with PSPS type 2 after SCS therapy. The studies also found contradictory outcomes measured using the Oswestry Disability Index, and in terms of the impact of psychopathological disorder on the clinical outcome and revision rate of the SCS system. CONCLUSION: In this systematic review, we found no convincing evidence that the presence of a psychopathological disorder affects the predicted outcome of SCS therapy in patients with PSPS type 2.

Integrative PTEN Enhancer Discovery Reveals a New Model of Enhancer Organization.

Enhancers possess both structural elements mediating promoter looping and functional elements mediating gene expression. Traditional models of enhancer-mediated gene regulation imply genomic overlap or immediate adjacency of these elements. We test this model by combining densely-tiled CRISPRa screening with nucleosome-resolution Region Capture Micro-C topology analysis. Using this integrated approach, we comprehensively define the cis-regulatory landscape for the tumor suppressor PTEN, identifying and validating 10 distinct enhancers and defining their 3D spatial organization. Unexpectedly, we identify several long-range functional enhancers whose promoter proximity is facilitated by chromatin loop anchors several kilobases away, and demonstrate that accounting for this spatial separation improves the computational prediction of validated enhancers. Thus, we propose a new model of enhancer organization incorporating spatial separation of essential functional and structural components.

Microstructural Changes in the Spinothalamic Tract of CPSS Patients: Preliminary Results from a Single-Center Diffusion-Weighted Magnetic Resonance Imaging Study.

INTRODUCTION: Chronic pain after spinal surgery (CPSS), formerly known as failed back surgery syndrome, encompasses a variety of highly incapacitating chronic pain syndromes emerging after spinal surgery. The intractability of CPSS makes objective parameters that could aid classification and treatment essential. In this study, we investigated the use of cerebral diffusion-weighted magnetic resonance imaging. METHODS: Cerebral 3T diffusion-weighted (DW-) MRI data from adult CPSS patients were assessed and compared with those of healthy controls matched by age and gender. Only imaging data without relevant artefacts or significant pathologies were included. Apparent diffusion coefficient (ADC) maps were calculated from the b0 and b1000 values using nonlinear regression. After skull stripping and affine registration of all imaging data, ADC values for fifteen anatomical regions were calculated and analyzed with independent samples T-tests. RESULTS: A total of 32 subjects were included (sixteen CPSS patients and sixteen controls). The mean ADC value of the spinothalamic tract was found to be significantly higher in CPSS patients compared with in healthy controls (p = 0.013). The other anatomical regions did not show statistically different ADC values between the two groups. CONCLUSION: Our results suggest that patients suffering from CPSS are subject to microstructural changes, predominantly within the cerebral spinothalamic tract. Additional research could possibly lead to imaging biomarkers derived from ADC values in CPSS patients.

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

CBF-Beta Mitigates PI3K-Alpha-Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer.

PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%-25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein-Barr virus-associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform-specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study, we identified modulators of the response to the PI3Kα-specific inhibitor, BYL719, in PIK3CA-mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hypersensitivity to BYL719, through increased cell-cycle arrest and cell death, respectively. In addition, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to upregulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Kα inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Kα inhibitor response in PIK3CA-mutant gastric tumors and can inform future work as mutant-selective inhibitors are in development for diverse tumor types. IMPLICATIONS: Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

Endogenous and imposed determinants of apoptotic vulnerabilities in cancer.

The intrinsic apoptosis pathway is controlled by the BCL-2 family of proteins. Although the pro-survival members of this family can help cancer cells evade apoptosis, they may also produce apoptotic vulnerabilities that can potentially be exploited therapeutically. Apoptotic vulnerabilities can be driven by endogenous factors including altered genetics, signaling, metabolism, structure and lineage or differentiation state as well as imposed factors, the most prominent being exposure to anti-cancer agents. The recent development of BH3 mimetics that inhibit pro-survival BCL-2 family proteins has allowed these apoptotic vulnerabilities to be targeted with demonstrable clinical success. Here, we review the key concepts that are vital for understanding, uncovering, and exploiting apoptotic vulnerabilities in cancer for the potential improvement of patient outcomes.