Efficacy and tolerability of osimertinib with dabrafenib and trametinib in BRAF V600E acquired EGFR-mutant non-small cell lung cancer: a case series.

Background: Acquired mutations within bypass pathways including BRAF V600E have been observed in post-osimertinib progression in EGFR-mutant non-small cell lung cancer (NSCLC). The combination of dabrafenib and trametinib is currently Food and Drug Administration-approved in BRAF V600E-mutant NSCLC. However, the application of osimertinib and dabrafenib and trametinib in the setting of acquired BRAF V600E mutation resistance from osimertinib therapy has not been clearly defined. In this case series, we evaluate the efficacy and tolerability of continued osimertinib in combination with dabrafenib and trametinib in BRAF V600E acquired EGFR-mutant NSCLC. Case Description: We retrospectively reviewed our clinical patient cohort at the University of California San Diego and patients from published case studies. Individuals who had metastatic EGFR-mutant lung adenocarcinoma treated with osimertinib at any line whom subsequently developed an acquired BRAF V600E mutation confirmed by next-generation sequencing were included for analysis. All patients had subsequent dabrafenib and trametinib in combination with osimertinib after detection of the novel BRAF V600E mutation post-osimertinib therapy. We identified three cases from our practice and nine cases from literature review. In our study cohort (n=12), we observed a median progression-free survival of 7 months on triplet therapy (osimertinib, dabrafenib, and trametinib) post progression on osimertinib, median overall survival of 46.2 months, and 60% partial response on first scan after treatment initiation. Dose reductions were required in 5/12 patients due to adverse events and treatment discontinuation in 2/12 patients. The most common adverse events were pyrexia and rash, and two cases of pneumonitis were observed (grade 1 & unreported grade). Conclusions: We concluded that the addition of combination dabrafenib and trametinib can be tolerable and effective in patients with acquired BRAF V600E mutation post progression on osimertinib. This study supports molecular profiling at osimertinib progression and provides additional information on the appropriate sequencing of targeted therapies in the EGFR tyrosine kinase inhibitor resistance setting.

TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity.

Long-chain free fatty acids (FFAs) accumulation and oxidative toxicity is a major cause for several pathological conditions. The mechanisms underlying FFA cytotoxicity remain elusive. Here we show that palmitic acid (PA), the most abundant FFA in the circulation, induces S403 phosphorylation of SQSTM1/p62 (sequestosome 1) and its aggregation, which sequesters KEAP1 and activates the non-canonical SQSTM1-KEAP1-NFE2L2 antioxidant pathway. The PA-induced SQSTM1 S403 phosphorylation and aggregation are dependent on SQSTM1 K7-D69 hydrogen bond formation and dimerization in the Phox and Bem1 (PB1) domain, which facilitates the recruitment of TBK1 that phosphorylates SQSTM1 S403. The ubiquitin E3 ligase TRIM21 ubiquitinates SQSTM1 at the K7 residue and abolishes the PB1 dimerization, S403 phosphorylation, and SQSTM1 aggregation. TRIM21 is oxidized at C92, C111, and C114 to form disulfide bonds that lead to its oligomerization and decreased E3 activity. Mutagenizing the three C residues to S (3CS) abolishes TRIM21 oligomerization and increases its E3 activity. TRIM21 ablation leads to decreased SQSTM1 K7 ubiquitination, hence elevated SQSTM1 S403 phosphorylation and aggregation, which confers protection against PA-induced oxidative stress and cytotoxicity. Therefore, TRIM21 is a negative regulator of SQSTM1 phosphorylation, aggregation, and the antioxidant sequestration function. TRIM21 is oxidized to reduce its E3 activity that helps enhance the SQSTM1-KEAP1-NFE2L2 antioxidant pathway. Inhibition of TRIM21 May be a viable strategy to protect tissues from lipotoxicity resulting from long-chain FFAs.Abbreviations: ER: endoplasmic reticulum; FFA: free fatty acid; HMOX1/HO-1: heme oxygenase 1; IB: immunoblotting; IF: immunofluorescence; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; MASH: metabolic dysfunction-associated steatohepatitis; MEF: mouse embryonic fibroblast; NFE2L2/Nrf2: NFE2 like BZIP transcription factor 2; PA: palmitic acid; PB1: Phox and Bem 1; ROS: reactive oxygen species; SLD: steatotic liver disease; SQSTM1: sequestosome 1; TBK1: TANK-binding kinase 1; TRIM21: tripartite motif containing 21.

A reciprocal relationship between mitochondria and lipid peroxidation determines the chondrocyte intracellular redox environment.

In orthopedic research, many studies have applied vitamin E as a protective antioxidant or used tert-butyl hydroperoxide to induce oxidative injury to chondrocytes. These studies often support the hypothesis that joint pathology causes oxidative stress and increased lipid peroxidation that might be prevented with lipid antioxidants to improve cell survival or function and joint health; however, lipid antioxidant supplementation was ineffective against osteoarthritis in clinical trials and animal data have been equivocal. Moreover, increased circulating vitamin E is associated with increased rates of osteoarthritis. This disconnect between benchtop and clinical results led us to hypothesize that oxidative stress-driven paradigms of chondrocyte redox function do not capture the metabolic and physiologic effects of lipid antioxidants and prooxidants on articular chondrocytes. We used ex vivo and in vivo cartilage models to investigate the effect of lipid antioxidants on healthy, primary, articular chondrocytes and applied immuno-spin trapping techniques to provide a broad indicator of high levels of oxidative stress independent of specific reactive oxygen species. Key findings demonstrate lipid antioxidants were pro-mitochondrial while lipid prooxidants decreased mitochondrial measures. In the absence of injury, radical formation was increased by lipid antioxidants; however, in the presence of injury, radical formation was decreased. In unstressed conditions, this relationship between chondrocyte mitochondria and redox regulation was reproduced in vivo with overexpression of glutathione peroxidase 4. In mice aged 18 months or more, overexpression of glutathione peroxidase 4 significantly decreased the presence of pro-mitochondrial peroxisome proliferation activated receptor gamma and deranged the relationship between mitochondria and the redox environment. This complex interaction suggests strategies targeting articular cartilage may benefit from adopting more nuanced paradigms of articular chondrocyte redox metabolism.

Spontaneous Resolution of Kyphoscoliosis Secondary to Guillain-Barre Syndrome: A Case Report.

CASE: Spinal deformity associated with Guillain-Barre syndrome (GBS) is not commonly reported. We present a 6-year-old girl who developed kyphoscoliosis after being diagnosed GBS. She had extensive motor deficits requiring 2 hospitalizations and treatment with IV immunoglobulin therapy. Five months after diagnosis, she presented to our clinic with a 15° coronal scoliosis and a 65° thoracic kyphosis. At 6-month follow-up, kyphosis progressed to 77° with no significant change in the coronal curve. At 1 year, sagittal alignment was within normal limits and the coronal curve had completely resolved. CONCLUSION: Spinal deformity in GBS can resolve spontaneously.

Identification of GTF2I Polymorphisms as Potential Biomarkers for Chronic Kidney Disease in the Han Chinese Population: Multicentric Collaborative Cross-Sectional Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) poses a global health challenge, but its molecular mechanisms are poorly understood. Genetic factors play a critical role, and phenome-wide association studies (PheWAS) and genome-wide association studies (GWAS) shed light on CKD's genetic architecture, shared variants, and biological pathways. METHODS: Using data from the multicenter collaborative precision medicine cohort, we conducted a retrospective prospectively maintained cross-sectional study. Participants with comprehensive information and genotyping data were selected, and GWAS and PheWAS analyses were performed using the curated Taiwan Biobank version 2 array to identify CKD-associated genetic variants and explore their phenotypic associations. RESULTS: Among 58,091 volunteers, 8,420 participants were enrolled. Individuals with CKD exhibited higher prevalence of metabolic, cardiovascular, autoimmune, and nephritic disorders. Genetic analysis unveiled two closely linked SNPs, rs117026326 and rs73366469, both associated with GTF2I and CKD (r2=0.64). Further examination revealed significant associations between these SNPs and various kidney-related diseases. The CKD group showed a higher proportion of individuals with specific genotypes (CT/TT for rs117026326 and CT/CC for rs73366469), suggesting potential associations with CKD susceptibility(p<0.001). Furthermore, individuals with these genotypes developed CKD at an earlier age. Multiple logistic regression confirmed the independent association of these genetic variants with CKD. Subgroup analysis based on estimated glomerular filtration rate (eGFR) demonstrated an increased risk of CKD among carriers of the rs117026326 CT/TT genotypes (OR=1.15, 95% CI: 1.07-1.24, p<0.001; OR=1.32; 95% CI: 1.04-1.66, p=0.02, respectively) and carriers of the rs73366469 CT/CC genotypes (OR=1.13, 95% CI=1.05-1.21, p<0.001; OR=1.31, 95% CI: 1.08-1.58, p=0.0049, respectively). Additionally, men had a higher CKD risk than women at lower eGFR levels (OR=1.35, 95%: 1.13-1.61, p<0.001). CONCLUSIONS: Our study reveals important links between genetic variants GTF2I and susceptibility to CKD, advancing our understanding of CKD development in the Taiwanese population and suggesting potential for personalized prevention and management strategies. More research is needed to validate and explore these variants in diverse populations.

Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance.

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6+ T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor-treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell-dependent immune checkpoint that regulates human T cell function.

The Impact of the Comprehensive Unit-Based Safety Program on the Perioperative Efficiency and Patient Safety of Adult Hip and Knee Arthroplasty Procedures: Retrospective Comparative Study.

BACKGROUND: The complexity of health care delivery systems presents a unique challenge for the perioperative space. In the area of arthroplasty procedures, the shift of complex patients into ambulatory surgery centers and reimbursement that is no longer commensurate with the inflated costs of performing these procedures have created difficulties for hospitals and physicians alike. Thus, there is a critical need to optimize perioperative workflows while maintaining high-quality care provision. METHODS: Our institution implemented the Comprehensive Unit-based Safety Program (CUSP) to improve the quality and efficiency of total knee and hip arthroplasties (TKAs and THAs). This initiative involved extensive collaboration with clinical and administrative teams, as well as 5 intervention-driven workgroups. First-case on-time start rates and duration of first-case delays, case length, anesthesia preparation, in-room patient preparation, operation, patient exit, and room turnover after CUSP implementation were analyzed using independent samples median testing, Mann-Whitney U testing, and a percentage-point difference calculation. RESULTS: After CUSP arthroplasty implementation, first-case on-time start rates increased from 43 to 81%. Statistically significant decreases were observed in median times for first-case delays, case length, in-room patient preparation, operation, patient exit, and room turnover for TKAs and THAs, but not anesthesia preparation. CONCLUSIONS: The implementation of CUSP arthroplasty for TKAs and THAs resulted in significant improvements in nearly all efficiency metrics, as well as preventions of patient safety missteps. These results exemplify the versatility of CUSP as a quality improvement method that can maintain patient safety and perioperative efficiency in the arthroplasty service of a large-scale medical center. LEVEL OF EVIDENCE: III.

Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.

PURPOSE: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRASG12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRASG12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRASG12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Evaluating compliance with the best practice guidelines for wrong-level surgery prevention in high-risk pediatric spine surgery.

PURPOSE: In 2018, Best Practice Guidelines (BPGs) were published for preventing wrong-level surgery in pediatric spinal deformity, but successful implementation has not been established. The purpose of this study was to evaluate BPG compliance 5 years after publication. We hypothesized higher compliance among BPG authors and among surgeons with more experience, higher caseload, and awareness of the BPGs. METHODS: We queried North American and European surgeons, authors and nonauthors, and members of pediatric spinal study groups on adherence to BPGs using an anonymous survey consisting of 18 Likert scale questions. Respondents provided years in practice, yearly caseload, and guideline awareness. Mean compliance scores (MCS) were developed by correlating Likert responses with MCS scores ("None of the time" = no compliance = MCS 0, "Sometimes" = weak to moderate = MCS 1, "Most of the time" = high = MCS 2, and "All the time" = perfect = MCS 3). RESULTS: Of the 134 respondents, 81.5% reported high or perfect compliance. Average MCS for all guidelines was 2.4 ± 0.4. North American and European surgeons showed no compliance differences (2.4 vs. 2.3, p = 0.07). Authors and nonauthors showed significantly different compliance scores (2.8 vs 2.4, p < 0.001), as did surgeons with and without knowledge of the BPGs (2.5 vs 2.2, p < 0.001). BPG awareness and compliance showed a moderate positive correlation (r = 0.48, p < 0.001), with non-significant associations between compliance and both years in practice (r = 0.41, p = 0.64) and yearly caseload (r = 0.02, p = 0.87). CONCLUSION: Surgeons reported high or perfect compliance 81.5% of the time with BPGs for preventing wrong-level surgery. Authorship and BPG awareness showed increased compliance. Location, study group membership, years in practice, and yearly caseload did not affect compliance. LEVEL OF EVIDENCE: Level V-expert opinion.

Machine-learning Algorithm-based Risk Prediction and Screening-detected Prostate Cancer in A Benign Prostate Hyperplasia Cohort.

BACKGROUND/AIM: Prostate cancer (PCa) is lethal. Our aim in this retrospective cohort study was to use machine learning-based methodology to predict PCa risk in patients with benign prostate hyperplasia (BPH), identify potential risk factors, and optimize predictive performance. PATIENTS AND METHODS: The dataset was extracted from a clinical information database of patients at a single institute from January 2000 to December 2020. Patients newly diagnosed with BPH and prescribed alpha blockers/5-alpha-reductase inhibitors were enrolled. Patients were excluded if they had a previous diagnosis of any cancer or were diagnosed with PCa within 1 month of enrolment. The study endpoint was PCa diagnosis. The study utilized the extreme gradient boosting (XGB), support vector machine (SVM) and K-nearest neighbors (KNN) machine-learning algorithms for analysis. RESULTS: The dataset used in this study included 5,122 medical records of patients with and without PCa, with 19 patient characteristics. The SVM and XGB models performed better than the KNN model in terms of accuracy and area under curve. Local interpretable model-agnostic explanation and Shapley additive explanations analysis showed that body mass index (BMI) and late prostate-specific antigen (PSA) were important features for the SVM model, while PSA velocity, late PSA, and BMI were important features for the XGB model. Use of 5-alpha-reductase inhibitor was associated with a higher incidence of PCa, with similar survival outcomes compared to non-users. CONCLUSION: Machine learning can enhance personalized PCa risk assessments for patients with BPH but more research is necessary to refine these models and address data biases. Clinicians should use them as supplementary tools alongside traditional screening methods.

Handling time-varying treatments in observational studies: A scoping review and recommendations.

OBJECTIVE: Time-varying treatments are common in observational studies. However, when assessing treatment effects, the methodological framework has not been systematically established for handling time-varying treatments. This study aimed to examine the current methods for dealing with time-varying treatments in observational studies and developed practical recommendations. METHODS: We searched PubMed from 2000 to 2021 for methodological articles about time-varying treatments, and qualitatively summarized the current methods for handling time-varying treatments. Subsequently, we developed practical recommendations through interactive internal group discussions and consensus by a panel of external experts. RESULTS: Of the 36 eligible reports (22 methodological reviews, 10 original studies, 2 tutorials and 2 commentaries), most examined statistical methods for time-varying treatments, and only a few discussed the overarching methodological process. Generally, there were three methodological components to handle time-varying treatments. These included the specification of treatment which may be categorized as three scenarios (i.e., time-independent treatment, static treatment regime, or dynamic treatment regime); definition of treatment status which could involve three approaches (i.e., intention-to-treat, per-protocol, or as-treated approach); and selection of analytic methods. Based on the review results, a methodological workflow and a set of practical recommendations were proposed through two consensus meetings. CONCLUSIONS: There is no consensus process for assessing treatment effects in observational studies with time-varying treatments. Previous efforts were dedicated to developing statistical methods. Our study proposed a stepwise workflow with practical recommendations to assist the practice.

Pediatric Community-Acquired Brain Abscesses: A Single-center Retrospective Study.

The European Society for Clinical Microbiology and Infectious Diseases recommends 3rd generation cephalosporins and metronidazole for empirical treatment of community-acquired brain abscesses. In 53 retrospectively analyzed pediatric patients with community-acquired brain abscesses at a German University Hospital Staphylococcus aureus was identified as a relevant pathogen (21%). Therefore, it may be reasonable to cover S. aureus when selecting empirical therapy.

Protocol of the development of a core outcome set for stroke in multidimensional value assessment of traditional Chinese medicine.

INTRODUCTION: Stroke is the most common cause of death in China. In Chinese clinical practise, traditional Chinese medicine (TCM) and integrative medicine have been widely used as adjuvant therapies for the treatment of stroke. However, their clinical effectiveness, particularly their clinical value, has been inconsistent in the literature mainly because various outcome measures have been used and reported in clinical research. Hence, obtaining a comprehensive list of outcomes for TCM value assessment is crucial for a multidimensional value assessment. Therefore, the main objective of this protocol was to develop an outcome set used in health technology assessment (HTA) decision-making for TCM treatment of stroke. METHODS AND ANALYSIS: The outcome set will be developed in four phases: (1) we will perform a systematic literature review to identify candidate outcomes that have been previously measured in published studies; (2) we will develop a comprehensive list of outcome measures by conducting a multistakeholder semistructured interview; (3) we will conduct two-round Delphi surveys to prioritise outcomes for each HTA domain; and (4) we will finalise the outcome sets by holding a ratification meeting with multiple stakeholder groups. The developed outcome set should be measured and reported as the minimum set of outcomes for HTA assessment for the TCM treatment of acute ischaemic stroke (AIS). ETHICS AND DISSEMINATION: This protocol was reviewed and approved by the Institutional Review Board of the Minhang Hospital of Fudan University. Our findings will be shared at academic conferences and in peer-reviewed publications.

Nephroscope-assisted single trocar peritoneal dialysis catheter insertion improves catheter survival compared with laparoscopic technique: Ten-year experience of a single-center.

BACKGROUND: An ideal technique for peritoneal dialysis (PD) catheter insertion should provide a long-term functioning catheter until permanent renal replacement therapy becomes available. We developed a technique using the nephroscope-assisted single-trocar approach in 2011. In this study, we report the outcomes, learning curve analysis and cost-effectiveness analysisof the nephroscopic approach compared with the traditional laparoscopic approach. METHOD: Between January 2005 and December 2020, we retrospectively reviewed 511 patients who received PD catheter insertions using the laparoscopic or nephroscopic approach. We compared the baseline characteristics of the patients, surgical outcomes, and complications of the two groups. We further analyzed the nephroscopic group to determine the cost-effectiveness analysis, learning curve and the complication frequency between the learning and mastery periods of the nephroscopic approach. RESULTS: A total of 208 patients underwent laparoscopic PD catheter insertion, whereas 303 patients received nephroscopic surgery. The median catheter survival in the nephroscopic group is significantly longer (43.1 vs. 60.5 months, p = 0.019). The incidence of peritonitis (29.3% vs.20.8%, p = 0.035) and exit site infection (12.5% vs. 6.6%, p = 0.019) were significantly lower in the nephroscopic group. The cost-effectiveness analysis showed a medical expense reduction of 16000 USD annually by using the nephroscopic technique. There was no difference in the frequency of surgical complications between the learning and mastery phases when examining the learning curve analysis for the nephroscopic technique. CONCLUSIONS: Compared with the traditional laparoscopic approach, the nephroscopic technique effectively prolonged catheter survival and reduces health care cost by reducing infectious complications. The low complication rate during the learning phase of surgery makes the procedure safe for patients and surgeons.

Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model.

Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca-/- KPC (named αKO) cancer cells induces clonal expansion of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally expanded CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally expanded T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

Evaluating compliance with the 2013 best practice guidelines for preventing surgical site infection in high-risk pediatric spine surgery.

PURPOSE: Best Practice Guidelines (BPGs) were published one decade ago to decrease surgical site infection (SSI) in pediatric spinal deformity. Successful implementation has not been established. This study evaluated surgeon compliance with items on the BPG. We hypothesized that BPG authors and surgeons with more experience, higher caseload, and awareness of the BPG would have higher compliance. METHODS: We queried North American and European surgeons, authors and non-authors, and members of various spine study groups on adherence to BPGs using an anonymous survey. Mean compliance scores (MCSs) were developed by correlating Likert responses with MCSs ("None of the time" = no compliance = MCS 0, "Sometimes" = weak to moderate = MCS 1, "Most of the time" = high = MCS 2, "All the time" = perfect = MCS 3). RESULTS: Of the 142 respondents, 73.7% reported high or perfect compliance. Average compliance scores for all guidelines was 2.2 ± 0.4. There were significantly different compliance scores between North American and European surgeons (2.3 vs 1.8, p < 0.001), authors and non-authors (2.5 vs. 2.2, p = 0.023), and surgeons with and without knowledge of the BPGs (2.3 vs. 1.8, p < 0.001). There was a weak correlation between BPG awareness and compliance (r = 0.34, p < 0.001) and no correlation between years in practice (r = 0.0, p = 0.37) or yearly caseload (r = 0.2, p = 0.78) with compliance. CONCLUSIONS: Compliance among our cohort of surgeons surveyed was high. North American surgeons, authors of the BPGs and those aware of the guidelines had increased compliance. Participation in a spine study group, years in practice, and yearly caseload were not associated with compliance. LEVEL OF EVIDENCE: Level V-expert opinion.

Reporting, handling, and interpretation of time-varying drug treatments in observational studies using routinely collected healthcare data.

BACKGROUND: Time-varying drug treatments are common in studies using routinely collected health data (RCD) for assessing treatment effects. This study aimed to examine how these studies reported, handled, and interpreted time-varying drug treatments. METHODS: A systematic search was conducted on PubMed from 2018 to 2020. Eligible studies were those used RCD to explore drug treatment effects. We summarized the reporting characteristics and methods employed for handling time-varying treatments. Logistic regressions were performed to investigate the association between study characteristics and the reporting of time-varying treatments. RESULTS: Two hundred and fifty-six studies were included, and 225 (87.9%) studies involved time-varying treatments. Of these, 24 (10.7%) reported the proportion of time-varying treatments and 105 (46.7%) reported methods used to handle time-varying treatments. Multivariable logistic regression showed that medical studies, prespecified protocol, and involvement of methodologists were associated with a higher likelihood of reporting the methods applied to handle time-varying treatments. Among the 105 studies that reported methods, as-treated analyses were the most commonly used analysis sets, which were employed in 73.9%, 75.3% and 88.2% of studies that reported approaches for treatment discontinuation, treatment switching and treatment add-on. Among the 225 studies involved time-varying treatments, 27 (12.0%) acknowledged the potential bias introduced by treatment change, of which 14 (51.9%) suggested that potential biases may impact acceptance or rejection of the null hypothesis. CONCLUSIONS: Among observational studies using RCD, the underreporting about the presence and methods for handling time-varying treatments was largely common. The potential biases due to time-varying treatments have frequently been disregarded. Collaborative endeavors are strongly needed to enhance the prevailing practices.

Comparative Survival Analysis of Dialysis and Renal Transplantation in HBV-Infected End-Stage Renal Disease Patients.

BACKGROUND: The potential risks and benefits of kidney transplantation in patients with end-stage renal disease (ESRD) infected with hepatitis B virus (HBV) have been a subject of debate. This study aimed to provide real-world data on the relative risks of death and clinical outcomes associated with kidney transplantation in this context. METHODS: We conducted a longitudinal cohort study using the National Health Insurance Research Database from 1997 to 2013, extracting cohorts of patients who are HBV-infected ESRD. The main outcome measure was overall survival, whereas the secondary measure was the relative risk of death and survival benefit through propensity-score matching (1:1). RESULTS: Of the 4895 patients who are HBV-infected with ESRD, 172 renal transplant recipients were enrolled for analysis. There was a numeric trend towards higher overall survival rates in renal transplant recipients, although this was not statistically significant (P = .057). A significant survival benefit was observed in the renal transplant group if the follow-up was longer than one year (P = 0.007). The relative risks of death among renal transplant recipients were initially higher at 2.0 times that of patients on chronic dialysis, presenting in a hyperbolic pattern with equal risks at 462 days. The likelihood of survival became equal until 1649 days. CONCLUSIONS: Our study suggests that kidney transplantation may be a viable option for patients who are HBV-infected with ESRD, given the significant improvement in quality of life and reduction of death risks observed four to five years after successful transplantation. This real-world data can help clinicians make informed decisions regarding the management of ESRD in patients who are HBV-infected.