Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases.

BACKGROUND & AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.

Pharmaceutical Pollution Alters the Structure of Freshwater Communities and Hinders Their Recovery from a Fish Predator.

Freshwater ecosystems are under threat from rising pharmaceutical pollution. While such pollutants are known to elicit biological effects on organisms, we have limited knowledge on how these effects might cascade through food-webs, disrupt ecological processes, and shape freshwater communities. In this study, we used a mesocosm experiment to explore how the community impacts of a top-order predator, the eastern mosquitofish (Gambusia holbrooki), are mediated by exposure to environmentally relevant low (measured concentration: ∼10 ng/L) and high concentrations (∼110 ng/L) of the pervasive pharmaceutical pollutant fluoxetine. We found no evidence that exposure to fluoxetine altered the consumptive effects of mosquitofish on zooplankton. However, once mosquitofish were removed from the mesocosms, zooplankton abundance recovered to a greater extent in control mesocosms compared to both low and high fluoxetine-exposed mesocosms. By the end of the experiment, this resulted in fundamental differences in community structure between the control and fluoxetine-treated mesocosms. Specifically, the control mesocosms were characterized by higher zooplankton abundances and lower algal biomass, whereas mesocosms exposed to either low or high concentrations of fluoxetine had lower zooplankton abundances and higher algal biomass. Our results suggest that fluoxetine, even at very low concentrations, can alter aquatic communities and hinder their recovery from disturbances.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience.

BACKGROUND: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. METHODS: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. RESULTS: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. CONCLUSION: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.

A Model for Rapid Transition to Virtual Care, VA Connecticut Primary Care Response to COVID-19.

INTRODUCTION: Traditionally, health care delivery in the USA has been structured around in-person visits. The COVID-19 pandemic has forced a shift to virtual care models in order to reduce patient exposure to high-risk environments and to preserve valuable health care resources. This report describes one large primary care system's model for rapid transition to virtual care (RTVC). SETTING AND PARTICIPANTS: A RTVC model was implemented at the VA Connecticut Health Care System (VACHS), which delivers care to over 58,000 veterans. PROGRAM DESCRIPTION: The RTVC model included immediate virtual care conversion, telework expansion, implementation of virtual respiratory urgent care clinics, and development of standardized note templates. PROGRAM EVALUATION: Outcomes include the rates of primary encounter types, staff teleworking, and utilization of virtual respiratory urgent care clinics. In under 2 weeks, most encounters were transitioned from in-person to virtual care, enabling telework for over half of the medical staff. The majority of virtual visits were telephone encounters, though rates of video visits increased nearly 18-fold. DISCUSSION: The RTVC model demonstrates expeditious and sustained transition to virtual care during the COVID-19 pandemic. Our experiences help inform institutions still reliant on traditional in-person visits, and future pandemic response.

Reducing avoidable admissions in rural community palliative care: a pilot study of care coordination by General Practice registrars.

OBJECTIVE: To investigate the feasibility of using a General Practice registrar (GPR) to coordinate rural palliative care services. DESIGN: A quasi-experimental design was used. Intervention group participants received the GPR service, which involved liaison among the patient, family, General Practitioner, specialist palliative care team and community nurses. Specified risk assessment, care planning and continuity of care were provided. Patients in the comparison group received the standard service. SETTING: Rural community palliative care. PARTICIPANTS: One hundred and ninety-one rural community palliative care patients (99 intervention and 92 control patients). MAIN OUTCOME MEASURES: Hospital admissions per 100 patient-days, bed-days per 100 patient-days and proportion of deaths at home. RESULTS: Patients receiving standard care were twice as likely to spend ≥8 bed-days in hospital (OR 2.09 (95%CI 1.10-3.97); P = 0.02) and were more likely to have ≥ 2 admissions to hospital (OR 3.37 (95%CI 1.83-6.21); P < 0.001), per 100 patient-days than the intervention group after adjusting for diagnosis group (cancer or not) and residence in residential aged care. Controls were significantly less likely to die at home than the intervention group (OR 0.41 (95%CI 0.20-0.86); P = 0.02). CONCLUSION: This is a small proof of concept pilot study limited by lack of randomisation. The results demonstrate the feasibility of using a GPR to manage continuity of care for rural community palliative care patients. Given the potential confounding factors, further investigation via a larger randomised trial is required.

Impact of a Curricular Change on Perceived Knowledge, Skills, and Use of Evidence in Occupational Therapy Practice: A Cohort Study.

OBJECTIVE: We evaluated the impact of a curriculum revision that emphasized experiential use of evidence in clinical environments on occupational therapy graduates' attitudes, perceived knowledge and skill, and use of evidence in practice. METHODS: We used a retrospective cohort design to compare two curriculum cohorts of recent graduates exposed to different evidence-based practice (EBP) educational approaches. Responses on a validated survey of attitudes, knowledge/skill, and use of evidence in practice were compared using t tests and Mann-Whitney U tests for Cohort 1 (n = 63) and Cohort 2 (n = 62) graduates. RESULTS: Findings suggest similar attitudes and use of evidence between cohorts; Cohort 2 reported statistically greater perceived knowledge of and skill in EBP. CONCLUSIONS: Emphasis on experiential learning in school with reinforcement of skills in clinical learning environments is not sufficient to change graduates' use of evidence. Although the curriculum revision improved perceived knowledge/skill, our study suggests systems or other factors may influence use after graduation.

Compound-specific δ13C and δ15N analysis of amino acids: a rapid, chloroformate-based method for ecological studies.

RATIONALE: Compound-specific stable isotope analysis of amino acids has proven informative to many ecological systems, but only a handful of analytical methods are routinely employed. We evaluated a simple, rapid procedure in which biological samples undergo short-duration acid hydrolysis and the resulting amino acids are derivatized with methyl chloroformate for gas chromatography/combustion/isotope-ratio mass spectrometry (GC/C/IRMS). METHODS: Amino acid derivatives were separated on a polar gas chromatography column, combusted, and δ(13)C and δ(15)N values were measured. Tests of reproducibility and accuracy were conducted for amino acid reference mixtures and biological samples. A brief case study of turtles was used to assess whether isotopic data were consistent with a priori ecological expectations. RESULTS: The methyl chloroformate based reaction successfully converted 15 amino acids from acid hydrolysates of biological materials into separable derivatives. The δ(13)C and δ(15)N values had high average measurement precision (σ <1‰). Reference materials were measured accurately, with good agreement between EA/IRMS and GC/C/IRMS determinations. Analysis of turtle blood samples yielded data consistent with their trophic ecology. CONCLUSIONS: This derivatization method is a rapid means of determining carbon and nitrogen isotopic ratios of amino acids present in the biological materials often sampled for ecological studies. While amino acids with charged or polar side chains do not have uniformly high recoveries, the average precision of measurements is comparable with that of other, more established methods. Batches of samples may be prepared from many raw materials in less than a day, representing a significant reduction in preparation time over prevailing methods.

Intraoperative MRI for neurosurgical and general surgical interventions.

PURPOSE OF REVIEW: The use of intraoperative magnetic resonance imaging (IMRI) during surgeries and procedures has expanded in the last decade. Not only is it becoming more commonly used for a variety of adult and pediatric neurosurgical procedures, but also its use has expanded to other types of surgeries. Along with using IMRI for removing tumors of the spinal cord, surgeons are now using it for other types of surgical operations of the kidney and liver. The increased utilization during the intraoperative period warrants the anesthesia provider to assure that patients and staff are unharmed because of increased risk of the powerful magnet. RECENT FINDINGS: Recent literature is reviewed regarding the expansive use of IMRI in the operating and procedure room. Safety issues and anesthetic implications are also addressed. SUMMARY: IMRI is becoming increasingly more popular, especially with neurosurgeons, but its use is also expanding to other types of surgeries. Because of the increased use, the anesthesia provider must be aware of the dangers that it imposes to those involved and take necessary safety precautions. This will help assure that no one is harmed during the operation or procedure.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit.

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre. Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022. Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75). Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.

Development of Preliminary Integrated Health Care Clinical Competencies for United States Doctor of Chiropractic Programs: A Modified Delphi Consensus Process.

Background: There has been rapid growth of chiropractors pursuing career opportunities in both public and private hospitals and other integrated care settings. Chiropractors that prosper in integrated care settings deliver patient-centered care, focus on the institutional mission, understand and adhere to organizational rules, and are proficient in navigating complex systems. The Council on Chiropractic Education Accreditation Standards do not outline specific meta-competencies for integrated care clinical training. Objective: The purpose of this study was to develop preliminary integrated health care competencies for DC programs to guide the advancement of clinical chiropractic education. Methods: A systematic literature search was performed. Articles were screened for eligibility and extracted in duplicate. Domains and seed statements were generated from this literature, piloted at a conference workshop, and evaluated via a modified Delphi consensus process. Of 42 invited, 36 chiropractors participated as panelists. Public comment period yielded 20 comments, none resulting in substantive changes to the competencies. Results: Of 1718 citations, 23 articles met eligibility criteria. After 2 modified Delphi rounds, consensus was reached on all competency statements. A total of 78 competency statements were agreed upon, which encompassed 4 domains and 11 subdomains. The 4 domains were: 1) Collaboration, (2) Clinical Excellence, (3) Communication, and (4) Systems Administration. Conclusion: We identified 78 preliminary competencies appropriate for preparing DC students and early career chiropractors for clinical practice in integrated healthcare settings. Educational programs may consider these competencies for curricular design and reform to strengthen DC program graduates for integrated practice, advanced training, and employment.

Combined effects of a valgus knee brace and lateral wedge foot orthotic on the external knee adduction moment in patients with varus gonarthrosis.

OBJECTIVE: To test the hypothesis that a custom-fit valgus knee brace and custom-made lateral wedge foot orthotic will have greatest effects on decreasing the external knee adduction moment during gait when used concurrently. DESIGN: Proof-of-concept, single test session, crossover trial. SETTING: Biomechanics laboratory within a tertiary care center. PARTICIPANTS: Patients (n=16) with varus alignment and knee osteoarthritis (OA) primarily affecting the medial compartment of the tibiofemoral joint (varus gonarthrosis). INTERVENTIONS: Custom-fit valgus knee brace and custom-made full-length lateral wedge foot orthotic. Amounts of valgus angulation and wedge height were tailored to each patient to ensure comfort. MAIN OUTCOME MEASURES: The external knee adduction moment (% body weight [BW]*height [Ht]), frontal plane lever arm (cm), and ground reaction force (N/kg), determined from 3-dimensional gait analysis completed under 4 randomized conditions: (1) control (no knee brace, no foot orthotic), (2) knee brace, (3) foot orthotic, and (4) knee brace and foot orthotic. RESULTS: The reduction in knee adduction moment was greatest when concurrently using the knee brace and foot orthotic (effect sizes ranged from 0.3 to 0.4). The mean decrease in first peak knee adduction moment compared with control was .36% BW*Ht (95% confidence interval [CI], -.66 to -.07). This was accompanied by a mean decrease in frontal plane lever arm of .59cm (95% CI, -.94 to -.25). CONCLUSIONS: These findings suggest that using a custom-fit knee brace and custom-made foot orthotic concurrently can produce a greater overall reduction in the knee adduction moment, through combined effects in decreasing the frontal plane lever arm.

Evaluation of enzyme-linked immunosorbent assays performed on milk and serum samples for detection of neosporosis and leukosis in lactating dairy cows.

Serum and milk samples from 1229 cows on 22 Ontario dairy farms were individually tested for antibodies specific for bovine leukosis virus (BLV) and Neospora caninum by enzyme-linked immunosorbent assay (ELISA). Antibodies against BLV were present in 361 serum samples (29.4%) and 369 milk samples (30.0%). Comparing the 2 tests, agreement was almost perfect (k = 0.86; 95% CI = 0.83 to 0.90) and the proportions of samples positive were not significantly different (P = 0.56). Both tests identified the same 3 herds free of bovine leukosis virus. Antibodies against N. caninum were detected in 138 serum samples (11.2%), and 111 milk samples (9.0%). Agreement between the 2 tests was moderate (k = 0.52; 95% CI = 0.43 to 0.59). Four herds were free of neosporosis by the serum test, while 10 herds were negative by the milk test. The ELISA on milk samples facilitates sample collection to classify herds free of BLV; the milk N. caninum ELISA was less reliable in predicting herd-level infection.

Évaluation des tests ELISA réalisés sur des échantillons de lait et de sérum pour la détection de la néosporose et de la leucose chez les vaches laitières en lactation. Des échantillons de sérum et de lait provenant de 1229 vaches dans 22 fermes laitières de l'Ontario ont été testés individuellement pour déceler des anticorps particuliers au virus de la leucose bovine (VLB) et de Neospora caninum à l'aide d'un test ELISA. Les anticorps contre le VLB étaient présents dans 361 échantillons de sérum (29,4 %) et 369 échantillons de lait (30,0 %). En comparant les 2 tests, la concordance était quasiment parfaite (k = 0,86; IC de 95 % = de 0,83 à 0,90) et les proportions d'échantillons positifs n'étaient pas significativement différentes (P = 0,56). Les deux tests ont identifié les même 3 troupeaux comme étant libres du virus de la leucose bovine. Des anticorps contre N. caninum ont été détectés dans 138 échantillons de sérum (11,2 %) et 111 échantillons de lait (9,0 %). La concordance entre les 2 tests était modérée (k = 0,52; IC de 95 % = de 0,43 à 0,59). Quatre troupeaux étaient libres de néosporose lors du test pour le sérum, tandis que 10 troupeaux étaient négatifs lors du test pour le lait. Le test ELISA sur les échantillons de lait facilite le prélèvement d'échantillons pour déclarer les troupeaux comme étant libre du VLB; le test ELISA du lait pour N. caninum était moins fiable pour prédire l'infection au niveau du troupeau.(Traduit par Isabelle Vallières).

A review of strategies to overcome immune resistance in the treatment of advanced prostate cancer.

Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.

Clinical efficacy and long-term immunogenicity of an early triple dose regimen of SARS-CoV-2 mRNA vaccination in cancer patients.

INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.