Non-Islet Cell Tumor Hypoglycemia Secondary to a 20 cm Intra-Abdominal Leiomyoma in a Male Patient: A Case Report and Literature Review.

Non-islet cell tumor hypoglycemia (NICTH) is a rare clinical entity associated with large mesenchymal tumors. Its pathogenesis is most commonly mediated by tumor overproduction of "big" insulin-like growth factor-2. Here, we present a 54-year-old male who presented with noninsulin-mediated hypoglycemia and a 20 cm intra-abdominal leiomyoma. His hypoglycemic episodes resolved after the resection of his tumor. To our knowledge, this is the only documented case in the English literature of NICTH associated with leiomyoma in a male patient. NICTH due to a benign leiomyoma should be in the differential diagnosis for any patient with hypoglycemia and an abdominal mass.

Body weight and composition endpoints in cancer cachexia clinical trials: Systematic Review 4 of the cachexia endpoints series.

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series.

Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

Quality of life endpoints in cancer cachexia clinical trials: Systematic review 3 of the cachexia endpoints series.

The use of patient-reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self-report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990-2023). Seven thousand four hundred thirty-five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full-text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty-four (48%) were double-blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty-nine trials (78%) included multiple cancer types. Twenty-seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4-96). The most frequent QOL measure was the EORTC QLQ-C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well-validated QOL measures, including cachexia-specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co-primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific-based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.

Appetite and dietary intake endpoints in cancer cachexia clinical trials: Systematic Review 2 of the cachexia endpoints series.

There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40-628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

Radiologic and Clinical Evaluation of Posterolateral Versus Transforaminal Interbody Fusion in Degenerative Lumbar Spondylolisthesis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The primary objective is to compare foraminal height (FH) and disk height (DH) differences in posterolateral (PLF) and transforaminal interbody fusions (TLIFs) and secondarily correlate these measurements with patient-reported outcomes. BACKGROUND: The impact FH has on patient outcomes in degenerative lumbar spinal fusion surgery is unknown. Postoperative FH change and how it relates to patient-reported outcomes in posteriorly based procedures has not been well evaluated. METHODS: A retrospective review of a subset of patients from a prospective cohort from the Canadian Spine Outcomes and Research Network was undertaken. Radiographic assessment preoperatively, at 3 months and 1 year, with standing lumbar spine radiographs were completed. FH and DH were recorded at each time interval, differences between groups were compared, and correlations with patient-reported outcomes were assessed. RESULTS: One hundred nine patients were included (23 PLF and 86 TLIF). At 3-month follow-up, the change in FH was greater in the TLIF group (mean difference =2.3; 95% CI: 0.8-3.5, P =0.002). The change in FH remained significantly different at 12 months (mean difference=1.6, 95% CI: 0.2, 3.0 mm, P =0.028). The change in DH was greater in the TLIF group, with a mean difference between groups of 4.1 mm (95% CI: 2.5, 5.7, P <0.001) and 3.6 mm (95% CI: 2.0, 5.3, P <0.001). A positive change in FH correlated with less back pain, less disability, and improved physical function in the TLIF group ( P <0.05). CONCLUSIONS: Patients treated with PLF lost FH over time. An increased difference in FH at 1 year was associated with improved function and less back pain in the TLIF group.

Development of a high-throughput image cytometric screening method as a research tool for immunophenotypic characterization of patient samples from clinical studies.

Immunophenotyping has been the primary assay for characterization of immune cells from patients undergoing therapeutic treatments in clinical research, which is critical for understanding disease progression and treatment efficacy. Currently, flow cytometry has been the dominant methodology for characterizing surface marker expression for immunological research. Flow cytometry has been proven to be an effective and efficient method for immunophenotyping, however, it requires highly trained users and a large time commitment. Recently, a novel image cytometry system (Cellaca® PLX Image Cytometer, Revvity Health Sciences, Inc., Lawrence, MA) has been developed as a complementary method to flow cytometry for performing rapid and high-throughput immunophenotyping. In this work, we demonstrated an image cytometric screening method to characterize immune cell populations, streamlining the analysis of routine surface marker panels. The T cell, B cell, NK cell, and monocyte populations of 46 primary PBMC samples from subjects enrolled in autoimmune and oncological disease study cohorts were analyzed with two optimized immunophenotyping staining kits: Panel 1 (CD3, CD56, CD14) and Panel 2 (CD3, CD56, CD19). We validated the proposed image cytometry method by comparing the Cellaca® PLX and the AuroraTM flow cytometer (Cytek Biosciences, Fremont, CA). The image cytometry system was employed to generate bright field and fluorescent images, as well as scatter plots for multiple patient PBMC samples. In addition, the image cytometry method can directly determine cell concentrations for downstream assays. The results demonstrated comparable CD3, CD14, CD19, and CD56 cell populations from the primary PBMC samples, which showed an average of 5% differences between flow and image cytometry. The proposed image cytometry method provides a novel research tool to potentially streamline immunophenotyping workflow for characterizing patient samples in clinical studies.

Physical function endpoints in cancer cachexia clinical trials: Systematic Review 1 of the cachexia endpoints series.

In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.

Socioeconomic Status Among Cochlear Implant Candidates and Association With Surgical Pursuance.

Importance: Despite the sizeable global burden of hearing loss, cochlear implants have poor penetrance among eligible hearing-impaired individuals. Identifying populations who may benefit from a cochlear implant but among whom penetrance is poor is an important aim in reducing the health-related and economic effects of hearing loss on both individuals and society. Objectives: To explore the association of socioeconomic status (SES) with cochlear implant candidacy and the decision to undergo cochlear implantation. Design, Setting, and Participants: This retrospective cohort study was performed in a tertiary academic center. All adult patients evaluated for cochlear implant candidacy from January 1, 1999, through December 31, 2022, were included in the analysis. Exposures: Household income quintile and rural or urban residence were used as proxies for SES based on zip code linkage to US Census and US Department of Agriculture data. Main Outcomes and Measures: Odds of cochlear implant candidacy and surgery. Results: A total of 754 individuals underwent candidacy evaluations and were included in the analysis (386 [51.2%] women; mean [SD] age, 64.0 [15.7] years). Of these, 693 (91.9%) were cochlear implant candidates, and 623 candidates (89.9%) underwent cochlear implantation. Multivariable analyses demonstrated that individuals in the highest income quintile had lower odds of cochlear implant candidacy compared with those in the lowest income quintile (odds ratio [OR], 0.26 [95% CI, 0.08-0.91]), and candidates in the highest income quintile had greater odds of undergoing cochlear implant surgery compared with those in the lowest quintile (OR, 2.59 [95% CI, 1.14-5.86]). Living in a small town or a micropolitan or rural area was associated with lower odds of undergoing cochlear implant surgery compared with living in a metropolitan core (OR, 0.18 [95% CI, 0.04-0.83]) after controlling for distance to the primary implant center. Conclusions and Relevance: The findings of this cohort study suggest that individuals with higher SES are less likely to qualify for a cochlear implant; however, those who qualify are more likely to undergo surgery compared with those with lower SES. These findings highlight a hearing health care disparity that should be addressed through further studies to guide population-based initiatives.

Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci.

Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation. SIGNIFICANCE: Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.

The Microbiome of Osteoarthritic Hip and Knee Joints: A Prospective Multicenter Investigation.

BACKGROUND: Recent advances in high-throughput DNA sequencing technologies have made it possible to characterize the microbial profile in anatomical sites previously assumed to be sterile. We used this approach to explore the microbial composition within joints of osteoarthritic patients. METHODS: This prospective multicenter study recruited 113 patients undergoing hip or knee arthroplasty between 2017 and 2019. Demographics and prior intra-articular injections were noted. Matched synovial fluid, tissue, and swab specimens were obtained and shipped to a centralized laboratory for testing. Following DNA extraction, microbial 16S-rRNA sequencing was performed. RESULTS: Comparisons of paired specimens indicated that each was a comparable measure for microbiological sampling of the joint. Swab specimens were modestly different in bacterial composition from synovial fluid and tissue. The 5 most abundant genera were Escherichia, Cutibacterium, Staphylococcus, Acinetobacter, and Pseudomonas. Although sample size varied, the hospital of origin explained a significant portion (18.5%) of the variance in the microbial composition of the joint, and corticosteroid injection within 6 months before arthroplasty was associated with elevated abundance of several lineages. CONCLUSIONS: The findings revealed that prior intra-articular injection and the operative hospital environment may influence the microbial composition of the joint. Furthermore, the most common species observed in this study were not among the most common in previous skin microbiome studies, suggesting that the microbial profiles detected are not likely explained solely by skin contamination. Further research is needed to determine the relationship between the hospital and a "closed" microbiome environment. These findings contribute to establishing the baseline microbial signal and identifying contributing variables in the osteoarthritic joint, which will be valuable as a comparator in the contexts of infection and long-term arthroplasty success. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Health Reporting from Different Data Sources: Does it Matter for Mental Health?

BACKGROUND: Mental disorders are typically stigmatized conditions associated with negative stereotypes, which may lead individuals to underreport them. Thus, survey data may be subject to biases. Although administrative data has some limitations, it is an alternative data source that may be considered more objective. AIMS OF THE STUDY: This study aimed to identify the degree of agreement between survey and administrative health care data for mental health conditions, factors affecting underreporting, and whether underreporting also occurs for physical health conditions. METHODS: We used Ontario data from the Canadian Community Health Survey linked to health records to examine the presence of mental health conditions (i.e., schizophrenia and mood disorders) and select physical health conditions (i.e., diabetes and cancer). Using administrative data as the reference standard, we created four categories for each health condition based on the level of agreement between the two data sources: consistent cases and non-cases (i.e. individuals with concordant data based on their reported health condition), and people who were found to underreport and overreport a condition (i.e. where the condition was present in the administrative data, but not in the survey data and vice-versa, respectively). The overall level of agreement was assessed using Cohen's kappa statistic. Probit regressions were estimated to determine the factors affecting underreporting. RESULTS: The Kappa statistics for mood disorder was fair (k= 0.26) and moderate for schizophrenia (k = 0.49). Physical health conditions had higher kappa values (diabetes, k = 0.81; ever having cancer, k = 0.68), with the exception of currently having cancer (k = 0.24). Underreporting was highest for the most stigmatizing condition, schizophrenia (63%), followed by mood disorders (39%) and cancer (39%), and lowest for diabetes (25%). Older age, being born in Africa and Asia, and being employed all increased the probability of underreporting among individuals identified in the administrative data; the opposite held for social assistance. DISCUSSION: We extended previous work on mental health reporting by combining survey data with administrative data to examine the level of agreement between respondents' self-reported mental health and administrative records. The data include some mental disorders not studied previously. We examined the entire adult population; this is important because prevalence of schizophrenia may be less common among older population groups due to higher mortality among this patient population. Additionally, there may be potential age-related differences in stigma and mental health conditions. The administrative health data captured only health services covered by the public provincial health insurance plan and thus did not capture medical care provided by psychologists, social workers, and nurses. While this would affect Kappa statistic values, it does not directly affect the underreporting analyses. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Our results suggest that disclosure of mental health conditions may differ by the level of stigma, which has implications for obtaining accurate estimates of mental health prevalence from self-reported data sources.

Lutispora saccharofermentans sp. nov., a mesophilic, non-spore-forming bacterium isolated from a lab-scale methanogenic landfill bioreactor digesting anaerobic sludge, and emendation of the genus Lutispora to include species which are non-spore-forming and mesophilic.

A novel anaerobic, mesophilic, non-spore-forming bacterium (strain m25T) was isolated from methanogenic enrichment cultures obtained from a lab-scale methanogenic landfill bioreactor containing anaerobic digester sludge. Cells were Gram-stain-negative, catalase-positive, oxidase-negative, rod-shaped, and motile by means of a flagellum. The genomic DNA G+C content was 40.11 mol%. The optimal NaCl concentration, temperature and pH for growth were 2.5 g l-1, 35 °C and at pH 7.0, respectively. Strain m25T was able to grow in the absence of yeast extract on glycerol, pyruvate, arginine and cysteine. In the presence of 0.2 % yeast extract, strain m25T grew on carbohydrates and was able to use glucose, cellobiose, fructose, raffinose and galactose. The novel strain could utilize glycerol, urea, pyruvate, peptone and tryptone. The major fatty acids were iso-C15  :  0, C14  :  0, C16  :  0 DMA (dimethyl acetal) and iso-C15 : 0 DMA. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the new isolate was closely related to Lutispora thermophila EBR46T (95.02 % 16S rRNA gene sequence similarity). Genome relatedness was determined using both average nucleotide identity and amino acid identity analyses, the results of which both strongly supported that strain m25T belongs to the genus Lutispora. Based on its unique phylogenetic features, strain m25T is considered to represent a novel species within the genus Lutispora. Moreover, based on its unique physiologic features, mainly the lack of spore formation, a proposal to amend the genus Lutispora is also provided to include the non-spore-forming and mesophilic species. Lutispora saccharofermentans sp. nov. is proposed. The type strain of the species is m25T (=DSM 112749T=ATCC TSD-268T).

Cytoreduction and HIPEC for Gastric Carcinomatosis: Multi-institutional Analysis of Two Phase II Clinical Trials.

INTRODUCTION: There are no approved locoregional therapies for peritoneal carcinomatosis from gastric adenocarcinoma (GA). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) represents a potential treatment for advanced GA with isolated peritoneal metastasis. PATIENTS AND METHODS: Two separate single-institution phase II, single-arm studies evaluating CRS-HIPEC using cisplatin with mitomycin C (NIH: NCT03092518, MDACC: NCT02891447) in patients with GA and confirmed peritoneal metastasis were analyzed. The primary endpoint of each trial was overall survival (OS). Clinical, pathologic, and treatment variables were analyzed for association with outcomes. RESULTS: Over 4 years, 41 patients with peritoneal carcinomatosis from GA underwent CRS-HIPEC. All patients had synchronous peritoneal metastasis and received systemic chemotherapy as front-line therapy. A total of 23 patients also received laparoscopic HIPEC prior to open CRS-HIPEC. The majority (63%, n = 26) were male, and median PCI score at CRS-HIPEC was 2. Median OS was 24.9 months from diagnosis and 14.4 months from CRS-HIPEC. Three-year OS was 25% from diagnosis and 22% from CRS-HIPEC. Median RFS was 7.4 months. The rate of 30-day Clavien-Dindo grade ≥ 3 complications was 32%; specifically, the rate of anastomotic leak was 22%. Multivariable analysis identified the number of pathologically positive lymph nodes as an independent predictor of postoperative OS. CONCLUSIONS: In patients with gastric adenocarcinoma and isolated peritoneal metastasis treated with CRS-HIPEC, 3-year OS was 22% from CRS-HIPEC, and complications were common. The number of pathologic lymph node metastases was inversely correlated with overall survival. Further investigation of CRS-HIPEC for GA should include patient selection based on response to systemic chemotherapy or incorporate novel intraperitoneal treatment strategies.

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer.

BACKGROUND: Novel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Preclinical work has shown that DNA methyltransferase inhibitors (DNMTis) can reverse the immunosuppressive tumor microenvironment in OC. Inhibiting DNA methyltransferases activate transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon (IFN) signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by IFN signaling and edits mammalian dsRNA with an A-to-I nucleotide change, which is read as an A-to-G change in sequencing data. These edited dsRNAs cannot be sensed by dsRNA sensors, and thus ADAR1 inhibits the type I IFN response in a negative feedback loop. We hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response. METHODS: Human OC cell lines were treated in vitro with DNMTi and then RNA-sequenced to measure RNA editing. Adar1 was stably knocked down in ID8 Trp53-/- mouse OC cells. Control cells (shGFP) or shAdar1 cells were tested with mock or DNMTi treatment. Tumor-infiltrating immune cells were immunophenotyped using flow cytometry and cell culture supernatants were analyzed for secreted chemokines/cytokines. Mice were injected with syngeneic shAdar1 ID8 Trp53-/- cells and treated with tetrahydrouridine/DNMTi while given anti-interferon alpha and beta receptor 1, anti-CD8, or anti-NK1.1 antibodies every 3 days. RESULTS: We show that ADAR1 edits transposable elements in human OC cell lines after DNMTi treatment in vitro. Combining ADAR1 knockdown with DNMTi significantly increases pro-inflammatory cytokine/chemokine production and sensitivity to IFN-ß compared with either perturbation alone. Furthermore, DNMTi treatment and Adar1 loss reduces tumor burden and prolongs survival in an immunocompetent mouse model of OC. Combining Adar1 loss and DNMTi elicited the most robust antitumor response and transformed the immune microenvironment with increased recruitment and activation of CD8+ T cells. CONCLUSION: In summary, we showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I IFN signaling. Thus, epigenetically inducing transposable element transcription combined with inhibition of RNA editing is a novel therapeutic strategy to reverse immune evasion in OC, a disease that does not respond to current immunotherapies.

Hospital Surgical Volume Is Poorly Correlated With Delivery of Multimodal Treatment for Localized Pancreatic Cancer: A National Retrospective Cohort Study.

Using Donabedian's quality of care model, this study assessed process (hospital multimodal treatment) and structure (hospital surgical case volume) measures to evaluate localized pancreatic cancer outcomes. Background: Treatment at high surgical volume hospitals has been shown to improve short-term outcomes. However, multimodal treatment-surgery and chemotherapy-is the standard of care yet only received by 35% of US patients and has not been examined at the hospital level. Methods: The National Cancer Database was used to identify a cohort of clinical stage I pancreatic cancer patients eligible for multimodal treatment from 2004 to 2016. Hospital multimodal treatment was defined as the number of patients receiving surgery and chemotherapy by the number of eligible patients per hospital. Descriptive statistics and survival analyses were conducted. Results: A total of 16,771 patients met inclusion criteria, of whom 68.0% received curative-intent surgery and 35.8% received multimodal treatment. There was poor correlation between hospital surgical volume and delivery of multimodal treatment (Spearman correlation 0.214; P < 0.001). Of patients cared for at the highest surgical volume hospitals, 18.8% and 52.1% were treated at hospitals with low (0%-25%) and moderate (>25%-50%) multimodal treatment delivery, respectively. Higher hospital multimodal treatment delivery was associated with improved overall survival. Discussion: Although the volume-outcome relationship for pancreatic cancer has demonstrated improved outcomes, this work identified poor correlation between hospital surgical volume and delivery of multimodal treatment. The role of care coordination in the delivery of multimodal treatment warrants further investigation as it is associated with improved survival for patients with localized pancreatic cancer.

Development of an Electronic Health Record Registry to Facilitate Collection of Commission on Cancer Metrics for Patients Undergoing Surgery for Breast Cancer.

PURPOSE: Accurate and efficient data collection is a challenge for quality improvement initiatives and clinical research. We describe the development of a custom electronic health record (EHR)-based registry to automatically extract structured Commission on Cancer axillary surgery-specific metrics from a custom synoptic note template included in the operative reports for patients with breast cancer undergoing surgery. METHODS: The smart functionality of our enterprise-based EHR system was leveraged to create a custom smart phrase to capture axillary surgery-specific variables. A multidisciplinary team developed structured data elements correlating to each axillary surgery-specific variable. These data elements were then included in a note template for the operative report. Each variable could be aggregated and converted into a single flat database through the EHR's reporting workbench and serve as a live, prospective registry for all users within the EHR. RESULTS: The final axillary surgery-specific note template in a synoptic format allowed for efficient and easy entry and automatic collection of breast cancer-specific metrics. From initial adoption in February 2021-December 2021, there were 1,254 patients who underwent breast surgery with axillary surgery. The operative notes allowed for automatic capture of metrics from 60.5% (n = 759) of patients. Data capture improved from 37.6% in the initial adoption period of 6 months to 86.2% in the last 5 months. CONCLUSION: We were able to demonstrate successful implementation of provider-driven structured data entry into EHR systems that permits automatic data capture. The end result is a custom synoptic note template and a real-time, prospective registry of breast cancer-specific Commission on Cancer metrics that are robust enough to use for quality improvement initiatives and clinical research.

An Enhanced Understanding of Culture-Negative Periprosthetic Joint Infection with Next-Generation Sequencing: A Multicenter Study.

BACKGROUND: The challenges of culture-negative periprosthetic joint infection (PJI) have led to the emergence of molecular methods of pathogen identification, including next-generation sequencing (NGS). While its increased sensitivity compared with traditional culture techniques is well documented, it is not fully known which organisms could be expected to be detected with use of NGS. The aim of this study was to describe the NGS profile of culture-negative PJI. METHODS: Patients undergoing revision hip or knee arthroplasty from June 2016 to August 2020 at 14 institutions were prospectively recruited. Patients meeting International Consensus Meeting (ICM) criteria for PJI were included in this study. Intraoperative samples were obtained and concurrently sent for both routine culture and NGS. Patients for whom NGS was positive and standard culture was negative were included in our analysis. RESULTS: The overall cohort included 301 patients who met the ICM criteria for PJI. Of these patients, 85 (28.2%) were culture-negative. A pathogen could be identified by NGS in 56 (65.9%) of these culture-negative patients. Seventeen species were identified as common based on a study-wide incidence threshold of 5%. NGS revealed a polymicrobial infection in 91.1% of culture-negative PJI cases, with the set of common species contributing to 82.4% of polymicrobial profiles. Escherichia coli, Cutibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus ranked highest in terms of incidence and study-wide mean relative abundance and were most frequently the dominant organism when occurring in polymicrobial infections. CONCLUSIONS: NGS provides a more comprehensive picture of the microbial profile of infection that is often missed by traditional culture. Examining the profile of PJI in a multicenter cohort using NGS, this study demonstrated that approximately two-thirds of culture-negative PJIs had identifiable opportunistically pathogenic organisms, and furthermore, the majority of infections were polymicrobial. LEVEL OF EVIDENCE: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Mapping Canadian Data Assets to Generate Real-World Evidence: Lessons Learned from Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration's RWE Data Working Group.

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8-11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration's Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.