United States

BACKGROUND: Incisional hernia (IH) is a common problem following abdominal wall closure after midline laparotomy. Prophylactic mesh placement has been advocated by many randomized controlled trials (RCTs). This meta-analysis seeks to define what population benefits the most from prophylactic mesh (PM) placement, what is the optimal position of PM (onlay vs. sublay), and what type of mesh is preferred (absorbable vs. non-absorbable). 

METHODS: A search of RCTs under PRISMA guidelines was conducted using keywords: mesh, prevention, laparotomy or abdominal surgery, and incisional hernia. 19 RCTs conducted in adults between 1990-2022 included the development of IH as the primary outcome.   

RESULTS: Pooled analysis of all patient populations found lower IH incidence when PM was used over primary fascial closure (PFC) (OR 2.69 [2.23-3.25]). On subgroup analysis, this trend remained true among patients undergoing AAA, bariatric, elective, &amp; emergency surgeries. Both onlay (superficial to anterior rectus fascia) and sublay (deep to anterior rectus fascia) positions were associated with reduced IH risk when compared to PFC, with onlay mesh insignificantly favored over sublay (OR 0.68 [95% CI 0.39-1.19]). Additionally, both non-absorbable and absorbable mesh types demonstrated IH reduction over PFC, but no existing studies compared one mesh type over another. 

CONCLUSION: Prophylactic mesh closure is associated with a lower risk of incisional hernia after midline laparotomy when compared to primary fascial closure. Further research should examine the benefits of PM in other patient populations, specifically emergency operations with contaminated fields, as well as the utility of different mesh positions and mesh typing.

AMA Research Challenge 2023

Prophylactic mesh reduces the risk of incisional hernia following midline laparotomy

BACKGROUND: Incisional hernia (IH) is a common problem following abdominal wall closure after midline laparotomy. Prophylactic mesh placement has been advocated by many randomized controlled trials (RCTs). This meta-analysis seeks to define what population benefits the most from prophylactic mesh (PM) placement, what is the optimal position of PM (onlay vs. sublay), and what type of mesh is preferred (absorbable vs. non-absorbable). 

METHODS: A search of RCTs under PRISMA guidelines was conducted using keywords: mesh, prevention, laparotomy or abdominal surgery, and incisional hernia. 19 RCTs conducted in adults between 1990-2022 included the development of IH as the primary outcome.   

RESULTS: Pooled analysis of all patient populations found lower IH incidence when PM was used over primary fascial closure (PFC) (OR 2.69 [2.23-3.25]). On subgroup analysis, this trend remained true among patients undergoing AAA, bariatric, elective, & emergency surgeries. Both onlay (superficial to anterior rectus fascia) and sublay (deep to anterior rectus fascia) positions were associated with reduced IH risk when compared to PFC, with onlay mesh insignificantly favored over sublay (OR 0.68 [95% CI 0.39-1.19]). Additionally, both non-absorbable and absorbable mesh types demonstrated IH reduction over PFC, but no existing studies compared one mesh type over another. 

CONCLUSION: Prophylactic mesh closure is associated with a lower risk of incisional hernia after midline laparotomy when compared to primary fascial closure. Further research should examine the benefits of PM in other patient populations, specifically emergency operations with contaminated fields, as well as the utility of different mesh positions and mesh typing.

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Background 
Despite advances in surgical technique, perioperative management, and prophylaxis measures, post-discharge venous thromboembolism (pdVTE) remains a life-threatening complication following resection for pancreatic cancer (PC). While current guidelines recommend up to 28 days of thromboprophylaxis after discharge, it must be balanced with the risks of bleeding complications, and cost to the patient. Currently, prediction models to stratify patients by risk of developing pdVTE are limited in accuracy and therefore rarely used. Our preliminary analysis of five models revealed that simple logistic regression outperforms a range of higher-fidelity tree models and neural network models in stratifying patients by risk of developing pdVTE. We hypothesized this is likely due to the machine’s inability to overcome data bias and skewedness when predicting Low Incidence High Mortality (LIHM) post-operative complications. Our goal therefore, was to overcome this challenge by testing the utility of anomaly detection models (ADMs) in identifying patients at high risk of pdVTE after surgery for PC. 

Methods 
We analyzed data from all patients undergoing pancreatectomy for PC using the American College of Surgeons’ National Surgical Quality Improvement Program database from 2014 - 2021. We trained predictive models using 80% of the dataset and 213 input variables including demographics, clinical, laboratory, cancer and operation-specific variables. An unpenalized Logistic Regression (LR) model was used for baseline comparison. The ADMs deployed included Elliptical Envelope (EE), Isolation Forest (IF) and Local Outlier Factor (LOF). Due its low prevalence, pdVTE was defined as an “outlier” for the ADMs to identify amongst “normal” (non-VTE) patients. Models were tested on a 20% hold out dataset using Area-under-the-curve (AUC) scores. Sensitivity, specificity, negative predictive value and positive predictive value were also calculated and compared. 

Results 
A total of 53757 patients were included. The mean age was 63.6 ± 12.8 years, 50.0% were male, and 21,403 (39.8%) underwent Whipple procedures. A total of 1757 (3.3%) developed a pdVTE. In terms of model performance, IF and EE outperformed the LR in terms of both accuracy (Figure 1) and sensitivity. IF had a sensitivity of 0.60, followed by EE 0.57. LR had a sensitivity of 0.50. 

Conclusion 
ADMs provide superior outlier screening capability compared to traditional prediction models thereby bringing a promising opportunity to build risk stratification for LIHM complications such as pdVTE for patients with pancreatic cancer. 


Can Machine-Driven Anomaly Detection Models Identify Patients at Risk for Post-Discharge Venous Thromboembolism After Pancreatectomy for Pancreas Cancer?

Background: 
In addition to surgery, treatment for extremity soft tissue sarcoma (ESTS) should include radiation therapy (RT) for tumors that are high grade and >5 cm. Whether RT should be given in the neoadjuvant (NAT) versus adjuvant (AT) setting is controversial. The aim of this study was to determine if NAT improved adherence with RT compared to AT.

Methods:
Patients with ESTS diagnosed from 2004 through 2020 were identified in the National Cancer Database. The analytic cohort was restricted to patients with high grade tumors >5 cm in size without nodal or distant metastases who received limb-sparing surgery and RT with R0 margins. A multivariable logistic regression analysis identified factors associated with RT adherence, defined according to current guidelines as a dose of 50 Gy for NAT and a dose of 60 Gy for AT. A multivariable Cox Proportional Hazards model was used to assess overall survival.
Results: A total of 2374 patients were evaluated, with 47.3% undergoing NAT (n=1123) and 52.7% (n=1249) undergoing AT. A greater proportion of patients treated with NAT (86.1%) were compliant with the recommended doses of RT when compared to patients treated with AT (69.4%, p<0.0001). A greater proportion of patients with private insurance (51.8% vs. 46.7%, p=0.027) received NAT, as did a greater proportion of patients at academic medical centers (68.0% vs. 56.6%, p<0.001). On multivariable analysis, patients who received AT were more likely to receive an insufficient dose of RT (OR 3.01 [95% CI 2.30-3.96]) as were those who underwent treatment in the South (OR 1.51 [1.05-2.19]) and the Midwest (OR 1.52 [1.02-2.27]). Neither RT adherence nor radiation sequencing (AT vs. NAT) were independent predictors of overall survival. 

Conclusions: Patients who receive RT in the NAT setting are more likely to complete therapy and receive an optimal dose of RT compared to AT. Demographic disparities in receipt of NAT were observed, highlighting an opportunity to improve treatment in patients with high-risk ESTS.

Preoperative Radiation Therapy Increases Adherence in Patients with High-Risk Extremity Soft Tissue Sarcoma

Background
Short bowel syndrome (SBS) arises secondary to insufficient intestinal length to support complete enteral nutrition, often requiring prolonged dependance on parenteral nutrition and potentially invasive surgical lengthening procedures. Recent advancements in the field have introduced distraction enterogenesis as a potential therapeutic approach for lengthening the intestine in SBS patients. The biomechanics and efficiency of our novel intestinal expansion sleeve (IES) has previously been shown to cause sufficient distraction force to cause intestinal expansion ex vivo. In this current investigation, we aim to evaluate the novel intestinal expansion sleeve (IES) to facilitate distraction enterogenesis. We hypothesize that the IES device can achieve significant bowel lengthening in vivo by promoting distraction enterogenesis.
Methods
The IES was made using a proprietary cylindrical material with helicoid trusses cut to an initial length of 30mm. A Roux-en-Y in the jejunum of 6 rats was performed. The IES was precontracted over a Bucatini noodle and inserted into the isolated roux limb. Post-operatively, rats were examined daily, and weight was recorded. After 4 weeks, the rats were sacrificed, final weight was recorded, and the intestines were examined. A paired t-test was performed to compare change in roux limb lengths as well as change in weight post-operatively. Intestinal tissue was sampled from each specimen for histological examination.
Results
Intestinal distraction was evaluated at 4 weeks post deployment of the IES. Use of the IES resulted in a significant increase in roux limb length from an average of 42.5±15mm to 54.2±21.8 mm (p=.043, n=6). Additionally, average final weight was increased following implantation of the IES, although not significant. Average initial weight was 649.2±75.2 grams and final weight was 657.2±86.1 grams (p=0.15). Furthermore, all 6 rats had no post-operative complications because of surgical implantation.
Conclusion
Distraction enterogenesis with significant intestinal lengthening in vivo has been achieved with the IES. Surgical insertion of the IES did not lead to a reduction in rat weight, indicating that the rats tolerated the procedure. Additionally, the IES did not give rise to any complications, such as bowel obstruction. Increasing intestinal mass with these devices may change the treatment paradigm for SBS.

Preliminary Results of a Novel Intestinal Expansion Sleeve on Promoting
Distraction Enterogenesis

Background: Endoscopy is commonly used to diagnose upper gastrointestinal (GI) system disorders. However, excess mucus can significantly impair visualization, and reducing mucus intra-procedurally can increase procedure time. Several studies have evaluated the efficacy of pre-medication with mucolytic agents prior to gastroscopy to improve the diagnostic yield of endoscopy and reduce procedural time. Here, we systematically review recent evidence assessing the efficacy of mucolytic agents, including N-acetyl cysteine (NAC), in improving visibility in upper GI endoscopy.
Methods: Studies were identified by interrogating the PubMed database using the search terms "endoscopy" and "N-acetyl cysteine" for the period of 2016-2023. Only randomized control trials were included in the search. Records written in languages other than English were excluded. Ten (10) records matching these criteria were retrieved. Title and abstract screening resulted in five (5) records, which were subsequently extracted.
Results: The studies were conducted in the United Kingdom, Chile, Portugal, Thailand, and the Czech Republic. Four (4) studies consisted of randomized, double-blinded, placebo-controlled trials, while the remaining study was a randomized, non-blinded controlled trial. Four (4) of the studies showed that pre-administration of NAC (600 mg) plus simethicone (100 mg) significantly improved the visibility of the upper GI tract (esophagus, stomach, and duodenum) when compared to placebo control. The only study that failed to show an improvement in visibility scores was attributed to sub-threshold doses of NAC (400 mg) and simethicone (20 mg). Although none of the studies included an arm consisting of NAC alone, one study comparing simethicone +/- NAC showed superior visibility when NAC was administered at a high dose (1000 mg), while another study comparing simethicone +/- NAC failed to show improvement when NAC was administered at a moderate dose (600 mg). Lastly, one study found that the procedure time and volume of mucosal cleansing solution required were significantly reduced when NAC and simethicone were administered together.


Conclusion: Our survey of recent randomized control trials supports that pre-medication with NAC (600-1000 mg) and simethicone (100 mg) significantly improves the visibility of the upper GI mucosal surfaces during upper endoscopic procedures and, therefore, may improve diagnostic yield in settings where visibility is impaired. This approach may be particularly useful in lower-resource settings where less sophisticated endoscopic tools are utilized.

Efficacy of N-Acetyl Cysteine in the Prevention of Post-Operative Atrial Fibrillation and Acute Kidney Injury Post-Cardiac Surgery: A Systematic Review

Background: Osteosarcoma is the most common primary bone tumor in children and adolescents. Prognostic biomarkers are limited, and post-treatment surveillance relies heavily on radiologic imaging. Capture and analysis of cell-free DNA (cfDNA) from the bloodstream is an emerging technique that could be used to provide additional prognostic information and track residual disease following treatment. 5-hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression, and tumor specific patterns of global 5-hmC deposition are identifiable in several cancers and vary according to disease burden. We profiled 5-hmC using plasma-derived cfDNA from osteosarcoma patients and healthy children to assess its utility as a biomarker of disease status. 

Methods: cfDNA was isolated from patients diagnosed with osteosarcoma and well child controls. Nano-hmC-Seal, a technique developed to isolate 5-hmC-modified DNA fragments, was used to generate sequencing libraries of cfDNA. Genomic DNA from osteosarcoma cell lines was serially diluted with healthy donor-derived cfDNA. DESeq2 was used to identify genes with high 5-hmC deposition in osteosarcoma cell line DNA relative to serial dilutions. In patient cfDNA samples, the relative abundance of 5-hmC deposition on these osteosarcoma genes was determined using gene set variation analysis (GSVA). GSVA returns a score ranging from -1 to 1, with positive values indicating a relative abundance of 5-hmC deposition on osteosarcoma genes.

Results: The cohort consisted of 33 healthy children and 17 patients with osteosarcoma including 53 serially collected samples from these patients. 139 osteosarcoma genes were identified and used for GSVA analysis. Patients with osteosarcoma had significantly higher GSVA scores than well children (0.26 vs -0.38; p<0.001). Hierarchal clustering identified two clusters of samples from children with osteosarcoma. Cluster 1 contained samples with scores correlating with osteosarcoma-derived DNA compared to Cluster 2 (0.14 vs -0.18; p<0.001). Furthermore, Cluster 1 contained 17 of 23 samples from patients with active disease on clinical imaging (sensitivity = 74%, specificity = 57%). High 5-hmC deposition on MYC was readily identified in one sample obtained at diagnosis from the only patient with a MYC amplified tumor. Additional samples from this patient during treatment showed decreasing 5-hmC deposition on MYC, consistent with a treated tumor shedding less DNA into the blood. Additionally, decreased disease burden following surgical resection was identifiable in 5-hmC profiles (presurgical GSVA score 0.22 vs postsurgical -0.08; p=0.004). 

Conclusions: Osteosarcoma 5-hmC signatures can identify patients with active disease. Monitoring cfDNA in osteosarcoma using 5-hmC profiling is a promising technique that warrants further investigation with larger patient cohorts.

Identifying osteosarcoma signatures in cell free DNA using 5-hydroxymethylcytosine profiling

Neuropilin 2 (NRP2) expression in tissue is an independent prognostic factor for aggressive prostate cancer. To investigate if this biomarker is also prognostic when measured using a less invasive sampling method, NRP2 and its ligand, vascular endothelial growth factor C (VEGF-C), were quantified using enzyme-linked immunoassay in 145 prostate cancer patient plasma samples and 15 controls from an opportunistic biobank. Statistical analysis investigated NRP2 and VEGF-C level associations with disease progression, tumor stage, Gleason score, and prostate-specific antigen (PSA). Plasma NRP2 was not associated with more aggressive disease, in contrast to what has been shown in tissue. Increased plasma VEGF-C was associated with less severe disease, including remission, Stage I/II, and intermediate-risk Gleason score. Further studies are needed to identify non-invasive methods to assess NRP2 status.

Association of plasma NRP2 and VEGF-C levels with prostate cancer disease severity

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**Abstract:**



Rare Presentation of HPV-related Retroperitoneal Squamous Cell Carcinoma of Unknown Primary: A case report

Background
Both hepatocellular cancer and liver metastases are associated with poor clinical outcome and limited therapeutic response to immunotherapy. Tumor antigen specific CD8 T cells in the liver have been studied in the setting of both immunotherapy and cellular therapy with the predominant dogma that these cells have equivalent functionality in the liver as compared to other organ sites. Herein, we detail that tumor antigen specific or potentially tumor reactive CD 8 T cells are uniquely nonfunctional in the liver immune microenvironment in both mice and humans. 
Methods
Both a colon cancer line (CT26) and a melanoma model (B16F10) were injected intrahepatically, into the tail vein, and subcutaneously in BALB/c and C57BL/6 mice to create liver, pulmonary and subcutaneous tumors respectively. CD8 T cells were depleted by ⍺CD8 treatment. Liver and tumor infiltrating immune cells and splenocytes were analyzed by flow cytometry. Peptide loaded tetramers were used to identify antigen-specific T cells and tumor growth was monitored. Additionally, publically available single cell RNA sequencing data from 10 patient samples with primary colon cancer and liver metastasis were used. Human single cell data was analyzed using the Seurat pipeline and single cell gene enrichment analysis in R. 
Results
Both in mice and humans, a higher frequency of tumor antigen specific or potentially tumor reactive CD8 T cells was found in the liver as compared to other organ sites. Additionally, a higher frequency of these were found to be exhausted in the liver (TIM3+ and CD39+ in mice and an exhausted cluster similarly defined in humans). Surprisingly, CD8 T cell depletion had no effect on tumor growth in the liver while depletion caused tumor growth in the subcutaneous model. Additionally, through Cell Chat analysis, SPP1 positive macrophages were found to be key mediators of this exhausted phenotype and these interactions were enriched in the liver. 
Conclusion
Tumor reactive CD8 T cells are found at significantly higher frequency in the liver. Despite the higher frequency of “killer” T cells in the liver, tumor growth in the liver was not impacted by tumor reactive CD8 T cells in contrast to subcutaneous tumors, which were smaller in the presence of tumor-specific T cells. Spp1+ macrophages seem to be key mediators in tumor reactive CD8 T cell dysfunction uniquely in the liver. These findings may explain the poor clinical response seen in these patients as well as present as a potentially target for therapeutic affects.

Macrophage-Mediated Hepatic Dysfunction Impairs Tumor Antigen-Specific CD8+ T Cell Function in the Liver

Background: Chronic Lymphocytic Leukemia (CLL) is a very common hematological malignancy, with an expected incidence of 18,740 cases in 2023, which makes up approximately 1% of all new cancer diagnoses. Cytogenetic (CG) characteristics play a critical role in the prognostic outcome and therapy of CLL. As per the National Comprehensive Cancer Network (NCCN), CLL prognosis has been categorized into 3 groups: favorable, intermediate, and unfavorable based on FISH abnormalities. The older staging and classification methods for CLL are inferior when compared to the new classification that incorporates cytogenetic analysis. The incidence of cytogenetic abnormalities is unknown in African-American populations. 

Methods: Records of adult patients with CLL were reviewed at Brooklyn Cancer Care, NY, from 2012 through 2023. The cytogenetic data were stratified into three prognostic groups; favorable: del (13q), del (11q); intermediate: normal cytogenetics, trisomy 12; and Unfavorable: del (17p), multiple cytogenetic abnormalities. In the general population, the incidence of CG abnormalities is as follows: del (13q) (55%), del (11q) (18%), trisomy 12 (16%), del (17p) (7%), and del (6q) (7%). Based on cytogenetic abnormalities found by FISH, IGHV mutation status, and CD38 expression, the Integrated CLL Scoring System (ICSS) puts patients into one of three risk groups: low, intermediate, or high. 

Results: Our study included 19 CLL patients. Among them, 42.1% (n = 8) had del (13q), 31.5% (n = 6) had trisomy 12, 10.5% (n = 2) had multiple CG abnormalities, and none of them had del (11q) or del (17p). According to the ICSS scoring system, 42.1% of the patients (n = 8) had a favorable prognosis, 47.3% (n = 9) had an intermediate prognosis, and 10.5% (n = 2) had an unfavorable prognosis. 

Conclusion: The incidence of CG abnormalities in CLL patients of African-American descent remains unknown. In our small study of 19 patients, we observed a lower incidence of the 13q mutation and a higher incidence of trisomy 12 among African-American patients compared to the general population. Del 17p was not present in any of our patients, while multiple cytogenetic abnormalities were observed. In conclusion, African American patients exhibited a higher proportion of intermediate and high-risk cytogenetics and a lower incidence of low-risk cytogenetics compared to the general population.

Incidence of Cytogenetic Abnormalities in CLL Patients of African American Origin in New York City

Background
Chat GPT is a natural language processing model that has been evaluated and used in a variety of different applications. However, its ability to provide references for the appropriate use of immunohistochemistry staining in dermatopathology has not been evaluated.

Methods
Both ChatGPT v3.5 and v4.0 were evaluated. Data collection occurred from May through June 2023. A total of 33 diagnoses involving benign growths, carcinomas, benign and malignant adnexal tumors, and cutaneous lymphomas were queried. For each condition or differential, ChatGPT was queried with “I am a dermatopathologist trying to work up a skin biopsy case with immunohistochemistry. I suspect the diagnosis to be _. Please supply a list of references that I can use to evaluate the utility of specific immunohistochemical stains for this diagnosis.” For ChatGPT v3.5, each prompt was regenerated 10 times; for ChatGPT v4.0, each prompt was regenerated 5 times. The outputs were recorded and compiled.

Results
ChatGPT v3.5 rarely provided clinically useful citations (15.0%), and over half were confabulated (51.5%). In ChatGPT v4.0, performance was improved with a greater proportion of clinical relevant, useful citations (23.5%) and much less confabulated references (27.0%). However, there was still a substantial portion of irrelevant references (22.9%), general textbooks (16.2%), and instances where ChatGPT failed to even provide references (9.0%).

Conclusion
ChatGPT can provide clinically useful references, but significant supervision and validation is required for the tendencies of ChatGPT to fabricate material. Future natural language processing models designed to augment diagnostic medicine may improve dermatopathologists' ability to find clinically useful references.

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Next from AMA Research Challenge 2023

Can Machine-Driven Anomaly Detection Models Identify Patients at Risk for Post-Discharge Venous Thromboembolism After Pancreatectomy for Pancreas Cancer?