Symptom duration is not associated with per oral endoscopic myotomy (POEM) failure.

INTRODUCTION: Per oral endoscopic myotomy (POEM) is a relatively novel technique to address achalasia; however, little is known about the efficacy of POEM for patients with long-standing achalasia. We hypothesize that patients with long-standing achalasia prior to intervention will be more recalcitrant to POEM than patients with symptoms for a short duration. METHODS: We performed a retrospective analysis of patients with achalasia who received a POEM at a single institution from 2012 to 2022. Patients were grouped into cohorts based on the time of symptom duration: < 1 year, 1-3 years, 4-10 years, > 10 years. POEM failure was defined as need for repeat intervention, symptom recurrence, and a high postoperative Eckart score. Demographic and clinical data were compared between cohorts. Measures of failure multivariable logistic regression analyzed the association between symptom duration and response to POEM. RESULTS: During the study period, 132 patients met inclusion criteria. Patient age at surgery, sex, BMI, Charleston-Deyo Comorbidity Index, and patients with diabetes with and without end organ complications, connective tissue diseases, and patients with ulcer diseases did not differ among cohorts. Patients who have had symptoms for greater than 10 years had significantly more endoscopic interventions prior to their POEM (30% vs, 60% p = 0.002). Patients in all cohorts experienced the same number of symptoms post-POEM. Manometric measurements did not vary across cohorts after POEM. Symptom recurrence, need for repeat endoscopic intervention, repeat surgical intervention, or repeat POEM also did not vary across cohorts. Having symptoms of achalasia > 10 years did not increase the odds POEM failure on multivariable logistical regression. CONCLUSIONS: These data suggest that longer symptom duration is not associated with increased rates of POEM failure. This is promising as clinicians should not exclude patients for POEM eligibility based on duration of symptoms alone.

Carbohydrate ligand engagement with CD11b enhances differentiation of tumor-associated myeloid cells for immunotherapy of solid cancers.

BACKGROUND: Efforts to modulate the function of tumor-associated myeloid cell are underway to overcome the challenges in immunotherapy and find a cure. One potential therapeutic target is integrin CD11b, which can be used to modulate the myeloid-derived cells and induce tumor-reactive T-cell responses. However, CD11b can bind to multiple different ligands, leading to various myeloid cell functions such as adhesion, migration, phagocytosis, and proliferation. This has created a major challenge in understanding how CD11b converts the differences in the receptor-ligand binding into subsequent signaling responses and using this information for therapeutic development. METHODS: This study aimed to investigate the antitumor effect of a carbohydrate ligand, named BG34-200, which modulates the CD11b+ cells. We have applied peptide microarrays, multiparameter FACS (fluorescence-activated cell analysis) analysis, cellular/molecular immunological technology, advanced microscopic imaging, and transgenic mouse models of solid cancers, to study the interaction between BG34-200 carbohydrate ligand and CD11b protein and the resulting immunological changes in the context of solid cancers, including osteosarcoma, advanced melanoma, and pancreatic ductal adenocarcinoma (PDAC). RESULTS: Our results show that BG34-200 can bind directly to the activated CD11b on its I (or A) domain, at previously unreported peptide residues, in a multisite and multivalent manner. This engagement significantly impacts the biological function of tumor-associated inflammatory monocytes (TAIMs) in osteosarcoma, advanced melanoma, and PDAC backgrounds. Importantly, we observed that the BG34-200-CD11b engagement triggered endocytosis of the binding complexes in TAIMs, which induced intracellular F-actin cytoskeletal rearrangement, effective phagocytosis, and intrinsic ICAM-1 (intercellular adhesion molecule I) clustering. These structural biological changes resulted in the differentiation in TAIMs into monocyte-derived dendritic cells, which play a crucial role in T-cell activation in the tumor microenvironment. CONCLUSIONS: Our research has advanced the current understanding of the molecular basis of CD11b activation in solid cancers, revealing how it converts the differences in BG34 carbohydrate ligands into immune signaling responses. These findings could pave the way for the development of safe and novel BG34-200-based therapies that modulate myeloid-derived cell functions, thereby enhancing immunotherapy for solid cancers.

Preoperative manometric data can predict symptom improvement after per oral endoscopic myotomy for treatment of achalasia.

BACKGROUND: While per oral endoscopic myotomy (POEM) has been shown to be efficacious in the treatment of achalasia, it can be difficult to predict who will have a robust and durable response. Historically, high lower esophageal sphincter pressures have been shown to predict a worse response to endoscopic therapies such as botox therapy. This study was designed to evaluate if modern preoperative manometric data could predict a response to therapy after POEM. METHODS: This was a retrospective study of 144 patients who underwent a POEM at a single institution by a single surgeon over an 8-year period (2014-2022) who had high-resolution manometry performed preoperatively and had an Eckardt symptom score performed both preoperatively and postoperatively. The achalasia type and integrated relaxation pressures (IRP) were then tested for potential correlation with need for any further achalasia interventions postoperatively as well as the degree of Eckardt score reduction using univariate analysis. RESULTS: The achalasia type on preoperatively manometry was not predictive of need for further interventions or degree of Eckardt score reduction (p = 0.74 and 0.44, respectively). A higher IRP was not predictive of need for further interventions however it was predictive of a greater reduction in postoperative Eckardt scores (p = 0.03) as shown by a nonzero regression slope. CONCLUSION: In this study, achalasia type was not a predictive factor in need for further interventions or degree of symptom relief. While IRP was not predictive of need for further interventions, a higher IRP did predict better symptomatic relief postoperatively. This result is opposite that of other endoscopic treatment modalities. Therefore, patients with higher IRP on high-resolution manometry would likely benefit from myotomy which provides significant symptomatic relief postoperatively.

Do preoperative endoscopic interventions predict symptom recurrence or reintervention after peroral endoscopic myotomy?

BACKGROUND: Studies assessing outcomes of patients undergoing peroral endoscopic myotomy (POEM) after botulinum injection or dilation have had various results with respect to failure, although this has not been differentiated between lack of clinical response and recurrence. We hypothesize that patients with previous endoscopic intervention(s) are more likely to recur than treatment-naïve patients. METHODS: This is a retrospective cohort study of patients that underwent POEM for achalasia at a single tertiary care center between 2011 and 2022. Patients were excluded if they had previous myotomy (POEM or Heller). The remaining patients were stratified into treatment-naïve patients (TN), those with previous botulinum injection (BTX), those with previous dilatation (BD), and those with both previous endoscopic interventions (BOTH). Primary outcome was recurrence indicated by clinical symptoms or need for repeat endoscopic intervention or surgery after originally having clinical resolution (Eckardt ≤ 3). Multivariate logistic regression using preoperative and intraoperative factors was completed to assess odds of recurrence. RESULTS: A total of 164 patients were included in the analysis, 90 TN, 34 BD, 28 BTX, and 12 BOTH. There were no other significant differences in demographics or in preoperative Eckardt score (p = 0.53). There was no difference in the proportion of patients that had postoperative manometry (p = 0.74), symptom recurrence (p = 0.59), surgical intervention (p = 0.16). BTX (14.3%) and BOTH (16.7%) patients had a higher rate of repeat endoscopic intervention than BD and TN patients (5.9% and 1.1%). In the logistic regression analysis, there was no association among the BTX, BD, or BOTH groups compared to the TN group. No odds ratios achieved statistical significance. CONCLUSIONS: There were no increased likelihood of recurrence with botulinum injection or dilatation prior to POEM, implying that they are similarly good candidates compared to treatment-naïve patients.

Preoperative patient factors and anatomy do not predict who will develop reflux after per oral endoscopic myotomy.

BACKGROUND: Per oral endoscopic myotomy (POEM) has been shown to be an efficacious and safe therapy for the treatment of achalasia. Compared to laparoscopic Heller myotomy however, no antireflux procedure is routinely combined with POEM and therefore the development of symptomatic or silent reflux is of concern. This study was designed to determine if various patient factors and anatomy would predict the development of gastroesophageal reflux disease post-operatively. METHODS: This was a retrospective cohort study of all patients who underwent a POEM at a single institution by a single surgeon over an eight-year period (2014-2022). It has been our practice to obtain a postoperative ambulatory pH test on all patients 6 months after POEM off all acid reducing medications. Patients without a postoperative ambulatory esophageal pH monitoring test were excluded. Age, sex, obesity (BMI > 30), achalasia type, presence of a hiatal hernia, history of prior endoscopic achalasia treatments or myotomy were analyzed using univariate analysis as predictive factors for the development of postoperative GERD (DeMeester score > 14.7 on ambulatory pH monitoring). RESULTS: There were 179 total patients included in the study with 42 patients (23.5%) having undergone postoperative ambulatory pH testing. The majority of patients (137 or 76.5%) were lost to follow up and did not undergo ambulatory pH testing. Twenty-three out of those 42 patients (55%) had evidence of GERD on ambulatory pH testing. Multiple preoperative patient characteristics including demographics, manometric results, EGD findings, and history of prior achalasia interventions did not correlate with the development of post-operative GERD. CONCLUSIONS: Despite the high rate of reflux after POEM, there does not appear to be any reliable preoperative indicators of which patients have a higher risk of developing post-operative GERD after POEM.

Risk factors for adverse outcomes following paraesophageal hernia repair among obese patients.

BACKGROUND: Although obesity is an established risk factor for adverse outcomes after paraesophageal hernia repair (PEHR), many obese patients nonetheless receive PEHR. The purpose of this study was to explore risk factors for adverse outcomes of PEHR among this high-risk cohort. We hypothesized that obese patients may have other risk factors for adverse outcomes following PEHR. METHODS: A retrospective study of adult obese patients who underwent minimally invasive PEHR from 2017 to 2019 was performed. Patients were excluded for BMI < 30 or if they had concomitant bariatric surgery at time of PEHR. The primary outcome of interest was a composite adverse outcome (CAO) defined as having any of the four following outcomes after PEHR: persistent GERD > 30 d, persistent dysphagia > 30 d, recurrence, or reoperation. Chi-square and t-test analysis was used to compare demographic and clinical characteristics. Multivariable logistic regression analysis was used to evaluate independent predictors of CAO. RESULTS: In total, 139 patients met inclusion criteria with a median follow-up of 19.7 months (IQR 8.8-81). Among them, 51/139 (36.7%) patients had a CAO: 31/139 (22.4%) had persistent GERD, 20/139 (14.4%) had persistent dysphagia, 24/139 (17.3%) had recurrence, and 6/139 (4.3%) required reoperation. On unadjusted analysis, patients with a CAO were more likely to have a history of prior abdominal surgery (86.3% vs 70.5%, p = 0.04) and were less likely to have undergone a preoperative CT scan (27.5% vs 45.5%, p = 0.04). On multivariable analysis, previous abdominal surgery was independently associated with an increased likelihood of CAO whereas age and preoperative CT scan had a decreased likelihood of CAO. CONCLUSIONS: Although there were adverse outcomes among obese patients, minimally invasive PEHR may be feasible in a subset of patients at specialized centers. These findings may help guide the appropriate selection of obese patients for PEHR.

BG34-200 Immunotherapy of Advanced Melanoma.

High levels of myeloid-derived cells are characteristic of the tumor microenvironment (TME) of advanced melanoma. These cells interact with tumor cells to suppress the development of antitumor immune responses, regulate tumor metastasis, and drive cancer's resistance to virtually all types of therapy. Therefore, methods to disrupt tumor-associated myeloid cell function are actively being sought to find a cure. Our team has recently developed a plant-derived carbohydrate molecule, BG34-200, that modulates tumor-associated myeloid cells by targeting the cell surface receptor CD11b. In this study, we found that BG34-200 IV administration could significantly inhibit tumor growth and improve survival in B16F10 mice with advanced melanoma. Our data supported a model that the entry of BG34-200 into circulating melanoma tumor-associated inflammatory monocytes (TAIMs) could trigger a sequential immune activation: the BG34-200+ TAIM subsets migrated to tumor and differentiated into monocyte-derived dendritic cells (mo-DCs); then, the BG34-200+ mo-DCs migrated to tumor draining lymph nodes, where they triggered the generation of tumor-antigen-specific T cells. Based upon these results, we combined BG34-200 treatment with adoptive transfer of TdLN-derived T cells to treat advanced melanoma, which significantly improved animal survival and helped tumor-free survivors be resistant to a second tumor-cell challenge. The scientific findings from this study will allow us to develop new technology and apply BG34-200-based immunotherapy to patients with advanced melanoma who have not responded to current standard of care therapies with and without immunotherapy.

Weight Loss as an Untapped Early Detection Marker in Pancreatic and Periampullary Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has the worst survival of common cancers, partly because there are no reliable early detection tests. Unintentional weight loss (≥ 5% decrease from baseline) has been linked to PDAC, but the frequency and severity of weight loss using objective measures, and its relationship to prognosis, have not been well characterized. METHODS: We identified 390 patients with PDAC (all stages) and two or more prediagnosis weights in the electronic medical record. Percentage weight loss in the 365 and 180 days preceding diagnosis was calculated. Results were compared with raw weights of age- and sex-matched non-cancer controls (n = 780). Odds ratios for PDAC were calculated using conditional logistic regression. Cox proportional hazards models were used for survival. RESULTS: Within 1 year of diagnosis, more PDAC patients lost ≥ 5% weight relative to controls (74.9% vs. 11.2%; p < 0.001), with a median weight loss of 14.2 versus 2.9 lbs. The odds ratio for PDAC comparing weight loss within 1 year of 5 to < 10% was 10.30 (p < 0.001) and 77.82 for ≥ 10% (p < 0.001), compared with stable weight. Weight loss prior to diagnosis was also associated with early-stage PDAC. PDAC cases with ≥ 10% prediagnosis weight loss had worse survival compared with stable weights (hazard ratio [HR] 1.60; p = 0.01). Greater prediagnosis weight loss was associated with poor survival after pancreatectomy (5 to < 10% vs. < 5%, HR 2.40, p = 0.03; ≥ 10% vs. < 5%, HR 2.59, p = 0.03). CONCLUSIONS: Diagnosis of PDAC is preceded by unintentional weight loss in the majority of patients, even at an early stage. Greater prediagnosis weight loss severity is also associated with poor postoperative survival.

Utilization of a Novel Program-Specific Evaluation Tool Results in a Decidedly Different Interview Pool Than Traditional Application Review.

BACKGROUND: There are almost twice as many applicants as there are general surgery internships, each utilizing a common application with standard components. These elements are frequently not useful in determining affinity for a program or overall ability, and resultant poor fit may be partially responsible for program attrition. Alternative evaluation instruments would be beneficial to both programs and applicants. METHODS: An application review committee comprised of resident representatives, faculty representing all program-affiliated institutions, and program leadership completed a written evaluation developed by a third party (SurgWise Consulting) that specializes in industrial and organizational psychology. The responses were compiled to create a standardized assessment tool. This assessment was sent to applicants who were subsequently ranked according to fit with our program. The pool of applicants was separately evaluated using our traditional application review. Two residents independently graded each applicant on a 5-point Likert scale to evaluate common application elements; applicants were subsequently assigned an overall score. RESULTS: The assessment was completed by 507 (99%) of 512 qualifying applicants. Separately, 378 applications were reviewed by the traditional method for a total of 756 reviews. Of the 96 applicants identified by the assessment tool to invite for interviews, 22 (23%) qualified for interview invitations according to the traditional review method. The assessment produced 74 applicants that otherwise would not have been interviewed. CONCLUSION: Traditional application review strategies have many shortcomings. A competency-based assessment tool in the residency application selection process identifies a pool of applicants not identified by traditional review methods.

A targeted initiative to discharge surgical patients earlier in the day is associated with decreased length of stay and improved hospital throughput.

BACKGROUND: The timing of inpatient discharges can impact hospital throughput with later discharges leading to decreased patient satisfaction, increased length of stay (LOS), and longer boarding times. METHODS: A 12-month targeted intervention that included both pre-operative and inpatient components was implemented across all surgical inpatient services to increase the proportion of patients discharged by noon. RESULTS: Discharge by noon rates increased from 14.3% to 21.5% during the 12-month initiative (p < 0.01). The case mix index adjusted LOS (aLOS) decreased from 2.17 to 2.02 days (p < 0.01). ED, PACU, and ICU boarding times were all significantly lower during the initiative (p < 0.01, p < 0.01, p = 0.03 respectively). CONCLUSIONS: A targeted initiative to discharge surgical patients earlier resulted in a 50% increase in the proportion of patients discharged by noon. Associated with this finding were improvements in hospital throughput as measured by aLOS and boarding times in the ED, ICUs, and PACU.

The true meshing ratio of skin graft meshers.

Skin meshing is frequently used in the coverage of extensive burn injuries as well as other skin and soft tissue wounds. This technique allows coverage of more extensive areas with smaller donor sites and prevents fluid from collecting beneath the skin grafts. The devices used to achieve this expansion differ in their technology and the use of skin carriers. In addition, many of the devices permit meshing at single or multiple ratios depending upon the device chosen. Although commonly used, there have been few definitive studies analyzing the actual expansion ratios achieved by many of these devices. The purpose of this study was to measure the actual meshing ratios achieved using some of the most commonly used skin meshers. The authors used split-thickness cadaveric skin samples provided by the regional tissue bank to compare the area of skin both before and after meshing to determine the actual expansion ratio and compared that with the ratio claimed by the device manufacturer. For all ratios greater than 1:1, the extent of actual expansion was significantly less than that expected for each device (P < .001). In addition, using devices that claimed to yield increasingly greater expansion ratios resulted in increasingly greater discrepancies between the area predicted by the device manufacturer and the actual surface area of skin (P < .01). These findings suggest that there is great variability in the expected and observed expansion ratios achieved by skin graft meshing devices. This has significant applicability to practice as it is likely to affect surgical decisions related to estimating the extent of donor area needed to cover skin and soft tissue defects.