Non-Operative Approach to Contained Perforated Marginal Ulcers: A Systematic Review and Case Series.

BACKGROUND: Perforated marginal ulcers (PMUs) are a rare but known complication of bariatric surgery. Management typically involves prompt surgical intervention, but limited data exists on non-operative approaches. This study reviews published data on non-operative management of PMUs and presents a case series of patients who were managed non-operatively. Our hypothesis is that certain patients with signs of perforation can be successfully managed non-operatively with close observation. METHODS: We completed a systematic review searching PubMed, Embase, Web of Science, Cochrane, and clinicaltrials.gov. Ultimately 3 studies described the presentation and non-operative management of 5 patients. Additionally, we prospectively collected data from our institution on all patients who presented between Dec. 2022 and Dec. 2023 with PMUs confirmed on imaging and managed non-operatively. RESULTS: In our literature review, three patients had Roux-en-Y gastric bypass (RYGB), while two had one anastomosis gastric bypass. One patient required surgery two days after admission. Another underwent elective conversion surgery weeks later for a non-healing ulcer. Two received endoscopic interventions. One patient recovered with nil-per-os (NPO) status, and intravenous proton pump inhibitor (PPI) treatment. The patients in our case series presented with normal vital signs, an average of 30 months after RYGB, and with CT scan signs of perforation. None of these patients required surgical or endoscopic intervention. CONCLUSION: In conclusion, while perforated marginal ulcers have traditionally been considered a surgical emergency, some patients can be successfully treated with non-operative management. More research is needed to identify the clinical presentation features, comorbidities, and imaging findings of this group.

Outcomes of light and midweight synthetic mesh use in clean-contaminated and contaminated ventral incisional hernia repair: an ACHQC comparative analysis.

BACKGROUND: Use of macroporous synthetic mesh in contaminated ventral hernia repair has become more frequent. The objective of this study is to compare the outcomes of ventral incisional hernia repair with permanent synthetic mesh in contaminated fields to those in a clean field. METHODS: The Abdominal Core Health Quality Collaborative registry, a prospectively updated longitudinal hernia-specific national database, was retrospectively queried for adults who underwent open ventral incisional hernia repair using light or medium-weight synthetic mesh and classified as clean (CDC Class I) or contaminated (CDC Class II/III). Univariate analysis was used to compare demographic information, hernia characteristics, and operative details. Odds ratios (OR) were calculated using multivariable logistic regression for the primary outcome of 30-day surgical site infection (SSI) and secondary outcomes of 30-day surgical site occurrence (SSO), SSO requiring procedural intervention (SSO-PI), and clinical recurrence at one year. RESULTS: 7219 cases met criteria for inclusion; 13.2% of these were contaminated. 83.4% of patients had follow-up data at 30 days and 20.8% at 1 year. The adjusted OR for 30-day SSI in contaminated fields compared to clean was 2.603 (95% CI 1.959-3.459). OR for 30-day SSO was 1.275 (95% CI 1.017-1.600) and 2.355 (95%CI 1.817-3.053) for 30-day SSO-PI. OR for recurrence at one year was 1.489 (95%CI 0.892-2.487). Contaminated cases had higher rates of mesh infection (3.9% vs 0.8%, p < 0.001) and mesh removal (7.3 vs 2.5%, p < 0.001) at 1 year. CONCLUSIONS: After adjusting for baseline differences, patients undergoing ventral incisional hernia repair using light or midweight synthetic mesh in contaminated fields have higher odds of 30-day SSI, SSO, and SSO-PI than those performed in clean wounds. The odds of recurrence did not statistically differ and further studies with long-term outcomes are needed to better evaluate the best treatment options for this patient population.

Benefits of Adjuvant Medical Weight Loss Intervention in Setting of Weight Regain and Inadequate Weight Loss After Weight Loss Surgery.

BACKGROUND: Currently, there is no nationally accepted protocol for addressing weight regain or inadequate weight loss after MBS. OBJECTIVES: To devise, implement, and evaluate a protocol targeting weight regain or inadequate weight loss in MBS patients at our institution. SETTING: Vanderbilt University Medical Center, Nashville, TN, United States. METHODS: Patients at least 6 months following primary sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) who achieved or were trending toward <50% excess body weight loss or who regained ≥10% of their lowest postoperative weight, were identified and referred for medical weight loss (MWL) intervention. Exclusion criteria were body mass index (BMI) ≤ 27 kg/m2, treatment with adjustable gastric banding, and conversion from SG to RYGB. RESULTS: 2274 patients who were >6 months out from surgery were evaluated over 12 months. 93 patients (86% female) met criteria for inclusion. 69 (74%) patients agreed to intervention and were followed for an average of 165 days (SD 106.89 days), demonstrating a mean weight change of -5.11 kg (SD 6.86 kg), and BMI change of -1.81 kg/m2 (SD 2.37 kg/m2). Patients who spent <90 days in a MWL program demonstrated less average weight loss (1.75 kg vs 6.48 kg) (P = .0042), and less change in BMI (-.63 kg/m2 vs -2.29 kg/m2) (P = .0037) when compared to patients who spent >90 days in the MWL intervention. CONCLUSIONS: This study identifies criteria for intervention in patients suffering weight regain or inadequate weight loss after MBS and demonstrates that standardized identification and referral for treatment results in modest weight loss.

Evaluation of Treatment Differences Between Men and Women Undergoing Ventral Hernia Repair: An Analysis of the Abdominal Core Health Quality Collaborative.

BACKGROUND: Sex is emerging as an important clinical variable associated with surgical outcomes and decision making. However, its relevance in regard to baseline and treatment differences in primary and incisional ventral hernia repair remains unclear. STUDY DESIGN: This is a retrospective cohort study using the Abdominal Core Health Quality Collaborative database to identify elective umbilical, epigastric, or incisional hernia repairs. Propensity matching was performed to investigate confounder-adjusted treatment differences between men and women. Treatments of interest included surgical approach (minimally invasive or open), mesh use, mesh type, mesh position, anesthesia type, myofascial release, fascial closure, and fixation use. RESULTS: A total of 8,489 umbilical, 1,801 epigastric, and 16,626 incisional hernia repairs were identified. Women undergoing primary ventral hernia repair were younger (umbilical 46.4 vs 54 years, epigastric 48.7 vs 52.7 years), with lower BMI (umbilical 30.4 vs 31.5, epigastric 29.2 vs 31.1), and less likely diabetic (umbilical 9.9% vs 11.4%, epigastric 6.8% vs 8.8%). Women undergoing incisional hernia repair were also younger (mean 57.5 vs 59.1 years), but with higher BMI (33.1 vs 31.5), and more likely diabetic (21.4% vs 19.1%). Propensity-matched analysis included 3,644 umbilical, 1,232 epigastric, and 12,480 incisional hernias. Women with incisional hernia were less likely to undergo an open repair (60.2% vs 63.4%, p < 0.001) and have mesh used (93.8% vs 94.8%, p = 0.02). In umbilical and incisional hernia repairs, women had higher rates of intraperitoneal mesh placement and men had higher rates of preperitoneal and retro-muscular mesh placement. CONCLUSIONS: Small but statistically significant treatment differences in operative approach, mesh use, and mesh position exist between men and women undergoing ventral hernia repair. It remains unknown whether these treatment differences result in differing clinical outcomes.

Guidelines for the performance of minimally invasive splenectomy.

BACKGROUND: Minimally invasive splenectomy (MIS) is increasingly favored for the treatment of benign and malignant diseases of the spleen over open access approaches. While many studies cite the superiority of MIS in terms of decreased morbidity and length of stay over a traditional open approach, the comparative effectiveness of specific technical and peri-operative approaches to MIS is unclear. OBJECTIVE: To develop evidence-based guidelines that support clinicians, patients, and others in decisions on the peri-operative performance of MIS. METHODS: A guidelines committee panel of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) including methodologists used the Grading of Recommendations Assessment, Development and Evaluation approach to grade the certainty of evidence and formulate recommendations. RESULTS: Informed by a systematic review of the evidence, the panel agreed on eight recommendations for the peri-operative performance of MIS for adults and children in elective situations addressing six key questions. CONCLUSIONS: Conditional recommendations were made in favor of lateral positioning for non-hematologic disease, intra-operative platelet administration for patients with idiopathic thrombocytopenic purpura instead of preoperative administration, and the use of mechanical devices to control the splenic hilum. Further, a conditional recommendation was made against routine intra-operative drain placement.

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

Minimally Invasive Approaches to Pancreatic Cancer.

In pancreatic cancer, resection combined with neoadjuvant and/or adjuvant therapy remains the only chance for cure and/or prolonged survival. A minimally invasive approach to pancreatic cancer has gained increased acceptance and popularity. The aim of minimally invasive surgery of the pancreas includes limiting trauma, decreasing length of hospitalization, lessening cost, decreasing blood loss, and allowing for a more meticulous oncologic dissection. New advances and routine use in practice have helped progress the field making the minimally invasive approach more feasible. In this article, the minimally invasive surgical approaches to proximal, central, and distal pancreatic cancer are described and literature reviewed.

Image-Guided Navigation in Lymph Node Biopsy.

BACKGROUND AND OBJECTIVES: Image-guided navigation is an effective intra-operative technology in select surgical sub-specialties. Laparoscopic and open lymph node biopsy are frequently undertaken to obtain adequate tissue of difficult lesions. Image-guided navigation may positively augment the precision and success of surgical lymph node biopsies. METHODS: In this prospective pilot study, pre-operative imaging was uploaded into the navigation platform software, which superimposed the imaging and the subject's real-time anatomy. This required anatomical landmarks on the subject's body to be spatially registered with the platform using an infrared camera. This was then used to guide dissection and biopsy in laparoscopic and subcutaneous biopsies. RESULTS: Image-guided lymph node biopsy was undertaken in 15 cases. Successful biopsy locations included: retroperitoneum, porta hepatis, mesentery, iliac region, para-aortic, axilla, and inguinal region. There was an 87% total absolute success rate in biopsies (89% in laparoscopic image-guided navigation [LIGN] and 83% in subcutaneous image-guided navigation [SIGN]). There was a 92% absolute success rate in lesions with fixed locations. There was a 67% absolute success rate in lesions with mobile locations. CONCLUSION: The investigators successfully incorporated image-guidance into surgical biopsy of lymph nodes in a diverse variety of locations. This image-guided technique for surgical biopsy can accurately and safely localize target lesions minimizing unnecessary dissection, conversion to open procedure, and re-operation for further tissue characterization. This technique was useful in the morbidly obese, instances of limited foci of disease, PET-active lesions, identifying areas of highest PET-avidity, and lesions with critical surrounding anatomy.

Metastasectomy following incomplete response to high-dose interleukin-2.

OBJECTIVE: To evaluate our experience with metastasectomy following partial response or stable disease after treatment with high-dose interleukin-2 (HD IL-2). METHODS: A total of 305 patients with metastatic renal cell carcinoma or melanoma treated with HD IL-2 over a 12-year period were reviewed. Age, objective response, and overall survival data were evaluated using standard RECIST criteria and Kaplan-Meier estimates. RESULTS: The average age was 55.3 years (range, 15-85) and 245 (80.3%) patients had melanoma and 60 (19.7%) had renal cell carcinoma. The objective response rate to IL-2 for all patients was 13.6% and median survival was 16.8 months. Complete follow-up data were available for 236 patients with 147 (62.3%) progressing after treatment and 8 (3.3%) with a complete response. Incomplete responses were seen in 81 (34.3%) patients, including 57 (24.2%) patients with stable disease and 24 (10.1%) with partial responses. Of these 81 incomplete responders, 15 (18.5%) underwent subsequent metastasectomy. Patients without surgery had overall survival of 38.2 months and median survival has not yet been reached in those who underwent metastasectomy (P = 0.026). CONCLUSION: The data support prospective evaluation of metastasectomy following incomplete therapeutic responses to immunotherapy and defines a new role for surgical resection following IL-2 and perhaps other immunotherapy regimens.

Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma.

Recombinant interleukin-2 (rIL-2) is associated with objective responses in 15-20 % of patients with metastatic melanoma and renal cell carcinoma. More recently, rIL-2 has also demonstrated improved clinical activity in patients with melanoma. Given the toxicity of high-dose rIL-2 and the availability of many new immunotherapy agents, it has been suggested that lower doses of rIL-2 may be preferred for combination clinical studies. In order to determine the impact of low doses of rIL-2 on anti-tumor immunity and therapeutic effectiveness, we challenged C57BL/6 mice with poorly immunogenic B16-F10 melanoma and treated them with varying doses of rIL-2 (range 103-105 IU). Tumor growth at day 14 was significantly reduced when rIL-2 was administered at 10,000 (P < 0.02) and 100,000 (P < 0.02) IU doses, but tumor growth was significantly increased when mice were treated at 1000 IU rIL-2 (P < 0.02), as compared to placebo treatment. While the proportions of CD8+ and CD4+ T cells in the tumor were similar at all doses tested, the proportion of NK cells was decreased and the proportion of Tregs was increased in tumors exposed to low-dose rIL-2. The ratio of gp100-specific CD8+ to CD4+ regulatory T cells was increased in tumors treated at 10,000 and 100,000 IU of rIL-2 but was decreased at the 1000 IU dose compared to placebo-treated mice. These findings suggest that low-dose rIL-2 may impair host anti-tumor immunity and promote tumor growth. Early-phase adjuvant and combination clinical studies should include patient cohorts with higher doses of rIL-2.

Non-oncogenic Acute Viral Infections Disrupt Anti-cancer Responses and Lead to Accelerated Cancer-Specific Host Death.

In light of increased cancer prevalence and cancer-specific deaths in patients with infections, we investigated whether infections alter anti-tumor immune responses. We report that acute influenza infection of the lung promotes distal melanoma growth in the dermis and leads to accelerated cancer-specific host death. Furthermore, we show that during influenza infection, anti-melanoma CD8+ T cells are shunted from the tumor to the infection site, where they express high levels of the inhibitory receptor programmed cell death protein 1 (PD-1). Immunotherapy to block PD-1 reverses this loss of anti-tumor CD8+ T cells from the tumor and decreases infection-induced tumor growth. Our findings show that acute non-oncogenic infection can promote cancer growth, raising concerns regarding acute viral illness sequelae. They also suggest an unexpected role for PD-1 blockade in cancer immunotherapy and provide insight into the immune response when faced with concomitant challenges.

NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade.

BACKGROUND: Melanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response. METHODS: Here, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100 µg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4-8, or both. RESULTS: A highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells. CONCLUSIONS: These results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.

The prognostic significance of stable disease following high-dose interleukin-2 (IL-2) treatment in patients with metastatic melanoma and renal cell carcinoma.

High-dose interleukin-2 (HD IL-2) is an approved immunotherapy agent for metastatic melanoma and renal cell carcinoma resulting in objective responses in 15-20 % of patients. An additional subset of patients achieves stable disease, and the natural history of these patients has not been well documented. We hypothesized that stable disease following HD IL-2 is associated with a survival advantage. To explore this hypothesis, a retrospective chart review of 305 patients diagnosed with metastatic melanoma or renal cell carcinoma treated with HD IL-2 was conducted. Patient characteristics, response based on standard RECIST criteria and overall survival were analyzed using the Kaplan-Meier method and associations with clinical response were compared using a log-rank test. Two hundred and forty-five patients had melanoma and 60 had renal cell carcinoma. Of these, 217 had complete data available for analysis. Fifty-nine percentage had progressive disease (PD), 26 % had stable disease (SD) and 15 % had an objective complete (CR) or partial response (PR). Median overall survival was 16.8 months for all patients with available survival data; patients with PD had a median survival of 7.9 months compared to 38.2 months for stable disease, while the median has not been reached for those with objective responses. This retrospective data support an association between overall survival and stable disease, suggesting that clinical benefit may be underestimated for patients treated with HD IL-2. The data further support the use of disease control rate (CR + PR + SD) as a more meaningful endpoint for future clinical studies of tumor immunotherapy, including future studies of HD IL-2.

Interleukin-2 alters distribution of CD144 (VE-cadherin) in endothelial cells.

BACKGROUND: High-dose IL-2 (HDIL2) is approved for the treatment of metastatic melanoma and renal cell carcinoma, but its use is limited in part by toxicity related to the development of vascular leak syndrome (VLS). Therefore, an understanding of the mechanisms that underlie the initiation and progression of HDIL2-induced increases in endothelial cell (EC) permeability leading to VLS are of clinical importance. METHODS: We established a novel ex vivo approach utilizing primary human pulmonary microvascular ECs to evaluate EC barrier dysfunction in response to IL-2. RESULTS: Complementary in vitro studies using exogenous IL-2 and ex vivo studies using serum from patients treated with IL-2 demonstrate that HDIL2 induces VLS through CD144 (vascular endothelial (VE)-cadherin) redistribution. CONCLUSIONS: These findings provide new insight into how IL-2 induces VLS and identifies VE-cadherin as a potential target for preventing IL-2-related VLS.

Radiographic predictability of hiatal hernia prior to gastric band surgery.

BACKGROUND: Hiatal hernia (HH) is closely associated with morbid obesity. There is controversy over the need for preoperative imaging before laparoscopic adjustable gastric band placement. The aim of this study is to determine the predictive value of preoperatively diagnosing HH with upper gastrointestinal (UGI) series imaging. METHODS: A retrospective review of a single surgeon's experience with laparoscopic adjustable gastric band placements was performed. All patients received a preoperative UGI series. The decision to perform an HH repair at the time of gastric banding was based on intraoperative findings. Each patient's UGI study was compared with the operative report. Patients' outpatient records were also reviewed for subjective reflux symptoms or use of antireflux medications. RESULTS: Of 146 patients, 63 (43%) had intraoperative findings consistent with an HH and underwent repair. Of these, only 32 (50%) had a preoperative UGI study that showed an HH (positive predictive value, 50%). Of the 83 patients who did not have an intraoperative HH, only 51 (61%) had a congruent UGI (negative predictive value, 62%). No correlation was found between patient-reported symptoms and either radiologic or intraoperative findings. CONCLUSIONS: UGI series have poor positive and negative predictive values in preoperatively diagnosing HH. In addition, subjective patient symptoms and the need for antireflux medication did not correlate with either radiologic or intraoperative findings of HH. Our results suggest that direct operative diagnosis is a more accurate method of detecting HH.

High-dose IL-2 induces rapid albumin uptake by endothelial cells through Src-dependent caveolae-mediated endocytosis.

High-dose interleukin-2 (HDIL2) treatment of patients with metastatic melanoma and renal cell carcinoma is associated with durable responses, but therapy is accompanied by significant toxicity related to vascular leak syndrome (VLS). Currently, the cause of VLS is not well defined; however, based on the role of endothelial cell (EC) permeability in VLS and the commonly observed hypoalbuminemia in patients receiving HDIL2 therapy, we established an in vitro approach utilizing primary human pulmonary microvascular ECs to monitor the effect of HDIL2 therapy on albumin uptake. We found that HDIL2 treatment of ECs results in albumin colocalization with caveolin-1 leading to albumin uptake by ECs. This albumin uptake occurs through caveolae-mediated but not clathrin-mediated endocytosis and is abrogated with inhibition of the Src tyrosine kinase pathway. These findings provide insight into how IL-2 induces VLS and may help identify potential targets for prevention of toxicity without affecting the therapeutic activity of HDIL2.

Results of a randomized phase I gene therapy clinical trial of nononcolytic fowlpox viruses encoding T cell costimulatory molecules.

Oncolytic viruses have shown promise as gene delivery vehicles in the treatment of cancer; however, their efficacy may be inhibited by the induction of anti-viral antibody titers. Fowlpox virus is a nonreplicating and nononcolytic vector that has been associated with lesser humoral but greater cell-mediated immunity in animal tumor models. To test whether fowlpox virus gene therapy is safe and can elicit immune responses in patients with cancer, we conducted a randomized phase I clinical trial of two recombinant fowlpox viruses encoding human B7.1 or a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3; TRICOM). Twelve patients (10 with melanoma and 2 with colon adenocarcinoma) enrolled in the trial and were randomized to rF-B7.1 or rF-TRICOM administered in a dose escalation manner (~3.7×10(7) or ~3.7×10(8) plaque-forming units) by intralesional injection every 4 weeks. The therapy was well tolerated, with only four patients experiencing grade 1 fever or injection site pain, and there were no serious adverse events. All patients developed anti-viral antibody titers after vector delivery, and posttreatment anti-carcinoembryonic antigen antibody titers were detected in the two patients with colon cancer. All patients developed CD8(+) T cell responses against fowlpox virus, but few responses against defined tumor-associated antigens were observed. This is the first clinical trial of direct (intratumoral) gene therapy with a nononcolytic fowlpox virus. Treatment was well tolerated in patients with metastatic cancer; all subjects exhibited anti-viral antibody responses, but limited tumor-specific T cell responses were detected. Nononcolytic fowlpox viruses are safe and induce limited T cell responses in patients with cancer. Further development may include prime-boost strategies using oncolytic viruses for initial priming.