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.

Does Stage Migration Occur as a Consequence of Omitting Completion Lymph Node Dissection for Melanoma?

INTRODUCTION: Completion lymph node dissection (CLND) is no longer recommended routinely in the treatment of melanoma. CLND omission may understage patients for whom the distinction between stage IIIA and IIIB-C could alter adjuvant therapy recommendations. The aim of this study is to determine if stage migration has occurred with the declining use of CLND. METHODS: Patients with clinically node-negative ≥ T1b cutaneous melanoma were identified from the National Cancer Database (NCDB) from 2012 to 2018. CLND utilization and changes in AJCC staging were analyzed. Patients undergoing sentinel lymph node biopsy (SLNB) alone were compared with those undergoing SLNB + CLND. RESULTS: Overall, 68,933 patients met inclusion criteria and 60,536 underwent SLNB, of which 9031 (14.9%) were tumor positive. CLND was performed in 3776 (41.8%). Patients undergoing CLND were younger (58 versus 62 years, p < 0.0001) and more likely male (61.5% versus 57.9%, p = 0.0005). Patients were more likely to have an N classification >N1a if they received SLNB + CLND (36.8%) versus SLNB alone (19.3%), p < 0.0001. This translated to a small difference in stage IIIA patients between groups (SLNB alone 34.0%, SLNB + CLND 31.8%, p < 0.0001). Of the patients with T1b/T2a tumors who would be upstaged from IIIA to IIIC with identification of additional positive nodes, IIIC incidence was only slightly higher after SLNB + CLND compared with SLNB alone (4.4% versus 1.1%, p < 0.0001). CLND utilization dramatically decreased from 59% in 2012 to 12.6% in 2018, p < 0.0001. However, the incidence of stage IIIA disease for all patients remained stable over the 7-year study period. CONCLUSIONS: While the utilization of CLND after positive SLNB has declined dramatically in the last 7 years, stage migration that may affect adjuvant therapy decisions has not occurred to a clinically meaningful degree.

Continuous manual agitation significantly improves temperature distribution during closed hyperthermic intraperitoneal chemotherapy: Results of a porcine model.

BACKGROUND: Debate persists regarding the need for shaking during hyperthermic intraperitoneal chemotherapy. Studies assessing the thermal behaviors of the perfusate throughout the abdomen during hyperthermic intraperitoneal chemotherapy are limited. METHODS: A closed hyperthermic intraperitoneal chemotherapy technique was performed in an institutional International Animal Care and Use Committee approved porcine model targeting a 41°C outflow temperature. Continuous temperature monitoring was conducted. Abdominal shaking was performed for 60 second intervals and temperatures were allowed to equilibrate without shaking between intervals. Temperature distributions and changes due to shaking were evaluated. These findings were validated against human subjects' data. RESULTS: The experimental procedure was conducted in 2 different animals and with 6 total shaking intervals assessed. Without shaking, temperatures were highly variable ranging between 38.0 to 42.2°C. Shaking the abdomen reduced the mean range of temperatures across all locations observed from 3.9°C to 0.8°C (P < .01). The locations of the most divergent temperatures varied based on perfusion cannula position. The point of minimum temperature heterogeneity was achieved in 28.3 (19.1-37.5) seconds. After shaking stopped, heterogeneity equal to the baseline measurements was seen on average within 25.7 (13.3-38.0) seconds. The outflow catheter differed from the system mean temperature by 1.4°C and from the coldest-reading probe by 2.8°C and outperformed the inflow catheter for all time points. With shaking these were significantly reduced to 0.4°C (P < .01) and 0.6°C (P < .01). The patient data mirrored that of the pig data. CONCLUSION: Shaking significantly reduces temperature variability within the abdomen during hyperthermic intraperitoneal chemotherapy, and significantly improves the ability of the outflow catheter to estimate internal temperatures.

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.

Intratumoral Immunotherapy and Tumor Ablation: A Local Approach with Broad Potential.

Several intratumoral immunotherapeutic agents have shown efficacy in controlling local disease; however, their ability to induce a durable systemic immune response is limited. Likewise, tumor ablation is well-established due to its role in local disease control but generally produces only a modest immunogenic effect. It has recently been recognized, however, that there is potential synergy between these two modalities and their distinct mechanisms of immune modulation. The aim of this review is to evaluate the existing data regarding multimodality therapy with intratumoral immunotherapy and tumor ablation. We discuss the rationale for this therapeutic approach, highlight novel combinations, and address the challenges to their clinical utility. There is substantial evidence that combination therapy with intratumoral immunotherapy and tumor ablation can potentiate durable systemic immune responses and should be further evaluated in the clinical setting.

Factors Influencing the Entrustment of Resident Operative Autonomy: Comparing Perceptions of General Surgery Residents and Attending Surgeons.

BACKGROUND: General surgery residents may be underprepared for practice, due in part to declining operative autonomy during training. The factors that influence entrustment of autonomy in the operating room are unclear. OBJECTIVE: To identify and compare the factors that residents and faculty consider influential in entrustment of operative autonomy. METHODS: An anonymous survey of 29-item Likert-type scale (1-7, 1 = strongly disagree, 7 = strongly agree), 9 multiple-choice, and 4 open-ended questions was sent to 70 faculty and 45 residents in a large ACGME-approved general surgery residency program comprised of university, county, and VA hospitals in 2018. RESULTS: Sixty (86%) faculty and 38 (84%) residents responded. Faculty were more likely to identify resident-specific factors such as better resident reputation and higher skill level as important in fostering entrustment. Residents were more likely to identify environmental factors such as a focus on efficiency and a litigious malpractice environment as impeding entrustment. Both groups agreed that work hour restrictions do not decrease autonomy and entrustment does not increase risk to patients. More residents considered low faculty confidence level as a barrier to operative autonomy, while more faculty considered lower resident clinical skill as a barrier. Improvement in resident preparation for cases was cited as an important intervention that could enhance entrustment. CONCLUSIONS: Differences in perspectives exist between general surgery residents and faculty regarding entrustment of autonomy. Residents cite environmental and attending-related factors, while faculty cite resident-specific factors as most influential. Residents and faculty both agree that entrustment is integral to surgical training.

Opioid Prescribing Patterns After Anorectal Surgery.

BACKGROUND: Anorectal procedures are frequently performed and have the potential to be particularly painful. There are no evidence-based guidelines regarding opioid prescribing after anorectal surgery and limited data on how surgeons determine opioid prescriptions after anorectal procedures. We hypothesize significant variations in prescribing practices. The aim of this study is to determine current opioid prescribing patterns after anorectal surgery. METHODS: A survey was sent to members of the American Society of Colon and Rectal Surgeons. It included demographics, opioid prescribing habits after anorectal procedures, and factors influencing prescribing. Median morphine equivalents were calculated. Respondents prescribing higher than the median for >4 procedures were considered high prescribers. RESULTS: 519 surveys were completed (3160 sent). 38.6% of respondents were high prescribers, and 61.4% were low prescribers. There were significant differences by years in practice (P = 0.049), hospital type (P = 0.037), region (P < 0.001), and procedures performed per month (P < 0.001). 73% prescribed a standard quantity of opioids for each procedure. The mean milligrams of ME prescribed overall was 129 (SD 82); by procedure the quantities were as follows: hemorrhoidectomy 188 (111), condyloma treatment 149 (105), fistulotomy 146 (98), advancement flap 144 (97), LIFT 140 (93), abscess drainage 107 (91), sphincterotomy 105 (85), chemodenervation 64 (34). Nearly, all (98%) surgeons used local anesthesia. 91% typically prescribed adjunctive medications. In multivariable analysis, performing <10 anorectal procedures per month or practicing in the Northeast or outside the US was associated with low prescribers. High prescribers were more likely to be in practice for >10 y, report >25% of patients request refills, or significantly consider patient satisfaction or phone calls when prescribing. CONCLUSIONS: Opioid prescribing patterns are highly variable after anorectal procedures. Creating opioid prescribing guidelines for anorectal surgery is important to improve patient safety and quality of care.

Perioperative outcomes and survival of octogenarians undergoing curative resection for esophagogastric adenocarcinoma.

BACKGROUND AND OBJECTIVES: Current data are conflicting as to whether the outcomes of octogenarians undergoing resection for esophagogastric adenocarcinoma are comparable to younger patients. This study aims to compare perioperative outcomes and survival of patients ≥80 years old with younger patients undergoing curative resection for esophagogastric adenocarcinoma. METHODS: Retrospective data were collected on 190 patients who underwent resection with curative intent for adenocarcinomas found in the stomach and esophagogastric junction from 2004 to 2015 at a single institution. RESULTS: Of the 190 patients, 34 (18%) were ≥80 years old. Octogenarians were more likely to have chronic kidney disease (CKD) and were less likely to have received neoadjuvant chemotherapy. Pathologic features were similar between groups. Octogenarians' tumors were more likely to be located in the gastric body as compared to the esophagogastric junction in younger patients. Although the length of stay was comparable, octogenarians were significantly less likely to be discharged home (P < .01). Both groups had a single death during the index admission. Incidence and severity of 90 days postoperative complications were not significantly different between groups. There was no difference in 30-day, 90-day, 1-year, or median survival. CONCLUSIONS: Perioperative outcomes and survival of octogenarians undergoing curative resection for esophagogastric cancer are comparable to younger patients at our institution.

Improving Resident-To-Attending Communication: Implementing a Tool to Facilitate Attending Notification of Critical Patient Events at a Single Academic Institution.

Ineffective communication between surgical trainees and attending surgeons is a significant contributor to patient harm. The aim of this study was to evaluate a tool to improve resident-to-attending communication regarding changes in patient clinical status. Ten critical patient events were compiled into a list of triggers for direct attending surgeon notification at a single academic institution. Residents and faculty were surveyed to assess communication before and after implementation of the list. Institution of the triggers list was associated with a nonstatistically significant increase in resident-to-attending notification regarding 7 of 10 critical patient events. There was no reported change in frequency of calls associated with the list's implementation. Most residents felt that the list improved patient care and increased their comfort with calling attending surgeons. Comments were generally positive; however, both groups expressed concern that the list could negatively impact resident autonomy and supervision. Implementing a list of triggers for attending notification of critical patient events subjectively improved resident-to-attending communication in an environment with high baseline levels of communication.

Systemic administration of ß-glucan of 200 kDa modulates melanoma microenvironment and suppresses metastatic cancer.

Converting an immunosuppressive melanoma microenvironment into one that favors the induction of antitumor immunity is indispensable for effective cancer immunotherapy. In the current study we demonstrate that oat-derived ß-(1-3)-(1-4)-glucan of 200 kDa molecular size (BG34-200) previously shown to mediate direct interaction with macrophages could alter the immune signature within melanoma microenvironment. Systemic administration of BG34-200 resulted in reversion of tolerant melanoma microenvironment to an immunogenic one that allows M1-type activation of macrophages, the induction of pro-inflammatory cytokines/chemokines including IFN-γ, TNF-α, CXCL9, and CXCL10, and enhanced IRF1 and PD-L1 expression. In turn, BG34-200 induced a superior antitumor response against primary and lung metastatic B16F10 melanoma compared to untreated controls. The enhanced tumor destruction was accompanied with significantly increased tumor infiltration of CD4+ and CD8+ T cells as well as elevated IFN-γ in the tumor sites. Systemic administration of BG34-200 also provoked systemic activation of tumor draining lymph node T cells that recognize antigens naturally expressing in melanoma (gp100/PMEL). Mechanistic studies using CD11b-knockout (KO), CD11 c-DTR transgenic mice and nude mice revealed that macrophages, DCs, T cells and NK cells were all required for the BG34-200-induced therapeutic benefit. Studies using IFN-γ-KO transgenic mice showed that IFN-γ was essential for the BG34-200-elicited antitumor response. Beyond melanoma, the therapeutic efficacy of BG34-200 and its immune stimulating activity were demonstrated in a mouse model of osteosarcoma. Together, BG34-200 is highly effective in modulating antitumor immunity. Our data support the potential therapeutic use of this novel immune modulator in the treatment of metastatic melanoma.

Chronic mesenteric ischemia after partial coverage of the celiac artery during TEVAR, case report, and review of the literature.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has emerged as a safe and effective alternative to open surgery for treatment of thoracic aortic aneurysms. It has recently been reported that stent-graft coverage of the celiac artery (CA) during TEVAR is associated with a low risk of acute mesenteric ischemia. However, the long-term effect of CA coverage on foregut perfusion is unknown. Here, we report the case of a patient who underwent TEVAR with partial coverage of the CA and subsequently developed symptoms of chronic mesenteric ischemia (CMI). She was successfully treated with CA stent placement. METHODS: Preoperative imaging included computed tomography (CT) angiography of the abdomen and conventional aortogram of a redo-TEVAR, revealing near complete coverage of the CA orifice. Endovascular repair was done using a 7 mm × 20 mm biliary balloon-expandable stent (Cook Medical Inc, Bloomington, IN). A review of the current literature for this rare problem was performed. RESULTS: Completion arteriography demonstrated successful revascularization of the CA without evidence of endoleak. Postoperatively, the abdominal pain was alleviated with early improved diet tolerance and weight gain. Follow-up CT at 6 month demonstrated widely patent CA. A PubMed review showed no reported cases of CMI secondary to CA coverage during TEVAR in the literature. CONCLUSIONS: CMI may develop with coverage of the CA during TEVAR. When other causes of abdominal pain and weight loss have been ruled out, revascularization of the CA can help alleviate the symptoms.

The incidence of pulmonary embolism (PE) after spinal fusions.

BACKGROUND: Pulmonary embolism (PE) is a rare but serious event that may occur after spinal surgery. OBJECTIVE: To correlate PE incidence after spinal arthrodesis with surgical approach, region of spine operated, and primary spinal pathology. To identify PE incidence trends in this population. METHODS: The Nationwide Inpatient Sample was queried using ICD-9 codes (81.01-81.08) for spinal fusion procedures over a 21-year period (1988-2008). Other data points included PE occurrence, surgical approach, spinal region, surgical indication, and mortality. Multivariate and relational analyses were performed. RESULTS: 4,505,556 patients were identified and 9530 had PE (incidence=0.2%). PE patients had higher odds of combined A/P surgical approaches than posterior approaches (OR=1.97; 95% CI=1.66-2.33), and PE incidence was higher in thoracic versus cervical or lumbar fusions (OR=2.54; 95% CI=2.14-3.02). PE was more likely with vertebral fracture (OR=1.85; 95% CI=1.53-2.23) and SCI with vertebral fracture (OR=4.59; 95% CI=3.72-5.70) than without trauma. Between 1988 and 2008, the PE incidence remained stable for patients with intervertebral disk degeneration and scoliosis, but increased for patients with vertebral fracture, and SCI with vertebral fracture. There was greater inpatient mortality with occurrence of a PE (OR=12.92; 95% CI=10.55-14.41). CONCLUSION: Although the incidence of PE in spinal arthrodesis patients is only 0.2%, there is a higher incidence after combined A/P approaches, thoracic procedures, and trauma surgical procedures. Despite the overall PE incidence remaining stable since 1988, incidence steadily increased among trauma patients. Further research is needed to explain these trends, given the context of changing patient populations and improving surgical techniques and prophylaxis measures. Greater caution and prophylaxis among trauma patients may be warranted.