Neoadjuvant Chemotherapy is Associated with Increased Risk of Postoperative DVT After Distal Pancreatectomy for Pancreatic Adenocarcinoma: a NSQIP Analysis.

BACKGROUND: Venous thromboembolism (VTE) remains a persistent source of postoperative morbidity despite prevention and mitigation efforts. Cancer, surgery, and chemotherapy are known risk factors for VTE. Existing literature suggests that neoadjuvant therapy (NAT) may contribute to increased VTE risk in the postoperative period, but few authors specifically examine this relationship in distal pancreatic adenocarcinoma (PDAC). In this study, we analyze the association of NAT and postoperative VTE in patients who underwent distal pancreatectomy (DP) for PDAC. PATIENTS AND METHODS: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, we analyzed the Procedure Targeted files for pancreatectomy from 2014 to 2020. Adults with PDAC who underwent DP were grouped by receipt of NAT. The primary outcome was the rate of deep venous thrombosis (DVT) and the secondary outcome was the rate of pulmonary embolism (PE). We performed univariate and multivariate logistic regression analysis to determine risk factors associated with postoperative DVT. RESULTS: There were 4327 patients with PDAC who underwent DP. Of these, 1414 (32.7%) had NAT. Receipt of NAT was significantly associated with postoperative DVT requiring therapy (3.5% vs. 2.3%, p = 0.02), but was not associated with PE (p = 0.42). On MVA, NAT was associated with a 73% greater chance of developing postoperative DVT [odds ratio (OR) 1.73, 95% CI 1.18-2.55]. CONCLUSIONS: Patients who receive NAT prior to DP for PDAC are 73% more likely to develop postoperative DVT compared with upfront resection. As NAT becomes more commonplace, these high-risk patients should be prioritized for guideline-recommended extended duration prophylaxis.

Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.

BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.

Sequential histologic evolution of gallbladder inflammation in acute cholecystitis over the first 10 days after onset of symptoms.

BACKGROUND: The timing of cholecystectomy during acute cholecystitis (AC) is controversial, especially whether it is advisable to perform in patients with duration of symptoms between 3 and 10 days. The purpose of this study is to define clearly the sequential evolution of histological changes following symptoms onset to guide recommendations regarding timing of cholecystectomy. METHODS: We identified patients with AC (2005-2018) who had cholecystectomy within 10 days of symptom onset of a first attack of AC. Histologic features of gallbladder injury including cellular and exudative inflammatory response to injury were determined on blinded pathologic slides. RESULTS: One hundred and forty-nine patients were divided into three groups; early-who underwent cholecystectomy 1-3 days after symptom-onset, intermediate-4-6 days, and late-7-10 days. Key features of injury were necrosis and hemorrhage. A subgroup of patients in the early phase developed severe necrosis and hemorrhage of an extent associated with difficult cholecystectomy. Large spikes in extent of necrosis and hemorrhage occurred at 7-10 days. Major inflammatory responses to injury were eosinophilic and lymphocytic infiltration and early fibrosis. CONCLUSIONS: Severe necrosis may develop rapidly and be present in the early period after symptom onset of AC. Cholecystectomy may be reasonable in some patients but by day 7-10, severe necrosis and hemorrhage may be expected to be present in most patients.

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

Clinical classification of symptomatic heterotopic pancreas of the stomach and duodenum: A case series and systematic literature review.

BACKGROUND: Heterotopic pancreas (HP) is an aberrant anatomic malformation that occurs most commonly in the upper gastrointestinal tract. While the majority of heterotopic pancreatic lesions are asymptomatic, many manifest severe clinical symptoms which require surgical or endoscopic intervention. Understanding of the clinical manifestations and symptoms of HP is limited due to the lack of large volume studies in the literature. The purpose of this study is to review symptomatic cases at a single center and compare these to a systematic review of the literature in order to characterize common clinical manifestations and treatment of this disease. AIM: To classify the common clinical manifestations of heterotopic pancreas. METHODS: A retrospective review was conducted of pathologic samples containing heterotopic pancreas from 2000-2018. Review was limited to HP of the upper gastrointestinal tract due to the frequency of presentation in this location. Symptomatic patients were identified from review of the medical records and clinical symptoms were tabulated. These were compared to a systematic review of the literature utilizing PubMed and Embase searches for papers pertaining to heterotopic pancreas. Publications describing symptomatic presentation of HP were selected for review. Information including demographics, symptoms, presentation and treatment were compiled and analyzed. RESULTS: Twenty-nine patient were identified with HP at a single center, with six of these identified has having clinical symptoms. Clinical manifestations included, gastrointestinal bleeding, gastric ulceration with/without perforation, pancreatitis, and gastric outlet obstruction. Systemic review of the literature yielded 232 publications detailing symptomatic cases with only 20 studies describing ten or more patients. Single and multi-patient studies were combined to form a cohort of 934 symptomatic patients. The majority of patients presented with abdominal pain (67%) combined with one of the following clinical categories: (1) Dyspepsia, (n = 445, 48%); (2) Pancreatitis (n = 260, 28%); (3) Gastrointestinal bleeding (n = 80, 9%); and (4) Gastric outlet obstruction (n = 80, 9%). The majority of cases (n = 832, 90%) underwent surgical or endoscopic resection with 85% reporting resolution or improvement in their symptoms. CONCLUSION: Heterotopic pancreas can cause significant clinical symptoms in the upper gastrointestinal tract. Better understanding and classification of this disease may result in more accurate identification and treatment of this malformation.

Dissemination and Implementation Science in Cardiothoracic Surgery: A Review and Case Study.

Dissemination and implementation (D&I) science is the practice of taking evidence-based interventions and sustainably incorporating them into routine clinical practice. As a relatively young field, D&I techniques are underutilized in cardiothoracic surgery. This review offers an overview of D&I science from the context of the cardiothoracic surgeon. First, we provide a general introduction to D&I science and basic terminology that is used in the field. Second, to illustrate D&I techniques in a real-world example, we discuss a case study for implementing lung protective management strategies for lung donor optimization nationally. Finally, we discuss challenges to successful implementation that are unique to cardiothoracic surgery and give several examples of evidence-based interventions that have been poorly implemented into surgical practice. We also provide examples of successful D&I interventions-including deimplementation strategies-from other surgical subspecialties. We hope that this review offers additional tools for cardiothoracic surgeons to explore when introducing evidence-based interventions into routine practice.

Memory-like Differentiation Enhances NK Cell Responses to Melanoma.

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined. EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNγ and kill melanoma targets in vitro and in vivo using a xenograft model. RESULTS: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNγ production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D- and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells. CONCLUSIONS: Blood NK cells from allogeneic HD or patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials.

Omental cyst: a case report and review of the literature.

BACKGROUND: Omental cysts are rare, predominantly occur in children, and often initially present with symptoms masquerading as other more common intra-abdominal pathologies. In this case report, we present the case of a child with an omental cyst that originated from the lesser sac. Due to the location of this cyst, resection presented unique technical challenges that have not been described in existing literature. CASE PRESENTATION: A 4-year-old male patient presented with symptoms initially concerning for appendicitis. Ultrasound showed a normal appendix but a large volume of complex intraperitoneal fluid. Computed tomography subsequently demonstrated a large cystic structure spanning from the stomach to the bladder. The patient was taken to the operating room where a large omental cyst was found to originate from the lesser sac. The resection was difficult due to the thin wall of the cyst and the intimate association of the superior-most aspect of the cyst with the tail of the pancreas, but was ultimately successful. CONCLUSIONS: Omental cysts are rarely suspected before detection on abdominal imaging. Surgical resection is the treatment of choice, and complete resection can result in a recurrence-free postoperative course. Laparoscopic resection has been reported, but laparotomy is reasonable when a minimally invasive approach may not allow for a safe resection without rupture of the cyst. Anatomical characteristics of the cyst, as demonstrated in our case, can present challenges in the treatment of this otherwise benign entity.

Less is more in the difficult gallbladder: recent evolution of subtotal cholecystectomy in a single HPB unit.

INTRODUCTION: Subtotal cholecystectomy (SC) is a technique to manage the difficult gallbladder and avoid hazardous dissection and biliary injury. Until recently it was used infrequently. However, because of reduced exposure to open total cholecystectomy in resident training, we recently adopted subtotal cholecystectomy as the bail-out procedure of choice for resident teaching. This study reports our experience and outcomes with subtotal cholecystectomy in the years immediately preceding adoption and since adoption. METHODS: A retrospective analysis was conducted of patients undergoing SC from July 2010 to June 2019. Outcomes, including bile leak, reoperation and need for additional procedures, were analyzed. Complications were graded by the Modified Accordion Grading Scale (MAGS). RESULTS: 1571 cholecystectomies were performed of which 71 were SC. Subtotal cholecystectomy patients had several indicators of difficulty including prior attempted cholecystectomy and previous cholecystostomy tube insertion. The most common indication for SC was marked inflammation in the hepatocystic triangle (51%). As our experience increased, fewer patients required open conversion to accomplish SC and SC was completed laparoscopically, usually subtotal fenestrating cholecystectomy (SFC). Most patients (85%) had a drain placed and 28% were discharged with a drain. The highest MAGS complication observed was grade 3 (11 patients, 15%). Six patients had a bile leak from the cystic duct resolved by ERCP. At mean follow-up of about 1 year no patient returned with recurrent symptoms. CONCLUSIONS: Subtotal fenestrating cholecystectomy is a useful technique to avoid biliary injury in the difficult gallbladder and can be performed with very satisfactory rates of bile fistula, ERCP, and reoperation.

Peritoneal Encapsulation With Incarcerated Meckel Diverticulum Contributing to Small Bowel Obstruction.

Background: Meckel diverticulum is the most common congenital gastrointestinal malformation, but it is rarely symptomatic. Peritoneal encapsulation is a rare abnormality of embryonic development and may present with obstruction, although it too is usually asymptomatic. Case Report: We report the case of an 82-year-old male who presented with symptoms and imaging findings consistent with small bowel obstruction. During laparotomy, a peritoneal encapsulation was observed containing the majority of the small bowel. A Meckel diverticulum was discovered tethered to the small bowel mesentery by a mesodiverticular band, preventing egress from the accessory peritoneal membrane and appearing to be the cause of the obstruction. Conclusion: This patient had 3 rare findings-peritoneal encapsulation, Meckel diverticulum, and a mesodiverticular band-contributing to cause an acute small bowel obstruction. The presence of all of these features in one patient is extremely rare, and we believe this is the first description of such a phenomenon.