Implementation of Staging Guidelines in Early Esophageal Cancer: A Study of the Society of Thoracic Surgeons General Thoracic Surgery Database.

OBJECTIVE: To evaluate the adoption and clinical impact of endoscopic resection (ER) in early esophageal cancer. BACKGROUND: Staging for early esophageal cancer is largely inaccurate. Assessment of the impact of ER on staging accuracy is unknown, as is the implementation of ER. METHODS: We retrospectively reviewed 2608 patients captured in the Society of Thoracic Surgeons General Thoracic Surgery Database between 2015 and 2020. Patients with clinical T1 and T2 esophageal cancer without nodal involvement (N0) who were treated with upfront esophagectomy were included. Staging accuracy was assessed by clinical-pathologic concordance among patients staged with and without ER. We also sought to measure adherence to National Comprehensive Cancer Network staging guidelines for esophageal cancer staging, specifically the implementation of ER. RESULTS: For early esophageal cancer, computed tomography/positron emission tomography/endoscopic ultrasound (CT/PET/EUS) accurately predicts the pathologic tumor (T) stage 58.5% of the time. The addition of ER to staging was related to a decrease in upstaging from 17.6% to 10.8% ( P =0.01). Adherence to staging guidelines with CT/PET/EUS improved from 58.2% between 2012 and 2014 to 77.9% between 2015 and 2020. However, when ER was added as a staging criterion, adherence decreased to 23.3%. Increased volume of esophagectomies within an institution was associated with increased staging adherence with ER ( P =0.008). CONCLUSIONS: The use of CT/PET/EUS for the staging of early esophageal cancer is accurate in only 56.3% of patients. ER may increase staging accuracy as it is related to a decrease in upstaging. ER is poorly utilized in staging of early esophageal cancer. Barriers to the implementation of ER as a staging modality should be identified and corrected.

Robotic Belsey Mark IV Repair of the Paraesophageal Hernia.

OBJECTIVE: Surgical repair of paraesophageal hernias in patients with hostile abdomen is challenging. Despite its utility as an open procedure, the adoption of the minimally invasive Belsey Mark IV procedure has been limited because of the complexity of using traditional video-assisted thoracoscopic instrumentation. The robotic platform offers additional degrees of freedom, which enables minimally invasive transthoracic approach despite challenging anatomy. The purpose of this article is to describe a technique of robotic approach for the Belsey Mark IV operation. METHODS: We retrospectively reviewed 5 cases of the robotic Belsey Mark IV procedure completed at a single institution between June 2018 and November 2021. Data were collected from a review of the medical records, including operative reports, anesthesia records, imaging, and clinical notes. The operative technique is described in the present article. There were 4 men and 1 woman. The average age of the patients was 64.4 ± 13.6 years, with an average body mass index of 24.5 kg/m2. Three patients had undergone previous transabdominal hiatal hernia repair, and 2 of them had 2 prior repairs. One patient underwent simultaneous pulmonary left lower lobectomy for cancer with the Belsey Mark IV procedure. RESULTS: The average operative time was 209 ± 95 min (110 to 360 min). The average postoperative length of stay was 4.2 days, and 2 patients experienced complications including bleeding and persistent air leak (after lobectomy). The average blood loss was 67 ± 25 mL. CONCLUSIONS: The robotic platform enables a transthoracic minimally invasive approach to the Belsey Mark IV operation.

Incremental cost-effectiveness of extracorporeal membranous oxygenation as a bridge to cardiac transplant or left ventricular assist device placement in patients with refractory cardiogenic shock.

Objective: Emerging literature has described using venoarterial extracorporeal membranous oxygenation (ECMO) as a bridge to transplant or left ventricular assist device (LVAD) placement. We sought to identify the incremental cost-effectiveness ratio (ICER) of ECMO used as a bridge to cardiac transplant or LVAD. Methods: Patients with refractory cardiogenic shock who received venoarterial ECMO and were bridged to either cardiac transplant (n = 7) or a HeartMate 3 LVAD (n = 6) placement were included. Markov modeling was used, comparing ECMO bridging with non-ECMO-bridged patients. Cohorts entered the model alive and at every 1-year cycle, were exposed to risk of death, and ran forward for 20 years after transplant or LVAD. Results: Patients bridged with ECMO to cardiac transplant were stratified as group 1 whereas those bridged with ECMO to LVAD were stratified as group 2. The average ECMO run was 3 days in group 1 versus 11 days in group 2. Among group 1 patients, the ICER was $246,629 but was paired with a longer life expectancy. The ICER of group 2 patients was -$107,088 and was not paired with a longer life expectancy. The average inpatient cost for group 1 was found to be $636,023 versus $769,471 for group 2 patients. The average inpatient costs for patients not bridged to ECMO who received cardiac transplant or LVAD was $538,928 and $325,242, respectively. Conclusions: Using ECMO to bridge to transplant or LVAD placement is not cost effective. However, patients bridged to transplant are paired with longer life expectancy in contrast to patients bridged to LVAD.

Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation.

The portal venous circulation provides a conduit for pancreatic ductal adenocarcinoma (PDAC) tumor cells to the liver parenchyma sinusoids, a frequent site of metastasis. Turbulent flow in the portal circulation promotes retention of PDAC shed circulating tumor cells (CTC) and myeloid-derived immunosuppressor cells (MDSC). Excessive colony stimulating factor-1 receptor (CSF1R) signaling can induce myeloid differentiation to MDSC and transformation of MDSC to myeloid-derived fibroblasts (M-FB). Interactions between PDAC CTC and M-FB in the portal blood promotes the formation of immunoresistant clusters that enhance CTC proliferation, migration, and survival. Analysis of portal and peripheral blood samples collected intraoperatively from 30 PDAC patients undergoing pancreatico-duodenectomy showed that PDAC patient plasma contained high levels of macrophage colony stimulating factor (M-CSF/CSF1), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2), interleukin-8 (IL-8), and interleukin-34 (IL-34) compared to healthy control levels. Moreover, the level of M-CSF in portal blood was significantly higher than that detected in the peripheral blood of PDAC patients. PDAC CTC aseptically isolated by fluorescence activated cell sorting (FACS) out of freshly collected patient portal blood mononuclear cells (PortalBMC) had elevated RNA expression of IL34 (IL-34 gene) and CSF1 (M-CSF/CSF1 gene) which both signal through CSF1R. PDAC CTC also had high levels of RNA expression for CXCL8, the gene encoding chemokine interleukin-8 (IL-8) which can attract myeloid cells through their CXCR2 receptors. FACS-isolated portal PDAC CTC and M-FB co-cultured ex vivo had increased CTC proliferation, motility, and cluster formation compared to CTC cultured alone. CSF1R and CXCR2 cell surface expression were found on PDAC portal blood CTC and M-FB, suggesting that both cell types may respond to M-CSF, IL-34, and IL-8-mediated signaling. Portal PDAC CTC displayed enhanced RNA expression of CSF1 and IL34, while CTC+M-FB+ clusters formed in vivo had increased RNA expression of CSF2 and IL34. Portal M-FB were found to have high CSF1R RNA expression. CTC isolated from ex vivo 7-day cultures of PDAC patient portal blood mononuclear cells (PortalBMC) expressed elevated CSF1, IL34, and IL8 RNA, and CSF1 expression was elevated in M-FB. Treatment with rabbit anti-CSF1R antibodies decreased CTC proliferation. Treatment of PortalBMC cultures with humanized anti-CSF1R, humanized anti-IL-8, or anti-IL-34 antibodies disrupted CTC cluster formation and increased CTC apoptosis. U937 myeloid precursor cell line cultures treated with conditioned media from PortalBMC ex vivo cultures without treatment or treated with anti-IL-8 and/or anti-CSF1R did not prevent myeloid differentiation in the myeloid precursor cell line U937 to macrophage, dendritic cell, MDSC, and M-FB phenotypes; whereas, U937 cultures treated with conditioned media from PortalBMC ex vivo cultures exposed to anti-IL-34 were significantly inhibited in their myeloid differentiation to all but the M-FB phenotype. PDAC patient T cells that were found phenotypically anergic (CD3+CD25+CTLA4+PD1L1+) in PortalBMC could be re-activated (CD3+CD25+CTLA4-PD1L1-), and displayed increased interferon gamma (IFNγ) production when PortalBMC ex vivo cultures were treated with anti-CSF1R, anti-IL-8, and anti-IL-34 antibodies alone or in combination. These findings suggest that PDAC CTC have the potential to influence myeloid differentiation and/or antigen presenting cell activation in the PDAC portal blood microenvironment, and that disruption of CTC/M-FB interactions may be potential targets for reversing the immunosuppression supporting CTC survival in the portal blood.

Clinical and Financial Implications of Consulting Physicians in the Management of Surgical Patients.

BACKGROUND: The present study was designed to evaluate the immediate consequences that the number of consulting physicians has on length of stay (LOS), in-hospital mortality, 30-day readmission rates, direct health care costs, and contribution margins. METHODS: A retrospective review of administrative databases for the years 2013 and 2014 was performed at the Florida Hospital Adventist Healthcare System. RESULTS: 11 274 patients were included in the analysis. Total and variable costs increased by $1347 and $592, respectively, with each consulting physician service per patient. The contribution margin decreased by $354 per patient/consulting physician. Each consulting physician increased LOS by .72 days and increased odds ratio of mortality and 30-day readmission by 5% and 3%, respectively. CONCLUSIONS: Our research suggests that each consulting physician added to the care of an individual surgical patient negatively affected LOS, readmission rates, in-hospital mortality, and costs.

Differential gene expression identifies KRT7 and MUC1 as potential metastasis-specific targets in sarcoma.

BACKGROUND: Despite numerous discoveries regarding the molecular genesis and progression of primary cancers, the biology of metastasis remains poorly understood. Compared to very large numbers of circulating tumor cells that are now known to accompany nearly all cancers, a relatively limited number of lesions actually develop in most patients with metastases. We hypothesized that phenotypic changes driven by differential gene expression in a finite subpopulation of tumor cells render those cells capable of metastasis and sought to identify key pathways through analysis of gene expression in primary and metastatic lesions from the same patients. METHODS: We compared whole-genome expression in 4 matched samples of primary and metastatic sarcoma, then evaluated candidate genes with differential expression via quantitative PCR in 30 additional matched sets, tumor tissue immunostaining, siRNA loss-of-function in a sarcoma cell migration assay, and clinical correlation with overall and disease-free survival after metastasectomy. RESULTS: Comparison of microarray signals identified differential expression of cell adhesion genes, including upregulation of KRT7 and MUC1 in metastases; KRT7 and MUC1 upregulation was confirmed in 22 (73%) and 20 (67%) matched sets of metastatic/primary tumors, respectively. Silencing of KRT7 and MUC1 via targeted siRNAs suppressed sarcoma cell migration in vitro, and a significant correlation (two-sided) was observed between both KRT7 and MUC1 expression in metastases and overall patient survival. CONCLUSION: KRT7 and MUC1 may play a significant role in enabling sarcoma metastasis, and they may therefore be important prognostic biomarkers as well as potential targets for therapeutic prevention of metastasis.

K-RAS Mutant Gene Found in Pancreatic Juice Activated Chromatin From Peri-ampullary Adenocarcinomas.

External pancreatic duct stents inserted after resection of pancreatic head tumors provide unique access to pancreatic juice analysis of genetic and metabolic components that may be associated with peri-ampullary tumor progression. For this pilot study, portal venous blood and pancreatic juice samples were collected from 17 patients who underwent pancreaticoduodenectomy for peri-ampullary tumors. Portal vein circulating tumor cells (CTC) were isolated by high-speed fluorescence-activated cell sorting (FACS) and analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) for K-RAS exon 12 mutant gene expression (K-RASmut). DNA, chromatin, and histone acetylated active chromatin were isolated from pancreatic juice samples by chromatin immunoprecipitation (ChIP) and the presence of K-RASmut and other cancer-related gene sequences detected by quantitative polymerase chain reaction (PCR) and ChIP-Seq. Mutated K-RAS gene was detectable in activated chromatin in pancreatic juice secreted after surgical resection of pancreatic, ampullary and bile duct carcinomas and directly correlated with the number of CTC found in the portal venous blood (P = .0453). ChIP and ChIP-Seq detected acetylated chromatin in peri-ampullary cancer patient juice containing candidate chromatin loci, including RET proto-oncogene, not found in similar analysis of pancreatic juice from non-malignant ampullary adenoma. The presence of active tumor cell chromatin in pancreatic juice after surgical removal of the primary tumor suggests that viable cancer cells either remain or re-emerge from the remnant pancreatic duct, providing a potential source for tumor recurrence and cancer relapse. Therefore, epigenetic analysis for active chromatin in pancreatic juice and portal venous blood CTC may be useful for prognostic risk stratification and potential identification of molecular targets in peri-ampullary cancers.

Pancreatic and bile duct cancer circulating tumor cells (CTC) form immune-resistant multi-cell type clusters in the portal venous circulation.

Circulating tumor cells (CTC) enter the blood from many carcinomas and represent a likely source of metastatic dissemination. In contrast to the peripheral circulation, KRAS mutation- positive CTC thrive in the portal venous blood of patients with pancreatic ductal adenocarcinoma (PDAC). To analyze the essential interactions that contribute to carcinoma CTC growth and immune resistance, portal venous blood was collected during pancreatico-duodenectomy in 41 patients with peri-ampullary pathologies (PDAC = 11; ampullary adenocarcinoma (AA) = 15; distal cholangiocarcinoma (CC) = 6; IPMN = 7; non-malignant pancreatitis = 2). FACS-isolated cell populations from the portal circulation were reconstituted ex vivo using mixed cell reaction cultures (MCR). During the first 48hr, PDAC, AA, and CC patient CTC were all highly proliferative (mean 1.7 hr/cell cycle, 61.5% ± 20% growing cells) and resistant to apoptosis (mean 39% ±  25% apoptotic cells). PDAC CTC proliferation and resistance to T cell cytotoxicity were decreased among patients who received pre-operative chemotherapy (p = 0.0019, p = 0.0191, respectively). After 7 days in culture, CTC from PDAC, CC, and AA patients recruited multiple immune cell types, including CD105 + CD14 + myeloid fibroblasts, to organize into spheroid-like clusters. It was only in PDAC and CC-derived MCR that cluster formation promoted CTC survival, growth, and fibroblast differentiation. FACS depletion of CTC or myeloid fibroblast cells eliminated cluster network formation, and re-introduction of these cell populations reconstituted such ability. Our findings suggest that PDAC and CC CTC survival within the portal venous circulation is supported by their interactions with immune cells within multi-cell type clusters that could represent vectors of local recurrence and metastatic progression.

A Large Intussuscepting Gastric Lipoma.

Lipomas of the lower foregut are exceptionally rare. Presenting symptoms often include bleeding, weight loss, and obstructive symptoms. Surgical resection remains the standard treatment. We report a case of a large intussuscepting gastric lipoma.

Aggressive and minimally invasive surgery for pulmonary metastasis of sarcoma.

BACKGROUND: Pulmonary metastasectomy has become a standard approach for sarcoma, but uncertainty remains regarding risk factors that accurately assess postoperative prognosis and can be used to guide surgical decision making. METHODS: We identified 145 patients who underwent 204 consecutive pulmonary metastasectomies for sarcoma between 1996 and 2009, and examined 174 complete resections in 118 patients. Predictors included surgical procedure, number/size of lesions, repeat resection, intervals to metastasis and to recurrence, chemotherapy, sarcoma subtype, distribution of pulmonary and extrapulmonary metastasis, and patient age/sex. Survival estimates were based on Kaplan-Meier analysis and compared using a log-rank test. Predictors were compared using univariate and multivariate Cox proportional hazards modeling. RESULTS: Among patients undergoing R0 resections, median survival was 35 months (95% confidence interval, 22-60 months), with 3-, 5- and 10-year survival of 48%, 42%, and 31%, respectively. The number or size of lesions did not influence survival. Metastasis synchronous to the primary tumor, but not disease-free interval, was a significant predictor of worse survival on single variable and adjusted modeling (hazard ratio, 3.0; 95% confidence interval, 1.4-6.6; P = .005); the presence of extrapulmonary metastasis and a need for anatomic resection were also likely predictors (P = .06 and P = .07). Recurrence of pulmonary metastasis was not associated with a reduction in survival if completely resected, and a more aggressive and less invasive surgical approach during the later half of the study period was not associated with a significant decline in survival. CONCLUSIONS: Evolving surgical practice may allow an increasingly aggressive approach to pulmonary sarcoma metastasis, which may be facilitated by increased use of a minimally invasive approach.

VATS lobectomy facilitates the delivery of adjuvant docetaxel-carboplatin chemotherapy in patients with non-small cell lung cancer.

BACKGROUND: To evaluate the safety and tolerability of docetaxel/carboplatin regimen in the post-operative setting of patients with non-small cell lung cancer (NSCLC). METHODS: Enrolment of 133 patients with stage Ib - IIIa NSCLC was undertaken in an open-label, single arm study to assess the safety and tolerability of docetaxel (75 mg/kg) and carboplatin (AUC 5.5) administered for 3 cycles after resection for curative intent. The primary endpoint of the study was safety, as reflected by a febrile neutropenia rate of <10%. Other endpoints assessed protocol compliance and the impact of minimally invasive surgical technique. RESULTS: Patient accrual was completed at 1 center in the US and 10 centers in China in <6 months. Febrile neutropenia complicated treatment in 12 patients (9.0%), below the predetermined safety threshold of 14 patients. Four VATS and 8 open thoracotomy patients experienced febrile neutropenia (P=0.26). Completion of the three-cycle adjuvant regimen was achieved in 86% (95% CI, 77-95%) of patients. Sixty-two of 66 VATS patients compared to 53 of 67 open thoracotomy patients received all three doses according to protocol (P<0.01). Thirteen serious adverse events (9.8%) and no deaths were attributed to the study regimen. CONCLUSIONS: In this rapidly accrued study, docetaxel and carboplatin were well-tolerated in the adjuvant treatment of NSCLC. Adjuvant treatment compliance was higher among patients undergoing a minimally invasive surgical approach. (ClinicalTrials.gov number NCT00883675).