Contemporary outcomes for resected type 1-3 gastroesophageal junction adenocarcinoma: a single-center experience.

BACKGROUND: Surgical resection remains the mainstay of treatment for tumors of the gastroesophageal junction (GEJ). However, contemporary analyses of the Western experience for GEJ adenocarcinoma are sparsely reported. METHODS: Patients with GEJ adenocarcinoma undergoing resection between 2012 and 2022 at a single institution were grouped based on Siewert subtype and analyzed. Pathologic and treatment related variables were assessed with relation to outcomes. RESULTS: A total of 302 patients underwent resection: 161 (53.3%) with type I, 116 (38.4%) with type II, and 25 (8.3%) with type III tumors. Most patients received neoadjuvant therapy (86.4%); 86% of cases were performed in a minimally invasive fashion. Anastomotic leak occurred in 6.0% and 30-day mortality in only 0.7%. The rate of grade 3+ morbidity was lower for the last 5 years of the study than for the first 5 years (27.5% vs 49.3%, P < .001), as was median length of stay (7 vs 8 days, P < .001). There was a significantly greater number of signet ring type tumors among type III tumors (44.0%) than type I/II tumors (11.2/12.9%, P < .001). Otherwise, there was no difference in the distribution of pathologic features among Siewert subtypes. Notably, there was a significant difference in 3-year overall survival based on Siewert classification: type I 60.0%, type II 77.2%, and type III 86.3% (P = .011). Siewert type I remained independently associated with worse survival on multivariable analysis (hazard ratio, 4.5; P = .023). CONCLUSIONS: In this large, single-institutional series, operative outcomes for patients with resected GEJ adenocarcinoma improved over time. On multivariable analysis, type I tumors were an independent predictor of poor survival.

Relevance of Subcarinal Lymph Node Dissection for Gastroesophageal Junction Adenocarcinoma.

INTRODUCTION: Reported rates of subcarinal lymph node (LN) metastases for esophageal carcinoma vary from 20% to 25% and the relevance of subcarinal lymph node dissection (LND) for gastroesophageal junction (GEJ) adenocarcinoma is poorly defined. This study aimed to evaluate rates of subcarinal LN metastasis in GEJ carcinoma and determine their prognostic significance. METHODS: Patients with GEJ adenocarcinoma undergoing robotic minimally invasive esophagectomy from 2019 to 2021 were retrospectively assessed within a prospectively maintained database. Baseline characteristics and outcomes were examined with attention to subcarinal LND and LN metastases. RESULTS: Among 53 consecutive patients, the median age was 62, 83.0% were male, and all had Siewert type I/II tumors (49.1% and 50.9%, respectively). Most patients (79.2%) received neoadjuvant therapy. Three patients had subcarinal LN metastases (5.7%) and all had Siewert type I tumors. Two had clinical evidence of LN metastases preoperatively and all three additionally had non-subcarinal nodal disease. A greater proportion of patients with subcarinal LN disease had more advanced (T3) tumors compared to patients without subcarinal metastases (100.0% versus 26.0%; P = 0.025). No patient with subcarinal nodal metastases remained disease free at 3 y after surgery. CONCLUSIONS: In this consecutive series of patients with GEJ adenocarcinoma undergoing minimally invasive esophagectomy, subcarinal LN metastases were found only in patients with type I tumors and were noted in just 5.7% of patients, which is lower than historical controls. Subcarinal nodal disease was associated with more advanced primary tumors. Further study is warranted to determine the relevance of routine subcarinal LND, especially for type 2 tumors.

Phosphohistidine signaling promotes FAK-RB1 interaction and growth factor-independent proliferation of esophageal squamous cell carcinoma.

Current clinical therapies targeting receptor tyrosine kinases including focal adhesion kinase (FAK) have had limited or no effect on esophageal squamous cell carcinoma (ESCC). Unlike esophageal adenocarcinomas, ESCC acquire glucose in excess of their anabolic need. We recently reported that glucose-induced growth factor-independent proliferation requires the phosphorylation of FAKHis58. Here, we confirm His58 phosphorylation in FAK immunoprecipitates of glucose-stimulated, serum-starved ESCC cells using antibodies specific for 3-phosphohistidine and mass spectrometry. We also confirm a role for the histidine kinase, NME1, in glucose-induced FAKpoHis58 and ESCC cell proliferation, correlating with increased levels of NME1 in ESCC tumors versus normal esophageal tissues. Unbiased screening identified glucose-induced retinoblastoma transcriptional corepressor 1 (RB1) binding to FAK, mediated through a "LxCxE" RB1-binding motif in FAK's FERM domain. Importantly, in the absence of growth factors, glucose increased FAK scaffolding of RB1 in the cytoplasm, correlating with increased ESCC G1→S phase transition. Our data strongly suggest that this glucose-mediated mitogenic pathway is novel and represents a unique targetable opportunity in ESCC.

Acute gastric conduit dilation after minimally invasive esophagectomy: a 10-year experience.

Despite decreasing overall morbidity with minimally invasive esophagectomy (MIE), conduit functional outcomes related to delayed emptying remain challenging, especially in the immediate postoperative setting. Yet, this problem has not been described well in the literature. Utilizing a single institutional prospective database, 254 patients who underwent MIEs between 2012 and 2020 were identified. Gastric conduit dilation was defined as a conduit occupying >40% of the hemithorax on the postoperative chest X-ray. Sixty-seven patients (26.4%) demonstrated acute conduit dilation. There was a higher incidence of conduit dilation in the patients who underwent Ivor Lewis esophagectomy compared to those with a neck anastomosis (67.2% vs. 47.1%; P = 0.03). Patients with dilated conduits required more esophagogastroduodenoscopies (EGD) (P < 0.001), conduit-related reoperations within 180 days (P < 0.001), and 90-day readmissions (P = 0.01). Furthermore, in 37 patients (25.5%) undergoing Ivor Lewis esophagectomy, we returned to the abdomen after intrathoracic anastomosis to reduce redundant conduit and pexy the conduit to the crura. While conduit dilation rates were similar, those who had intraabdominal gastropexy required EGD significantly less and trended toward a lower incidence of conduit-related reoperations (5.6% vs. 2.7%). Multivariable analysis also demonstrated that conduit dilation was an independent predictor for delayed gastric conduit emptying symptoms, EGD within 90 days, conduit-related reoperation within 180 days, and 30-day as well as 90-day readmission. Patients undergoing MIE with acute gastric conduit dilation require more endoscopic interventions and reoperations.

Robotic versus thoraco-laparoscopic minimally invasive Ivor Lewis esophagectomy, a matched-pair single-center cohort analysis.

Minimally invasive esophagectomy (MIE) is becoming more widespread with a documented improvement in postoperative morbidity based on level I evidence. However, there is a lack of consensus regarding the optimal MIE approach, conventional thoracoscopy/laparoscopy vs robotics as well as the ideal anastomotic technique. All patients who underwent MIE via an Ivor Lewis approach with a side-to-side stapled anastomosis were included. The thoracoscopy-laparoscopy (TL) group was compared to the robotic group with respect to perioperative outcomes using the entire cohorts and after 1:1 propensity score matching. Comparisons were made using the Mann-Whitney U and Fisher's exact tests. Between July 2013 and November 2020, 72 TL and 67 robotic Ivor Lewis MIE were performed. After comparing the two unadjusted cohorts and 51 propensity matched pairs, there was a decrease in Clavien-Dindo Grade 2 or above complications in the robotic vs TL group (59.7% vs 41.8% [P = 0.042], (62.7% vs 39.2% [P = 0.029]), respectively. In both analyses, there was a reduction in hospital length of stay (median of 8 vs 7 days, P < 0.001) and a trend toward less anastomotic leaks in the robotic group (Unadjusted: 12.5 vs 3% [P = 0.057], Propensity-matched analysis: 13.7% vs 3.9% [P = 0.16]), respectively. A clinically significant decrease in overall morbidity, cardiac complications and hospital length of stay was observed in the robotic Ivor Lewis cohort when compared with the TL group at a high volume MIE program. Side-to-side stapled thoracic anastomoses utilizing a robotic platform provides the best outcomes in this single institution experience.

Clinical and Lifestyle-Related Prognostic Indicators among Esophageal Adenocarcinoma Patients Receiving Treatment at a Comprehensive Cancer Center.

PURPOSE: The incidence of esophageal adenocarcinoma (EAC) has risen substantially in recent decades, while the average 5-year survival remains only ~20%. Disease stage and treatment are the strongest prognostic factors. The role of lifestyle factors in relation to survival remains uncertain, with a handful of studies to date investigating associations with obesity, smoking, physical activity, diet, or medications. METHODS: This study included patients diagnosed with primary adenocarcinoma of the esophagus, gastroesophageal junction, or cardia (N = 371) at Roswell Park Comprehensive Cancer Center between 2003 and 2019. Leveraging extensive data abstracted from electronic medical records, epidemiologic questionnaires, and a tumor registry, we analyzed clinical, behavioral, and environmental exposures and evaluated stage-specific associations with survival. Survival distributions were visualized using Kaplan-Meier curves. Cox proportional hazards regression models adjusted for age, sex, stage, treatment, and comorbidities were used to estimate the association between each exposure and all-cause or cancer-specific mortality. RESULTS: Among patients presenting with localized/regional tumors (stages I-III), current smoking was associated with increased overall mortality risk (HR = 2.5 [1.42-4.53], p = 0.002), while current physical activity was linked to reduced risk (HR = 0.58 [0.35-0.96], p = 0.035). Among patients with stage IV disease, individuals reporting pre-diagnostic use of statins (HR = 0.62 [0.42-0.92], p = 0.018) or NSAIDs (HR = 0.61 [0.42-0.91], p = 0.016) had improved overall survival. Exploratory analyses suggested that high pre-diagnostic dietary consumption of broccoli, carrots, and fiber correlated with prolonged overall survival in patients with localized/regional disease. CONCLUSION: Our data suggest that lifestyle exposures may be differentially associated with EAC survival based on disease stage. Future investigation of larger, diverse patient cohorts is essential to validate these findings. Our results may help inform the development of lifestyle-based interventions to improve EAC prognosis and quality of life.

Robotic Enucleation of a Large Gastroesophageal Junction Leiomyoma.

In this multimedia article, we demonstrate transabdominal robotic enucleation of a large, multilobulated leiomyoma at the gastroesophageal junction (GEJ). The robotic platform provides stereoscopic visualization and wristed motion, which improved ease of an organ-sparing resection in a challenging anatomic location. Alternative minimally invasive approaches to tumors in this location have been reported including endoscopic, endoscopic with laparoscopic assistance, laparoscopic, and thoracoscopic approaches, with choice of approach dependent upon the location and configuration of the tumor Milito et al. in J Gastrointest Surg 24:499-504, 2020;Li et al. in Dis Esophagus. 22:185-189, 2009;Armstrong et al. in Am Surg. 79:968-972, 2013;Kent et al. in J Thorac Cardiovasc Surg. 134:176-181, 2007.

Risk-stratified analysis of pasireotide for patients undergoing pancreatectomy.

BACKGROUND AND OBJECTIVES: Pasireotide was shown in a randomized trial to decrease the rate of postoperative pancreatic fistula (POPF). However, retrospective series from other centers have failed to confirm these results. METHODS: Patients who underwent pancreatoduodenectomy or distal pancreatectomy between January 2014 and February 2019 were included. Patients treated after November 2016 routinely received pasireotide and were compared to a retrospective cohort. Multivariate analysis was performed for the outcome of clinically relevant POPF (CR-POPF), with stratification by fistula risk score (FRS). RESULTS: Ninety-nine of 300 patients received pasireotide. The distribution of high, intermediate, low, and negligible risk patients by FRS was comparable (P = .487). There were similar rates of CR-POPF (19.2% pasireotide vs 14.9% control, P = .347) and percutaneous drainage (12.1% vs 10.0%, P = .567), with greater median number of drain days in the pasireotide group (6 vs 4 days, P < .001). Multivariate modeling for CR-POPF showed no correlation with operation or pasireotide use. Adjustment with propensity weighted models for high (OR, 1.02, 95% CI, 0.45-2.29) and intermediate (OR, 1.02, CI, 0.57-1.81) risk groups showed no correlation of pasireotide with reduction in CR-POPF. CONCLUSIONS: Pasireotide administration after pancreatectomy was not associated with a decrease in CR-POPF, even when patients were stratified by FRS.

Technique for Robotic Transhiatal Esophagectomy.

Minimally invasive esophagectomy is increasing performed for cancers of the esophagus and gastroesophageal junction. This video demonstrates the setup and key steps for a robotic transhiatal esophagectomy with a cervical anastomosis.

The value of enhanced CT scanning for predicting lymph node metastasis along the right recurrent laryngeal nerve in esophageal squamous cell carcinoma.

BACKGROUND: The right recurrent laryngeal nerve (RRLN) is the region most prone to lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Nodal involvement may be underestimated by traditional imaging prediction criteria, such as a short axis diameter of 10 mm. The purpose of this study was to determine a more accurate imaging criterion to guide clinical treatment strategy selection. METHODS: The clinical data of 307 patients with thoracic ESCC who underwent surgery at Shanghai Chest Hospital between January 2018 and December 2018 were retrospectively analyzed. Utilizing 1-mm layer thickness enhanced computed tomography (CT), the RRLN lymph node short diameter (LNSD) size was measured. Univariate and multivariate analyses were performed to determine the risk factors for lymph node metastasis along the RRLN. RESULTS: In our study, RRLN lymph node metastasis occurred in 60 (19.5%) patients and general lymph node metastasis occurred in 150 (48.9%) patients. Of the resected lymph nodes along the RRLN, 14.5% (121/832) were positive. Multivariate analysis identified LNSD [odds ratio (OR), 1.236] as an independent risk factor for RRLN lymph node metastasis. In CT evaluation, a short diameter of 6.5 mm in the RRLN lymph nodes is a critical predictor of metastasis at this site (sensitivity =50%, specificity =83.4%) and a larger short diameter was associated with a higher risk of metastasis (P<0.001). CONCLUSIONS: A 6.5 mm cutoff in LNSD can be applied to clinically predict lymph node metastasis in the RRLN region for patients with ESCC.

Minimally Invasive Ivor Lewis Esophagectomy with Linear Stapled Anastomosis Associated with Low Leak and Stricture Rates.

BACKGROUND: Minimally invasive foregut surgery is increasingly performed for both benign and malignant diseases. We present a retrospective series of patients who underwent minimally invasive Ivor Lewis esophagectomy (MIE) with linear stapled anastomosis performed at two centers in the USA, with a focus on evaluating leak and stricture rates. METHODS: Patients treated from 2007 to 2018 were included, and data on demographics, oncologic treatment, pathology, and outcomes were analyzed. The surgical technique utilized laparoscopic and thoracoscopic access, with an intrathoracic esophagogastric anastomosis using a 6-cm linear stapled side-to-side technique. RESULTS: A total of 124 patients were included and 114 resections (91.9%) were completed in a minimally invasive fashion with a 6-cm linear stapled side-to-side anastomosis. Patients were predominantly male (90.7%) with a median age of 66.0 years and body mass index of 28.8 kg/m2. Of 121 patients with malignancy, negative margins were obtained in 94.3% and median lymph node yield was 15 (IQR 12-22). In the intention to treat analysis, median operative time was 463 min (IQR 403-515), blood loss was 150 mL (IQR 100-200), and length of stay was 8 days (IQR 7-11). Postoperative complications were experienced by 64 patients (51.6%) including respiratory failure in 14 (11.3%) and pneumonia in 12 (9.7%). In patients who successfully underwent a 6-cm stapled side-to-side anastomosis, anastomotic leaks occurred in 6 patients (5.1%) without need for operative intervention, and anastomotic strictures occurred in 6 patients (5.1%) requiring endoscopic management. CONCLUSIONS: Ivor Lewis MIE with a 6-cm linear stapled anastomosis can be completed with a high technical success rate, and low rates of anastomotic leak and stricture.

The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials.

BACKGROUND: We conducted a meta-analysis to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy or immunotherapy combined with chemotherapy and further estimated the value of PD-L1 expression in predicting the response from anti-PD-1/PD-L1 treatments as monotherapy or in combination with chemotherapy. METHODS: Clinical trial data were searched from electronic databases, which evaluated PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC) and correlated with PD-L1 expression levels. RESULTS: Fifteen randomized-controlled trials involving 10,074 patients were identified. Comparing anti-PD-1/PD-L1 monotherapy to chemotherapy, the pooled HR for overall survival (OS) was 0.77 (95% CI: 0.69-0.85, P<0.00001). Subgroup analyses revealed that patients had longer OS at ≥1%, ≥5%, ≥10% and ≥50% PD-L1 expression levels. Patients with higher PD-L1 expression may get increased benefit from PD-1/PD-L1 inhibitors. Moreover, patients with PD-L1 ≥50% had an objective response rate (ORR) improvement from anti-PD-1/PD-L1 therapy (RR =1.87, 95% CI: 1.27-2.75, P=0.001), but no ORR benefits were observed in patients with PD-L1 expression <1% (RR =0.82, 95% CI: 0.56-1.22, P=0.33) or 1-49% (RR =0.80, 95% CI: 0.64-0.98, P=0.03). OS was significantly better in patients receiving second-or-third line treatments (P<0.00001) with PD-L1 ≥1%. The efficacy of PD-1 inhibitors was similar to that of PD-L1 inhibitors, with no significant difference (P=0.63, I2=0%). Furthermore, immunotherapy combined with chemotherapy had better OS (HR =0.64, 95% CI: 0.48-0.84, P=0.001) than chemotherapy alone. Subgroup analyses showed that patients benefited from the combined chemo-IO treatment in the first-line setting regardless of PD-L1 expression level. CONCLUSIONS: PD-L1 expression may be a valuable predictor of the efficacy of anti-PD-1/PD-L1 monotherapy in certain NSCLC patients. However, the combination of chemotherapy plus immunotherapy significantly improved survival regardless of the PD-L1 expression level in the first-line treatment of NSCLC.

Discovery of Aberrant Alteration of Genome in Colorectal Cancer by Exome Sequencing.

BACKGROUND: This study analyzed multiple parameters including somatic single nucleotide variations (SNVs), Insertion/Deletions, significantly mutated genes (SMGs), copy number variations and frequently altered pathways aims to discover novel aberrances in the tumorigenesis of colorectal cancer (CRC). MATERIALS AND METHODS: Exome sequencing was performed on an Illumina platform to identify novel potential somatic variances in 34 paired tumor and adjacent normal tissues from 17 CRC patients. Results were compared with databases (dbSNP138, 1000 genomes SNP, Hapmap, Catalogue of Somatic Mutation of Cancer and ESP6500) and analyzed. MuSic software was used to identify SMGs. RESULTS: In total, 1,637 somatic SNVs in 17 analyzed tumors were identified. Only 7 SNVs were shared by more than 1 tumor, suggesting that over 99% of the analyzed SNVs were independent events. Mutation of KRAS p. G12D and ZNF717 p. L39V were the most common SNVs. Moreover, 10 SMGs namely KRAS, TP53, SMAD4, ZNF717, FBXW7, APC, ZNF493, CDR1, the Armadillo repeat containing 4 (ARMC4) and sulfate-modifying factor 2 (SUMF2) were found. Among those, ZNF717, ZNF493, CDR1, ARMC4 and SUMF2 were novel frequent genes in CRC. For copy number variations analysis, gains in 10q25.3, 1p31.1, 1q44, 10q23.33, 11p15.4 and 20q13.33, and loss of 3q21.3 and 3q29 were frequent aberrations identified in our results. CONCLUSIONS: We frequently found novel genes ZNF717, ZNF493, CDR1, ARMC4 and SUMF2 and gains in 10q25.3, which may be functional mutation in CRC. The high-frequency private events such as SNVs confirm the highly heterogeneous mutations found in CRCs. The mutated genes sites in different patients may vary significantly, which may also be more challenging for clinical treatment.

Minimally Invasive Esophageal Cancer Surgery.

Laparoscopic and thoracoscopic or robotic-assisted minimally invasive esophagectomy offers benefits in decreased postoperative complications and faster recovery. The choice of operation depends on patient and surgeon factors. McKeown or 3-field esophagectomy requires dissection in the abdomen, chest, and neck, with a cervical anastomosis. Ivor Lewis esophagectomy is performed with abdominal and right chest dissection and intrathoracic anastomosis. Transhiatal or transmediastinal esophagectomy is performed with abdominal and cervical dissections and a cervical anastomosis and is preferential in patients with significant pulmonary risk factors. Preparation and operative conduct for laparoscopic and robotic approaches for these operations, and the expected postoperative recovery are detailed.