Impact of telehealth postoperative care on early outcomes following esophagectomy.

OBJECTIVES: To address the short-term clinical outcomes of patients postesophagectomy who underwent telehealth care following surgery. The primary objective was to compare the frequency of emergency department admission between telehealth and in-person cohorts. Secondary objectives included comparing the frequency of endoscopies and clinic visits, as well as reasons for emergency department admission. METHODS: We conducted a retrospective cohort study to assess the clinical outcomes of patients who underwent esophagectomy between March 2018 and May 2022. Patients attending telehealth (phone or video call) surgical follow-up visits, largely due to the COVID-19 pandemic, were compared with a pre-COVID cohort of patients attending standard in-person care. Demographic data, clinical and disease characteristics, and hospital visit data within 6 months of operation were collected. This included surgical clinic visits, endoscopies, and emergency department admissions. RESULTS: There were 168 patients who underwent esophagectomy and had follow-up care between March 2018 and May 2022; 76 telehealth and 92 in-person. Patients attending telehealth appointments had significantly fewer emergency department admissions (0.45 vs 0.79, P = .037) and more endoscopy visits (1.37 vs 0.91, P = .020) compared with patients attending in-person visits. The number of follow-up surgical clinic visits did not differ between the groups. The most frequent reasons for emergency visits for the telehealth cohort included dysphagia, feeding-tube problems, and failure to thrive. For the in-person cohort, feeding-tube complications, inflammation/infection, and failure to thrive were the most common reasons. CONCLUSIONS: A program of virtual follow-up, with integrated in person visits and endoscopy as required, is feasible and safe for following patients postesophagectomy.

Intestinal Stem Cell Marker ASCL2 is a Novel Prognostic Predictor in Esophageal Adenocarcinoma.

Purpose Intestinal stem cell markers play a significant role in esophageal adenocarcinoma carcinogenesis via Barrett's esophagus; however, its utility as a prognostic biomarker has not been established. Methods We analyzed the immunohistochemical expression of intestinal stem cell markers, ASCL2 and LGR5, using whole slides (35 cases) and tissue microarray (TMA; 64 cases). On TMA slides, adjacent normal squamous epithelium, metaplastic glandular epithelium (Barrett's esophagus), and dysplastic glandular epithelium were inserted when applicable. Two pathologists semi-quantitatively scored stained slides independently, and the results were correlated with clinicopathologic factors and outcomes. Results In whole slides, 51% and 57% expressed high ASCL2 and high LGR5; in TMA, 69% and 88% expressed high ASCL2 and high LGR5, respectively. In TMA, high ASCL2 and low LGR5 expression significantly correlated to a higher number of involved lymph nodes (p=0.027 and p=0.0039), and LGR5 expression significantly correlated to the pathological stage (p=0.0032). Kaplan-Meier analysis showed a negative impact of high ASCL2 expression on overall survival (OS; WS p=0.0168, TMA p=0.0276) as well as progression-free survival (PFS; WS p=0.000638, TMA p=0.0466) but not LGR5. Multivariate Cox regression analysis revealed that ASCL2 expression is an independent prognostic factor for esophageal adenocarcinoma (OS; WS p=0.25, TMA p=0.011. PFS; WS p=0.012, TMA p=0.038). Analysis of the TCGA dataset showed that ASCL2 mRNA levels were correlated to nodal status but not overall survival. Conclusion High expression of the intestinal stem cell marker ASCL2 may predict unfavorable outcomes in surgically resected esophageal adenocarcinoma.

Prognostic Significance of Pulmonary Multifocal Neuroendocrine Proliferation With Typical Carcinoid.

BACKGROUND: The clinical significance of multifocal pulmonary neuroendocrine proliferation (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with typical carcinoid (TC), is still debated. METHODS: We evaluated a retrospective series of TC with long-term follow-up data prospectively collected from 2 institutions and compared the outcome between TC alone and MNEP plus TC. Several baseline covariates were imbalanced between the MNEP plus TC and TC groups; therefore, we conducted 1:1 propensity score matching and inverse probability of treatment weighting in the full sample. In the matched group, the association of clinical, respiratory, and work-related factors with the group was determined through univariable and multivariable conditional logistic regression analysis. RESULTS: A total of 234 TC patients underwent surgery: 41 MNEP plus TC (17.5%) and 193 TC alone (82.5%). In the MNEP plus TC group, older age (P < .001), peripheral tumors (P = .0032), smaller tumor size (P = .011), and lymph node spread (P = .02) were observed compared with the TC group. Relapses occurred in 8 patients in the MNEP plus TC group (19.5%) and 7 in the TC group (3.6%). After matching, in 36 pairs of patients, a significantly higher 5-year progression-free rate was observed for the TC group (P < .01). Similar results were observed using inverse probability of treatment weighting in the full sample. The odds of being in the MNEP plus TC group was higher for those with work-related exposure to inhalant agents (P = .008), asthma or bronchitis (P = .002), emphysema, fibrosis, and inflammatory status (P = .032), or micronodules on the chest computed tomography scan and respiratory insufficiency (P = .036). CONCLUSIONS: The association with MNEP seems to represent a clinically and prognostic relevant factor in TC. Hence, careful preoperative workup, systematic pathologic evaluation, including nontumorous lung parenchyma, and long-term postoperative follow-up should be recommended in these patients.

Prognostic Impact of CXCR7 and CXCL12 Expression in Patients with Esophageal Adenocarcinoma.

BACKGROUND: Chemokines are major regulators of cell trafficking and adhesion. The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, have been reported as biomarkers in various cancers, including esophageal cancer; however, there are few studies in esophageal adenocarcinoma (EAC). In this study, we investigated the relationship between expression of CXCL12, CXCR4, and CXCR7, and prognosis in patients with EAC. METHODS: This study examined 55 patients with EAC who were treated in Toronto General Hospital from 2001 to 2010. Tissue microarray immunohistochemistry was used to evaluate the expression of CXCL12, CXCR4, and CXCR7. Evaluation of immunohistochemistry was performed by a pathologist without knowledge of patients' information and results were compared with the patients' clinicopathological features and survival. RESULTS: High CXCR7 expression was significantly associated with lymphatic invasion (present vs absent, P = 0.005) and higher number of lymph node metastases (pN0-1 vs pN2-3, P = 0.0014). Patients with high CXCR7 expression (n = 23) were associated with worse overall (OS) and disease-free survival (DFS) (P = 0.0221, P = 0.0090, respectively), and patients with high CXCL12 (n = 24) tended to have worse OS and DFS (P = 0.1091, P = 0.1477, respectively). High expression of both CXCR7 and CXCL12 was an independent prognostic factor for OS and DFS on multivariate analysis (HR = 0.3, 95% CI: 0.1-0.9, P = 0.0246, HR = 0.3, 95% CI: 0.1-0.8, P = 0.0134, respectively). CONCLUSIONS: High CXCR7 expression was associated with poor prognosis in patients with EAC, and high expression of CXCR7 with its ligand CXCL12 had a stronger association with prognosis. Further study of this potential biomarker using whole tissue samples and a larger sample size is warranted.

Prognostic significance of nutritional markers in metastatic gastric and esophageal adenocarcinoma.

BACKGROUND: Malnutrition and sarcopenia are poor prognostic factors in many cancers. Studies in gastric and esophageal (GE) cancer have focused on curative intent patients. This study aims to evaluate the prognostic utility of malnutrition and sarcopenia in de novo metastatic GE adenocarcinoma. METHODS: Patients with de novo metastatic GE adenocarcinoma seen at the Princess Margaret Cancer Centre from 2010 to 2016 with an available pre-treatment abdominal computed tomography (CT) were included. Malnutrition was defined as nutritional risk index (NRI) <97.5. Skeletal muscle index (SMI) was measured at the L3 level (sarcopenia defined as SMI <34.4 cm2 /m2 in women and <45.4 cm2 /m2 in men). Patients receiving chemotherapy had NRI and SMI recalculated at the time of first restaging CT. RESULTS: Of 175 consecutive patients, 33% were malnourished and 39% were sarcopenic at baseline. Patients with pretreatment malnourishment had significantly shorter overall survival (OS; 5.8 vs. 10.9 months, p = 0.000475). Patients who became malnourished during chemotherapy had worse OS compared to those who maintained their nutrition (12.2 vs. 17.5 months p = 0.0484). On univariable analysis, ECOG (p < 0.001), number of metastatic sites (p = 0.029) and NRI (p < 0.001) were significant prognostic factors while BMI (p = 0.57) and sarcopenia (p = 0.19) were not. On multivariable analysis, ECOG (p < 0.001), baseline NRI (p = 0.025), and change in NRI during treatment (p < 0.001) were significant poor prognostic factors for OS. CONCLUSIONS: In de novo metastatic GE adenocarcinoma patients, ECOG, pretreatment NRI and change in NRI were significant prognostic factors for OS while sarcopenia was not. Use of NRI at baseline and during treatment can provide useful prognostic information.

From Emergency Department Visit to Readmission After Esophagectomy: Analysis of Burden and Risk Factors.

BACKGROUND: Frequent emergency department (ED) visits occur after esophagectomy. We aimed to identify the incidence of and risk factors for conversion from ED visit to inpatient admission. METHODS: A retrospective cohort study was performed of consecutive esophagectomies at a tertiary Canadian center (1999 to 2014). Multivariable regression analyses identified factors associated with conversion from ED visit to admission. RESULTS: There were 520 esophagectomies with 6% inhospital mortality (n = 31). Of those discharged, 29.7% (n = 145) had one or more emergency visit and 43.4% (n = 63) of these patients were readmitted to the hospital. First-time ED visits resulted in inpatient conversion 23.4% of the time (n = 34); successive ED visits resulted in increasing conversion. On multivariable analysis, anastomotic leak (adjusted odds ratio 2.45; 95% confidence interval, 1 to 6.01; P = .05) was independently associated with higher odds of conversion to admission. Sensitivity analysis using Poisson regression to model conversion as a rate identified that living in regions further away was associated with lower conversion rate to admission (risk ratio 0.35; 95% confidence interval, 0.13 to 0.94; P = .04). CONCLUSIONS: Although postesophagectomy ED utilization is high, the majority of visits do not convert to admission. With each increasing ED visit, likelihood of converting to admission increases. Anastomotic leakage was associated with higher odds of conversion to admission, possibly related to development of strictures. Access to urgent outpatient endoscopy may help reduce the incidence of ED visits and admission. Although living in regions further away is associated with lower conversion rates to admission at the index hospital, that may be due to patients utilizing closer local hospitals.

EGFR-mutated lung adenocarcinomas from patients who progressed on EGFR-inhibitors show high engraftment rates in xenograft models.

OBJECTIVE: Patient-derived xenografts (PDX) are useful preclinical models to study cancer biology and mechanisms of drug response/resistance, particularly in molecularly targetable tumors. However, PDX engraftment may not be stochastic. We investigated clinical, histological and molecular features associated with PDX engraftment in a large cohort of EGFR-mutated lung adenocarcinoma (LUAD). MATERIAL AND METHODS: Samples were collected by different methods from patients at various disease stages and phases of treatment. PDX engraftment was defined as an ability to passage tumors twice in NOD-SCID mice. Uni- and multivariate logistic regression evaluated factors associated with engraftment. RESULTS: Among 138 EGFR-mutated LUAD implanted into NOD-SCID mice, the overall engraftment rate was only 10% (14/138). However, engraftment was significantly higher in specimens from surgical resections or core-needle biopsies collected from metastatic sites (5/5; 100%) or from patients who had progressed on EGFR-inhibitors (7/10; 70%). Engrafted tumors usually showed poor histological differentiation, a solid morphologic pattern, and presence of either EGFR T790 M and/or TP53 mutations. CONCLUSIONS: Population level analyses of mutant EGFR-PDX show that these models might not fully recapitulate the inter-patient heterogeneity of EGFR-LUAD. However, mutant EGFR-PDXs may be useful to address key clinical questions, notably development of resistance to EGFR-inhibitors and disease progression to distant metastases.

Adjuvant Therapy for Node-Positive Esophageal Cancer After Induction and Surgery: A Multisite Study.

BACKGROUND: The benefit of adjuvant treatment for esophageal cancer patients with positive lymph nodes after induction therapy and esophagectomy is uncertain. This in-depth multicenter study assessed the benefit of adjuvant therapy in this population. METHODS: A retrospective cohort study from 9 institutions included patients who received neoadjuvant treatment, underwent esophagectomy from 2000 to 2014, and had positive lymph nodes on pathology. Factors associated with administration of adjuvant therapy were assessed using multilevel random-intercept modeling to account for institutional variation in practice. Kaplan-Meier analyses were performed based on adjuvant treatment status. Variables associated with survival were identified using Cox proportional hazards modeling. RESULTS: The study analyzed 1082 patients with node-positive cancer after induction therapy and esophagectomy: 209 (19.3%) received adjuvant therapy and 873 (80.7%) did not. Administration of adjuvant treatment varied significantly from 3.2% to 50.0% between sites (P < .001). Accounting for institution effect, factors associated with administration of adjuvant therapy included clinically positive and negative prognostic characteristics: younger age, higher pathologic stage, pathologic grade, no neoadjuvant radiotherapy nonsmoking status, and absence of postoperative infection. Kaplan-Meier analysis showed patients receiving adjuvant therapy had a longer median survival of 2.6 years vs 2.3 years (P = .02). Cox modeling identified adjuvant treatment as independently associated with improved survival, with a 24% reduction in mortality (hazard ratio, 0.76; P = .005). CONCLUSIONS: Adjuvant therapy was associated with improved overall survival. Therefore, consideration should be given to administration of adjuvant therapy to esophageal cancer patients who have persistent node-positive disease after induction therapy and esophagectomy and are able to tolerate additional treatment.

Metachronous or synchronous primary lung cancer in the era of computed tomography surveillance.

OBJECTIVES: The purpose of this study was to determine the frequency, characteristics, and survival of second primary lung cancer initially identified as an indeterminate lesion on the original computed tomography scan and then diagnosed during the surveillance period in a prospective study. METHODS: A prospective database of 271 patients enrolled in a surveillance study was updated. Indeterminate lesions present on the original computed tomography at the time of initial primary lung cancer diagnosis that subsequently grew and were diagnosed as cancer were termed "synchronous primary lung cancer." Lesions that were not present on the original computed tomography scan and subsequently diagnosed on surveillance were termed "metachronous primary lung cancer." RESULTS: Thirty patients (11.1%) developed 37 second primary lung cancers over a median surveillance period of 84.7 (range, 15.9-147.6) months. Of these, 15 of 37 (40.5%) were identified as synchronous primary lung cancer, and 22 of 37 (59.5%) were identified as metachronous primary lung cancer. At first identification, ground-glass lesions were identified in 9 of 15 (60%) synchronous primary lung cancers compared with only 5 of 22 (22.7%) of metachronous primary lung cancers (P = .034). Compared with metachronous primary lung cancer, from first identification to diagnosis, synchronous primary lung cancer developed over a longer interval (33.6 vs 7.2 months, P = .001) and had a slower growth rate (0.17 vs 0.45 mm/month, P = .027). The 5-year overall survival from second lung cancer was 73.0%. No significant differences were observed between the synchronous primary lung cancer and metachronous primary lung cancer cohorts in overall survival from initial primary lung cancer (P = .583) or from second lung cancer (P = .966). CONCLUSIONS: Computed tomography surveillance identifies 2 types of curable second lung cancers leading to excellent overall survival.

Emergency department use is high after esophagectomy and feeding tube problems are the biggest culprit.

OBJECTIVES: Esophagectomy is a complex operation with potential for prolonged recovery. We aimed to identify the incidence of and risk factors for any and frequent emergency department visits within 1 year of esophagectomy. METHODS: A retrospective cohort study was performed looking at consecutive esophagectomies at a tertiary Canadian center (1999-2014). Multivariable analyses identified factors associated with any emergency department visits and frequent emergency department use (≥3 visits) within 1 year postesophagectomy. RESULTS: There were 520 esophagectomies with in-hospital mortality of 6% (n = 31). Of those discharged, 29.7% (n = 145) had ≥ 1 emergency department visit. Most common causes were feeding tube problems (39.3%; n = 57) and dysphagia/stricture (13.1%; n = 19). Higher income (adjusted odds ratio [aOR], 1.22; 95% confidence interval [CI], 1.04-1.42 per $10,000) and use of hybrid/minimally invasive esophagectomy (aOR, 3.24; 95% CI, 1.71-6.11) were independently associated with having emergency department visits. Patients with hybrid/minimally invasive esophagectomy were discharged earlier than others (P < .0001). Living outside of our metropolitan area (aOR, 0.36; 95% CI, 0.27-0.49) and having surgery in the later years of the study period (aOR, 0.91; 95% CI, 0.86-0.97; P = .006) were both independently associated with lower odds of emergency department visits. Forty-three patients (8.8%) were frequent emergency department users, with the most common causes of repeat emergency visits being feeding tube problems. Living outside of our metropolitan area was associated with lower odds of frequent emergency visits (aOR, 0.25; 95% CI, 0.14-0.45). CONCLUSIONS: There is high emergency department use within 1 year postesophagectomy. Patients living farther away from our hospital had a lower rate of emergency department use. It is possible that they are utilizing emergency departments nearer to home; this needs further study. Feeding tube problems are the biggest culprits and are potentially modifiable.

Minimal-dose computed tomography is superior to chest x-ray for the follow-up and treatment of patients with resected lung cancer.

OBJECTIVES: A minimal-dose computed tomography scan of the thorax (MnDCT) delivers a radiation dose comparable with a chest x-ray (CXR). We hypothesized that in patients with completely resected lung cancer, surveillance with MnDCT, when compared with CXR, leads to earlier detection and a higher rate of treatment of new or recurrent lung cancer. METHODS: After lung cancer resection, patients prospectively were enrolled for surveillance with MnDCT and CXR at 3, 6, 12, 18, 24, 36, 48, and 60 months. Images were interpreted by different blinded radiologists. When new or recurrent cancer was suspected, standard-dose CT and/or a tissue biopsy were performed for confirmation. RESULTS: Between 2007 and 2012, 271 patients were included and 1137 pairs of CXR and MnDCT were analyzed. MnDCT was more sensitive (94% vs 21%; P < .0001) and had a higher negative predictive value (99% vs 96%; P = .007) than CXR for the diagnosis of new or recurrent lung cancer. The prevalence of new or recurrent lung cancer was 23.2% (63 of 271), of whom 78% (49 of 63) had asymptomatic disease. The majority of asymptomatic patients (75%; 37 of 49) were treated with curative intent and had a median survival of 69 months. The remainder of patients received palliative treatment (24%; 12 of 49) and had a median survival of 25 months (P < .0001). CONCLUSIONS: After curative resection of lung cancer, MnDCT is superior to CXR for the detection of new or recurrent lung cancer. The majority of new or recurrent cancer was detected by MnDCT at an asymptomatic phase, allowing for curative treatment, leading to a long survival.