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Background Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated. Methods Patients with stage II–III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response. Results Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P Conclusion In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.

While preoperative tobacco cessation has been associated with decreased pulmonary complications in lung cancer patients in the postoperative period, this relationship has not been explored among patients undergoing esophagectomy in this era of increasingly prevalent tobacco cessation campaigns and enhanced recovery after surgery. Methods We reviewed ever-smokers who underwent esophagectomy at a single institution from January 2004 through June 2019 for esophageal cancer. Occurrence of Clavien-Dindo classification ≥3 major postoperative morbidity (MPM), including anastomotic leak, chylothorax, reoperation, organ dysfunction, respiratory failure, and ICU readmission was calculated. In an effort to evaluate an effect of smoking cessation on outcome, never-smokers were excluded from analyses. Multivariable logistic regression with backwards stepwise elimination was completed to determine the optimal cessation interval associated with reduction in MPM. Robust standard errors were used to account for clustering among surgeons. Results 725 patients met inclusion criteria, including 666 (92%) with adenocarcinoma and a smaller proportion with squamous cell carcinoma. Most patients were male (650, 90%), and the median age was 63 years (IQR 57–69). Records showed that 505 patients (60%) had quit >5 years prior to esophagectomy, and 82 (11%) were current smokers or had quit within the month preceding esophagectomy. MPM occurred in 213 (29%). After univariate regression, age, gender, pack-year history, operative duration, and FEV1 were included in a multivariable model. While age remained associated wtih MPM, preoperative tobacco cessation of any interval was not associated with outcomes. Conclusion Our previous publication showed increased complication risk for smokers undergoing esophagectomy compared to non-smokers. However, among ever-smokers, no specific interval of preoperative cessation demonstrated decreased MPM. In a setting of active tobacco cessation programs, patients who have not completely achieved abstinence may still be offered surgery with equivalent perioperative outcomes.

Most patients undergoing esophagectomy will experience intermittent reflux of gastric and biliary content into the remnant esophagus over the course of their lives. The incidence of new or recurrent intestinal metaplasia (IM) following chemoradiation and surgery has not been well-described. Furthermore, post-resection guidelines do not exist regarding surveillance for IM in the esophageal remnant. We hypothesized that the incidence of IM in patients who underwent active post-treatment surveillance would be low. Methods Patients undergoing Ivor Lewis esophagectomy after concurrent chemoradiation for a diagnosis of esophageal adenocarcinoma at a single institution from 2006–2018 were identified. Pathology records were reviewed for the presence of IM on pretreatment biopsies, surgical specimen, or post-resection biopsies. Categorical variables were compared using Pearson’s chi-square test or Fisher’s exact test, where appropriate, and continuous variables were compared using Kruskal-Wallis test. Time-to-event outcomes were assessed using the Kaplan–Meier method. Results 621 patients were included, and 242 (39%) were known to have had IM prior to esophagectomy. An additional 26 (4%) patients without a preexisting diagnosis of IM were found to have IM in the surgical specimen. During a median follow-up of 62 months, development of new IM was rare, occurring only in 12 (2%) patients, 7 of whom had a prior history of IM(Table); incidence was 0.6 cases per patient-years. Of these 12, 3 (25%) developed local adenocarcinoma recurrence. Overall, local recurrence of adenocarcinoma was uncommon, and occurred at similar rates in patients with and without a history of IM(p = 0.774). Conclusion Despite several factors predisposing to mucosal damage following esophagectomy, occurrence of new IM after trimodality therapy in our patient population appears to be rare, even among patient with a previous history of metaplasia.

Introduction Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. Methods We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) Src Tyr419 . Results For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-Src Tyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5–110), and the median posttreatment score was 41.9 (interquartile range 4.2–60) ( p = 0.004). A decrease in p-Src Tyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [ p = 0.03]), suggesting that p-Src Tyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy ( p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. Conclusions In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

Purpose NCT01725165 was a phase II prospective trial in which patients with non-small cell lung cancer were randomized to local consolidative therapy (LCT) versus maintenance therapy or observation (MT/O). Methods and Materials Peripheral blood from patients enrolled on NCT01725165 were labeled as (1) baseline, (2) early follow-up (FU) if obtained in the first or second FU evaluation (6-18 weeks), and (3) late FU if obtained in the third to sixth FU evaluations (22-50 weeks). All patients who underwent LCT and were included in this analysis received radiation. Among 49 randomized patients, 21 patients underwent T cell CDR3 variable region sequencing using immunoSEQ, 31 patients underwent circulating tumor DNA (ctDNA) analysis using next-generation sequencing with a 1021 cancer gene panel, and cytokine concentration was assayed in 19 patients using enzyme-linked immunosorbent assay. All analyses were exploratory and not corrected for multiple testing. Results No associations were identified between baseline T cell repertoire and ctDNA metrics with patient outcomes. Among baseline cytokines, interleukin 1α was the only cytokine associated with both overall survival (hazard ratio, 0.02; 95% confidence interval, 0.1-0.5; P = .0006) and progression-free survival (hazard ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .03). At early FU, LCT was associated with decreased ctDNA burden, including lower number of detected mutations (median, 2 [interquartile range {IQR}, 1-6] vs 6 [IQR, 4-18]) and decreased average variable allele frequency (VAF; median, 0.006 [IQR, 0.003-0.010] vs 0.011 [IQR, 0.007-0.014]) compared with MT/O. Among 6 patients with serial ctDNA analysis, a rise in ctDNA detected mutation burden preceded clinical progression by 6.7 months. At early FU, LCT was associated with changes in T cell clonality that suggested oligoclonal expansion specifically increased T cell clonality (median, 0.15 [IQR, 0.12-0.24] vs 0.10 [IQR, 0.05-0.13]) and frequency of top 10 clones (median, 0.14 [IQR, 0.06-0.18] vs 0.21[IQR, 0.19-0.28]). Conclusion LCT was associated with decreased ctDNA burden and oligoclonal expansion at early FU timepoints. Baseline interleukin 1α was associated with improved patient outcomes.

SUMMARY The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.

Background Lung squamous cell carcinoma (LUSC) accounts for 20–30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We performed whole-exome sequencing (WES) and comprehensive immune profiling of a unique set of clinically annotated early-stage LUSCs to increase our understanding of the pathobiology of this malignancy. Methods Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n = 108) were analyzed by WES. Immunohistochemistry and image analysis-based profiling of 10 immune markers were done on a subset of LUSCs (n = 91). Associations among mutations, immune markers and clinicopathological variables were statistically examined using analysis of variance and Fisher’s exact test. Cox proportional hazards regression models were used for statistical analysis of clinical outcome. Results This early-stage LUSC cohort displayed an average of 209 exonic mutations per tumor. Fourteen genes exhibited significant enrichment for somatic mutation: TP53, MLL2, PIK3CA, NFE2L2, CDH8, KEAP1, PTEN, ADCY8, PTPRT, CALCR, GRM8, FBXW7, RB1 and CDKN2A. Among mutated genes associated with poor recurrence-free survival, MLL2 mutations predicted poor prognosis in both TP53 mutant and wild-type LUSCs. We also found that in treated patients, FBXW7 and KEAP1 mutations were associated with poor response to adjuvant therapy, particularly in TP53-mutant tumors. Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response. Conclusion(s) Our findings pinpoint mutated genes that may impact clinical outcome as well as personalized strategies for targeted immunotherapies in early-stage LUSC.

BACKGROUND Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a

Summary Pretreatment clinical staging in esophageal cancer influences prognosis and treatment strategy. Current staging strategies utilize multiple imaging modalities, and often the results are contradictory. No studies have examined the implications of concordance of computed tomography (CT), positron emission tomography (PET), and endoscopic ultrasound (EUS) when used for the evaluation of nodal disease. The objective of this study was to determine if concordance of CT, PET, or EUS for nodal disease predicts worse overall survival. We reviewed 615 esophageal cancer patients with pretreatment CT, PET, and EUS that underwent esophagectomy for survival outcomes based on concordance of studies for nodal disease. Concordant N+ is defined as two or three studies positive for nodal disease; non-concordant N+ is defined as only one positive study. Node-positive disease by any study predicted shorter survival than node-negative disease (42% vs. 73% 5-year survival; P < 0.001). Additionally, non-concordant N+ patients had shorter survival than N− patients (52% vs. 73% 5-year survival; P < 0.001). Concordant N+ patients had shorter survival than non-concordant N+ patients (38- vs. 61-month median survival; P = 0.017). There were no statistically significant differences in survival based on specific combinations of studies. When PET was disregarded, patients with both CT+ and EUS+ had shorter survival than patients with either CT+ or EUS+ (39- vs. 58-month median survival; P = 0.029). Pretreatment CT, PET, or EUS concordance for node-positive disease predicts shorter overall survival in patients that undergo esophagectomy for esophageal cancer. Predicting survival in esophageal cancer should consider the synergistic capabilities of CT, PET, and EUS in evaluating nodal status.

Background Postesophagectomy diaphragmatic hernia (PDH) is a recognized but severely under-reported and potentially hazardous event. Information regarding the natural course of this condition and guidelines regarding indications for reoperative intervention are lacking. In this study we aim to describe the frequency, predictors of incidence, and indications for repair. Methods Cross-sectional imaging (computed tomography scan) from patients who underwent esophagectomy between January 2001 and December 2007 at a single center were reviewed by two radiologists blinded to previous reports and clinical outcomes. Patients with PDH were compared with a similar cohort who did not have hernia. Patient characteristics, outcomes, and hernia descriptors including longitudinal progression were recorded. Multivariable logistic regression analyses identified predictors of PDH and need for repair. Results Of a total of 440 patients who underwent esophagectomy, 67 (15%) were radiologically diagnosed with PDH. Of these, only 7 of 67 cases (10%) were prospectively reported by the radiologist. Median time interval from esophagectomy to hernia was 2 years. Type of esophagectomy was an independent predictor for hernia developing ( p = 0.027). Patients with high body mass index were less prone to have PDH ( p = 0.043). Thus far, 9 patients (2%) have required surgical intervention, all for hernia-related symptoms or progression. Despite mesh repair, 4 of 9 have recurred and 2 were re-repaired. There was 1 PDH-associated death, 8 years after transhiatal resection. Conclusions Variables contributing to PDH are both technical and patient dependent. Whereas the majority of patients with PDH have not required repair, a small portion who became symptomatic or had large, progressive hernia required remedial surgery. Postesophagectomy patients require long-term surveillance for PDH.

Chemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR).Two hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan-Meier method, and log-rank test were used.Of 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P0.001).clinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.

Purpose We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer. Methods and Materials Treatment plans were generated using four different approaches (two-dimensional conformal radiotherapy [2D-CRT] to 50.4 Gy, 2D-CRT to 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure. Results The 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). Conclusions The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation.

Minimally invasive esophagectomy (MIE) is used with hope to decrease the morbidity associated with an open esophagectomy. Reflux and dumping syndromes are the most important functional complaints in patients after esophagectomy. This study compares the functional benefits of MIE with open esophagectomy. The study enrolled patients who underwent either minimally invasive or open esophagectomy for cancer between 2004 and 2009. No patients in the MIE group had a pyloroplasty or myotomy. Each patient in the MIE group was paired to a patient in the open esophagectomy group via propensity matching. Matching variables included age, race, gender, preoperative treatment, history of prior cancer, American Society of Anesthesiologists Risk Scale, performance status, clinical stage, body mass index, histology, level of anastomosis, and time elapsed since surgery. The patients were asked to answer 26 questions about their reflux and dumping using validated questionnaires. A total of 181 patients were included in the study. From this group, 44 pairs of patients were created and used for the analysis. The median follow-up was 12.1 months for the MIE group and 18.3 months for the open group. The reflux score was slightly worse in the MIE group (5.5 versus 3.5, P= 0.021). There was no difference in the dumping symptoms between the two groups. The most common complaints seen in the dumping questionnaire in almost one-third of all patients were early satiety, abdominal discomfort, nausea, and diarrhea. Of the patients, 77% were satisfied or very satisfied with their condition in the MIE group compared with 93% in the open group (P= 0.287). Reflux, dumping, and overall satisfaction after MIE without pyloroplasty are comparable with those obtained after open esophagectomy with a pyloric drainage procedure.

Background Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. Methods We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry (IHC) in a subset of LUADs (n = 92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fisher’s exact test. Cox proportional hazards regression models were used for multivariate analysis of clinical outcome. Results LUADs in this cohort exhibited an average of 243 coding mutations. We identified 28 genes with significant enrichment for mutation. SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis revealed that LUADs in smokers and with relatively high mutation burdens exhibited increased levels of immune markers. Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+ T-cells indicative of a muted immune response. Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression. LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration. Conclusion(s) Our study highlights molecular and immune phenotypes that warrant further analysis for their roles in clinical outcomes and personalized immune-based therapy of LUAD.

SUMMARY. Thromboembolic event (TEE) is the most common complication and a second cause of mortality in cancer patients. Multiple hypotheses for occurrence of TEE have been proposed. There are no reports on the frequency/impact of TEE in localized gastroesophageal cancer patients. We hypothesized that TEE at baseline and during chemoradiotherapy (CTRT) in gastroesophageal cancer patients would have an impact on overall survival (OS) of these patients. All consecutive patients with gastroesophageal cancer undergoing CTRT from 2001 to 2004 were eligible for this analysis. Baseline and subsequent TEEs were documented and correlated with patient characteristics and OS. One hundred ninety-eight patients were analyzed. TEEs were documented in 9.6% of the patients. At baseline, TEEs were documented in 4.0% of the patients. During CTRT, TEEs were documented in 6.1% of the patients. Pulmonary embolism (43.5%) and lower extremity venous thromboses (39%) were the most frequent TEEs. Median OS for patients with a TEE occurring at anytime was 17.7 versus 32.0 months for patients who never developed a TEE (P = 0.014). TEEs at baseline correlated with poor median survival: 13.1 versus 30.7 months for those without a TEE (P = 0.029). In a multivariable analysis, TEE at baseline and/or during CTRT was an independent predictor of OS (hazard ratio, 1.818; P = 0.040). Our data are the first to document the frequency of TEE in gastroesophageal cancer patients undergoing CTRT, and that TEE is an independent prognosticator of OS. Active research to prevent and treat TEEs is needed to improve survival of patients with localized gastroesophageal cancer.

The dramatically increased incidence and poor survival rates of esophageal adenocarcinoma (EAC) underscore the need for novel targets useful for risk assessment and therapeutic intervention. Altered expression of cyclin D1 has been proposed as an early predictor for malignant transformation in EAC; however, the mechanisms underlying cyclin D1 deregulation have not been identified. A single nucleotide polymorphism, A870G, of the cyclin D1 gene has been associated with the preferential encoding of a protein with an extended half-life. We investigated the association of the cyclin D1 A870G polymorphism with cyclin D1 protein expression and clinical characteristics and outcome in 124 patients treated at our institution for EAC. Our results indicate that the cyclin D1 AA/AG genotype is associated with earlier age of cancer onset, cyclin D1 protein deregulation in the primary tumors, and increased frequency of distant metastasis. Our findings suggest that cyclin D1 status could be useful to assess risk of progression to EAC, and strategies directed to modulate cyclin D1 expression may prove useful for interventions to slow or interrupt the EAC tumorigenesis process.