Circulating tumor DNA and radiological tumor volume identify patients at risk for relapse with resected, early-stage non-small-cell lung cancer.

BACKGROUND: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome. PATIENTS AND METHODS: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation. RESULTS: Our results showed that patients with detectable ctDNA at baseline or after treatment and patients who did not clear ctDNA after treatment had a significantly worse clinical outcome. Integrating radiological analysis allowed the stratification in risk groups prognostic of clinical outcome as confirmed in an independent cohort of 32 patients. CONCLUSIONS: Our findings suggest ctDNA and radiological monitoring could be valuable tools for guiding follow-up care and treatment decisions for early-stage NSCLC patients.

Analysis of trimodal and bimodal therapy in a selective-surgery paradigm for locally advanced oesophageal squamous cell carcinoma.

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 < 0.001); 26 of 29 patients with locoregional recurrence in the BMT groupunderwent salvage resection. Cox multivariable analysis demonstrated that upper-mid oesophageal tumour location (hazard ratio (HR) 2.04; P = 0.024) and tumour length (HR 1.18; P = 0.046) were associated with worse survival. Although TMT was not associated with survival, it was a predictor of reduced recurrence (HR 0.28; P = 0.028). The maximum standardized uptake value after chemoradiation also predicted recurrence (HR 1.33; P < 0.001). 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.

Morbidity following salvage esophagectomy for squamous cell carcinoma: the MD Anderson experience.

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.

Obesity and outcomes in patients treated with chemoradiotherapy for esophageal carcinoma.

Body mass index (BMI) is a risk factor for comorbid illnesses and cancer development. It was hypothesized that obesity status affects disease outcomes and treatment-related toxicities in esophageal cancer patients treated with chemoradiotherapy (CRT). From March 2002 to April 2010, 405 patients with non-metastatic esophageal carcinoma at MD Anderson Cancer Center treated with either definitive or neoadjuvant CRT were retrospectively analyzed. Patients were categorized as either obese (BMI ≥ 25 kg/m(2) ) or nonobese (BMI < 25 kg/m(2) ). Progression-free survival and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. One hundred fifteen (28.4%) patients were classified as nonobese and 290 (71.6%) as obese. Obese patients were more likely than others to have several comorbid diseases (P < 0.001), adenocarcinoma located distally (P < 0.001), and have undergone surgery (P = 0.004). Obesity was not associated with either worse operative morbidity/mortality (P > 0.05) or worse positron emission tomography tumor response (P = 0.46) on univariate analysis, nor with worse pathologic complete response (P = 0.98) on multivariate analysis. There was also no difference in overall survival, locoregional control, or metastasis-free survival between obese and nonobese patients (P = 0.86). However, higher BMI was associated with reduced risk of chemoradiation-induced high-grade esophagitis (P = 0.021), esophageal stricture (P < 0.001), and high-grade hematologic toxicity (P < 0.001). In esophageal cancer patients treated with CRT, obesity is not predictive of poorer disease outcomes or operative morbidities; instead, data suggest it may be associated with decreased risk of acute chemotherapy- and radiotherapy-related treatment toxicities.

Concordance of studies for nodal staging is prognostic for worse survival in esophageal cancer.

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.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation.

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

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Utilization of surgery in trimodality-eligible patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting.

Trimodality therapy with neoadjuvant chemoradiation followed by surgery significantly improves the survival of locally advanced (clinical stage IIA-III) esophageal cancer patients compared to treatment with surgery alone. This has resulted in an increased use of neoadjuvant therapy in recent years, yet little is known regarding how this increase has impacted the utilization of surgery in the treatment of locally advanced disease. Although previous reports of experimental protocols suggest that 90-95% of patients complete trimodality therapy including a surgical resection, trimodality therapy completion among adenocarcinoma patients eligible for curative resection has not been evaluated in a nonprotocol setting. We sought to (i) assess the completion of trimodality therapy among locally advanced esophageal adenocarcinoma patients; (ii) characterize the reasons for avoiding surgery; and (iii) identify factors associated with failure to complete trimodality therapy. We identified 296 patients with locally advanced esophageal adenocarcinoma eligible for trimodality therapy at our institution. All patients were evaluated in a multidisciplinary setting and considered eligible for curative resection after initial staging and physiologic assessment. Multivariable logistic regression was used to identify factors associated with failure to complete trimodality therapy. Of 296 trimodality-eligible patients, 33% (97/296) did not complete trimodality therapy. Reasons for not undergoing surgery included patient choice (27.8%, 27/97), distant progression of disease during chemoradiation (23.7%, 23/97), and physician preference for surveillance (23.7%, 23/97). In addition, 17.5% (17/97) of patients had physical deterioration in performance status, and treatment-related deaths occurred in 7.2% (7/97) prior to surgery. In the total study population (n = 296), multivariable logistic regression identified older age (≥70 years: odds ratio [OR] = 6.611, 95% confidence interval [CI]: 2.900-15.071), pretreatment standard uptake value (6.8-10.1: OR = 2.393, 95% CI: 1.050-5.455; ≥15.8: OR = 3.623, 95% CI: 1.604-8.186), and a radiation dose of 50.4 Gy (OR = 5.312, 95% CI: 2.365-11.929) as being significantly associated with failure to complete trimodality therapy. Among the subgroup of patients that successfully completed chemoradiation (n = 266), older patients (≥70 years: OR = 9.606, 95% CI: 3.637-25.372), those with a comorbidity score of 2 or higher (OR = 4.059, 95% CI: 1.257-13.103), and those that received a radiation dose of 50.4 Gy (OR = 4.878, 95% CI: 1.974-12.054) were at a significantly higher risk of not completing trimodality therapy. Trimodality therapy completion among patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting is considerably lower than what has previously been reported in clinical trials. Our findings suggest that a selective approach to surgery is commonly utilized in clinical practice. Trimodality-eligible patients that are older and have a higher comorbidity score are at risk for not completing trimodality therapy.

Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk. PATIENTS AND METHODS: Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months. RESULTS: Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively. CONCLUSION: Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort.

BACKGROUND: 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). PATIENTS AND METHODS: 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. RESULTS: 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 (P < 0.001). CONCLUSIONS: 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.

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Patients with high body mass index tend to have lower stage of esophageal carcinoma at diagnosis.

High body mass index (H-BMI; ≥25 kg/m(2) ) is common in US adults. In a small cohort of esophageal cancer (EC) patients treated with surgery, H-BMI and diagnosis of early stage EC appeared associated. We evaluated a much larger cohort of EC patients. From a prospectively maintained database, we analyzed 925 EC patients who had surgery with or without adjunctive therapy. Various statistical methods were used. Among 925 patients, 69% had H-BMI, and 31% had normal body mass index (<25 kg/m(2) ; N-BMI). H-BMI was associated with men (P<0.001), Caucasians (P=0.064; trend), lower esophageal localization (P<0.001), adenocarcinoma histology (P<0.001), low baseline cT-stage (P=0.003), low baseline overall clinical stage (P=0.003), coronary artery disease (P=0.036), and diabetes (P<0.001). N-BMI was associated with weight loss (P<0.001), alcohol abuse (P=0.056; trend), ever/current smoking (P=0.014), and baseline cN+ (P=0.018). H-BMI patients with cT1 tumors (n=110) had significantly higher rates of gastresophageal reflux disease symptoms (P<0.001), gastresophageal reflux disease history (P<0.001), and Barrett's esophagus history (P<0.001) compared with H-BMI patients with cT2 tumors (n=114). Median survival of N-BMI patients was 36.66 months compared with 53.20 months for H-BMI patients (P=0.005). In multivariate analysis, older age (P<0.001), squamous histology (P=0.002), smoking (P=0.040), weight loss (P=0.002), high baseline stage (P<0.001), high number of ypN+ (P=0.005), high surgical stage (P<0.001), and American Society of Anesthesia scores, three out of four (P<0.001) were independent prognosticators for poor overall survival. We were able to perform propensity-based analysis of surgical complications between H-BMI and N-BMI patients. A comparison of fully matched 376 patients (188 with H-BMI and 188 with N-BMI) found no significant differences in the rate of complications between the two groups. This larger data set confirms that a fraction of H-BMI patients with antecedent history is diagnosed with early baseline EC. Upon validation of our data in an independent cohort, refinements in surveillance of symptomatic H-BMI patients are warranted and could be implemented. Our data also suggest that H-BMI patients do not experience higher rate of surgical complications compared with N-BMI patients.

A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypT0N0M0R0 esophageal cancer.

OBJECTIVE: To evaluate 5-year survival of patients with locally advanced esophageal cancer (LAEC) who have undergone multimodality treatment with complete histopathologic response. BACKGROUND: Patients with LAEC may obtain excellent local-regional response to multimodality therapy. The overall benefit of a complete histopathologic response, when no viable tumor is present in the surgical specimen, is incompletely understood and existing data are limited to single-center studies with relatively few patients. The aim of this multicenter study was to define the outcome of patients with complete histopathologic response after multimodality therapy for LAEC. METHODS: The study population included 299 patients (229 male, 70 female; median age: 60 years) with LAEC (cT2N1M0, T3-4N0-1M0; 181 adenocarcinomas, 118 squamous carcinomas) who underwent either neoadjuvant radiochemotherapy (n = 284) or chemotherapy (n = 15) followed by esophagectomy at 6 specialized centers: Europe (3) and United States (3). All patients in the study had stage ypT0N0M0R0 after resection. RESULTS: Esophagectomy with thoracotomy (n = 255) was more frequent than with a transhiatal approach (n = 44). The median number of analyzed lymph nodes in the surgical specimens was 20 (minimum-maximum: 1-77). Thirty-day mortality rate was 2.4% and 90-day mortality rate was 5.7%. Overall 5-year survival rate was 55%. The disease-specific 5-year survival rate was 68%, with a recurrence rate of 23.4% (n = 70; local vs distant recurrence: 3.3% vs 20.1%). Cox regression analysis identified age as the only independent predictor of survival, whereas gender, histology, type of esophagectomy, type of neoadjuvant therapy, and the number of resected lymph nodes had no prognostic impact. CONCLUSION: Patients with histopathologic complete response at the time of resection of LAEC achieve excellent survival.

Worldwide esophageal cancer collaboration.

The aim of this study is to report assemblage of a large multi-institutional international database of esophageal cancer patients, patient and tumor characteristics, and survival of patients undergoing esophagectomy alone and its correlates. Forty-eight institutions were approached and agreed to participate in a worldwide esophageal cancer collaboration (WECC), and 13 (Asia, 2; Europe, 2; North America, 9) submitted data as of July 1, 2007. These were used to construct a de-identified database of 7884 esophageal cancer patients who underwent esophagectomy. Four thousand six hundred and twenty-seven esophagectomy patients had no induction or adjuvant therapy. Mean age was 62 +/- 11 years, 77% were men, and 33% were Asian. Mean tumor length was 3.3 +/- 2.5 cm, and esophageal location was upper in 4.1%, middle in 27%, and lower in 69%. Histopathologic cell type was adenocarcinoma in 60% and squamous cell in 40%. Histologic grade was G1 in 32%, G2 in 33%, G3 in 35%, and G4 in 0.18%. pT classification was pTis in 7.3%, pT1 in 23%, pT2 in 16%, pT3 in 51%, and pT4 in 3.3%. pN classification was pN0 in 56% and pN1 in 44%. The number of lymph nodes positive for cancer was 1 in 12%, 2 in 8%, 3 in 5%, and >3 in 18%. Resection was R0 in 87%, R1 in 11%, and R2 in 3%. Overall survival was 78, 42, and 31% at 1, 5, and 10 years, respectively. Unlike single-institution studies, in this worldwide collaboration, survival progressively decreases and is distinctively stratified by all variables except region of the world. A worldwide esophageal cancer database has been assembled that overcomes problems of rarity of this cancer. It reveals that survival progressively (monotonically) decreased and was distinctively stratified by all variables except region of the world. Thus, it forms the basis for data-driven esophageal cancer staging. More centers are needed and encouraged to join WECC.

Adenocarcinoma of the lower esophagus with Barrett's esophagus or without Barrett's esophagus: differences in patients' survival after preoperative chemoradiation.

It remains unclear whether the overall survival (OS) of patients with localized esophageal adenocarcinoma (LEA) with Barrett's esophagus (BE) (Barrett's-positive) and those with LEA without BE (Barrett's-negative) following preoperative chemoradiation is different. Based on the published differences in the molecular biology of the two entities, we hypothesized that the two groups will have a different clinical biology (and OS). In this retrospective analysis, all patients with LEA had surgery following preoperative chemoradiation. Apart from age, gender, baseline clinical stage, location, class of cytotoxics, post-therapy stage, and OS, LEAs were divided up into Barrett's-positive and Barrett's-negative groups based on histologic documentation of BE. The Kaplan-Meier and Cox regression analytic methods were used. We analyzed 362 patients with LEA (137 Barrett's-positive and 225 Barrett's-negative). A higher proportion of Barrett's-positive patients had (EUS)T2 cancers (27%) than those with Barrett's-negative cancer (17%). More Barrett's-negative LEAs involved gastroesophageal junction than Barrett's-positive ones (P = 0.001). The OS was significantly shorter for Barrett's-positive patients than that for Barrett's-negative patients (32 months vs. 51 months; P = 0.04). In a multivariate analysis for OS, Barrett's-positive LEA (P = 0.006), old age (P = 0.016), baseline positive nodes (P = 0.005), more than 2 positive (yp)N (P = 0.0001), higher (yp)T (P = 0.003), and the use of a taxane (0.04) were the independent prognosticators. Our data demonstrate that the clinical biology (reflected in OS) is less favorable for patients with Barrett's-positive LEA than for patients with Barrett's-negative LEA. Our intriguing findings need confirmation followed by in-depth molecular study to explain these differences.

JNK-deficiency enhanced oncolytic vaccinia virus replication and blocked activation of double-stranded RNA-dependent protein kinase.

Vaccinia virus has recently been used as an expression vector for gene delivery and an oncolytic agent for cancer therapy. Although it has been established that interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) and RNase L interfere with viral replication, little else is known about the other host factors that might affect viral replication and virus-mediated host cell killing. In this study, we evaluated the roles of c-Jun NH2-terminal kinase (JNK) in oncolytic vaccinia virus replication and vaccinia virus-mediated host cell killing. We found that JNK knockout mouse embryonic fibroblasts (MEFs) were more susceptible to oncolytic vaccinia virus infection than wild-type MEFs. Moreover, viral replication and the production of infectious viral progeny were up to 100-fold greater in JNK-deficient MEFs than in wild-type MEFs. A similar result was observed for wild-type vaccinia virus. The increased killing of infected cells and the production of viral progeny was also observed in wild-type MEFs that had been treated with JNK inhibitors and in human colon cancer cells that had been transfected with dominant-negative JNK constructs. Moreover, testing on several human lung cancer cell lines and HeLa cells showed an inverse correlation between levels of JNK expression and susceptibility to oncolytic vaccinia virus. Our study also revealed that oncolytic virus infection-mediated PKR activation was blocked or diminished in JNK-deficient MEFs. The adenovirus-mediated ectopic expression of human PKR in JNK-deficient MEFs reduced vaccinia virus replication to the levels observed in wild-type MEFs, indicating that JNK is required for vaccinia virus to efficiently activate PKR. Our results demonstrated that the cellular status of JNK function can dramatically affect oncolytic vaccinia virus replication and vaccinia virus-mediated host cell killing. This finding may enable further improvements in oncolytic virotherapy using vaccinia virus.

Significance of thromboembolic phenomena occurring before and during chemoradiotherapy for localized carcinoma of the esophagus and gastroesophageal junction.

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.

Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue.

Our previous studies demonstrated that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7 (Ad-mda7) leads to rapid induction of double-stranded RNA-dependent protein kinase (PKR) and activation of its downstream targets, resulting in apoptosis induction in human lung cancer cells. Here, we report that Ad-mda7 and the benzoquinone ansamycin geldanamycin (GA) interact in a highly synergistic manner to induce cell death in human lung cancer cells. Co-administration of Ad-mda7 and GA did not modify expression of MDA-7, and was not associated with further PKR induction and activation; instead the enhanced cytotoxicity of this combination was associated with inactivation of AKT by GA. By surface staining using anti-E-cadherin monoclonal antibody and flow cytometry, we found that treatment with the combination of Ad-mda7 and GA increased E-cadherin levels in these cancer cells. Ad-mda7 and GA cotreatment also inhibited lung cancer cell motility by increasing the beta-catenin/E-cadherin association. Moreover, combination of GA derivative 17-allyl-amino, 17-demethoxygeldanamycin (17AAG), with Ad-mda7 resulted in enhancement of cell death in A549 and H460 human lung cancer cells.

Gender-based analysis of esophageal cancer patients undergoing preoperative chemoradiation: differences in presentation and therapy outcome.

The purpose of this study was to identify gender-dependent differences in presentation at baseline and therapy outcome in esophageal carcinoma patients treated with preoperative chemoradiotherapy (CTRT). We stratified patients according to gender and statistically compared pretreatment clinical stage, post-CTRT effect on carcinoma in the resected specimen, overall survival (OS), and patterns of failure. Of the 235 patients who underwent preoperative CTRT, 203 were men and 32 were women. Carcinomas in women correlated significantly with clinical stage II classification (78%vs. 55%) while cancers in men correlated significantly with clinical stage III classification (39%vs. 16%; P = 0.02). Carcinomas in women also correlated significantly with lower clinical N classification; more women had cN0 (52%) compared to men (28%; P = 0.01). Similarly, in the surgical specimens, more women had pN0 (78%) compared to men (64%; P = 0.06). At a median follow-up of 37 months, 10% more women than men remain alive (63%vs. 53%; P = 0.3). Distant metastases-free survival time was longer for women than men. Our results suggest that localized esophageal carcinoma is diagnosed in more advanced stages in men than in women. The reasons for these differences remain unclear and further expansion of these observations and study of biologic differences that might exist are warranted.

Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53.

Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a cytoprotective agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21(WAF1), Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.