Actionable Locoregional Relapses after Therapy of Localized Esophageal Cancer: Insights from a Large Cohort.

OBJECTIVE: The goal of surveillance after therapy of localized esophageal cancer (LEC) is to identify actionable relapses amenable to salvage; however, the current surveillance algorithms are not optimized. We report on a large cohort of LEC patients with actionable locoregional relapses (LRRs). METHODS: Between 2000 and 2013, 127 (denominator = 752) patients with actionable LRR were identified. Histologic/cytologic confirmation was the gold standard. All surveillance tools (imaging, endoscopy, fine needle aspiration) were assessed. RESULTS: Most patients were men (89%), had adenocarcinoma (79%), and had no new symptoms (72%) when diagnosed with LRR. In trimodality patients, endoscopic confirmation of positron emission tomography-computed tomography-suspected LRR occurred in only 44%, and 56% required additional tools (e.g., fine needle aspiration). Alternatively, in bimodality patients, endoscopy confirmed LRRs in 81%. Trimodality patients had a higher risk of subsequent LRR/distant metastases after the first LRR than the bimodality patients (p = 0.03). In all patients, 78% of the subsequent relapses were distant. For patients who were salvaged, survival was significantly prolonged (50.6 vs. 25.1 months, p < 0.01). CONCLUSIONS: Patients live longer after successful salvage of the LRR than if salvage is not possible. After LRR, patients have a high risk of subsequent distant metastasis and whether the second relapse is local or distant, survival is uniformly poor.

Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients.

BACKGROUND: Predictive biomarkers or signature(s) for oesophageal cancer (OC) patients undergoing preoperative therapy could help administration of effective therapy, avoidance of ineffective ones, and establishment new strategies. Since the hedgehog pathway is often upregulated in OC, we examined its transcriptional factor, Gli-1, which confers therapy resistance, we wanted to assess Gli-1 as a predictive biomarker for chemoradiation response and validate it. METHODS: Untreated OC tissues from patients who underwent chemoradiation and surgery were assessed for nuclear Gli-1 by immunohistochemistry and labelling indices (LIs) were correlated with pathologic complete response (pathCR) or

The Proportion of Signet Ring Cell Component in Patients with Localized Gastric Adenocarcinoma Correlates with the Degree of Response to Pre-Operative Chemoradiation.

BACKGROUND: Patients with localized gastric adenocarcinoma (LGAC), who get pre-operative therapy, have heterogeneous/unpredictable outcomes. Predictive clinical variables/biomarkers are not established. METHODS: We analyzed 107 LGAC patients who had chemoradiation and surgery. LGACs were grouped for (1) presence/absence of signet ring cell histology (SRC) and (2) histologic grade: G2 or G3. %SRC was assessed (0, 1-10, 11-49, and 50-100%) and correlated with pathologic complete response (pathCR) or

Metastatic Gastroesophageal Adenocarcinoma Patients Treated with Systemic Therapy Followed by Consolidative Local Therapy: A Nomogram Associated with Long-Term Survivors.

OBJECTIVE: Patients with metastatic gastroesophageal adenocarcinoma (MGEAC) have a poor but heterogeneous clinical course. Some patients have an unusually favorable outcome. We sought to identify clinical variables associated with more favorable outcomes. METHODS: Of 246 patients with MGEAC, we identified 64 who received systemic therapy and eventually received local consolidation therapy. Univariate and multivariate Cox regression models were used, and a nomogram was developed. RESULTS: Of these 64 patients, 61% had received consolidation chemoradiation (CRT) with doses of 50-55 Gy and 78% did not undergo surgery. The median follow-up time of survivors was 3.9 years, and the median overall survival (OS) from CRT start was 1.5 years (95% CI, 1.2-2.2). Surgery (as local consolidation) was an independent prognosticator for longer OS in the multivariate analysis (p = 0.02). The 5-year OS rate was 25% (SE = 6%). The contributors to the nomogram were longer duration of systemic therapy before CRT and the type of local therapy. CONCLUSIONS: Our data suggest that a subset of patients with MGEAC have an excellent prognosis (OS >5 years). However, these patients need to be identified during their clinical course so that local consolidation (CRT, surgery, or both) may be offered.

A Nomogram to Predict Distant Metastases After Multimodality Therapy for Patients With Localized Esophageal Cancer.

BACKGROUND: Among patients with localized esophageal cancer (LEC), 35% or more develop distant metastases (DM) as first relapse, most in the first 24 months after local therapy. Implementation of novel strategies may be possible if DM can be predicted reliably. We hypothesized that clinical variables could help generate a DM nomogram. PATIENTS AND METHODS: Patients with LEC who completed multimodality therapy were analyzed. Various statistical methods were used, including multivariate analysis to generate a nomogram. A concordance index (c-index) was established and validated using the bootstrap method. RESULTS: Among 629 patients analyzed (356 trimodality/273 bimodality), 36% patients developed DM as first relapse. The median overall survival from DM was only 8.6 months (95% CI, 7.0-10.2). In a multivariate analysis, the variables associated with a higher risk for developing DM were poorly differentiated histology (hazard ratio [HR], 1.76; P<.0001), baseline T3/T4 primary (HR, 3.07; P=.0006), and baseline N+ LEC (HR, 2.01; P<.0001). Although variables associated with a lower risk for DM were age of 60 years or older (HR, 0.75; P=.04), squamous cell carcinoma (HR, 0.54; P=.013), and trimodality therapy (HR, 0.58; P=.0001), the bias-corrected c-index was 0.67 after 250 bootstrap resamples. CONCLUSIONS: Our nomogram identified patients with LEC who developed DM with a high probability. The model needs to be refined (tumor and blood biomarkers) and validated. This type of model will allow implementation of novel strategies in patients with LEC.

Early versus Delayed Therapy of Advanced Gastric Cancer Patients--Does It Make a Difference?

BACKGROUND: Nearly 50% of gastric cancer patients are diagnosed with advanced gastric cancer (AGC). Therapy is palliative but results in ill effects. The median overall survival (OS) of AGC patients is often <12 months. It is unclear if the early initiation of therapy in all AGC patients is beneficial. METHODS: A retrospective analysis of AGC patients in our database was carried out. The patients were divided into two groups: asymptomatic or symptomatic. We sought to assess whether the delay of systemic therapy was harmful in asymptomatic patients. RESULTS: A total of 135 patients were analyzed. Most patients were symptomatic (68%), males (67%), and had low ECOG scores (0-1; 85%). In univariate analyses, ECOG performance status 0 (p = 0.005), delayed initiation of therapy (p = 0.03), and lack of symptoms (p = 0.03) were associated with a longer OS. The multivariate model for OS identified only ECOG performance status as an independent prognosticator of longer OS (p = 0.02). Asymptomatic patients who had delayed (≥ 4 weeks) systemic therapy had an OS rate of 77% at 1 year compared to 58% for patients treated within 4 weeks (p = 0.47). CONCLUSION: Symptomatic AGC patients had a poor outcome compared to asymptomatic AGC patients. Treatment delay in asymptomatic patients had no detrimental effect on OS, suggesting that the timing of therapy can be based on patient selection.

Geographic distribution of regional metastatic nodes affects the outcome of trimodality-eligible patients with esophageal adenocarcinoma.

BACKGROUND/AIM: Malignant nodes in patients with localized esophageal adenocarcinoma (L-EAC) portend a poor prognosis. We assessed the correlation of the distribution of nodes with the outcome of patients undergoing chemoradiation/surgery (trimodality therapy). METHODS: We studied 209 L-EAC patients who had confirmed or suspicious nodes at baseline staging. All patients received trimodality therapy and were grouped according to the nodal geography: above the diaphragm (AD), below the diaphragm (BD), or above and below the diaphragm (ABD). Survival estimates were calculated using the Kaplan-Meier method, and the outcomes of the groups were assessed by the log-rank test. RESULTS: Patients were primarily Caucasian (91%) and male (93%), with a baseline stage III L-EAC (89%). The median follow-up was 2.8 years (range, 0.4-11.7). Of the 209 patients, 35% (n = 73) had AD nodes, 20% (n = 41) had BD nodes, and 45% (n = 95) had ABD nodes. ABD patients had a 5-year overall survival rate of 33%, whereas this rate was 55% in AD patients and 60% in BD patients (p = 0.02). Patients with a higher histology grade were also at a higher risk of relapse and had a poor survival (p < 0.01 for both). CONCLUSIONS: L-EAC patients in the ABD group had the worst outcome after trimodality treatment compared to those in the AD or BD group. Novel strategies are needed for ABD patients.

Initial Standardized Uptake Value of Positron Emission Tomography Influences the Prognosis of Patients with Localized Gastric Adenocarcinoma Treated Preoperatively.

BACKGROUND: In patients with localized gastric adenocarcinoma (LGAC) who receive preoperative therapy, tools to predict response or prognosticate outcome before therapy are lacking. We used initial standardized uptake value (iSUV) of positron emission tomography (PET) to evaluate its association with overall survival (OS). METHODS: We identified 60 patients with confirmed LGAC who were treated with preoperative chemoradiation and had a baseline PET in addition to other routine staging. Fisher's exact test and Wilcoxon's rank sum test were used to determine the association between iSUV and other variables, and the log-rank test and Cox proportional hazards model were used for survival analysis. RESULTS: The median iSUV was 6 (range, 0-28). The presence of signet ring cells in pretreatment biopsies correlated highly with low iSUV (≤ 6; p = 0.0017). Patients with a high iSUV (> 6) had a longer OS compared to those with a low iSUV (≤ 6; p = 0.0344). iSUV was not an independent predictor (p = 0.12); however, the risk of death was reduced for patients with an iSUV > 6 (hazard ratio = 0.26). CONCLUSION: Our novel findings show that among LGAC patients treated with preoperative chemoradiation and surgery, those with a high iSUV have longer OS than patients with a low iSUV. iSUV appears to have a predictive role in patients with LGAC when treated with preoperative chemoradiation.

Distribution of Resistant Esophageal Adenocarcinoma in the Resected Specimens of Clinical Stage III Patients after Chemoradiation: Its Clinical Implications.

BACKGROUND: We have limited knowledge of the geographic distribution of resistant esophageal adenocarcinoma (EAC) in resected specimens, but its clinical importance can be enormous. METHOD: We selected patients with baseline stage III EAC who had had chemoradiation followed by surgery and had residual EAC (resistant cases only). Outcomes were correlated with various endpoints (percentage of resistant EAC and anatomic distribution). RESULTS: A total of 100 clinical stage III patients were studied; 90% had an R0 resection, and 99% had either moderate or poorly differentiated EAC. Twelve percent had >50% residual cancer, 31% had 11-50% residual cancer, 53% had 1-10% residual cancer, and 3% had positive nodes only. Each compartment was frequently involved: mucosa/submucosa (66%), muscularis propria (76%), and serosa (62%); all compartments were involved in 35% of the cases. Lack of EAC (meaning response) was observed in the mucosa/submucosa (34%), muscularis propria (24%), serosa (38%), and nodes (42%). Although the endoscopic biopsies prior to surgery showed no EAC in 79% of the patients, in the surgical specimens, resistant EAC was frequently occurring in the mucosa/submucosa (66%). CONCLUSION: Contrary to our hypothesis that resistant EAC would be frequent in the nodes, our data show that its distribution is heterogeneous and unpredictable. Most importantly, the postchemoradiation biopsies are misleading, and a decision to delay/avoid surgery based on negative biopsies can be detrimental for the patients.

Molecular biomarkers in gastric cancer.

Gastric cancer (GC) represents a serious health problem on a global scale. Despite some recent advances in the field, the prognosis in metastatic GC remains poor. Even in localized disease the adjunctive therapies improve overall survival (OS) by only approximately 10%. A better understanding of molecular biology, which would lead to improved treatment options, is needed and is the basis for this review. Many potential biomarkers of prognostic significance have been identified, including ALDH, SHH, Sox9, HER2, EGFR, VEGF, Hippo/YAP, and MET. However, inhibition of only HER2 protein has led to a modest survival benefit. A new approach to GC treatment, which is a disease influenced by inflammation, is the exploitation of the immune system to fight disease. Two interesting targets/prognostic markers that bear further investigation in GC are PD1 and PDL, particularly given their success in the treatment of other inflammation/immune-associated malignancies.

Potentially functional variants in the core nucleotide excision repair genes predict survival in Japanese gastric cancer patients.

Functional genetic variants of DNA repair genes may alter the host DNA repair capacity, and thus influence efficiency of therapies. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in genes (i.e. ERCC1, XPA, XPC, XPD and XPG) involved in the nucleotide excision repair (NER) pathway in 496 Japanese gastric cancer patients, and assessed overall survival and recurrence-free survival. The combined effects of risk genotypes of these eight SNPs in Japanese patients were further replicated in 356 North-American gastric cancer patients. In Japanese patients, we found that the XPC rs2228000 TT genotype was associated with shorter overall survival [hazards ratio (HR) = 1.75, 95% confidence interval (95% CI) = 1.07-2.86] and recurrence-free survival (HR = 2.17, 95% CI = 1.19-3.95), compared with CC/CT genotypes, and the XPG rs17655 CC genotype was associated with shorter overall survival (HR = 1.60, 95% CI = 1.08-2.36), compared with GG/CG genotypes. The number of observed risk genotypes in the combined analysis was associated with shorter overall survival and recurrence-free survival in a dose-response manner (P(trend) = 0.006 and P(trend) < 0.000) in Japanese patients; specifically, compared with those with ≤1 risk genotypes, those with ≥2 risk genotypes showed markedly shorter overall survival (HR = 1.79, 95% CI = 1.18-2.70) and recurrence-free survival (HR = 2.80, 95% CI = 1.66-4.73). The association between ≥2 risk genotypes and shorter overall survival was not significant (HR = 1.26, 95% CI = 0.82-1.94) in North-American patients, but the trends were similar in these two groups of patients. These data show that functional SNPs in NER core genes may impact survival in Japanese gastric cancer patients.

A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma.

BACKGROUND: In the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma. METHODS: Three patient cohorts (discovery, n = 10; model, n = 43; and validation, n = 65) with locally advanced esophageal adenocarcinoma were analyzed. In the discovery cohort 754 miRNAs were examined in pretreatment tumor biopsy specimens using a TaqMan array. Of these, the 44 most significantly altered between tumors with pCR and non-pCR were examined in an additional 43 tumors using a Fluidigm 48.48 array. The 4 miRNAs (mir-505*, mir-99b, mir-451, and mir-145*) significantly predicting pCR in both cohorts were examined in an additional validation cohort (n = 65) using an Illumina array. These 4 miRNAs were used to generate an miRNA expression profile (MEP) score. RESULTS: The 4 miRNAs profiled are highly significantly associated with pCR in the model cohort (Ptrend = .008), the validation cohort (Ptrend = .025), and the combined cohort (Ptrend = 4.6 × 10(-4) ). The receiver-operator characteristic areas under the curves (AUCs) for the MEP score were 0.78 for the model cohort, 0.71 for the validation cohort, and 0.72 for the combined cohort. When combined with clinical variables, the MEP score AUCs increased to 0.89, 0.77, and 0.81, respectively Estimates from logistic regression based on the MEP were determined and used to generate a probability of pCR plot, which identifies a group of patients with very high (≥80%) and very low (≤10%) probability of pCR. CONCLUSIONS: The MEP score provides a validated means of predicting pCR to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma that is robust across several analysis platforms.

Distribution and timing of distant metastasis after local therapy in a large cohort of patients with esophageal and esophagogastric junction cancer.

BACKGROUND: Patients with localized esophageal and esophagogastric junction cancer (EAC) receive chemoradiation and then surgery (trimodality, TMT) or definitive chemoradiation (bimodality, BMT). Distant metastases (DMs) are common but the details of their distribution and timing in a large cohort have not been described. METHODS: 629 patients with localized EAC who had TMT or BMT were analyzed. Standard statistical methods were used to define the end points. RESULTS: The median follow-up time was 37.2 months (interquartile range 17.8-65.0). Of 356 TMT patients, 33% (119) developed DM as their first relapse and of 273 BMT patients, 40% (109) developed DM; 91% (TMT) and 96% (BMT) of the DMs were diagnosed within 2 years of local therapy. The most common sites of DM were: lung, distant nodes, liver, peritoneal cavity, bone, brain and pleura in order of frequency. The median overall survival of TMT patients with DM was 10.2 months (95% CI 7.8-12.7) and that for BMT patients with DM was 7.8 months (95% CI 5.7-9.9). CONCLUSIONS: Following TMT or BMT, ≥33% of patients developed DMs and most of these occurred within 2 years (>90%) of local therapy. A clinical model is desirable that associates clinical parameters with a high risk for DM in TMT-eligible patients prior to surgery.

Post-chemoradiation surgical pathology stage can customize the surveillance strategy in patients with esophageal adenocarcinoma.

Current algorithms for surveillance of patients with esophageal adenocarcinoma (EAC) after chemoradiation and surgery (trimodality therapy [TMT]) remain empiric. The authors hypothesized that the frequency, type, and timing of relapses after TMT would be highly associated with surgical pathology stage (SPS), and therefore SPS could be used to individualize the surveillance strategy. Between 2000 and 2010, 518 patients with EAC were identified who underwent TMT at The University of Texas MD Anderson Cancer Center and were frequently surveyed. Frequency, type, and timing of the first relapse (locoregional and/or distant) were tabulated according to SPS. Standard statistical approaches were used. The median follow-up time after esophageal surgery was 55.4 months (range, 1.0-149.2 months). Disease relapse occurred in 215 patients (41.5%). Higher SPS was associated with a higher rate of relapse (0/I vs II/III, P≤.001; 0/I vs II, P=.002; SPS 0/I vs III, P≤.001; and SPS II vs III, P=.005) and with shorter time to relapse (P<.001). Irrespective of the SPS, approximately 95% of all relapses occurred within 36 months of surgery. The 3- and 5-year overall survival rates were shorter for patients with a higher SPS than those with a lower SPS (0/I vs II/III, P≤.001; 0/I vs II, P≤.001; 0/I vs III, P≤.001; and II vs III, P=.014). The compelling data show an excellent association between SPS and frequency/type/timing of relapses after TMT in patients with EAC. Thus, the surveillance strategy can potentially be customized based on SPS. These data can inform a future evidence-based surveillance strategy that can be efficient and cost-effective.

Incidence of brain metastases after trimodality therapy in patients with esophageal or gastroesophageal cancer: implications for screening and surveillance.

BACKGROUND: It is unclear whether patients undergoing trimodality therapy (TMT) should be screened or surveyed for brain metastases. METHODS: We retrospectively analyzed esophageal cancer (EC) patients who underwent TMT between the years 2000 and 2010. All were systematically staged and surveyed but none had screening or surveillance brain imaging. RESULTS: The median follow-up time for 518 patients was 29.3 months (range 1-149.2); all patients had adenocarcinoma of the esophagus. Of 188 (36.3%) patients who developed distant metastases, 20 (10.6% of 188 patients or 3.9% of 518 patients) had brain metastases. A higher baseline clinical stage (stage III or IVa) was associated with brain metastases. Most (90%) patients with brain metastases were diagnosed within 24 months of surgery. Sixteen patients had central nervous system symptoms at diagnosis. Twelve (60%) patients had solitary metastasis and 8 (40%) patients had multiple metastases. Although 17 patients received therapy for brain metastases, the median overall survival time of 20 patients was only 10.5 months (95% CI 6.6-14.0). CONCLUSION: After TMT, 3.9% of EC patients developed brain metastases and their prognosis was poor. Our data suggest that screening and/or surveillance for brain metastases in the EC population undergoing TMT is not warranted.

Propensity-based matching between esophagogastric cancer patients who had surgery and who declined surgery after preoperative chemoradiation.

BACKGROUND: Trimodality therapy (TMT; chemoradiation plus surgery) has level-1 evidence for survival advantage for TMT-eligible esophagogastric cancer patients. Some patients, however, decline surgery after preoperative chemoradiation. The question of which patient should have esophagectomy and which one should not is unlikely to be answered by a prospective comparison; therefore, we matched the clinical covariates of several patients who had surgery with those who declined surgery (DS). METHODS: Between 2002 and 2011, we identified 623 patients in our databases. Of 623 patients, 244 patients had TMT and 61 TMT-eligible patients were in the DS group. Using the propensity-score method, we matched 16 covariates between 36 DS patients and 36 TMT patients. RESULTS: Baseline characteristics between the two groups were balanced (p = NS). The median overall survival times were: 57.9 months (95% CI: 27.7 to not applicable, NA) for the DS group and 50.8 months (95% CI: 30.7 to NA) for the TMT group (p = 0.28). The median relapse-free survival times were: 18.5 (95% CI: 11.5-30.4) for the DS group and 26.5 months (95% CI: 15.5-NA) for the TMT group (p = 0.45). Eleven (31%) of 36 patients in the DS group had salvage surgery. CONCLUSIONS: Our results are intriguing but skewed by the patients who had salvage surgery in the DS group. Until highly reliable predictive models are developed for esophageal preservation, TMT must be encouraged for all TMT-eligible gastroesophageal cancer patients.

Ramucirumab: a novel antiangiogenic agent.

Ramucirumab (IMC-1121B) is a fully humanized monoclonal antibody that binds to VEGFR2 and can inhibit angiogenesis, a quintessential mechanism for promoting tumor growth and metastasis. Several antiangiogenesis agents are already approved for cancer therapy; however, ramucirumab's selectivity for VEGFR2 makes it interesting. The selectivity of an agent can improve safety and efficacy. This article describes the mechanism of action, pharmacokinetics, safety and clinical trial results of ramucirumab with particular emphasis on gastric cancer.

Multiple-Choice Tests: A-Z in Best Writing Practices.

Multiple-choice tests are the most used method of assessment in medical education. However, there is limited literature in medical education and psychiatry to inform the best practices in writing good-quality multiple-choice questions. Moreover, few physicians and psychiatrists have received training and have experience in writing them. This article highlights the strategies in writing high-quality multiple-choice items and discusses some common flaws that can impact validity and reliability of the assessment examinations.

The Networked Computer Metaphor: A Novel Tool for Psychiatric Trainees to Enhance Utility of the Biopsychosocial Model of Health and Illness.

The biopsychosocial (BPS) model proposed by George Engel posited that a disease developed through a complex interaction of biological, psychological and social factors. This popular model, despite its limitations, continues to influence the practice and treatment of illness and service delivery worldwide. We propose the networked computer metaphor as a novel and pragmatic tool to help psychiatric trainees appreciate and enhance the utility of the BPS model as it pertains to psychiatric disorders. We also propose that the application of this metaphor would help provide some clues to answer the question of achieving the goal envisioned by Engel of providing holistic and comprehensive patient-centered care. We also discuss the utility of this metaphor from trainee, teacher and patient perspectives and describe various examples of the application of this metaphor so as to deepen our understanding of the BPS model. We discuss the criticisms of this model, summarize the applications of this metaphor and outline future directions for research.

The Safety and Efficacy of Repetitive Transcranial Magnetic Stimulation in the Treatment of Major Depression Among Children and Adolescents: A Systematic Review.

Major depression is a chronic debilitating condition affecting people of all ages and is rising over the past decade. Major depression among children and adolescents is often resistant to traditional treatments, thus necessitating the exploration of novel strategies. Repetitive transcranial magnetic stimulation (rTMS) is gaining increasing attention as a useful tool in treating various conditions and has received the US Food and Drug Administration (FDA) approval to treat depression and obsessive-compulsive disorder among adults. Favorable outcomes among adults generated interest in using it among children. Until recently, the existing literature lacked randomized sham-controlled trials on this topic among children and adolescents. The newest additions in the literature necessitated another in-depth look at the data to explore the safety and efficacy of rTMS in the context of depression among children and adolescents. We searched the Medline and Cochrane databases and included 18 articles for our systematic review. Our systematic review indicates level 1 evidence that rTMS is safe but failed to show its superiority to placebo as a stand-alone treatment for resistant depression among children and adolescents. However, there is level 2 evidence favoring add-on rTMS to treat major depression among children and adolescents. The study subjects appear to tolerate the rTMS treatment well with some minor and mostly self-limited side effects. Risks of treatment-emergent hypomanic symptoms and seizure appear to be very low. There is no evidence of worsening of suicidal ideation or cognitive decline during rTMS treatment.