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1.
Brain Behav Immun ; 115: 26-37, 2024 01.
Article in English | MEDLINE | ID: mdl-37748567

ABSTRACT

Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.


Subject(s)
Adverse Childhood Experiences , Schizophrenia , Humans , Genome-Wide Association Study , Healthy Volunteers , Cognition/physiology
2.
World J Surg ; 47(1): 227-235, 2023 01.
Article in English | MEDLINE | ID: mdl-36264338

ABSTRACT

BACKGROUND AND AIMS: Esophageal adenocarcinoma (EAC) is associated with visceral obesity (VO). Non-alcoholic fatty liver disease (NAFLD) is common within this phenotype; however, its incidence and clinical significance in EAC have not been studied. STUDY DESIGN: A total of 559 patients with hepatic stetatosis (HS) defined by unenhanced CT were enrolled. In a sub-study, in 140 consecutive patients a liver biopsy was taken intraoperatively to study HS and non-alcoholic steatohepatitis (NASH). Postoperative complications were defined as per the Esophageal Complications Consensus Group (ECCG). Liver biochemistry was measured peri-operatively, with an ALT > 5 defined as acute liver injury (ALI). Mann-Whitney U test or Fisher's exact test was utilized and the Kaplan-Meier method for survival. RESULTS: 42% (n = 234/559) of patients had CT-defined HS. HS was associated with VO in 56% of cases, metabolic syndrome (Met S) in 37% and type 2 diabetes in 25%, compared with 44, 21, and 15% in non-HS patients (p < 0.01). Pathologic HS was present in 32% (45/140) and graded as mild, moderate, and severe in 73, 24, and 3%, respectively, with NASH reported in 16% and indefinite/borderline NASH in 42% of HS cases. Postoperative ALI was similar (p = 0.88) in both HS (10%) and non-HS cohorts (11%). Operative complication severity was similar in both cohorts. 5-yr survival was 53% (HS) vs 50% (p = 0.890). CONCLUSION: This study establishes for the first time the incidence and clinical impact of NAFLD in EAC patients undergoing surgery and highlights no major impact on oncologic outcomes, nor in the severity of complications.


Subject(s)
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology
3.
Ann Surg ; 276(5): e400-e406, 2022 11 01.
Article in English | MEDLINE | ID: mdl-33201133

ABSTRACT

OBJECTIVE: To analyze the spectrum of Centers for Disease Control and Prevention (CDC)-defined pneumonia after esophageal cancer surgery. SUMMARY BACKGROUND DATA: Pneumonia is commonly documented after esophageal cancer surgery, and reducing its incidence is central to both ERAS development and to the evidence-base for minimally invasive approaches. The existing definitions of pneumonia based on hospital acquired pneumonia classifications may be suboptimal in this context and merits strict academic scrutiny. METHODS: Patients (2013-2018) treated with curative intent by open surgery were studied. Pneumonia was defined per the CDC definition. Risk factors and associations were analyzed, as was the implications of positive cultures. Multivariable logistic regression examined independently predictive factors of pneumonia and oncologic outcomes. RESULTS: Of 343 patients, 56 (16%) had defined pneumonia, 22 (39%) with positive cultures. Preoperative respiratory disease predicted pneumonia ( P = 0.043). Neoadjuvant therapy was significantly ( P = 0.004) associated with culture negative pneumonia, and age ( P = 0.001) with culture positive pneumonia. In multivariable analysis, pneumonia was associated ( P < 0.05) with respiratory comorbidity, tumor site, and neoadjuvant chemoradiation. Pneumonia did not impact on overall survival (P = 0.807). DISCUSSION: CDC-defined pneumonia occurred in 16% of cases. Culture-negative pneumonia accounted for 61% of cases and was significantly associated with neoadjuvant chemoradiation. Pneumonia as currently defined seems to represent a spectrum of etiology and severity in the post-esoph-agectomy patient, with infection per se rarely proven, suggesting a need to reevaluate its definition, severity classification, and preventive and treatment strategies.


Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Lung Injury , Pneumonia , Esophagectomy/adverse effects , Humans , Pneumonia/epidemiology , Pneumonia/etiology , Postoperative Complications/etiology , Retrospective Studies
4.
Ann Surg ; 276(5): 792-798, 2022 11 01.
Article in English | MEDLINE | ID: mdl-35876385

ABSTRACT

BACKGROUND: The FLOT protocol and the CROSS trimodality regimen represent current standards in the management of locally advanced esophageal adenocarcinoma. In the absence of published Randomised Controlled Trial data, this propensity-matched comparison evaluated tolerance, toxicity, impact on sarcopenia and pulmonary physiology, operative complications, and oncologic metrics. METHODS: Two hundred and twenty-two patients, 111 in each arm, were included from 2 high-volume centers. Computed tomography-measured sarcopenia, and pulmonary function (forced expiratory volume in first second/forced vital capacity/diffusion capacity for carbon monoxide) were compared pretherapy and posttherapy. Operative complications were defined as per the Esophageal Complications Consensus Group (ECCG) criteria, and severity per Clavien-Dindo. Tumor regression grade and R status were measured, and survival estimated per Kaplan-Meier. RESULTS: A total of 83% were male, cT3/cN+ was 92%/68% for FLOT, and 86%/60% for CROSS. The full prescribed regimen was tolerated in 40% of FLOT patients versus 92% for CROSS. Sarcopenia increased from 16% to 33% for FLOT, and 14% to 30% in CROSS ( P <0.01 between arms). Median decrease in diffusion capacity for carbon monoxide was -8.25% (-34 to 25) for FLOT, compared with -13.8%(-38 to 29), for CROSS ( P =0.01 between arms). Major pathologic response was 27% versus 44% for FLOT and CROSS, respectively ( P =0.03). In-hospital mortality, respectively, was 1% versus 2% ( P =0.9), and Clavien Dindo >III 22% versus 27% ( P =0.59), however, respiratory failure was increased by CROSS, at 13% versus 3% ( P <0.001). Three-year survival was similar at 63% (FLOT) and 60% (CROSS) ( P =0.42). CONCLUSIONS: Both CROSS and FLOT resulted in equivalent survival. Operative outcomes were similar, however, the CROSS regimen increased postoperative respiratory failure and atrial fibrillation. Less than half of patients received the prescribed FLOT regimen, although toxicity rates were acceptable. These data support clinical equipoise, caution, however, may be advised with CROSS in patients with greatest respiratory risk.


Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Respiratory Insufficiency , Sarcopenia , Stomach Neoplasms , Adenocarcinoma/drug therapy , Adenocarcinoma/surgery , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carbon Monoxide/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/surgery , Esophagogastric Junction/pathology , Female , Humans , Male , Neoadjuvant Therapy/adverse effects , Respiratory Insufficiency/etiology , Sarcopenia/complications , Stomach Neoplasms/surgery
5.
Ann Surg ; 275(5): e683-e689, 2022 05 01.
Article in English | MEDLINE | ID: mdl-32740248

ABSTRACT

OBJECTIVE: To determine the incidence, risk factors, and consequences of AKI in patients undergoing surgery for esophageal cancer. SUMMARY OF BACKGROUND DATA: Esophageal cancer surgery is an exemplar of major operative trauma, with well-defined risks of respiratory, cardiac, anastomotic, and septic complications. However, there is a paucity of literature regarding AKI. METHODS: consecutive patients undergoing curative-intent surgery for esophageal cancer from 2011 to 2017 in 3 high-volume centers were studied. AKI was defined according to the AKI Network criteria. AKI occurred if, within 48 hours postoperatively, serum creatinine rose by 50% or by 0.3 mg/dL (26.5 µmol/L) from preoperative baseline. Complications were recorded prospectively. Multivariable logistic regression determined factors independently predictive of AKI. RESULTS: A total of 1135 patients (24.7%:75.3% female:male, with a mean age of 64, a baseline BMI of 27 kg m-2, and dyslipidemia in 10.2%), underwent esophageal cancer surgery, 85% having an open thoracotomy. Overall in-hospital mortality was 2.1%. Postoperative AKI was observed in 208 (18.3%) patients, with AKI Network 1, 2, and 3 in 173 (15.2%), 28 (2.5%), and 7 (0.6%), respectively. Of these, 70.3% experienced improved renal function within 48 hours. Preoperative factors independently predictive of AKI were age [P = 0.027, odds ratio (OR) 1.02 (1.00-1.04)], male sex [P = 0.015, OR 1.77 (1.10-2.81)], BMI at diagnosis [P < 0.001, OR 1.10 (1.07-1.14)], and dyslipidemia [P = 0.002, OR 2.14 (1.34-3.44)]. Postoperatively, AKI was associated with atrial fibrillation (P = 0.013) and pneumonia (P = 0.005). Postoperative AKI did not impact survival outcomes. CONCLUSION: AKI is common but mostly self-limiting after esophageal cancer surgery. It is associated with age, male sex, increased BMI, dyslipidemia, and postoperative morbidity.


Subject(s)
Acute Kidney Injury , Esophageal Neoplasms , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Esophageal Neoplasms/complications , Esophageal Neoplasms/surgery , Female , Humans , Incidence , Male , Middle Aged , Postoperative Complications/etiology , Retrospective Studies , Risk Factors
6.
Dis Esophagus ; 35(9)2022 Sep 14.
Article in English | MEDLINE | ID: mdl-35039840

ABSTRACT

Visceral obesity (VO) and metabolic syndrome (MetS) are risk factors for esophageal adenocarcinoma (EAC); however, their impact on operative and oncological outcomes is unclear. The aim of this study was to determine the incidence of VO and MetS among patients with EAC, and to assess their independent impact on operative and oncological outcomes. A total of 454 consecutive patients undergoing treatment with curative intent were studied. Total, subcutaneous, visceral fat area (VFA), and lean body mass (LBM) were measured by computed tomography pretreatment, with VO defined as VFA >163.8cm2 for men and 80.1cm2 for women. MetS was defined per the ATPIII definition. Multivariable logistic and Cox proportional hazards regression were utilized to determine independent predictors of oncologic and operative outcomes. A total of 227 patients (50.0%) had VO. A total of 134 (30%) overall had MetS, 44% in the VO cohort. VO was associated with Barrett's esophagus (P = 0.002) and lower cT (P = 0.006) and cN stage (P = 0.011), and improved disease-specific (P = 0.021) and overall survival (P = 0.012). No survival benefit existed for patients with VO who also had MetS. For operative complications, neither VO nor MetS increased the severity of complications, or mortality. However, VO was significantly (P = 0.035) associated with anastomotic leak and pneumonia (P = 0.037). MetS alone did not increase complication risk. VO increases specific major operative complications with no increase in mortality. VO improved survival, mainly relating to earlier stage disease; however, co-existent MetS abrogated this benefit. These seemingly paradoxical outcomes highlight manageable and potentially targetable perioperative challenges in the context of an overall favorable oncologic vista.


Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Metabolic Syndrome , Adenocarcinoma/complications , Adenocarcinoma/epidemiology , Adenocarcinoma/therapy , Esophageal Neoplasms/complications , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/therapy , Female , Humans , Incidence , Male , Metabolic Syndrome/complications , Metabolic Syndrome/epidemiology , Obesity, Abdominal/complications , Obesity, Abdominal/epidemiology , Postoperative Complications/etiology , Risk Factors
7.
Ann Surg ; 274(5): 814-820, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34310355

ABSTRACT

BACKGROUND AND AIMS: The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes. STUDY DESIGN: An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology. RESULTS: 175 patients (cT2-4a, Nany) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%. CONCLUSION: FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway.


Subject(s)
Adenocarcinoma/therapy , Antineoplastic Agents/therapeutic use , Esophageal Neoplasms/therapy , Esophagectomy/methods , Esophagogastric Junction , Neoplasm Staging , Thoracic Wall/surgery , Adenocarcinoma/diagnosis , Adult , Aged , Aged, 80 and over , Esophageal Neoplasms/diagnosis , Female , Humans , Male , Middle Aged , Treatment Outcome
8.
Brain Behav Immun ; 98: 388-396, 2021 11.
Article in English | MEDLINE | ID: mdl-34242739

ABSTRACT

OBJECTIVE: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. METHODS: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. RESULTS: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: ßindirect -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: ßindirect = -0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (ßindirect = -0.0618, 95% CI: -0.1523 to -0.285). CONCLUSION: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.


Subject(s)
Adverse Childhood Experiences , Schizophrenia , Brain , Brain Mapping , Cognition , Humans , Interleukin-6 , Magnetic Resonance Imaging , Neuropsychological Tests , Schizophrenia/diagnostic imaging
9.
Dis Esophagus ; 34(12)2021 Dec 24.
Article in English | MEDLINE | ID: mdl-33590037

ABSTRACT

SSIs represent common infection-related morbidity following major surgery. Modern care bundles have been established as prophylactic measures aimed at preventing SSI occurring postoperatively. SSI incidence and data on common culprit pathogens post-esophagectomy for cancer have not been previously reported. Patients (2013-2018) treated with curative intent were studied. SSI was defined as per the Center for Disease Control (CDC) definition. A care bundle pathway following the National Institute for Clinical Excellence (NICE) guidelines for prevention of SSIs was introduced in 2013 and was audited quarterly. Risk factors and associations of SSIs were analyzed, as was the prevalence of isolated pathogens. Multivariable logistic regression examined independently predictive factors of SSIs and oncologic outcomes. Of 343 patients, 34 (9.9%) developed a postoperative SSI, with a median (range) of 8 (6-17). Quarterly audit carried out over 6 years showed no significant annual variance or trend. The most prevalent pathogen cultured was Methicillin-sensitive Staphylococcus aureus (MSSA) in nine patients (32%) followed by Candida albicans (29%), Escherichia coli (14%), and Enterococcus faecium (11%). SSI was significantly associated with pneumonia (P = 0.001), respiratory failure (P = 0.014), atrial fibrillation (P = 0.004), anastomotic leak (P < 0.001), and in-hospital blood transfusions (P = 0.031). SSI did not impact the overall survival (P = 0.951). SSI rates can be maintained at less than 10% using strict care bundles and regular audit. The most common culprit pathogen is gram-positive MSSA representing 32% of cases. These data are novel and may represent a modern benchmark for SSI post-open esophagectomy for cancer. This study highlights the incidence and associations of SSI post-esophageal cancer surgery.


Subject(s)
Esophageal Neoplasms , Patient Care Bundles , Staphylococcal Infections , Esophageal Neoplasms/surgery , Humans , Incidence , Prospective Studies , Risk Factors , Surgical Wound Infection/epidemiology , Surgical Wound Infection/etiology
10.
Ann Surg ; 272(5): 814-819, 2020 11.
Article in English | MEDLINE | ID: mdl-32657924

ABSTRACT

OBJECTIVE: The aim of this study was to propose and test a novel adverse pathology classification in AEG. BACKGROUND: Recent scientific advances show genomic and molecular concordance across all AEG types, suggesting a rationale for a biologic classification. We tested a 3-dimension adverse pathology classification across the entire junction and per Siewert anatomic subtype. METHODS: Of 1625 patients with AEG, 650 underwent radical surgery, 55% post-neoadjuvant therapy (NeoT). Adverse features defined a priori were poor differentiation (PD), lymphatic invasion (LI), vascular invasion (VI), and perineural invasion (PN), with 3 groupings: 0 (no adverse feature), 1 to 2, and 3 to 4. Multivariable logistic and Cox proportional hazards regression were applied. RESULTS: For adverse pathology, 31%, 46%, and 23% had 0, 1 to 2, and 3 to 4, respectively. Fifty percent of cases were AEG I, 25% AEG II, and 25% AEG III. Median survival was not reached, 49 and 17 months for 0, 1 to 2, and 3 to 4 adverse pathology, respectively (P < 0.001), and 76, 51, and 34 months for AEG I, II, and III, respectively (P < 0.001); AEG I was significantly (P< 0.001) associated with lower c (y)pT and c (y)pN stages, and LI, VI, PN, and PD (poor vs other). The pathology model was significant for survival along with (y)pT and (y)pN, and predicted response to chemotherapy and chemoradiation irrespective of anatomic subtype (P < 0.001). CONCLUSION: A novel classification using standard pathology as proxy for poor biology is associated with survival and response to therapy. This effect is observed across the entire AEG spectrum, highlighting how biology should be aligned with anatomy in the modern paradigm of AEG management and design of clinical trials.


Subject(s)
Adenocarcinoma/pathology , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Adult , Aged , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Esophagectomy , Female , Humans , Ireland , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Invasiveness/pathology , Survival Rate
11.
CNS Spectr ; 24(1): 127-143, 2019 02.
Article in English | MEDLINE | ID: mdl-30859934

ABSTRACT

Neuropsychological dysfunction is a well-established finding in individuals with bipolar disorder type I (BP-I), even during euthymic periods; however, it is less clear whether this also pertains to bipolar disorder type II (BP-II) or those with subthreshold states (SBP; subthreshold bipolar disorder), such as bipolar not otherwise specified (BP-NOS). Herein, we compare the literature regarding neuropsychological performance in BP-II vs BP-I to determine the extent of relative impairment, and we present and review all related studies on cognition in SBP. After systematically searching PubMed, Medline, PsycINFO, and The Cochrane Library, we found 17 papers that comprise all the published studies relevant for this review. The areas that are consistently found to be impaired in BP are executive function, verbal memory, visual spatial working memory, and attention. More studies than not show no significant difference between BP-I and BP-II, particularly in euthymic samples. Preliminary evidence suggests that patients experiencing major depressive episodes who also meet criteria for SBP show similar profiles to BP-II; however, these results pertain only to a depressed sample. SBP were found to perform significantly better than both MDD and healthy controls in a euthymic sample. A consensus on mood state, patient selection, and neuropsychological testing needs to be agreed on for future research. Furthermore, no studies have used the most recent DSM-5 criteria for SBP; future studies should address this. Finally, the underlying bases of cognitive dysfunction in these diagnostic groups need to be further investigated. We suggest recommendations on all of the above current research challenges.


Subject(s)
Bipolar Disorder/physiopathology , Cognition , Attention , Executive Function , Humans , Memory
12.
J Cell Sci ; 129(9): 1769-74, 2016 05 01.
Article in English | MEDLINE | ID: mdl-26966185

ABSTRACT

Primary cilia are microtubule structures that extend from the distal end of the mature, mother centriole. CEP164 is a component of the distal appendages carried by the mother centriole that is required for primary cilium formation. Recent data have implicated CEP164 as a ciliopathy gene and suggest that CEP164 plays some roles in the DNA damage response (DDR). We used reverse genetics to test the role of CEP164 in the DDR. We found that conditional depletion of CEP164 in chicken DT40 cells using an auxin-inducible degron led to no increase in sensitivity to DNA damage induced by ionising or ultraviolet irradiation. Disruption of CEP164 in human retinal pigmented epithelial cells blocked primary cilium formation but did not affect cellular proliferation or cellular responses to ionising or ultraviolet irradiation. Furthermore, we observed no localisation of CEP164 to the nucleus using immunofluorescence microscopy and analysis of multiple tagged forms of CEP164. Our data suggest that CEP164 is not required in the DDR.


Subject(s)
Cell Nucleus/metabolism , DNA Repair , Microtubule Proteins/metabolism , Retinal Pigment Epithelium/metabolism , Animals , Cell Nucleus/pathology , Chickens , Cilia/genetics , Cilia/metabolism , DNA Damage , Gene Editing , HeLa Cells , Humans , Jurkat Cells , Microtubule Proteins/genetics , Retinal Pigment Epithelium/pathology , Ultraviolet Rays/adverse effects
13.
World J Surg ; 42(5): 1485-1495, 2018 05.
Article in English | MEDLINE | ID: mdl-29075858

ABSTRACT

INTRODUCTION: The standard of care for treatment of oesophageal squamous cell carcinoma (SCC) continues to evolve. Neoadjuvant chemoradiotherapy (neoCRT) provides a significant survival benefit compared to surgery alone but it is unclear whether definitive chemoradiation (dCRT) is superior. METHODS: Retrospective analysis of outcomes from patients treated in a national high-volume centre (2000-2014) where both neoCRT and dCRT are used with curative intent. Propensity score match analysis was used to match patients undergoing dCRT with those undergoing surgery ± neoCRT. RESULTS: A total of 668 patients were treated for SCC in this time period, 361 (54.0%) of whom were treated with curative intent. In patients treated with curative intent, 179 (49.6%) had dCRT, and of these 32 (18%) did not complete the treatment regimen. One hundred and seven patients (29.6%) underwent surgery only, and 75 patients (20.8%) had multimodal therapy. The proportion of patients treated with curative intent increased over this time period. The five-year disease-specific and overall survival rate of patients treated with multimodal therapy was 62 and 50%, respectively, compared with 25 and 20% for patients the dCRT group and 44 and 38%, respectively, for the surgery only cohort (p < 0.001). Patients with a complete pathological response had a 90% five-year disease-specific survival and 76% overall survival rate. Multimodal treatment rather than dCRT was a significant predictor of overall survival (OR 1.7 95% CI 1.3-2.4, p = 0.002). In 106 patients matched, those undergoing dCRT had a significantly poorer overall survival versus those receiving surgery as a component of their care (20.47 ± 3.74 months versus 30.65 ± 10.07 months, p = 0.002). CONCLUSION: This study provides evidence, consistent with CROSS data, that multimodal therapy for SCC can provide excellent outcomes with respect to overall survival, pathologic complete response rates, R0 resections and treatment-related mortality. A large RCT with specific arms for multimodal, dCRT and surgery alone is required.


Subject(s)
Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Chemoradiotherapy , Cohort Studies , Combined Modality Therapy , Esophageal Squamous Cell Carcinoma , Esophagectomy , Female , Humans , Male , Matched-Pair Analysis , Middle Aged , Neoadjuvant Therapy , Propensity Score , Retrospective Studies , Survival Rate
14.
Ann Surg ; 266(5): 822-830, 2017 11.
Article in English | MEDLINE | ID: mdl-28796017

ABSTRACT

OBJECTIVE: The aim of this article was to study the prevalence and significance of sarcopenia in the multimodal management of locally advanced esophageal cancer (LAEC), and to assess its independent impact on operative and oncologic outcomes. SUMMARY OF BACKGROUND DATA: Sarcopenia in cancer may confer negative outcomes, but its prevalence and impact on modern multimodal regimens for LAEC have not been systematically studied. METHODS: Two hundred fifty-two consecutive patients were studied. Lean body mass (LBM), skeletal muscle index (SMI), and fat mass (FM) were determined pre-treatment, preoperatively, and 1 year postoperatively. Sarcopenia was defined by computed tomography (CT) at L3 as SMI < 52.4 cm/m for males and SMI < 38.5 cm/m for females. All complications were recorded prospectively, including comprehensive complications index (CCI), Clavien-Dindo complication (CDC), and pulmonary complications (PPCs). Multivariable linear, logistic, and Cox regression analysis was performed. RESULTS: In-hospital mortality was 1%, and CCI was 21 ±â€Š19. Sarcopenia increased (P = 0.02) from 16% at diagnosis to 31% post-neoadjuvant therapy, with loss of LBM (-3.0 ±â€Š5.4 kg, P < 0.0001), but not FM (-0.3 ±â€Š2.7 kg, P= 0.31) during treatment. On multivariable analysis, preoperative sarcopenia was associated with CCI (P = 0.043), and CDC ≥IIIb (P = 0.003). PPCs occurred in 36% nonsarcopenic versus 55% sarcopenic patients (P = 0.01). Sarcopenia did not impact disease-specific (P = 0.14) or overall survival (P = 0.11) after resection. At 1 year, 35% had sarcopenia, significantly associated with pre-treatment BMI (P = 0.013) but not complications (P = 0.20). CONCLUSIONS: Sarcopenia increases through multimodal therapy, is associated with an increased risk of major postoperative complications, and is prevalent in survivorship. These data highlight a potentially modifiable marker of risk that should be assessed and targeted in modern multimodal care pathways.


Subject(s)
Adenocarcinoma/therapy , Carcinoma, Squamous Cell/therapy , Esophageal Neoplasms/therapy , Esophagectomy , Neoadjuvant Therapy , Postoperative Complications/etiology , Sarcopenia/etiology , Adenocarcinoma/complications , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/complications , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Female , Follow-Up Studies , Hospital Mortality , Humans , Incidence , Linear Models , Logistic Models , Male , Middle Aged , Multivariate Analysis , Postoperative Complications/epidemiology , Prevalence , Proportional Hazards Models , Prospective Studies , Risk Factors , Sarcopenia/diagnostic imaging , Sarcopenia/epidemiology , Survival Analysis , Tomography, X-Ray Computed , Treatment Outcome
15.
World J Surg ; 41(2): 487-497, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27778075

ABSTRACT

BACKGROUND: Benign anastomotic strictures occur frequently after esophagectomy, and impact on postoperative recovery, nutritional status, and quality of life. This large cohort study explored the incidence of stricture after transthoracic (2- and 3-stage) and transhiatal resections with uniform single-layer sutured anastomotic technique, and aimed to identify independent risk factors. METHODS: Patients undergoing esophagectomy with gastric conduit reconstruction between February 2001 and October 2014 were studied prospectively. Symptomatic anastomotic stricture was defined as dysphagia requiring endoscopic dilatation, and refractory strictures as those requiring >5 dilatations. Multivariable logistic regression was performed to determine factors independently associated with stricture development. RESULTS: Five-hundred and twenty-four patients, 77 % with adenocarcinoma, underwent esophagectomy [2-stage, n = 328 (62.6 %); 3-stage, n = 129 (23.3 %); transhiatal, n = 74 (14.1 %)], with an overall inhospital mortality rate of 2.7 %. 58.5 % of patients received neoadjuvant therapy [chemotherapy only, n = 119 (22.7 %); chemoradiation, n = 188 (35.9 %)]. Anastomotic stricture developed in 125 patients (24.5 %), was refractory in 20 (3.9 %) and required a median of 2 dilatations (range 1-18). On multivariable analysis, ASA grade (P < 0.05), cervical anastomosis (P < 0.001), and a significant postoperative cardiac event (P < 0.05) were independently associated with stricture risk. Refractory strictures were independently associated with anastomotic leak (P = 0.01) and transhiatal resections (P < 0.001). CONCLUSION: Benign anastomotic strictures are common, particularly with cervical reconstruction, and after transhiatal resection. Refractory strictures are rare. Where fitness and oncologic equivalence apply, a thoracic anastomosis provides significant advantages compared with a cervical anastomosis in terms of anastomotic stricture risk.


Subject(s)
Anastomosis, Surgical/adverse effects , Esophageal Stenosis/etiology , Esophagectomy , Adenocarcinoma/surgery , Cohort Studies , Deglutition Disorders/etiology , Esophageal Neoplasms/surgery , Esophagectomy/methods , Female , Humans , Male , Middle Aged , Risk Factors
18.
BMC Psychiatry ; 16: 52, 2016 Feb 27.
Article in English | MEDLINE | ID: mdl-26920578

ABSTRACT

BACKGROUND: A substantial number of patients do not benefit from first line psychological therapies for the treatment of depression and anxiety. Currently, there are no clear predictors of treatment outcomes for these patients. The PROMPT project aims to establish an infrastructure platform for the identification of factors that predict outcomes following psychological treatment for depression and anxiety. Here we report on the first year of recruitment and describe the characteristics of our sample to date. METHODS: One hundred and forty-seven patients awaiting treatment within an Improving Access to Psychological Therapies (IAPT) service were recruited between February 2014 and February 2015 (representing 48 % of those eligible). Baseline assessments were conducted to collect information on a variety of clinical, psychological and social variables including a diagnostic interview using the Mini International Neuropsychiatric Interview (MINI). RESULTS: Our initial findings showed that over a third of our sample were not presenting to IAPT services for the first time, and 63 % had been allocated to receive higher intensity IAPT treatments. Approximately half (46 %) were taking prescribed psychotropic medication (most frequently antidepressants). Co-morbidity was common: 72 % of the sample met criteria for 2 or more current MINI diagnoses. Our initial data also indicated that 16 % met criteria for borderline personality disorder and 69 % were at high risk of personality disorder. Sixty-one percent scored above the screening threshold for bipolarity. Over half of participants (55 %) reported experiencing at least one stressful life event in the previous 12 months, whilst 67 % reported experiencing at least one form of childhood trauma. CONCLUSIONS: Our results to date highlight the complex nature of patients seen within an urban IAPT service, with high rates of psychiatric comorbidity, personality disorder, bipolarity and childhood trauma. Whilst there are significant challenges associated with researching IAPT populations, we have also confirmed the feasibility of undertaking such research.


Subject(s)
Health Services Accessibility , Mental Disorders/therapy , Adolescent , Adult , Aged , Anxiety Disorders/psychology , Anxiety Disorders/therapy , Cohort Studies , Depressive Disorder/psychology , Depressive Disorder/therapy , Female , Humans , London , Male , Mental Disorders/psychology , Middle Aged , Treatment Outcome , Young Adult
19.
Ann Surg ; 262(5): 824-29; discussion 829-30, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26583672

ABSTRACT

OBJECTIVES: To characterize the gut hormone profile and determine the effect of satiety gut hormone blockade on food intake in disease-free postesophagectomy patients. BACKGROUND: Improved oncologic outcomes for esophageal cancer have resulted in increased survivorship and a focus on health-related quality of life. Anorexia and early satiety are common, but putative causative factors, in particular the gut-brain hormonal axis, have not been systematically studied. METHODS: In a double-blind, placebo-controlled, randomized crossover study, disease-free patients at least 1 year postresection and gastric conduit reconstruction received either 1 mL 0.9% saline or 1 mL (100 µg) octreotide acetate subcutaneously followed by a standardized ad libitum meal on each of two assessments. Fasting and postprandial plasma glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin immunoreactivity were measured. Gut hormone responses and calorie intake postsaline versus octreotide were compared between experimental and control groups. RESULTS: Eighteen subjects [esophagectomy (ES), n = 10, 2.4 ±â€Š0.75 years postresection; and unoperated control subjects, n = 8] were studied. ES demonstrated significant weight loss at 3, 6, 12, and 24 months postoperatively (all P < 0.05). Ghrelin levels were similar (P = 0.58) for both groups, but postprandial GLP-1 and PYY responses were significantly (P < 0.001) greater among ES as compared with controls. After octreotide, ad libitum calorie intake increased among ES (1.5 ±â€Š0.2 fold-change, P = 0.02) but not controls (1.1 ±â€Š0.1 fold-change, P = 0.30). CONCLUSIONS: ES demonstrated an exaggerated postprandial satiety gut hormone response that was attenuated by octreotide, thus identifying a potential therapeutic target to modulate in the ES patient with early satiety.


Subject(s)
Eating/drug effects , Esophageal Neoplasms/surgery , Esophagectomy , Gastrointestinal Hormones/antagonists & inhibitors , Gastroplasty , Octreotide/administration & dosage , Quality of Life , Body Mass Index , Cross-Over Studies , Double-Blind Method , Esophageal Neoplasms/metabolism , Female , Gastrointestinal Agents/administration & dosage , Humans , Injections, Subcutaneous , Male , Middle Aged
20.
Ann Surg ; 260(5): 772-8; discussion 778, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25379848

ABSTRACT

OBJECTIVE: To study new-onset postoperative atrial fibrillation in patients with esophageal and junctional cancer. DESIGN: Retrospective cohort study from a prospective data base. BACKGROUND: Atrial fibrillation (AF) is common after thoracic and esophageal surgical procedures. The full spectrum of risk factors, associations, and implications are unclear. METHODS: All patients undergoing multimodal therapy or surgery with curative intent from 2006 to mid-2013 were studied. New-onset AF was recorded prospectively. Risk factors, management and resolution, association with other complications, and impact on in-hospital mortality and longer-term oncologic outcomes were analyzed in retrospective cohort analysis. RESULTS: A total of 473 patients (mean age: 63 years; 73% male) underwent resection, 51% 2-stage, 18% 3-stage, 12% transhiatal, and 19% extended total gastrectomy. Ninety-six (20%) patients developed new-onset AF, in 18%, 27%, 29%, and 14% of 2-, 3-, transhiatal, and extended total gastrectomy cohorts, respectively (P=0.05). Age, diabetes, neoadjuvant therapy, and cardiac history predisposed (P<0.05) to AF, and AF was significantly (P<0.0001) associated with pneumonia, pleural effusions requiring drainage, and maximum postoperative C-reactive protein (CRP) (P<0.05) but not with anastomotic leak/conduit necrosis or mortality. Amiodarone was the primary treatment in 63% of cases, 1% underwent cardioversion, and 92% were in sinus rhythm on discharge. At a median follow-up of 40 months (7-109 months), the median survival was 40 months versus 53 months in the AF and non-AF cohorts, respectively (P=0.353) CONCLUSIONS: New-onset AF is common, linked to age, diabetes, cardiac disease, and neoadjuvant therapy. It is strongly associated with complications, principally respiratory sepsis, and systemic inflammation. For most, it resolves, with no impact on oncologic outcomes.


Subject(s)
Atrial Fibrillation/epidemiology , Atrial Fibrillation/therapy , Esophageal Neoplasms/surgery , Esophagogastric Junction/surgery , Postoperative Complications/epidemiology , Postoperative Complications/therapy , Adult , Age Factors , Aged , Aged, 80 and over , C-Reactive Protein/analysis , Comorbidity , Esophageal Neoplasms/pathology , Esophagectomy , Esophagogastric Junction/pathology , Female , Gastrectomy , Hospital Mortality , Humans , Incidence , Male , Middle Aged , Neoplasm Staging , Retrospective Studies , Risk Factors , Survival Rate
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