Impact on postoperative complications of changes in skeletal muscle mass during neoadjuvant chemotherapy for gastro-oesophageal cancer.

BACKGROUND: Risk assessment is relevant to predict postoperative outcomes in patients with gastro-oesophageal cancer. This cohort study aimed to assess body composition changes during neoadjuvant chemotherapy and investigate their association with postoperative complications. METHODS: Consecutive patients with gastro-oesophageal cancer undergoing neoadjuvant chemotherapy and surgery with curative intent between 2016 and 2019 were identified from a specific database and included in the study. CT images before and after neoadjuvant chemotherapy were used to assess the skeletal muscle index, sarcopenia, and subcutaneous and visceral fat index. RESULTS: In a cohort of 199 patients, the mean skeletal muscle index decreased during neoadjuvant therapy (from 51·187 to 49·19 cm2 /m2 ; P < 0·001) and the rate of sarcopenia increased (from 42·2 to 54·3 per cent; P < 0·001). A skeletal muscle index decrease greater than 5 per cent was not associated with an increased risk of total postoperative complications (odds ratio 0·91, 95 per cent c.i. 0·52 to 1·59; P = 0·736) or severe complications (odds ratio 0·66, 0·29 to 1·53; P = 0·329). CONCLUSION: Skeletal muscle index decreased during neoadjuvant therapy but was not associated with postoperative complications.

ANTECEDENTES: La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea. RESULTADOS: En una cohorte de 199 pacientes, el índice de masa muscular esquelética disminuyó durante el tratamiento neoadyuvante (de 51,87 cm2 /m2 a 49,19 cm2 /m2 , P < 0,001) y las tasas de sarcopenia aumentaron (de 42,2% a 54,2%, P < 0,001). Una disminución del índice de masa muscular esquelética > 5% no se asoció con un mayor riesgo de complicaciones postoperatorias globales (razón de oportunidades, odds ratio: 0,908; ic. del 95%: 0,520-1,587, P = 0,736) ni de complicaciones graves (odds ratio: 0,661; i.c. del 95%: 0,286-1,525, P = 0,329). CONCLUSIÓN: El índice de masa muscular esquelética disminuyó durante el tratamiento neoadyuvante, pero no se asoció con complicaciones postoperatorias.

Obesity surgery and Ehlers-Danlos syndrome: challenges and considerations based on a case report.

Ehlers-Danlos syndrome is a hereditary connective tissue disorder that has gastrointestinal manifestations in over 50% of its cases. We present the first case of bariatric surgery in a patient with Ehlers-Danlos syndrome and outline management challenges in the context of the relevant literature. A 56-year-old man with type IV Ehlers-Danlos syndrome and a body mass index of 41.8 kg/m2 was referred to the bariatric centre of the Churchill Hospital, Oxford, for consideration of surgery for morbid obesity. His comorbidity included type 2 diabetes, hypertension, dyslipidaemia and obstructive sleep apnoea. He underwent a laparoscopic Roux-en-Y gastric bypass. His initial recovery was uneventful and he was discharged on the first postoperative day. Six weeks later, he presented with 43.9% excess weight loss and improved glycaemic control. Three months postoperatively, however, he complained of dysphagia, regurgitation and postprandial pain. A barium meal and gastroscopy suggested the presence of a gastric diverticulum. A surgical exploration was planned. Intraoperative gastroscopy demonstrated an asymmetrical gastric pouch dilatation and the pouch was therefore refashioned laparoscopically. Despite the initial symptomatic relief, two months later he experienced retrosternal pain with progressive dysphagia. Since then, multiple endoscopic dilatations of the gastro-oesophageal junction have been performed for recurrence of symptoms. Finally, a laparoscopic hiatus hernia repair and adhesiolysis was performed resulting in complete relief of patient's symptoms. Bariatric management of patients with Ehlers-Danlos syndrome can prove challenging. The bariatric team must implement a careful management plan including a detailed consent process, a tailored surgical intervention and a follow-up focused on potential gastrointestinal manifestations.

Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.

Metabolic nodal response as a prognostic marker after neoadjuvant therapy for oesophageal cancer.

BACKGROUND: The ability to predict recurrence and survival after neoadjuvant chemotherapy (NAC) and surgery for oesophageal cancer remains elusive. This study evaluated the role of [18 F]fluorodeoxyglucose (FDG) PET-CT in assessing tumour and nodal response as a prognostic marker. METHODS: This was a single-centre UK cohort study. From 2006 to 2014, patients with oesophageal cancer staged with PET-CT before NAC, and restaged by CT or PET-CT before resection, were included. Pathological tumour response was evaluated using Mandard regression grades. Metabolic tumour and nodal responses (mTR and mNR respectively) were quantified using absolute and threshold reductions. RESULTS: Among 294 included patients, mTR and mNR independently predicted prognosis before surgery. After surgery, mNR (but not mTR), pathological tumour response, resection margin status and pathological node category predicted prognosis. Patients with FDG-avid nodal disease after NAC were at high risk of recurrence/death at 1 and 2 years (43 and 71 per cent respectively; P = 0·030 and P = 0·025 versus patients without avid nodes), and had a worse prognosis than patients with non-avid nodal metastases: hazard ratio 4·19 (95 per cent c.i. 1·87 to 9·40) and 2·11 (1·12 to 3·97) respectively versus patients without nodal metastases. Considering mTR and mNR response separately improved prognostication. CONCLUSION: mNR is a novel prognostic factor, independent of conventional N status. Primary and nodal tumours may respond discordantly and patients with FDG-avid nodes after NAC have a poor prognosis.

Pragmatic staging of oesophageal cancer using decision theory involving selective endoscopic ultrasonography, PET and laparoscopy.

BACKGROUND: Following CT, guidelines for staging oesophageal and gastro-oesophageal junction (GOJ) cancer recommend endoscopic ultrasonography (EUS), PET-CT and laparoscopy for T3-T4 GOJ tumours. These recommendations are based on generic utilities, but it is unclear whether the test risk outweighs the potential benefit for some patients. This study sought to quantify investigation risks, benefits and utilities, in order to develop pragmatic, personalized staging recommendations. METHODS: All patients with a histological diagnosis of oesophageal or GOJ cancer staged between May 2006 and July 2013 comprised a development set; those staged from July 2013 to July 2014 formed the prospective validation set. Probability thresholds of altering management were calculated and predictive factors identified. Algorithms and models (decision tree analysis, logistic regression, artificial neural networks) were validated internally and independently. RESULTS: Some 953 patients were staged following CT, by [(18) F]fluorodeoxyglucose PET-CT (918), EUS (798) and laparoscopy (458). Of these patients, 829 comprised the development set (800 PET-CT, 698 EUS, 397 laparoscopy) and 124 the validation set (118 PET-CT, 100 EUS, 61 laparoscopy). EUS utility in the 71.8 per cent of patients with T2-T4a disease on CT was minimal (0.4 per cent), its risk exceeding benefit. EUS was moderately accurate for pT1 N0 disease. A number of factors predicted metastases on PET-CT and laparoscopy, although none could inform an algorithm. PET-CT altered management in 23.0 per cent, and laparoscopy in 7.1 per cent, including those with T2 and distal oesophageal tumours. CONCLUSION: Although EUS provided additional information on T and N category, its risk outweighed potential benefit in patients with T2-T4a disease on CT. Laparoscopy seemed justified for distal oesophageal tumours of T2 or greater.

The effect of formalizing enhanced recovery after esophagectomy with a protocol.

Enhanced recovery after surgery (ERAS) pathways aim to accelerate functional return and discharge from hospital. They have proven effective in many forms of surgery, most notably colorectal. However, experience in esophagectomy has been limited. A recent study reported significant reductions in pulmonary complications, mortality, and length of stay following the introduction of an ERAS protocol alone, without the introduction of any clinical changes. We instituted a similar change 16 months ago, introducing a protocol to provide a formal framework, for our existing postoperative care. This retrospective analysis compared outcome following esophagectomy for the 16 months before and 20 months after this change. Data were collected from prospectively maintained secure web-based multidisciplinary databases. Complication severity was classified using the Clavien-Dindo scale. Operative mortality was defined as death within 30 days of surgery, or at any point during the same hospital admission. Lower respiratory tract infection was defined as clinical evidence of infection, with or without radiological signs. Respiratory complications included lower respiratory tract infection, pleural effusion (irrespective of drainage), pulmonary collapse, and pneumothorax. Statistical analysis was performed using SPSS v21. One hundred thirty-two patients underwent esophagectomy (55 protocol group; 77 before). All were performed open. There were no differences between the two groups in terms of age, gender, operation, use of neoadjuvant therapy, cell type, stage, tumor site, or American Society of Anesthesiologists grade. Median length of stay was 14.0 days (protocol) compared with 12.0 before (interquartile range 9-19 and 9.5-15.5, respectively; P = 0.073, Mann-Whitney U-test). Readmission within 30 days of discharge occurred in five (9.26%) and six (8.19%; P = 1.000, Fisher's exact test). There were four in-hospital deaths (3.03%): one (1.82%) and three (3.90%), respectively (P = 0.641). There were no differences in the severity of complications (P = non-significant; Pearson's chi-squared). There were no differences in the type of complications occurring in either group. The protocol was completed successfully by 26 (47.3%). No baseline factors were predictive of this. In contrast to previous studies, we did not demonstrate any improvement in outcome by formalizing our existing pathway using a written protocol. Consequently, improvements in short-term outcome from esophagectomy within ERAS would seem to be primarily due to improvements in components of perioperative care. Consequently, we would recommend that centers introducing new (or reviewing existing) ERAS pathways for esophagectomy focus on optimizing clinical aspects of such standardized pathways.

Attempted validation of the NUn score and inflammatory markers as predictors of esophageal anastomotic leak and major complications.

The ability to predict complications following esophagectomy/extended total gastrectomy would be of great clinical value. A recent study demonstrated significant correlations between anastomotic leak (AL) and numerical values of C-reactive protein (CRP), white cell count (WCC) and albumin measured on postoperative day (POD) 4. A predictive model comprising all three (NUn score >10) was found to be highly sensitive and discriminant in predicting AL and complications. We attempted a retrospective validation in our center. Data were collected on all resections performed during a 5-year period (April 2008-2013) using prospectively maintained databases. Our biochemistry laboratory uses a maximum CRP value (156 mg/L), unlike that of the original study; otherwise all variables and outcome measures were comparable. Analysis was performed for all patients with complete blood results on POD4. Three hundred twenty-six patients underwent resection, of which 248 had POD4 bloods. There were 21 AL overall (6.44%); 16 among those with complete POD4 blood results (6.45%). There were 8 (2.45%) in-hospital deaths; 7 (2.82%) in those with POD4 results. No parameters were associated with AL or complication severity on univariate analysis. WCC was associated with AL in multivariate binary logistic regression with albumin and CRP (OR 1.23 [95% CI 1.03-1.47]; P = 0.021). When a binary variable of CRP ≥ 156 mg/L was used rather than an absolute value, no factors were significant. Mean NUn was 8.30 for AL, compared with 8.40 for non-AL (P = 0.710 independent t-test). NUn > 10 predicted 0 of 16 leaks (sensitivity 0.00%, specificity 94.4%, receiver operator curve [ROC] area under the curve [AUC] 0.485; P = 0.843). NUn > 7.65 was 93% sensitive and 21.6% specific. ROC for WCC alone was comparable with NUn (AUC 0.641 [0.504-0.779]; P = 0.059; WCC > 6.89 93.8% sensitive, 20.7% specific; WCC > 15 6.3% sensitive and 97% specific). There were no associations between any parameters and other complications. In a comparable cohort with the original study, we demonstrated a similar multivariate association between WCC alone on POD4 and subsequent demonstration of AL, but not albumin or CRP (measured up to 156 mg/L). The NUn score overall (calculated with this caveat) and a threshold of 10 was not found to have clinical utility in predicting AL or complications.

Metabolic response at repeat PET/CT predicts pathological response to neoadjuvant chemotherapy in oesophageal cancer.

OBJECTIVES: Reports have suggested that a reduction in tumour 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) examination during or after neoadjuvant chemotherapy may predict pathological response in oesophageal cancer. Our aim was to determine whether metabolic response predicts pathological response to a standardised neoadjuvant chemotherapy regimen within a prospective clinical trial. METHODS: Consecutive patients staged with potentially curable oesophageal cancer who underwent treatment within a non-randomised clinical trial were included. A standardised chemotherapy regimen (two cycles of oxaliplatin and 5-fluorouracil) was used. PET/CT was performed before chemotherapy and repeated 24-28 days after the start of cycle 2. RESULTS: Forty-eight subjects were included: mean age 65 years; 37 male. Using the median percentage reduction in SUV(max) (42%) to define metabolic response, pathological response was seen in 71% of metabolic responders (17/24) compared with 33% of non-responders (8/24; P = 0.009, sensitivity 68%, specificity 70%). Pathological response was seen in 81% of subjects with a complete metabolic response (13/16) compared with 38% of those with a less than complete response (12/32; P = 0.0042, sensitivity 52%, specificity 87%). There was no significant histology-based effect. CONCLUSIONS: There was a significant association between metabolic response and pathological response; however, accuracy in predicting pathological response was relatively low.

Role of positron emission tomography-computed tomography in predicting survival after neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma.

BACKGROUND: Positron emission tomography combined with computed tomography (PET-CT) is increasingly being used in the staging of oesophageal cancer. Some recent reports suggest it may be used to predict survival. None of these studies, however, reported on the prognostic value of PET-CT performed before neoadjuvant chemotherapy and surgery. The aim of this study was to determine whether pretreatment PET-CT could predict survival. METHODS: Consecutive patients with oesophageal adenocarcinoma who underwent PET-CT before neoadjuvant chemotherapy and resection were included. Maximum standardized uptake value (SUV(max)), fluorodeoxyglucose (FDG)-avid tumour length and the presence of FDG-avid local lymph nodes were determined for all patients. Kaplan-Meier survival analysis was performed and multivariable analysis used to identify independent prognostic factors. RESULTS: A total of 121 patients were included (mean age 63 years, 97 men) of whom 103 underwent surgical resection. On an intention-to-treat basis, overall survival was significantly worse in patients with FDG-avid local lymph nodes (P < 0·001). SUV(max) and FDG-avid tumour length did not predict survival (P = 0·276 and P = 0·713 respectively). The presence of FDG-avid local lymph nodes was an independent predictor of poor overall survival (hazard ratio (HR) 4·75, 95 per cent confidence interval 2·14 to 10·54; P < 0·001) and disease-free survival (HR 2·97, 1·40 to 6·30; P = 0·004). CONCLUSION: The presence of FDG-avid lymph nodes, but not SUV(max) or FDG-avid tumour length, was an independent adverse prognostic factor.

Additional benefit of ¹8F-fluorodeoxyglucose integrated positron emission tomography/computed tomography in the staging of oesophageal cancer.

OBJECTIVE: ¹8F-fluorodeoxyglucose positron emission tomography (FDG PET) has been shown to improve the accuracy of staging in oesophageal cancer. We assessed the benefit of PET/CT over conventional staging and determined if tumour histology had any significant impact on PET/CT findings. METHODS: A retrospective cohort study, reviewing the results from 200 consecutive patients considered suitable for radical treatment, undergoing routine PET/CT staging comparing the results from CT and endoscopic ultrasound, as well as multi-disciplinary team records. Adenocarcinoma and squamous cell carcinoma were compared for maximum Standardised Uptake Value (SUV(max)), involvement of local lymph nodes and distant metastases. RESULTS: PET/CT provided additional information in 37 patients (18.5%) and directly altered management in 34 (17%): 22 (11%) were upstaged; 15 (7.5%) were downstaged, 12 of whom (6%) received radical treatment. There were 11 false negatives (5.5%) and 1 false positive (0.5%). SUV(max) was significantly lower for adenocarcinoma than squamous cell carcinoma (median 9.1 versus 13.5, p = 0.003). CONCLUSIONS: Staging with PET/CT offers additional benefit over conventional imaging and should form part of routine staging for oesophageal cancer. Adenocarcinoma and squamous cell carcinoma display significantly different FDG-avidity.

Left thoracoabdominal esophagectomy: results from a single specialist center.

The left thoracoabdominal approach to esophagectomy is not widely performed, despite offering excellent exposure to tumors of the esophagogastric junction. Criticisms of the approach have focused on historically high rates of mortality, complications, and positive resection margins. Our aim was to determine whether left thoracoabdominal esophagectomy could combine a radical oncological resection with acceptably low mortality and morbidity. A retrospective cohort study of all left thoracoabdominal esophagectomies was performed at a single specialist center over an 11-year period. Primary outcomes were in-hospital mortality, complications, resection margin involvement, and lymph node yield; secondary outcomes were 1-year and 5-year survival. Two hundred eleven esophagectomies were performed. In-hospital mortality was 5.7% (12/211). One hundred one subjects (47.9%) had an uncomplicated recovery; 110 subjects (52.1%) developed at least one complication. There were 15 clinically significant anastomotic leaks (7.1%). Twenty-four subjects (11.4%) required emergency reoperation, the most common indication being anastomotic leakage. Complete tumor excision (R0 resection) was achieved in 151 of 211 cases (71.6%); median lymph node yield was 24. One-year and 5-year survival rates were 70% (147/211) and 21% (24/116), respectively. Left thoracoabdominal esophagectomy can combine a radical oncological resection with acceptably low mortality and morbidity.