Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

AIM: To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy.METHODS: Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single institution were reviewed. Triplet neoadjuvant chemotherapy consisting of platinum, fluoropyrimidine and anthracycline was considered for operable patients (World Health Organization performance status ? 2) with clinical stage T2-4 N0-1. Response to neoadjuvant chemotherapy (NAC) was assessed using TRG, as described by Mandard et al. In addition lymph node downstaging was also assessed. Lymph node downstaging was defined by cN1 at diagnosis: assessed radiologically (computed tomography, positron emission tomography, endoscopic ultrasonography), then pathologically recorded as N0 after surgery; ypN0 if NAC given prior to surgery, or pN0 if surgery alone. Patients were followed up for 5 years post surgery. Recurrence was defined radiologically, with or without pathological confirmation. An association was examined between t TRG and lymph node downstaging with disease free survival (DFS) and a comprehensive range of clinicopathological characteristics.RESULTS: Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years (median follow up: 2.552, 95%CI: 2.022-3.081). There was a 1.8% (n = 4) inpatient mortality rate. One hundred and thirty-six (62.4%) patients received NAC, with 74.3% (n = 101) of patients demonstrating some signs of pathological tumour regression (TRG 1-4) and 5.9% (n = 8) having a complete pathological response. Forty four point one percent (n = 60) had downstaging of their nodal disease (cN1 to ypN0), compared to only 15.9% (n = 13) that underwent surgery alone (pre-operatively overstaged: cN1 to pN0), (P < 0.0001). Response to NAC was associated with significantly increased DFS (mean DFS; TRG 1-2: 5.1 years, 95%CI: 4.6-5.6 vs TRG 3-5: 2.8 years, 95%CI: 2.2-3.3, P < 0.0001). Nodal down-staging conferred a significant DFS advantage for those patients with a poor primary tumour response to NAC (median DFS; TRG 3-5 and nodal down-staging: 5.533 years, 95%CI: 3.558-7.531 vs TRG 3-5 and no nodal down-staging: 1.114 years, 95%CI: 0.961-1.267, P < 0.0001).CONCLUSION: Response to NAC in the primary tumour and in the lymph nodes are both independently associated with improved DFS

Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma

BACKGROUND: Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10-15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.MATERIALS AND METHODS: Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.RESULTS: Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.DISCUSSION: Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Hiatal Hernia After Esophagectomy for Cancer

BACKGROUND: Hiatal hernia (HH) after esophagectomy is becoming more relevant due to improvements in survival. This study evaluated and compared the occurrence and clinical course of HH after open and minimally invasive esophagectomy (MIE). METHODS: The prospectively recorded characteristics of patients treated with esophagectomy for cancer at 2 tertiary referral centers in the United Kingdom and the Netherlands between 2000 and 2014 were reviewed. Computed tomography reports were reviewed to identify HH. RESULTS: Of 657 patients, MIE was performed in 432 patients (66%) and open esophagectomy in 225 (34%). A computed tomography scan was performed in 488 patients (74%). HH was diagnosed in 45 patients after a median of 20 months (range, 0 to 101 months). The development of HH after MIE was comparable to the open approach (8% vs 5%, p = 0.267). At the time of diagnosis, 14 patients presented as a surgical emergency. Of the remaining 31 patients, 17 were symptomatic and 14 were asymptomatic. An elective operation was performed in 10 symptomatic patients, and all others were treated conservatively. During conservative treatment, 2 patients presented as a surgical emergency. An emergency operation resulted in a prolonged intensive care unit stay compared with an elective procedure (3 vs 0 days, p < 0.001). In-hospital deaths were solely seen after emergency operations (19%). CONCLUSIONS: HH is a significant long-term complication after esophagectomy, occurring in a substantial proportion of the patients. The occurrence of HH after MIE and open esophagectomy is comparable. Emergency operation is associated with dismal outcomes and should be avoided

Hiatal Hernia After Esophagectomy for Cancer

BACKGROUND: Hiatal hernia (HH) after esophagectomy is becoming more relevant due to improvements in survival. This study evaluated and compared the occurrence and clinical course of HH after open and minimally invasive esophagectomy (MIE). METHODS: The prospectively recorded characteristics of patients treated with esophagectomy for cancer at 2 tertiary referral centers in the United Kingdom and the Netherlands between 2000 and 2014 were reviewed. Computed tomography reports were reviewed to identify HH. RESULTS: Of 657 patients, MIE was performed in 432 patients (66%) and open esophagectomy in 225 (34%). A computed tomography scan was performed in 488 patients (74%). HH was diagnosed in 45 patients after a median of 20 months (range, 0 to 101 months). The development of HH after MIE was comparable to the open approach (8% vs 5%, p = 0.267). At the time of diagnosis, 14 patients presented as a surgical emergency. Of the remaining 31 patients, 17 were symptomatic and 14 were asymptomatic. An elective operation was performed in 10 symptomatic patients, and all others were treated conservatively. During conservative treatment, 2 patients presented as a surgical emergency. An emergency operation resulted in a prolonged intensive care unit stay compared with an elective procedure (3 vs 0 days, p < 0.001). In-hospital deaths were solely seen after emergency operations (19%). CONCLUSIONS: HH is a significant long-term complication after esophagectomy, occurring in a substantial proportion of the patients. The occurrence of HH after MIE and open esophagectomy is comparable. Emergency operation is associated with dismal outcomes and should be avoided

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies

Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.</p

Effect of Amoxicillin dose and treatment duration on the need for antibiotic re-treatment in children with Community-Acquired Pneumonia: The CAP-IT randomized clinical trial

Importance: The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear. Objective: To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days. Design, Setting, and Participants: Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019. Interventions: Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401). Main Outcomes and Measures: The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates. Results: Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI -∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI -∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P =.63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P =.04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P =.03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, -∞ to10%]; P value for interaction =.18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, -∞ to 7.4%]; P value for interaction =.73). Conclusions and Relevance: Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings. Trial Registration: ISRCTN Identifier: ISRCTN76888927