Potential Predictive Immune and Metabolic Biomarkers of Tumor Microenvironment Regarding Pathological and Clinical Response in Esophageal Cancer After Neoadjuvant Chemoradiotherapy: A Systematic Review.

INTRODUCTION: The tumor microenvironment (TME) plays a crucial role in therapy response and modulation of immunologic surveillance. Adjuvant immunotherapy has recently been introduced in post-surgery treatment of locally advanced esophageal cancer (EC) with residual pathological disease after neoadjuvant chemoradiotherapy (nCRT). F-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) remains a valuable imaging tool to assess therapy response and to visualize metabolic TME; however, there is still a paucity in understanding the interaction between the TME and nCRT response. This systematic review investigated the potential of TME biomarkers and 18F-FDG-PET/CT features to predict pathological and clinical response (CR) after nCRT in EC. METHODS: A literature search of the Medline and Embase electronic databases identified 4190 studies. Studies regarding immune and metabolic TME biomarkers and 18F-FDG-PET/CT features were included for predicting pathological response (PR) and/or CR after nCRT. Separate analyses were performed for 18F-FDG-PET/CT markers and these TME biomarkers. RESULTS: The final analysis included 21 studies-10 about immune and metabolic markers alone and 11 with additional 18F-FDG-PET/CT features. High CD8 infiltration before and after nCRT, and CD3 and CD4 infiltration after nCRT, generally correlated with better PR. A high expression of tumoral or stromal programmed death-ligand 1 (PD-L1) after nCRT was generally associated with poor PR. Moreover, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) of the primary tumor were potentially predictive for clinical and PR. CONCLUSION: CD8, CD4, CD3, and PD-L1 are promising immune markers in predicting PR, whereas TLG and MTV are potential 18F-FDG-PET/CT features to predict clinical and PR after nCRT in EC.

Significant variation in histopathological assessment of endoscopic resections for Barrett's neoplasia suggests need for consensus reporting: propositions for improvement.

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett's esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria.

Prognostic Value of the Circumferential Resection Margin in Esophageal Cancer Patients After Neoadjuvant Chemoradiotherapy.

BACKGROUND: Circumferential resection margins (CRM) for esophageal cancer (EC), defined by the College of American Pathologists (CAP; >0 mm) or the Royal College of Pathologists (RCP; >1 mm) as tumor-free (R0), are based on a surgery-alone approach. We evaluated the usefulness of both definitions in current practice with neoadjuvant chemoradiotherapy (nCRT). METHODS: CRMs were measured in 209 patients (104 with nCRT) with locally advanced EC after transthoracic esophagectomy. Local recurrence and cancer related death were scored as events. Patients were followed for at least 2 years or until death. Prognostic factors (P < 0.1 in univariate analyses) for 2-year disease-free survival (DFS) and local recurrence-free survival (LRFS) were incorporated in multivariate Cox regression analyses. Both CRM measurements were analyzed separately and prognostic cutoff values (0-1.0 mm) were assessed in both groups. RESULTS: Independent prognostic factors (P < 0.05) for 2-year DFS were tumor length, lymph node ratio, angioinvasion, and CAP R0 in the surgery-alone group and pN stage (P < 0.01) in the nCRT group. Prognostic factors (P < 0.05) for 2-year LRFS were CAP, lymph node ratio, and tumor length in the surgery-alone group, and CAP and grade in the nCRT group. Optimal CRM cutoff values between 0.0 and 0.2 mm were prognostic for 2-year DFS in the surgery-alone and at 0.3 mm for the nCRT group. CONCLUSIONS: nCRT affected the CRM cutoff values. After nCRT, the CRM R0 according to the CAP was only prognostic for 2-year LRFS. However, in the surgery-alone group, it was prognostic for both the 2-year DFS and LRFS.

Consequence of restaging after neoadjuvant treatment for locally advanced rectal cancer.

BACKGROUND: Locally advanced rectal cancer is customarily treated with neoadjuvant chemoradiotherapy (CRT) followed by a total mesorectal excision. During the course of CRT, previously non-detectable distant metastases can appear. Therefore, a restaging CT scan of the chest and abdomen was performed prior to surgery. The aim of this study was to determine the frequency of a change in treatment strategy after this restaging CT scan. METHODS: Patients treated with neoadjuvant CRT for locally advanced rectal cancer between January 2003 and July 2013 were included retrospectively. To determine the value of the restaging CT scan, the surgical treatment as planned before CRT was compared with the treatment ultimately received. RESULTS: A total of 153 patients (91 male) were eligible, and median age was 62 (32-82) years. The restaging CT scan revealed the presence of distant metastases in 19 patients (12.4, 95 % confidence interval [CI] 7.0-17.8). In 17 patients (11.1, 95 % CI 6.1-16.1), a change in treatment strategy occurred due to the detection of metastases with a restaging CT scan. CONCLUSION: A restaging CT scan after completion of neoadjuvant CRT may detect newly developed metastases and consequently alter the initial treatment strategy. This study demonstrated the added value of the restaging CT scan prior to surgery.

Severe mesenteric ischemia with multiple organ failure in a patient previously treated with a humanized monoclonal antibody against programmed death receptor-1 (pembrolizumab), a case of pembrolizumab associated catastrophic antiphospholipid syndrome?

Immune checkpoint inhibitors are used in the treatment of different types of tumors including melanoma and non-small cell lung carcinoma. The use of these inhibitors is associated with a broad spectrum of immune-related adverse effects. Here we report a case of a patient admitted to the intensive care unit with multiple organ failure due to catastrophic antiphospholipid syndrome following treatment with pembrolizumab, an immune checkpoint inhibitor, because of metastatic melanoma. The presented patient had multiple organ failure of lung, gastro-intestinal, renal, and the liver. Vascular thrombosis was confirmed by both imaging (pulmonary embolism on computed tomography-thorax) and histopathological examination of the intestines. In combination with the presence of IgA anti-cardiolipin antibodies and initially IgM anti-cardiolipin antibodies, catastrophic antiphospholipid syndrome was suspected. Despite treatment with plasmapheresis and corticosteroids, the patient died due to multiple organ failure. Catastrophic antiphospholipid syndrome is difficult to recognize and has high mortality rates despite supportive treatment. In this case report, discussion is provided regarding the possible immunological mechanism behind catastrophic antiphospholipid syndrome during or after treatment with immune checkpoint inhibitors. It is important to realize that in modern intensive care unit, more patients with immune-related adverse effects of the treatment with immune checkpoint inhibitors will be admitted, because of an increase in the number of patients treated with these checkpoint inhibitors. When these patients are admitted on the intensive care unit, multi-disciplinary consultation is important because of the difficulty of early recognition and optimal treatment of these possible lethal side effects.

Adherence to pre-set benchmark quality criteria to qualify as expert assessor of dysplasia in Barrett's esophagus biopsies - towards digital review of Barrett's esophagus.

Background: Dysplasia assessment of Barrett's esophagus biopsies is associated with low observer agreement; guidelines advise expert review. We have developed a web-based review panel for dysplastic Barrett's esophagus biopsies. Objective: The purpose of this study was to test if 10 gastrointestinal pathologists working at Dutch Barrett's esophagus expert centres met pre-set benchmark scores for quality criteria. Methods: Ten gastrointestinal pathologists twice assessed 60 digitalized Barrett's esophagus cases, enriched for dysplasia; then randomised (7520 assessments). We tested predefined benchmark quality criteria: (a) percentage of 'indefinite for dysplasia' diagnoses, benchmark score ≤14% for all cases, ≤16% for dysplastic subset, (b) intra-observer agreement; benchmark score ≥0.66/≥0.39, (c) percentage agreement with 'gold standard diagnosis'; benchmark score ≥82%/≥73%, (d) proportion of cases with high-grade dysplasia underdiagnosed as non-dysplastic Barrett's esophagus; benchmark score ≤1/78 (≤1.28%) assessments for dysplastic subset. Results: Gastrointestinal pathologists had seven years' Barrett's esophagus-experience, handling seven Barrett's esophagus-cases weekly. Three met stringent benchmark scores; all cases and dysplastic subset, three met extended benchmark scores. Four pathologists lacked one quality criterion to meet benchmark scores. Conclusion: Predefined benchmark scores for expert assessment of Barrett's esophagus dysplasia biopsies are stringent and met by some gastrointestinal pathologists. The majority of assessors however, only showed limited deviation from benchmark scores. We expect further training with group discussions will lead to adherence of all participating gastrointestinal pathologists to quality criteria, and therefore eligible to join the review panel.