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Background The thoracic lymphadenectomy during an esophagectomy for esophageal cancer includes resection of the thoracic duct (TD) compartment containing the thoracic duct lymph nodes (TDLN). However, the role of TD compartment resection is still a topic of debate since metastatic TDLNs have only been demonstrated in squamous cell carcinomas in Eastern esophageal cancer patients. Therefore, the aim of this study was to assess the presence and metastatic involvement of TDLNs in a Western population, in which adenocarcinoma is the predominant type of esophageal cancer. Methods From July 2017 to May 2020 all consecutive patients undergoing an open or robot-assisted transthoracic esophagectomy with concurrent lymphadenectomy and resection of the TD compartment in the University Medical Center Utrecht, The Netherlands and the Citta della Salute e della Scienza University Hospital in Turin, Italy were included. The TD compartment was resected en bloc and was separated in the operation room by the operating surgeon after which it was macro- and microscopically assessed for (metastatic) TDLNs by the pathologist. Results A total of 117 patients with an adenocarcinoma (73%) or squamous cell carcinoma (27%) of the esophagus were included. In 61 (52%) patients TDLNs were found, containing metastasis in 9 (15%) patients. No major complications related to TD compartment resection were observed. Conclusions This is the first study to demonstrate the presence of metastatic TDLNs in adenocarcinomas of the esophagus. This result provides a valid argument to routinely extend the thoracic lymphadenectomy with resection of the TD compartment during an esophagectomy for esophageal cancer.

Various lymph node functions are regulated by the sympathetic nervous system as shown in rodent studies. If human lymph nodes show a comparable neural regulation, their afferent nerves could represent a potential therapeutic target to treat, for example, infectious or autoimmune disease. Little information is available on human lymph node innervation and the aim of this study is to establish a comprehensive and accurate representation of the presence and location of sympathetic nerves in human lymph nodes. Since previous studies mention sympathetic paravascular nerves to occasionally extent into T cell‐rich regions, the relation of these nerves with T cells was studied as well. A total number of 15 inguinal lymph nodes were resected from six donated human cadavers. Lymph node sections were stained with HE and a double T/B cell staining for evaluation of their morphology and to screen for general pathologies. A triple stain was used to identify blood vessels, sympathetic nerves and T cells, and, to study the presence and location of sympathetic nerves and their relation to T cells. To evaluate whether the observed nerves were en route to other structures or were involved in local processes, adjacent slides were stained with a marker for varicosities (synaptophysin), which presence is suggestive for synaptic activity. All lymph nodes contained sympathetic nerves, both as paravascular and discrete structures. In 15/15 lymph nodes, nerves were observed in their capsule, medulla and hilum, whereas only 13/15 lymph nodes contained nerves in their cortex. The amount of sympathetic nerves varied between compartments and between and within individuals. In general, if a lymph node contained more paravascular nerves in a specific compartment, more discrete nerves were observed as well. Occasionally, discrete nerves were observed in relation to T cells in lymphoid tissues of the cortex and medulla. Furthermore, discrete nerves were frequently present in the capsule and hilum. The presence of varicosities in a portion of these nerves, independently to their compartment, suggested a local regulatory function for these nerves. Human lymph nodes contain sympathetic nerves in their capsule, trabeculae, cortex, medulla and hilum, both as paravascular or as discrete structures. Discrete nerves were observed in relation to T cells and non‐T cell‐rich areas such as the hilar and capsular connective tissue. The presence of discrete structures suggests neural regulation of structures other than blood vessels, which was further supported by the presence of varicosities in a portion of these nerves. These observations are of relevance in further understanding neural regulation of lymph node immune responses and in the development of neuromodulatory immune therapies., Human lymph nodes contain a significant number of sympathetic nerves (black encircled, pink stained TH positive structures). These nerves can be observed surrounding vascular structures, but also as discrete entities in the capsule, cortex, medulla and hilum. In the medulla, these nerves are frequently observed in proximity with immune cells such as T lymphocytes (CD3 positive cells as shown in the right images). Sympathetic nerves in lymph nodes might contribute to neuro immune regulation of lymph node immune function.

Background Extra-regional lymph node metastases strongly determine treatment options in patients with esophageal cancer. Staging modalities such as (FDG-PET) CT scanning frequently show activity in retroperitoneal and lung hilar lymph nodes. This study evaluated the incidence of histologically confirmed metastases, treatment approach and recurrence patterns in patients with (FDG-PET) CT positivity in these regions. Methods All patients with (FDG-PET-) CT positive hilar and/or retroperitoneal lymph nodes at primary staging or restaging discussed at a multidisciplinary tumor board meeting for staging of esophageal cancer between January 2012–December 2017 were included. Biopsies and follow-up were evaluated to determine the presence of metastases and progression rates. Results From 2012 to 2017, 65 of 857 patients (7.6%) were selected with positive retroperitoneal and/or hilar lymph nodes. A total of 47/65 (72.3%) patients had positive retroperitoneal lymph nodes, which contained metastases in 19 (29.2%). When no biopsy was performed and curative treatment was given (n = 14), 9 patients had progression or locoregional and distant recurrence. Positive hilar lymph nodes were identified in 21 (32.3%) patients; 4 were biopsied and none contained metastases. In these patients no recurrence of disease was seen during follow-up. Conclusions The majority of biopsied (PET)CT-positive retroperitoneal lymph nodes at staging contained metastases, while biopsied (PET)CT-positive hilar nodes did not. Histological evaluation of (PET)CT -positive retroperitoneal lymph nodes at staging imaging is recommended, while based on this small series, (PET)CT-positive hilar lymph nodes most likely represent reactive lymphadenopathy.

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global outbreak and prompted an enormous research effort. Still, the subcellular localization of the coronavirus in lungs of COVID-19 patients is not well understood. Here, the localization of the SARS-CoV-2 proteins is studied in postmortem lung material of COVID-19 patients and in SARS-CoV-2-infected Vero cells, processed identically. Correlative light and electron microscopy on semithick cryo-sections demonstrated induction of electron-lucent, lipid-filled compartments after SARS-CoV-2 infection in both lung and cell cultures. In lung tissue, the nonstructural protein 4 and the stable nucleocapsid N-protein were detected on these novel lipid-filled compartments. The induction of such lipid-filled compartments and the localization of the viral proteins in lung of patients with fatal COVID-19 may explain the extensive inflammatory response and provide a new hallmark for SARS-CoV-2 infection at the final, fatal stage of infection.

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John WileySons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Milky spots are unique lymphoid structures in the greater omentum that participate in both immune homeostasis of the peritoneal cavity and formation of omental metastases. We developed a rapid and simple staining method to enable macro- or stereomicroscopic identification of these miniscule structures in large samples of fixed human greater omentum. By immersing approximately 6 × 4 cm samples of omental tissue in hematoxylin, these samples could be evaluated quickly for the presence of milky spots. We used an alum hematoxylin variant containing 1 g hematoxylin, 50 g aluminium ammonium sulfate, 0.2 g sodium iodide, 1 g citric acid and 50 g chloral hydrate. This staining method enabled us to determine the number, location, dimensions and topographical relation of milky spots to other structures. Our method also facilitates isolation of milky spots for further investigation. Hematoxylin imparts a blue color to the milky spots, which remains in place during further processing for paraffin embedding. This enabled easy recognition of milky spots during transfer through various solutions and permitted selection of relevant paraffin slides prior to additional staining.

Summary: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy. Methods: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course. Findings: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41–78). Median disease course (time from onset of symptoms to death) was 22 days (range 5–44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5–44]; ten patients with neutrophilic plugs, 21 days [5–44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets.. Interpretation: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19. Funding: Amsterdam UMC Corona Research Fund.

Background Resection of the thoracic duct is part of the formal en bloc mediastinal esophagolymphadenectomy for cancer, although with the adaptation of minimally invasive techniques, some centers started to leave the thoracic duct compartment in situ. However, previous studies reported thoracic duct lymph nodes in this compartment that may contain metastasis. The aim of this study was to assess the presence and number of lymph nodes in the fatty tissue surrounding the thoracic duct. Methods A right-sided thoracoscopic esophagectomy was performed on seven fresh-frozen human cadavers (male, n = 3; female, n = 4). The esophagus and lymph node stations 7, 8, and 9 were resected en bloc, followed by resection of the thoracic duct compartment consisting of the fatty tissue covering the aorta, the thoracic duct and thoracic duct lymph nodes. Lymph nodes were visualized by a hematoxylin and eosin stain and counted macroscopically and microscopically. Results Thoracic duct lymph nodes were found in 6 of 7 cadavers (86%), with a median number of 1 (range, 0 to 6). Nodes were predominantly located in the area of the azygos vein. A median of 4 subcarinal nodes (range, 1 to 8) and 2 periesophageal nodes (range, 1 to 4) were present. Conclusions This study shows that thoracic duct lymph nodes are located within the fatty tissue surrounding the thoracic duct. Resection of this compartment during an esophagectomy for cancer increases lymph node yield.

Omental milky spots (OMSs), small lymphoid structures positioned in the greater omentum, are involved in peritoneal immune homeostasis and the formation of omental metastases. Sympathetic nerve activity is known to regulate immune function in other lymphoid organs (e.g. spleen and lymph nodes) and to create a favourable microenvironment for various tumour types. However, it is still unknown whether OMSs receive sympathetic innervation. Therefore, the aim of this study was to establish whether OMSs of the adult human greater omentum receive sympathetic innervation. A total of 18 OMSs were isolated from five omenta, which were removed from 3% formaldehyde‐perfused cadavers (with a median age of 84 years, ranging from 64 to 94). OMSs were embedded in paraffin, cut and stained with a general (PGP9.5) and sympathetic nerve marker (TH and DBH), and evaluated by bright field microscopy. A T‐cell, B‐cell, and macrophage staining was performed to confirm OMS identity. In 50% of the studied OMSs, sympathetic nerve fibres were observed at multiple levels of the same OMS. Nerve fibres were represented as dots or elongated structures and often observed in relation to small vessels and occasionally as individual structures residing between lymphoid cells. The current study shows that 50% of the investigated OMSs contain sympathetic nerve fibres. These findings may contribute to our understanding of neural regulation of peritoneal immune response and the involvement of OMSs in omental metastases., This study shows that human omental milky spots (OMSs) contain sympathetic nerve fibres. Often, these nerve fibres were located around small blood vessels and occasionally individual nerve fibres were observed between lymphoid cells. The presence of sympathetic fibres in OMSs contributes to our understanding of how OMS immune function might be regulated during an abdominal immune challenge and why they form primary implantation sites for peritoneal exfoliated cancer cells.

Background Chylothorax is a treacherous complication after esophagectomy associated with significant morbidity. Early enteral nutrition after esophagectomy is important for recovery but increases the pressure in the lymphatic system owing to the absorption of triglycerides. To lower the incidence of chylothorax after esophagectomy, the use of low fat–containing tube feeding was evaluated as a standard of care after esophagectomy. Methods All consecutive patients who underwent an esophagectomy with gastric tube reconstruction and placement of jejunostomy at the University Medical Center Utrecht between January 1, 2012, and December 31, 2017, were included. Tube feeding was started as standard of care on postoperative day 1 with a normal fat–containing formula in the period between 2012 and 2014 and with a low fat–containing formula between 2014 and 2017. Results Between 2012 and 2017, 198 patients were included. The tube feeding formula contained normal fat in 86 (43.4%) and low fat in 112 (53.6%). Chylothorax, associated with triglyceride levels exceeding 1.24 mmol/L in 27 patients (61.4%) with a clinical diagnosis of chylothorax, was significantly less observed in the low fat–formula group (15 [13.4%] vs 29 [33%], p = 0.001). No difference was seen in drain output, triglyceride levels in the pleura fluid, treatment strategy, and hospital mortality. At multivariable analysis, the normal-fat formula was associated with a 5.1 odds (95% confidence interval, 2.1 to 12.1) for postoperative chylothorax. Other factors independently associated with chylothorax were transthoracic resection, anastomotic leakage, number of resected lymph nodes, and lower body mass index. Conclusions Administration of low fat–containing tube feed after esophagectomy was associated with a lower incidence of chylothorax.

Introduction A subset of oesophageal cancer patients has residual nodal disease despite complete pathologic response of the primary tumour after neoadjuvant chemoradiation and resection. The aim of this study was to determine the exact location of metastatic nodes with regard to the neoadjuvant radiation field and to assess progression-free (PFS) and overall survival (OS) in this group of patients. Materials and methods From January 2010 to January 2017, complete tumour responders (ypT0) after neoadjuvant chemoradiotherapy and oesophagectomy were identified from a prospective database and grouped according to residual nodal disease (ypT0N + or ypT0N0). Radiation fields were analysed for location of the metastatic nodes and PFS and OS were determined. Results In a total of 192 patients, 53 complete responders (ypT0) were identified. Of those, 11 patients (20.8%) were ypT0N+ with a total of 12 metastatic nodes: 8 (66.7%) located within the neoadjuvant radiation field and 4 (33.3%) located outside this field. Although not statistically significant, 1- and 2-year PFS were worse in ypT0N + patients (ypT0N+ 64.3% vs. ypT0N0 84.4%; ypT0N+ 48.2% vs. ypT0N0 80.7%, respectively; p = 0.051), just as 1- and 2-year OS rates, however, to a lesser extent (ypT0N+ 75.0% vs. ypT0N0 76.3%; ypT0N+ 75.0% vs. ypT0N0 72.9%, respectively; p = 0.956). Conclusion Most ypT0N + lymph nodes are located within the neoadjuvant radiation field. Although a small heterogeneous population was included, this might be due to an inadequate response to neoadjuvant chemoradiotherapy leading to a trend towards worse PFS and OS in ypT0N + patients. Larger studies need to validate our findings.

Contains fulltext : 136013.pdf (Publisher’s version ) (Closed access) BACKGROUND: Gastrointestinal symptoms are frequently reported adverse effects of antidepressants, but antidepressants are also a treatment modality in functional gastrointestinal disorders. We aimed to assess the association between antidepressant use and gastrointestinal symptoms in the general adult population. METHODS: We assessed gastrointestinal symptoms, medication use, and comorbidity through structured questionnaires in randomly selected individuals. We compared presence of gastrointestinal symptoms in respondents who reported antidepressant use with those who did not. We used multivariable regression analysis to verify the association between antidepressant use and gastrointestinal symptoms. RESULTS: In total, 16,758 questionnaires were returned and eligible for analysis. Antidepressant use was reported by 701 respondents (4.2%). Gastrointestinal symptoms were more frequently reported by antidepressant users compared with nonusers (40% vs 25%, P < 0.01). This apparent association between antidepressant use and gastrointestinal symptoms did not remain after adjusting for demographic factors, comorbidity, and use of other medications (adjusted odds ratio, 0.94; 95% confidence interval, 0.74-1.18). CONCLUSIONS: In our cross-sectional population-based study, we did not find an association between antidepressant use and gastrointestinal symptoms.

Background Injury and subsequent leakage of unrecognized thoracic duct tributaries during transthoracic esophagectomy may lead to chylothorax. Therefore, we hypothesized that thoracic duct anatomy at the diaphragm is more complex than currently recognized and aimed to provide a detailed description of the anatomy of the thoracic duct at the diaphragm. Basic procedures The thoracic duct and its tributaries were dissected in 7 (2 male and 5 female) embalmed human cadavers. The level of origin of the thoracic duct and the points where tributaries entered the thoracic duct were measured using landmarks easily identified during surgery: the aortic and esophageal hiatus and the arch of the azygos vein. Main findings The thoracic duct was formed in the thoracic cavity by the union of multiple abdominal tributaries in 6 cadavers. In 3 cadavers partially duplicated systems were present that communicated with interductal branches. The thoracic duct was formed by a median of 3 (IQR: 3–5) abdominal tributaries merging 8.3 cm (IQR: 7.3–9.3 cm) above the aortic hiatus, 1.8 cm (IQR: −0.4 to 2.4 cm) above the esophageal hiatus, and 12.3 cm (IQR: 14.0 to −11.0 cm) below the arch of the azygos vein. Conclusion This study challenges the paradigm that abdominal lymphatics join in the abdomen to pass the diaphragm as a single thoracic duct. In this study, this occurred in 1/7 cadavers. Although small, the results of this series suggest that the formation of the thoracic duct above the diaphragm is more common than previously thought. This knowledge may be vital to prevent and treat post-operative chyle leakage.