Anesthesia-induced Lymphatic Dysfunction.

General anesthetics adversely alters the distribution of infused fluid between the plasma compartment and the extravascular space. This maldistribution occurs largely from the effects of anesthetic agents on lymphatic pumping, which can be demonstrated by macroscopic fluid kinetics studies in awake versus anesthetized patients. The magnitude of this effect can be appreciated as follows: a 30% reduction in lymph flow may result in a fivefold increase of fluid-induced volume expansion of the interstitial space relative to plasma volume. Anesthesia-induced lymphatic dysfunction is a key factor why anesthetized patients require greater than expected fluid administration than can be accounted for by blood loss, urine output, and insensible losses. Anesthesia also blunts the transvascular refill response to bleeding, an important compensatory mechanism during hemorrhagic hypovolemia, in part through lymphatic inhibition. Last, this study addresses how catecholamines and hypertonic and hyperoncotic fluids may mobilize interstitial fluid to mitigate anesthesia-induced lymphatic dysfunction.

Hyperdense Thymic Atrophy After Chemotherapy in Pediatric Patients With Extrathoracic Malignancies.

OBJECTIVE: The aim of the study was to evaluate computed tomography (CT) imaging findings of hyperdense thymic atrophy after chemotherapy in pediatric patients with extrathoracic malignancies. METHODS: Seventy-eight pediatric patients with extrathoracic malignancies, who developed thymic atrophy after chemotherapy, were included in this study. All patients underwent CT imaging before and after chemotherapy. We retrospectively reviewed the CT images. Hyperdense thymic atrophy was defined as thymic atrophy with high CT attenuation (≥80 HU). RESULTS: Hyperdense thymic atrophy after chemotherapy was observed in 7 (9%) of 78 patients. Age (4.3 ± 2.4 vs 8.4 ± 5.4 years, P < 0.01), thymic CT attenuation before chemotherapy (70.4 ± 18.8 vs 55.2 ± 11.9 HU, P < 0.01), reduction rate in thymic area (0.76 ± 0.06 vs 0.60 ± 0.22, P < 0.01), and thymic CT attenuation change (30.3 ± 15.2 vs -16.8 ± 24.0 HU, P < 0.01) were significantly different between patients with and without hyperdense thymic atrophy after chemotherapy. Thymic CT attenuation after chemotherapy (61.2 ± 23.8 vs 33.8 ± 30.1 HU, P < 0.01) and thymic CT attenuation change (-1.3 ± 21.2 vs -19.3 ± 27.9 HU, P < 0.01) were significantly different between patients 5 years or younger (n = 29) and 6 years or older (n = 49). CONCLUSIONS: Hyperdense thymic atrophy after chemotherapy was observed in 9% of pediatric patients with extrathoracic malignancies. It was associated with younger age, greater thymic CT attenuation before chemotherapy, larger reduction rate in thymic area, and greater thymic CT attenuation change.

Sarcoidosis-like reaction in metastatic triple negative breast cancer treated by anti-PD-L1.

We report the first case of sarcoidosis-like reaction in a patient treated by anti-PD-L1 for a breast cancer. A 69-year-old woman presented with a histologically confirmed lung metastasis of a triple negative breast cancer. She was treated by nab-paclitaxel plus anti-PD-L1 in first line. After 2 months, a dramatic lung response was noticed but an involvement of mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epitheloid granulomas without caseating necrosis in favour of a sarcoidosis-like reaction. The patient remained free of symptom and in complete lung response on anti-PD-L1 treatment as a maintenance therapy.

The Reparative Effects of Human Adipose-Derived Mesenchymal Stem Cells in the Chemotherapy-Damaged Thymus.

Hematological patients who accept chemotherapy always develop secondary tumor or even die of severe infections. As an important central lymphoid organ, the thymus is frequently damaged during chemotherapy. Previous studies showed that the mesenchymal stem cells (MSCs) can promote the proliferation and repair of epithelial cells in thymus. The purpose of our study is to investigate the reparative effects of human adipose-derived mesenchymal stem cells (hADMSCs) in chemotherapy-treated damaged thymus. Eighty mice were randomly divided into four groups: normal group, model control group, hADMSCs untreated group, and hADMSCs treated group. The mice were injected intraperitoneally with dexamethasone sodium phosphate (Dex 20 mg/kg), except the normal group. Then, the chemotherapy models were obtained after 1 week; the treated group was infused intraperitoneally with hADMSCs, whereas the model control group was injected with equal volumes of normal saline. The hADMSC's infusion day was regarded as day 0. The mice were sacrificed at different time points (days 3, 7, 10, and 14). The pathological structure and the function of the thymus, the recovery of T-lymphocyte subpopulation, and the proportion of regulatory T (Treg) cells in spleen and peripheral blood were detected. Additionally, we transfected hADMSCs by lentivirus with green fluorescent protein (GFP) to confirm whether they home to thymus and detected the expressions of cytokines that are associated with the development of thymus in hADMSCs and thymus. The results of the study showed that the hADMSCs treated group had a more rapid recovery in terms of thymic pathological structure and function. The hADMSCs could home to the damaged thymus and secrete cytokines that played important roles in repairing damaged thymus. The results indicated that hADMSCs could repair the damaged thymus caused by chemotherapy and improve the immune microenvironment, which may be a potential treatment for hematological patients.

Pirfenidone-Induced Sarcoid-Like Reaction: A Novel Complication.

Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia. Prognosis is poor with a median survival <3 years. Pirfenidone is one of two US Food and Drug Administration-approved medications that slow disease progression. We describe the development of lymphadenopathy or a sarcoid-like reaction following initiation of pirfenidone, a complication not previously reported.

Thymus atrophy is an efficient marker of illicit treatment with dexamethasone in veal calves: Results from a triennial experimental study.

Glucocorticoids, used in a wide range of pathologies thank to their therapeutical properties, are also illegally used as growth-promoters in animal breeding even if the European Union regulates their use to protect consumers' health from the adverse effects of residues in food. The first aim of the study was to establish the applicability of two histological parameters - atrophy and cortex-medulla ratio - to detect glucocorticoids misuse in calves. The second aim was to concurrently test the potentiality of both parameters to discriminate between treated and untreated animals. One hundred and seventy-two male Friesian veal calves were raised for six months and divided into two groups: Group A (106 calves) was given dexamethasone per os for twenty days (0.4mg/day), Group B (66 calves) used as control. Thymic samples were microscopically examined. Fat infiltration was evaluated and a degree of atrophy, ranging from 1 to 3 (mild, moderate, severe) was attributed; thymic cortex-medulla ratio was calculated too. Fisher's exact test and a Wilcoxon-Mann-Whitney test were performed to investigate the differences in thymic atrophy and cortex-medulla ratio between the groups. Results demonstrate that the thymic atrophy grading was significantly increased in group A (p=0,006), whereas the cortex-medulla ratio was decreased (p<0,004) when compared to group B; moreover, the parallel testing with fixed degree of atrophy and cortex-medulla ratio cut-off thresholds optimize the sensitivity (90%) in the detection of glucocorticoids anabolic treatments. These data suggest that microscopic thymus analysis represent a valid tool for the screening and monitoring of glucocorticoid illicit treatments.

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.

BACKGROUND: In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. METHODS: In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. RESULTS: The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users. INTERPRETATION: These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. FUNDING: Pfizer, Servier Research Group, and Leo Laboratories.

Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma.

To our knowledge, we report the first case of sarcoid-like granulomatous reaction induced by nivolumab, a fully human IgG4 anti-programmed death 1 (PD-1) immune checkpoint inhibitor antibody. A 57-year-old man was treated with nivolumab 3 mg/kg for 2 weeks for a desmoplastic melanoma stage III American Joint Commission on Cancer, with no BRAF, NRAS, and cKit mutations. At 10 months, although melanoma complete response was achieved, he developed sarcoid-like granulomatous reaction in the mediastinal lymph node and skin, which resumed after nivolumab arrest. Melanoma did not relapse after 12 months of follow-up. Considering the recently demonstrated role of activated PD-1/PDL-1 axis in sarcoidosis, granulomatous reaction in the patient seems to be a paradoxical reaction, but similar observations have been reported with ipilimumab, another immune checkpoint inhibitor. Sarcoid-like granulomatous reaction during immunotherapy treatment could be a manifestation of cell-mediated immunity induced by these drugs. Impact of granulomatous reaction induced by immune checkpoint inhibitor on melanoma progression is not known and requires further study. Melanoma patients treated by immunotherapy (anti-cytotoxic T-lymphocyte-associated protein-4/anti-PD-1) should be considered for developing sarcoid-like granulomatous reaction that must not be confused with tumor progression.

Sheep lymph-nodes as a biological indicator of environmental exposure to fluoro-edenite.

A significantly increased incidence of pleural mesothelioma in Biancavilla (Sicily, Italy) has been attributed to exposure to fluoro-edenite (FE), a fibrous amphibole extracted from a local stone quarry. The lymph-nodes draining the pulmonary lobes of sheep grazing around the town were examined, to gain insights into fibre diffusion. The pasture areas of six sheep flocks lying about 3km from Biancavilla were located using the global positioning system. The cranial tracheobronchial and one middle mediastinal lymph-node as well as four lung tissue samples were collected from 10 animals from each flock and from 10 control sheep for light and scanning electron microscopy (SEM) examination. The lymph-nodes from exposed sheep were enlarged and exhibited signs of anthracosis. Histologically, especially at the paracortical level, they showed lymph-follicle hyperplasia with large reactive cores and several macrophages (coniophages) containing grey-brownish particulate interspersed with elements with a fibril structure, forming aggregates of varying dimensions (coniophage nodules). Similar findings were detected in some peribronchiolar areas of the lung parenchyma. SEM examination showed that FE fibres measured 8-41µm in length and 0.4-1.39µm in diameter in both lymph-nodes and lung tissue. Monitoring of FE fibres in sheep lymph-nodes using appropriate techniques can help set up environmental pollution surveillance.

Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery.

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

Dasatinib-related Follicular Hyperplasia: An Underrecognized Entity With Characteristic Morphology.

Dasatinib, a second-generation tyrosine kinase inhibitor with activity against BCR-ABL1 and other Src family tyrosine kinases, is approved as a first-line treatment option for Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase. Recently, lymphadenopathy with morphologic features of reactive follicular hyperplasia was described in a cohort of patients with CML on long-term dasatinib therapy. However, the complete morphologic and immunophenotypic features of this previously underappreciated adverse effect have not been fully described. Herein, we report 3 cases of unexplained lymphadenopathy resulting in multiple diagnostic procedures in patients with CML and a history of long-term dasatinib therapy. Morphologic examination demonstrated preserved nodal architecture showing hybrid features of progressive transformation of germinal centers and Castleman-type changes in a background of florid follicular hyperplasia. Large germinal centers were disrupted by complex infolding of IgD+ mantle zones arranged as cuffs surrounding perforating capillaries. Other abnormalities variably present included decreased CD20 expression among polytypic B cells and increased Epstein-Barr virus reactivity in scattered paracortical cells and/or individual germinal centers. B-cell clonality studies showed no predominant clonal rearrangements. Consideration of dasatinib-related lymphadenopathy may pre-empt unnecessary repeat diagnostic procedures in patients with CML or other dasatinib-susceptible malignancies and persistent lymphadenopathy.

Acute Generalized Exanthematous Pustulosis Induced by Amoxicillin/Clavulanic Acid: Report of a Case Presenting With Generalized Lymphadenopathy.

Drug-induced acute generalized exanthematous pustulosis is a rare pustular skin reaction, most commonly triggered by antibiotics. Although its diagnosis is based primarily on the presence of specific clinical and histopathologic features, additional in vivo (patch testing) or in vitro testing may be required, especially in atypical cases, to more accurately determine the causative agent. The authors report a histologically confirmed case of acute generalized exanthematous pustulosis that was induced by amoxicillin/clavulanic acid, as documented by subsequent patch testing, and presented with generalized painful lymphadenopathy, mimicking an acute infectious process. This is a very rare and diagnostically challenging clinical presentation of acute generalized exanthematous pustulosis, which has been reported, to the best of our knowledge, only once previously.

Dapsone hypersensitivity syndrome-related lung injury without eosinophilia in the bronchoalveolar lavage fluid.

A 73-year-old man was admitted in respiratory failure that had subacutely progressed after five weeks of dapsone treatment for a skin rash. He also presented with fever, systemic erythroderma and liver dysfunction. Chest computed tomography showed diffuse reticular shadows with ground-glass opacity and bilateral mediastinal lymphadenopathy. Lymphocytes, but not eosinophils, were increased in the bronchoalveolar lavage fluid. Moreover, reactivation of human herpes virus-6 was confirmed on a paired serum test. Finally, we diagnosed the patient with dapsone hypersensitivity syndrome (DHS), a rare adverse event of this drug. Lung injury unaccompanied by eosinophilia in the bronchoalveolar lavage fluid is even more rare as a DHS-related lung manifestation.

[Pleural lymphatics and pleural diseases related to fibres]. / Lymphatiques pleuraux et pathologies liées aux fibres.

It is now well established that some pleural diseases, pleural plaques and malignant mesothelioma are related to asbestos fibre exposure although the mechanism of action of asbestos fibres is not fully understood. The development of artificial mineral fibres and carbon nanotubes, which share some morphological characteristics similar to asbestos fibres, is a present concern in the context of pleural diseases. Pleural plaques develop only in the parietal pleura, and in the 1990s, clinical observations have shown that the early development of mesothelioma also occurred on the parietal pleura. The peculiarity of the parietal pleura in contrast to the visceral pleura is the presence of "stomas" which are communication holes between the pleural cavity and the parietal pleura lymphatics. Morphological observations by thoracoscopy and experimental studies have shown that inhaled fibres translocate to the pleural space and, in human, are present in the parietal pleura at specific anthracotic areas (blackspots). Fibres accumulate on the stomas, up to block and locally induce an inflammatory reaction with cytokines release, that can be the bed of mesothelioma. However, despite the experimental data and observations in human pathology, the mechanisms of fibre translocation into the pleura is not yet clearly established.