Do Changes in Perioperative and Postoperative Treatment Protocol Influence the Frequency of Pulmonary Complications? A Retrospective Analysis of Four Different Bariatric Groups

The current understanding of prophylaxis of pulmonary complications in bariatric surgery is weak. Purpose: The aim of this study was to observe how changes in perioperative and postoperative treatments affect the incidence of pulmonary complications in bariatric patients. Materials: This is a retrospective clinical study of 400 consecutive bariatric patients. The patients, who either underwent a sleeve gastrectomy or a Roux-en-Y gastric bypass, were divided consecutively into four subgroups with different approaches to perioperative treatment. Methods: The first group (patients 0-100) was recovered in the intensive care unit with minimal mobilization (ICU). They had a urinary catheter and a drain. The second group (patients 101-200) was similar to the first group, but the patients used a continuous positive airway pressure (CPAP) device intermittently (ICU-CPAP). The third group (patients 201-300) was recovered on a normal ward without a urinary catheter or a drain and used a CPAP device (ward-slow). The fourth group (patients 301-400) walked to the operating theater and was mobilized in the recovery room during the first 2 h after the operation (ward-fast). CPAP was also used. Primary endpoints were pulmonary complications, pneumonia, and infection, non-ultra descriptus (NUD). Results: The number of pulmonary complications among the groups was significantly different. A long operation time increased the risk for infection (p <0.001 95 % CI from 2.02 to 6.59 %). Conclusions: Operation time increases the risk for pulmonary complications. Changes in perioperative care toward the ERAS protocol may have a positive effect on the number of pulmonary complications.Peer reviewe

A Retrospective 2-Year Follow-up of Late Complications Treated Surgically and Endoscopically After Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) and Laparoscopic Sleeve Gastrectomy (LSG) for Morbid Obesity

The laparoscopic Roux-en-Y gastric bypass (LRYGB) has been the gold standard for bariatric surgery, but recently, the laparoscopic sleeve gastrectomy (LSG) has gained popularity. At present, limited data is available on the long-term complications of these two types of surgery. The aim of this retrospective study was to compare the 2-year data about late (more than 30 days after surgery) complications that were treated surgically or endoscopically after LRYGB and LSG operations in a large hospital area with a single patient database. This was a retrospective, non-randomized, single-center study of 760 (545 LRYGB and 215 LSG) bariatric patients surgically treated between 2008 and 2013 in the Bariatric Surgery Unit of Helsinki University Central Hospital. The patients were followed for 2 years, and late complications (more than 30 days after surgery) that were surgically and/or endoscopically treated were registered. Weight loss and the risk factors for complications were also monitored. The study found a difference between the LRYGB and LSG patients in a number of late complications treated by both intervention types: surgical intervention were required in 9.4% of LRYGB patients vs. 0.9 of LSG patients, and endoscopic intervention were required by 4.6% of LRYGB patients vs. 1.4% of LSG patients (both p <0.05). The risk of surgical complications was increased by better weight loss results in 12 months. LRYGB was found to be associated with a greater risk of late complications. If larger databases confirm these results, the trend toward LSG is justified.Peer reviewe

Bile Reflux Scintigraphy After Mini-Gastric Bypass

Significant weight-loss and diabetes remission have been reported after mini-gastric bypass (MGB). Concern has been raised regarding postoperative bile reflux (BR), but it has not been demonstrated in previous studies. We set out to find out if BR is evident in hepatobiliary scintigraphy after MGB. Nine consecutive patients, seven with type 2 diabetes, underwent MGB (15 cm gastric tube, 250-275 cm biliary limb) at our institution with a 12-month follow-up, with none lost to follow-up. Then, 10.7 months (8.6-13.0) after MGB, all patients underwent hepatobiliary scintigraphy and a reflux symptom questionnaire (GerdQ) was filled out. A gastroscopy with biopsies was done for all patients with a bile-reflux-positive scintigraphy. Mean age at operation was 56 years (41-65) and preoperative BMI 43.1 kg/m(2) (34.2-54.6). Mean %EWL was 83.9 (49.5-128.3) at 12 months. Four patients reached diabetes remission and two became insulin-independent. Hepatobiliary scintigraphy showed a transient BR into the gastric tube for five patients. Bile tracer was found in the gastric tube at 23-58 min after the tracer injection and highest activity was 8% (1-8%) at 58 min. Bile tracer was not found in the esophagus of any of the patients. One patient with a positive scintigraphy in the gastric tube required re-operation. Two patients with reflux symptoms had a negative scintigraphy. Our results indicate that transient bile reflux is common after MGB in the gastric tube, but not in the esophagus. The clinical relevance of bile reflux needs further studies.Peer reviewe

Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment

Purpose: Tumor-infiltrating immune cells have prognostic sig-nificance and are attractive therapeutic targets. Yet, the clinical significance of their spatial organization and phenotype in diffuse large B-cell lymphoma (DLBCL) is unclear. Experimental Design: We characterized T cells, macrophages, and their spatial interactions by multiplex IHC (mIHC) in 178 patients with DLBCL and correlated the data with patient demo-graphics and survival. We validated the findings on gene expression data from two external DLBCL cohorts comprising 633 patients. Results: Macrophage and T-cell contents divided the samples into T cell-inflamed (60%) and noninflamed (40%) subgroups. The T cell-inflamed lymphoma microenvironment (LME) was also rich in other immune cells, defining immune hot phenotype, which did not as such correlate with outcome. However, when we divided the patients according to T-cell and macrophage contents, LME char-acterized by high T-cell/low macrophage content or a correspond-ing gene signature was associated with superior survival [5-year overall survival (OS): 92.3% vs. 74.4%, P = 0.036; 5-year progres-sion-free survival (PFS): 92.6% vs. 69.8%, P = 0.012]. High pro-portion of PD -L1-and TIM3-expressing CD163- macrophages in the T cell-inflamed LME defined a group of patients with poor outcome [OS: HR = 3.22, 95% confidence interval (CI), 1.63-6.37, P-adj = 0.011; PFS: HR = 2.76, 95% CI, 1.44-5.28, P-adj = 0.016]. Furthermore, PD-L1 and PD-1 were enriched on macrophages interacting with T cells. Conclusions: Our data demonstrate that the interplay between macrophages and T cells in the DLBCL LME is immune checkpoint dependent and clinically meaningful.Peer reviewe

Prognostic Impact of Tumor-Associated Macrophages on Survival Is Checkpoint Dependent in Classical Hodgkin Lymphoma

Tumor microenvironment and immune escape affect pathogenesis and survival in classical Hodgkin lymphoma (cHL). While tumor-associated macrophage (TAM) content has been associated with poor outcomes, macrophage-derived determinants with clinical impact have remained undefined. Here, we have used multiplex immunohistochemistry and digital image analysis to characterize TAM immunophenotypes with regard to expression of checkpoint molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO-1) from the diagnostic tumor tissue samples of 130 cHL patients, and correlated the findings with clinical characteristics and survival. We show that a large proportion of TAMs express PD-L1 (CD68+, median 32%; M2 type CD163+, median 22%), whereas the proportion of TAMs expressing IDO-1 is lower (CD68+, median 5.5%; CD163+, median 1.4%). A high proportion of PD-L1 and IDO-1 expressing TAMs from all TAMs (CD68+), or from CD163+ TAMs, is associated with inferior outcome. In multivariate analysis with age and stage, high proportions of PD-L1+ and IDO-1+ TAMs remain independent prognostic factors for freedom from treatment failure (PD-L1+CD68+/CD68+, HR = 2.63, 95% CI 1.17–5.88, p = 0.019; IDO-1+CD68+/CD68+, HR = 2.48, 95% CI 1.03–5.95, p = 0.042). In contrast, proportions of PD-L1+ tumor cells, all TAMs or PD-L1− and IDO-1− TAMs are not associated with outcome. The findings implicate that adverse prognostic impact of TAMs is checkpoint-dependent in cHL

Adverse prognostic impact of regulatory T-cells in testicular diffuse large B-cell lymphoma

Objectives Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival. Methods We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T-cells (CTLs; CD8(+), OX40(+), Granzyme B+, Ki-67(+), LAG-3(+), TIM-3(+), PD-1(+)), CD4(+)T-cells (CD3(+), CD4(+), TIM-3(+), LAG-3(+)), regulatory T-cells (Tregs; CD3(+), CD4(+), FoxP3(+)), and T helper 1 cells (Th1; CD3(+), CD4(+), T-bet(+)) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome. Results We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8(+)TILs were Ki-67(+)and TIM-3(+)CTLs, whereas the most prominent CD4(+)TILs were FoxP3(+)Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet(+)FoxP3(+)Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features. Conclusions Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.Peer reviewe

Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease

Background & Aims: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. Methods: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n = 62 and n = 63) or PNPLA3 genotype (PNPIA3(148MM/MI), n = 61 vs. PNPLA3(148II), n = 64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. Results: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI) vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. Conclusions: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Peer reviewe

Checkpoint protein expression in the tumor microenvironment defines the outcome of classical Hodgkin lymphoma patients

Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression profiling (n = 88), CIBERSORT, and multiplex immunohistochemistry (n = 131) to characterize the immunoprofile of cHL TME and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and -noninflamed TME. Several macrophage-related genes were upregulated in samples with the non-T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (programmed cell death protein 1, PD-1 ligands, indoleamine 2,3 dioxygenase 1, lymphocyte-activation gene 3, and T-cell immunoglobulin and mucin domain containing protein 3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs 96%; P = .010) and remained an independent prognostic factor for OS in multivariable analysis (HR, 4.34; 95% CI, 1.05-17.91; P = .043). cHL samples with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P < .001) and in an expan-sion cohort of 84 cHL relapse samples (P = .048). Our findings demonstrate the impact of T cell-and macrophage-mediated checkpoint system on the survival of patients with cHL.Peer reviewe

The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans

Non peer reviewe

T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma

Primary testicular lymphoma is a rare lymphoid malignancy, most often, histologically, representing diffuse large B-cell lymphoma. The tumor rnicroenvi.ro.nrnent and limited immune surveillance have a major impact on diffuse large B-cell lymphoma pathogenesis and. survival, but the impact on primary testicular lymphoma is unknown. Here, the purpose of the study was to characterize the tumor microenvironme.nt in primary testicular lymphoma, and associate the findings with outcome. We profiled the expression of 730 immune response enes in 60 primary testicular lymphomas utilizing the Nanostring platorm, and used multiplex imrnunohistochemistry to characterize the immune cell phenotypes in the tumor tissue. We identified a gene signature enriched for T-lymphocyte markers differentially expressed. between the patients. Low expression of the signature predicted poor outcome independently of the International Prognostic Index (progression -free survival: HR=2.810, 95%CI: 1.228-6.431, P=0.014; overall survival: HR=3.267, 95`)/0' CI: 1.406-7.590, P=0.006). The T-lymphocyte signature was associated with outcome also in an independent diffuse large B-cell lymphoma cohort (n=96). Multiplex immunohistochemistry revealed that poor survival of primary testicular lymphoma patients correlated with low percentage of CD3'CD4' and CD3+CD8' tumor-infiltrating lymphocytes (PPeer reviewe