This trial was designed to assess the prevalence and characteristics of Jackhammer esophagus (JE), a novel hypercontractile disorder associated with progression to achalasia and limited outcomes following anti-reflux surgery in patients with typical symptoms of GERD and responsiveness to proton pump inhibitor (PPI) therapy. Consecutive patients, who were referred for surgical therapy because of PPI responsive typical symptoms of GERD, were prospectively assessed between January 2014 and May 2017. Patients diagnosed with JE subsequently underwent rigorous clinical screening including esophagogastroduodenoscopy (EGD), ambulatory pH impedance monitoring off PPI and a PPI trial. Out of 2443 evaluated patients, 37 (1.5%) subjects with a median age of 56.3 (51.6; 65) years were diagnosed with JE and left for final analysis. Extensive testing resulted in 16 (43.2%) GERD positive patients and 5 (13.9%) participants were observed to have an acid hypersensitive esophagus. There were no clinical parameters that differentiated phenotypes of JE. The prevalence of JE in patients with typical symptoms of GERD and response to PPI therapy is low. True GERD was diagnosed in less than half of this selected cohort, indicating the need for objective testing to stratify phenotypes of JE. (NCT03347903)
OBJECTIVEAs decisions regarding tumor diagnosis and subsequent treatment are increasingly based on molecular pathology, the frequency of brain biopsies is increasing. Robotic devices overcome limitations of frame-based and frameless techniques in terms of accuracy and usability. The aim of the present study was to present a novel, minimally invasive, robot-guided biopsy technique and compare the results with those of standard burr hole biopsy.METHODSA tubular minimally invasive instrument set was custom-designed for the iSYS-1 robot-guided biopsies. Feasibility, accuracy, duration, and outcome were compared in a consecutive series of 66 cases of robot-guided stereotactic biopsies between the minimally invasive (32 patients) and standard (34 patients) procedures.RESULTSApplication of the minimally invasive instrument set was feasible in all patients. Compared with the standard burr hole technique, accuracy was significantly higher both at entry (median 1.5 mm [range 0.2–3.2 mm] vs 1.7 mm [range 0.8–5.1 mm], p = 0.008) and at target (median 1.5 mm [range 0.4–3.4 mm] vs 2.0 mm [range 0.8–3.9 mm], p = 0.019). The incision-to-suture time was significantly shorter (median 30 minutes [range 15–50 minutes] vs 37.5 minutes [range 25–105 minutes], p < 0.001). The skin incision was significantly shorter (median 16.3 mm [range 12.7–23.4 mm] vs 28.4 mm [range 20–42.2 mm], p = 0.002). A diagnostic tissue sample was obtained in all cases.CONCLUSIONSApplication of the novel instrument set was feasible in all patients. According to the authors’ data, the minimally invasive robot-guidance procedure can significantly improve accuracy, reduce operating time, and improve the cosmetic result of stereotactic biopsies.
Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.
Transfer of recipient regulatory T cells (Tregs) induces mixed chimerism and tolerance in an irradiation-free bone marrow (BM) transplantation (BMT) model involving short-course co-stimulation blockade and mTOR inhibition. Boosting endogenous Tregs pharmacologically in vivo would be an attractive alternative avoiding the current limitations of performing adoptive cell therapy in the routine clinical setting. Interleukin-6 (IL-6) potently inhibits Treg differentiation and its blockade was shown to increase Treg numbers in vivo. Therefore, we investigated whether IL-6 blockade can replace adoptive Treg transfer in irradiation-free allogeneic BMT. Treatment with anti-IL-6 instead of Treg transfer led to multi-lineage chimerism (persisting for ~12 weeks) in recipients of fully mismatched BM and significantly prolonged donor skin (MST 58 days) and heart (MST > 100 days) graft survival. Endogenous Foxp3+ Tregs expanded in anti-IL-6-treated BMT recipients, while dendritic cell (DC) activation and memory CD8+ T cell development were inhibited. Adding anti-IL-17 to anti-IL-6 treatment increased Treg frequencies, but did not further prolong donor skin graft survival significantly. These results demonstrate that IL-6 blockade promotes BM engraftment and donor graft survival in non-irradiated recipients and might provide an alternative to Treg cell therapy in the clinical setting.
TIPS should be considered in all liver transplant candidates, since it can obviate the need for OLT and optimize bridging to OLT.
Cell therapy with recipient Tregs achieves engraftment of allogeneic bone marrow (BM) without the need for cytoreductive conditioning (i.e., without irradiation or cytotoxic drugs). Thereby mixed chimerism and transplantation tolerance are established in recipients conditioned solely with costimulation blockade and rapamycin. However, clinical translation would be substantially facilitated if Treg-stimulating pharmaceutical agents could be used instead of individualized cell therapy. Recently, it was shown that interleukin-2 (IL-2) complexed with a monoclonal antibody (mAb) (clone JES6-1A12) against IL-2 (IL-2 complexes) potently expands and activates Tregs in vivo. Therefore, we investigated whether IL-2 complexes can replace Treg therapy in a costimulation blockade-based and irradiation-free BM transplantation (BMT) model. Unexpectedly, the administration of IL-2 complexes at the time of BMT (instead of Tregs) failed to induce BM engraftment in non-irradiated recipients (0/6 with IL-2 complexes vs. 3/4 with Tregs, p<0.05). Adding IL-2 complexes to an otherwise effective regimen involving recipient irradiation (1Gy) but no Treg transfer indeed actively triggered donor BM rejection at higher doses (0/8 with IL-2 complexes vs. 9/11 without, p<0.01) and had no detectable effect at two lower doses (3/5 vs. 9/11, p>0.05). CD8 T cells and NK cells of IL-2 complex-treated naïve mice showed an enhanced proliferative response towards donor antigens in vitro despite the marked expansion of Tregs. However, IL-2 complexes also expanded conventional CD4 T cells, CD8 T cells, NK cells, NKT cells and notably even B cells, albeit to a lesser extent. Notably, IL-2 complex expanded Tregs featured less potent suppressive functions than in vitro activated Tregs in terms of T cell suppression in vitro and BM engraftment in vivo. In conclusion, these data suggest that IL-2 complexes are less effective than recipient Tregs in promoting BM engraftment and in contrast actually trigger BM rejection, as their effect is not sufficiently restricted to Tregs but rather extends to several other lymphocyte populations.
SummaryBackgroundThe Neutrophil-to-lymphocyte-ratio has recently gained increased attention as a prognostic marker for malignant disease and short term outcomes. There is little data available in patients with Crohn’s disease, thus the present study was conducted to correlate preoperative Neutrophil-to-lymphocyte-ratio values with disease phenotype and postoperative course.MethodsWe comprised 373 patients, who underwent intestinal resection for symptomatic Crohn’s disease at an academic tertiary referral centre between 2000 and 2014. Preoperative Neutrophil-to-lymphocyte-ratio values were calculated and analyzed in regard to disease phenotype and 30-day morbidity rate. All relevant data were obtained from the institutional database and individual chart review.ResultsMale patients had significantly higher preoperative Neutrophil-to-lymphocyte-ratio values compared to female patients (5 vs. 4; p = 0.0075). A higher Neutrophil-to-lymphocyte-ratio was also found in patients with an acute indication for surgery (6.15 vs. 4.3; p = 0.0374), presenting with abscesses (5.36 vs. 4.28; p = 0.0254), inflammatory masses (5.23 vs. 4.08; p = 0.0294) or malignancy in the resected specimen (9.06 vs. 4.35, p = 0.0231). Surprisingly, patients developing postsurgical complications showed significantly lower Neutrophil-to-lymphocyte-ratio values (3.77 vs. 4.67; p = 0.0461).ConclusionsElevated preoperative Neutrophil-to-lymphocyte-ratio in symptomatic Crohn’s disease is not predictive for complications. However, Neutrophil-to-lymphocyte-ratio showed a significant correlation with specific disease phenotypes. Most strikingly, Neutrophil-to-lymphocyte-ratio was highly elevated in patients with a colorectal cancer in the resected specimen, which needs to be addressed in future studies.
AIMTo evaluate frequency and clinical course of incidental adenocarcinoma in patients with stricturing Crohn's disease (CD).METHODSIn this study, consecutive patients, who were operated on for stricturing CD between 1997-2012, were included at an academic tertiary referral center. Demographic data and clinical course were obtained by an institutional database and individual chart review. Besides baseline characteristics, intraoperative findings and CD related history were also recorded. Colorectal cancer was classified and staged according to the Union for International Cancer Control (UICC).RESULTSDuring the study period 484 patients underwent resections due to stricturing CD. Incidental adenocarcinoma was histologically confirmed in 6 (1.2%) patients (4 males, 2 females). Patients diagnosed with colorectal cancer had a median age of 43 (27-66) years and a median history of CD of 16 (7-36) years. Malignant lesions were found in the rectum (n = 4, 66.7%), descending colon (n = 1, 16.7%) and ileocolon (n = 1, 16.7%). According to the UICC classification two patients were stages as I (33.3%), whereas the other patients were classified as stage IIA (16.7%), stage IIIB (16.7%), stage IIIC (16.7%) and stage IV (16.7%), respectively. After a median follow-up of 2 (0.03-8) years only 1 patient is still alive.CONCLUSIONThe frequency of incidental colorectal cancer in patients, who undergo surgery for stenotic CD, is low but associated with poor prognosis. However, surgeons need to be aware about the possibility of malignancy in stricturing CD, especially if localized in the rectum.
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