Hybrid resistance to parental bone marrow grafts in nonlethally irradiated mice.

Resistance to parental bone marrow (BM) grafts in F1 hybrid recipients is due to natural killer (NK) cell-mediated rejection triggered through "missing self" recognition. "Hybrid resistance" has usually been investigated in lethally irradiated F1 recipients in conjunction with pharmacological activation of NK cells. Here, we investigated BM-directed NK-cell alloreactivity in settings of reduced conditioning. Nonlethally irradiated (1-3 Gy) or nonirradiated F1 (C57BL6 × BALB/c) recipient mice received titrated doses (5-20 x 106 ) of unseparated parental BALB/c BM without pharmacological NK cell activation. BM successfully engrafted in all mice and multilineage donor chimerism persisted long-term (24 weeks), even in the absence of irradiation. Chimerism was associated with the rearrangement of the NK-cell receptor repertoire suggestive of reduced reactivity to BALB/c. Chimerism levels were lower after transplantation with parental BALB/c than with syngeneic F1 BM, indicating partial NK-mediated rejection of parental BM. Activation of NK cells with polyinosinic-polycytidylic acid sodium salt poly(I:C), reduced parental chimerism in nonirradiated BM recipients but did not prevent hematopoietic stem cell engraftment. In contrast, equal numbers of parental lymph node cells were completely rejected. Hence, hybrid resistance leads to incomplete rejection of parental BM under reduced conditioning settings.

Challenging the osseous component of sphenoorbital meningiomas.

BACKGROUND: Intraosseous growth is a unique feature of sphenoorbital meningiomas (SOM). Its close relation to neurovascular structures limits complete surgical resection and possibly contributes to the high recurrence rate. OBJECTIVE: To evaluate the growth behavior of intraosseous remnants and develop a protocol for precise intraoperative visualization of intraosseous SOM. METHODS: We included 31 patients operated for SOM from 2004 to 2017. The growth velocity of the intraosseous tumor component was volumetrically calculated in 20 cases. To improve accuracy of image guidance, we implemented a specialized bone surface-based registration algorithm. For intraoperative bone visualization, we included CT in multimodality continuous image guidance in 23 patients. The extent of resection (EOR) was compared with a standard MR-only navigation group (n = 8). RESULTS: In 11/20 cases (55%), a progressive regrowth of the intraosseous SOM remnant was noted during a mean follow-up of 52 months (range 20-132 months). We observed a mean increase of 6.2 cm3 (range 0.2-23.7 cm3) per patient and side during the follow-up period. Bone surface-based registration was significantly more accurate than skin surface-based registration (mean 0.7 ± 0.4 mm and 1.9 ± 0.7 mm, p < 0.001). The EOR of the intraosseous component was significantly higher using CT + MRI navigation compared with controls (96% vs. 81%, p = 0.044). CONCLUSION: Quantitative assessment of the biological behavior of intraosseous remnants revealed a continuous slow growth rate independent of the soft tumor component of more than half of SOM. According to our data, application of a multimodal image guidance provided high accuracy and significantly increased the resection rate of the intraosseous component of SOM.

Single Burr-Hole Extended Transforaminal Approach for Concurrent Endoscopic Surgery in the Third Ventricle Posterior to the Foramen of Monro and Ventriculostomy: Clinical Series and Planning Steps.

OBJECTIVE: For endoscopic surgery of third ventricular lesions posterior to the foramen of Monro that frequently require a third ventriculostomy during the same procedure, the extended transforaminal approach (ETFA) through the choroid fissure has been proposed. This study reports clinical results and provides anatomic background and guidelines for individual planning of a single burr-hole approach and a safe transchoroid entry zone. METHODS: A retrospective review was undertaken of 25 cases of concurrent third ventricle surgery and third ventriculostomy via ETFA. Assessment was made of a safe transchoroidal entry zone on cadavers (6 hemispheres) and of planning guidelines on magnetic resonance imaging showing occlusive hydrocephalus (30 sides). RESULTS: ETFA was feasible in all 25 cases. The safe transchoroid entry zone was sufficient in 16 cases; in 9 cases, additional transchoroid opening with transection of the anterior septal vein was required without clinical consequences. The anatomic study showed a safe transchoroid entry zone of 5 mm (3-6 mm) for posterior enlargement of the foramen of Monro. Individual planning on magnetic resonance imaging of patients with enlarged third ventricles showed an optimal burr-hole position 22 mm (10-30 mm) lateral to the midline and 8 mm (27 to -23 mm) precoronal; a foramen of Monro diameter of 7 mm (3-11 mm) and a safe transchoroid entry zone of 6 mm (3-12 mm). CONCLUSIONS: According to our data, concurrent endoscopic surgery of third ventricular lesions posterior to the foramen of Monro and ventriculostomy are feasible through a single burr hole and a transchoroid extension of the transforaminal approach. Precise preoperative planning is recommended for anticipating the individual anatomic nuances.

Frameless Stereotactic Brain Biopsies: Comparison of Minimally Invasive Robot-Guided and Manual Arm-Based Technique.

BACKGROUND: Most brain biopsies are still performed with the aid of a navigation-guided mechanical arm. Due to the manual trajectory alignment without rigid skull contact, frameless aiming devices are prone to considerably lower accuracy. OBJECTIVE: To compare a novel minimally invasive robot-guided biopsy technique with rigid skull fixation to a standard frameless manual arm biopsy procedure. METHODS: Accuracy, procedural duration, diagnostic yield, complication rate, and cosmetic result were retrospectively assessed in 40 consecutive cases of frameless stereotactic biopsies and compared between a minimally invasive robotic technique using the iSYS1 guidance device (iSYS Medizintechnik GmbH) (robot-guided group [ROB], n = 20) and a manual arm-based technique (group MAN, n = 20). RESULTS: Application of the robotic technique resulted in significantly higher accuracy at entry point (group ROB median 1.5 mm [0.4-3.2 mm] vs manual arm-based group (MAN) 2.2 mm [0.2-5.2 mm], P = .019) and at target point (group ROB 1.5 mm [0.4-2.8 mm] vs group MAN 2.8 mm [1.4-4.9 mm], P = .001), without increasing incision to suture time (group ROB 30.0 min [20-45 min vs group MAN 32.5 min [range 20-60 min], P = .09) and significantly shorter skin incision length (group ROB 16.3 mm [12.7-23.4 mm] vs group MAN 24.2 mm [18.0-37.0 mm], P = .008). CONCLUSION: According to our data, the proposed technique of minimally invasive robot-guided brain biopsies can improve accuracy without increasing operating time while being equally safe and effective compared to a standard frameless arm-based manual biopsy technique.

An advanced protocol for intraoperative visualization of sinunasal structures: experiences from pituitary surgery.

OBJECTIVE: The transsphenoidal route to pituitary adenomas challenges surgeons because of the highly variable sinunasal anatomy. Orientation may be improved if the appropriate information is provided intraoperatively by image guidance. The authors developed an advanced image guidance protocol dedicated to sinunasal surgery that extracts information from multiple modalities and forms it into a single image that includes fine sinunasal structures and arteries.The aim of this study was to compare the advantages of this novel image guidance protocol with the authors' previous series, with emphasis on anatomical structures visualized and complication rate. METHODS: This retrospective analysis comprised 200 patients who underwent surgery for pituitary adenoma via a transnasal transsphenoidal endoscopic approach. The authors' standard image guidance protocol consisting of CT for solid bone, T1CEMRI for soft tissues, and MRA for the carotid artery was applied in 100 consecutive cases. The advanced image guidance protocol added a first-hit ray casting of the CT scan for visualization of fine sinunasal structures, and adjustments to the MRA to visualize the sphenopalatine artery (SPA) were applied in a subsequent 100 consecutive cases. RESULTS: A patent sphenoid ostium-i.e., an ostium not covered by a mucosal layer-was visualized significantly more often by the advanced protocol than the standard protocol (89% vs 40%, p < 0.001) in primary surgeries. The SPA and its branches were only visualized by the advanced protocol (87% and 91% of cases in primary surgeries and reoperations, respectively) and not once by the standard protocol. The number of visualized complete and incomplete sphenoid septations matched significantly more commonly with the surgical view when using the advanced protocol than the standard protocol at primary operation (mean 1.9 vs 1.6, p < 0.001). However, in 25% of all cases a complex and not a simple sinus anatomy was present. In comparison with the intraoperative results, a complex sphenoid sinus anatomy was always detected by the advanced but not by the standard protocol (25% vs 8.5%, p = 0.001).Furthermore, application of the advanced protocol reduced the cumulative rate of complications (25% vs 18% [standard vs advanced group]). Although an overall significant difference could not be determined (p = 0.228), a subgroup analysis of reoperations (35/200) revealed a significantly lower rate of complications in the advanced group (5% vs 30%, p = 0.028). CONCLUSIONS: The data show that the advanced image guidance protocol could intraoperatively visualize the fine sinunasal sinus structures and small arteries with a high degree of detail. By improving intraoperative orientation, this may help to reduce the rate of complications in endoscopic transsphenoidal surgery, especially in reoperations.

A novel robot-guided minimally invasive technique for brain tumor biopsies.

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.

The modified Glasgow prognostic score in Crohn's disease-does it predict short-term outcome?

BACKGROUND: The modified Glasgow prognostic score (mGPS) has recently gained increased attention as a prognostic marker for malignant disease survival and postoperative short-term complications. Due to lacking data, the present study was conducted to correlate the mGPS with the postoperative course in patients following surgery for Crohn's disease. METHODS: We enrolled 341 patients who underwent intestinal resection for symptomatic Crohn's disease at a tertiary referral centre between 2000 and 2014. All relevant data were obtained from the institutional database and individual chart review. Thirty-day morbidity was defined according to the Clavien-Dindo classification. RESULTS: A total of 79 (23.17%) postoperative complications were identified (grade I and II: n = 54, 15.84%; grade III and IV: n = 23, 6.74%; grade V: n = 2, 0.59%). The mGPS did not show any correlation with an eventful postoperative course following surgery (no complication: median mGPS: 1, range 0-2; complications: median mGPS: 1, range 0-2; p = 0.8521). In addition, the occurrence of an anastomotic leakage was not associated with a higher mGPS (p = 0.8592). Patients with an acute indication for surgery (n = 29, 11.44%) had higher median mGPS (median: 2, range 0-2) in contrast to patients who were operated on electively (median: 1, range 0-2; p = 0.0003). No other correlation between surgical characteristics and mGPS was detected. CONCLUSIONS: In the present study, we could clearly demonstrate that an acute indication for surgery in symptomatic Crohn's disease is associated with higher mGPS scores. However, the mGPS did not correlate with postoperative complications. Further studies are required to define the prognostic value of mGPS in Crohn's disease patients.

Prognostic value of preoperative neutrophil-to-lymphocyte ratio in Crohn's disease.

BACKGROUND: The 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. METHODS: We 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. RESULTS: Male 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). CONCLUSIONS: Elevated 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.

Phenotypes of Jackhammer esophagus in patients with typical symptoms of gastroesophageal reflux disease responsive to proton pump inhibitors.

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).

Outcome after liver transplantation in elderly recipients (>65 years) - A single-center retrospective analysis.

BACKGROUND: Liver transplantation (LT) in elderly recipients is controversially discussed in the literature with only little data on long-term outcome available. We aimed to evaluate the safety and efficiency of LT in elderly recipients (>65 years). METHODS: Between 1989-2016, 139 patients >65 years-old were listed for liver transplantation, and 76 (55%) were transplanted. Patient outcome and characteristics were evaluated separately for the time period before (1989-2004) and after (2005-2016) MELD-implementation. Post-transplant outcome was compared between the elderly cohort and LT-recipients aged 18-65 years (n = 1395). RESULTS: Overall survival of patients >65 years was better in the MELD-era compared to the earlier period (1- and 5-year-survival: 73%, 60% vs. 69%, 37%, respectively; p = 0.055). The main differences between the two groups included higher recipient age (p = 0.001) and BMI (p = 0.001), higher donor age (p < 0.001), less need of intraoperative red blood cells (p = 0.008) and a lower number of postoperative rejections (p = 0.03) after 2004. Comparing the overall survival of patients transplanted in the MELD-era aged 18-65 years vs. >65 years displayed comparable 1- and 5 year-survival rates (81%, 68% vs. 73% and 60%, respectively, p = 0.558). CONCLUSION: In the modern era, outcome of patients receiving LT with >65 years is comparable to <65 year-old patients. After careful evaluation, patients >65 years old should be considered for LT.

Incidental adenocarcinoma in patients undergoing surgery for stricturing Crohn's disease.

AIM: To evaluate frequency and clinical course of incidental adenocarcinoma in patients with stricturing Crohn's disease (CD). METHODS: In 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). RESULTS: During 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. CONCLUSION: The 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.

Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model.

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.

The role of TIPS in the management of liver transplant candidates.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is used for treatment of several complications in patients with liver cirrhosis. Recent studies have identified a survival benefit for patients on the waiting list after TIPS implantation, but the optimal time point for TIPS implantation prior to orthotopic liver transplantation (OLT) has not been established. STUDY: This study retrospectively assessed patients undergoing TIPS implantation before or after listing for OLT at the Medical University of Vienna. n = 98 patients with TIPS on the waiting list between January 1993 and December 2013 were identified (n = 73 (74.5%) pre-listing TIPS, n = 25 (25.5%) post-listing TIPS). A matched control group at the time of OLT without TIPS (n = 60) was included. RESULTS: More patients with post-listing TIPS (28.0%, 7/25) showed clinical improvement and went off-list than patients with pre-listing TIPS (8.2%, 6/73, p = .0119). A similar proportion of patients with pre-listing TIPS (19.2%, 14/73) and post-listing TIPS (20.0%, 5/25) died on the OLT waiting list. Transplant surgery time was similar in patients with and without TIPS: 348(±13) vs. 337(±10) minutes (p = .5139). Estimated 1-year post-transplant survival was similar across all groups (pre-listing TIPS: 76.2%, post-listing TIPS: 86.0%, no TIPS: 91.2%, log-rank p = .1506). CONCLUSION: TIPS should be considered in all liver transplant candidates, since it can obviate the need for OLT and optimize bridging to OLT.

Advanced age impacts surgical characteristics and postoperative course in patients with Crohn's disease.

PURPOSE: Due to a lack of data, the present study was designed to assess the impact of advanced age on surgical characteristics and short-term outcome of patients operated on for symptomatic Crohn's disease. METHODS: We enrolled 454 consecutive Crohn's disease patients, who underwent intestinal resection at an academic tertiary referral center between 1997 and 2012. Patients were divided into 3 groups according to their age (group I: <30 years, group II: 30-50 years, group III: >50 years) and analyzed retrospectively. RESULTS: Altogether, 152 (33.5%) patients were included in group I, 234 (51.5%) in group II and 68 (15.0%) in group III. Abscess formation and penetrating disease were significantly more common in younger patients (p = 0.0014 and p = 0.0182). The number of intestinal resections was higher in older patients (p < 0.0001), whereas the laparoscopic approach was more frequently observed in younger adults (p = 0.0006). Group II (n = 58 (24.8%)) and group III (n = 15 (22.1%)) showed significantly more complications compared to group I (n = 20 (13.2%)) (p = 0.0346). Notably, major complications and anastomotic leaks were significantly higher in older patients (p = 0.0004). CONCLUSION: Crohn's disease patients of advanced age show different surgical characteristics compared to younger patients and are at an increased risk of developing postoperative complications.

IL-2/α-IL-2 Complex Treatment Cannot Be Substituted for the Adoptive Transfer of Regulatory T cells to Promote Bone Marrow Engraftment.

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.