Remote ischemic preconditioning versus sham-control for prevention of anastomotic leakage after resection for rectal cancer (RIPAL trial): a pilot randomized controlled, triple-blinded monocenter trial.

PURPOSE: Remote ischemic preconditioning (RIPC) reportedly reduces ischemia‒reperfusion injury (IRI) in various organ systems. In addition to tension and technical factors, ischemia is a common cause of anastomotic leakage (AL) after rectal resection. The aim of this pilot study was to investigate the potentially protective effect of RIPC on anastomotic healing and to determine the effect size to facilitate the development of a subsequent confirmatory trial. MATERIALS AND METHODS: Fifty-four patients with rectal cancer (RC) who underwent anterior resection were enrolled in this prospectively registered (DRKS0001894) pilot randomized controlled triple-blinded monocenter trial at the Department of Surgery, University Medicine Mannheim, Mannheim, Germany, between 10/12/2019 and 19/06/2022. The primary endpoint was AL within 30 days after surgery. The secondary endpoints were perioperative morbidity and mortality, reintervention, hospital stay, readmission and biomarkers of ischemia‒reperfusion injury (vascular endothelial growth factor, VEGF) and cell death (high mobility group box 1 protein, HMGB1). RIPC was induced through three 10-min cycles of alternating ischemia and reperfusion to the upper extremity. RESULTS: Of the 207 patients assessed, 153 were excluded, leaving 54 patients to be randomized to the RIPC or the sham-RIPC arm (27 each per arm). The mean age was 61 years, and the majority of patients were male (37:17 (68.5:31.5%)). Most of the patients underwent surgery after neoadjuvant therapy (29/54 (53.7%)) for adenocarcinoma (52/54 (96.3%)). The primary endpoint, AL, occurred almost equally frequently in both arms (RIPC arm: 4/25 (16%), sham arm: 4/26 (15.4%), p = 1.000). The secondary outcomes were comparable except for a greater rate of reintervention in the sham arm (9 (6-12) vs. 3 (1-5), p = 0.034). The median duration of endoscopic vacuum therapy was shorter in the RIPC arm (10.5 (10-11) vs. 38 (24-39) days, p = 0.083), although the difference was not statistically significant. CONCLUSION: A clinically relevant protective effect of RIPC on anastomotic healing after rectal resection cannot be assumed on the basis of these data.

Robotic sectionectomy versus robotic hemihepatectomy for anatomic liver resection: a comparative analysis of perioperative outcomes.

Sectionectomy is a parenchma-sparing alternative to (extended) right or left hemihepatectomy. However, the effectiveness and safety of robotic sectionectomy (RS) versus robotic (extended) hemihepatectomy (RH) for the treatment of liver tumors remains unclear. We reviewed our prospective database for consecutive patients who had undergone robotic hepatectomies between March 2021 and July 2023 and included all patients with RS and RH. Demographic data, perioperative outcomes and long-term outcomes were analyzed and compared between both groups. Thirty patients met our inclusion criteria, of whom 16 patients underwent RS as opposed to 14 patients who underwent RH. Baseline characteristics were comparable between the study groups. The duration of Pringle maneuver was significantly longer in the RS group, while the remaining operative details were comparable. There were no significant differences in posthepatectomy outcomes between the study groups. All patients had negative resection margins. RS is a safe and effective parenchyma-sparing treatment modality.

Primary Tumor Resection Before Systemic Therapy in Patients With Colon Cancer and Unresectable Metastases: Combined Results of the SYNCHRONOUS and CCRe-IV Trials.

PURPOSE: Chemotherapy is established as primary treatment in patients with stage IV colorectal cancer and unresectable metastases. Data from nonrandomized clinical trials have fueled persistent uncertainty if primary tumor resection (PTR) before chemotherapy prolongs survival. We investigated the prognostic value of PTR in patients with newly diagnosed stage IV colon cancer who were not amenable to curative treatment. PATIENTS AND METHODS: Patients enrolled in the multicenter, randomized SYNCHRONOUS and CCRe-IV trials were included in the analysis. Patients with colon cancer with synchronous unresectable metastases were randomly assigned at 100 sites in Austria, Germany, and Spain to undergo PTR or up-front chemotherapy (No PTR group). The chemotherapy regimen was left at discretion of the local team. Patients with tumor-related symptoms, inability to tolerate surgery and/or systemic chemotherapy, and history of another cancer were excluded. The primary end point was overall survival (OS), and the analyses were performed with intention-to-treat. RESULTS: A total of 393 patients were randomly assigned to undergo PTR (n = 187) or no PTR (n = 206) between November 2011 and March 2017. Chemotherapy was not administered to 6.4% in the No PTR group and 24.1% in the PTR group. The median follow-up time was 36.7 months (95% CI, 36.6 to 37.3). The median OS was 16.7 months (95% CI, 13.2 to 19.2) in the PTR group and 18.6 months (95% CI, 16.2 to 22.3) in the No PTR group (P = .191). Comparable OS between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944 [95% CI, 0.738 to 1.209], P = .65) and across all subgroups. Patients with serious adverse events were more common in the No PTR group (10.2% v 18.0%; P = .027). CONCLUSION: Among patients with colon cancer and synchronous unresectable metastases, PTR before systemic chemotherapy was not associated with prolonged OS.

Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.

Remote ischemic preconditioning for reduction of ischemia-reperfusion injury after hepatectomy: A randomized sham-controlled trial.

BACKGROUND: Remote ischemic preconditioning reduces ischemia-reperfusion injury in patients undergoing hepatectomy. Moreover, there is evidence that the protective effects of remote ischemic preconditioning may be more pronounced in pre-damaged livers. The objective of this trial was to investigate the extent to which remote ischemic preconditioning can attenuate ischemia-reperfusion injury after hepatectomy and Pringle maneuver in patients with chronic liver disease. METHODS: In this randomized, controlled, triple-blind monocenter trial, a total of 102 patients with chronic liver disease and planned hepatectomy were enrolled between December 2019 and March 2022. Eligible patients were randomized to the remote ischemic preconditioning or sham arms. Remote ischemic preconditioning was induced through 3 10-minute cycles of alternating ischemia and reperfusion of the upper extremity. The study was prospectively registered in the German Clinical Trials Registry (DRKS00018931). RESULTS: A total of 102 patients were included in the study and were randomized (51 per arm). The median age was 69.5 years, approximately two-thirds of the patients were male (69/102, 67.7%), and the mean body mass index was 25.6 kg/m2. Most patients were classified as American Society of Anesthesiologists II (55/102, 53.9%) or III (45/102, 44.1%). The primary endpoint, the transaminases on the first postoperative day (alanine aminotransferase /aspartate aminotransferase: remote ischemic preconditioning arm: 250 (35-1721)/320 (42-1525) U/L versus sham control arm: 283 (32-792)/356 (20-1851) U/L, P = .820/0.639), clinical outcomes as well as remote ischemic preconditioning biomarker levels were comparable between both arms. CONCLUSION: Remote ischemic preconditioning did not achieve a significant reduction in postoperative transaminase levels, nor did it affect clinical results and biomarkers.

Robotic or laparoscopic repeat hepatectomy after open hepatectomy: a cohort study.

BACKGROUND: Repeat hepatectomies are technically complex procedures. The evidence of robotic or laparoscopic (= minimally invasive) repeat hepatectomies (MIRH) after previous open hepatectomy is poor. Therefore, we compared postoperative outcomes of MIRH vs open repeat hepatectomies (ORH) in patients with liver tumors after previous open liver resections. METHODS: Consecutive patients who underwent repeat hepatectomies after open liver resections were identified from a prospective database between April 2018 and May 2023. Postoperative complications were graded in line with the Clavien-Dindo classification. We stratified patients by intention to treat into MIRH or ORH and compared outcomes. Logistic regression analysis was performed to define variables associated with the utilization of a minimally invasive approach. RESULTS: Among 46 patients included, 20 (43%) underwent MIRH and 26 (57%) ORH. Twenty-seven patients had advanced or expert repeat hepatectomies (59%) according to the IWATE criteria. Baseline characteristics were comparable between the study groups. The use of a minimally invasive approach was not dependent on preoperative or intraoperative variables. All patients had negative resection margins on final histology. MIRH was associated with less blood loss (450 ml, IQR (interquartile range): 200-600 vs 600 ml, IQR: 400-1500 ml, P = 0.032), and shorter length of stay (5 days, IQR: 4-7 vs 7 days, IQR: 5-9 days, P = 0.041). Postoperative complications were similar between the groups (P = 0.298). CONCLUSIONS: MIRH is feasible after previous open hepatectomy and a safe alternative approach to ORH. (German Clinical Trials Register ID: DRKS00032183).

The impact of class I compression stockings on the peripheral microperfusion of the lower limb: A prospective pilot study.

OBJECTIVE: The use of medical compression stockings (MCS) in patients with peripheral arterial disease (PAD) and diabetes is the subject of an ongoing critical debate. While reducing leg edema of various origins by improving venous back flow, there is a concern about additional arterial flow obstruction when compression therapy is applied in pre-existing PAD. The aim of this study is to obtain further information on the use of class I MCS in patients with advanced PAD and to evaluate the framework conditions for a safe application. METHODS: The total collective (n = 55) of this prospective, clinical cohort study consisted of 24 patients with PAD Fontaine stage IIb and higher studied before revascularization, of whom 16 patients were examined again after revascularization, and 15 healthy participants included for reference. The microperfusion of the lower extremity of all participants was examined in a supine, elevated, and sitting position using the oxygen to see (O2C) method. RESULTS: The results indicate that leg positioning had the strongest influence on microcirculation (SO2 and flow: p = 0.0001), whereas MCS had no significant effect on the perfusion parameters (SO2: p = 0.9936; flow: p = 0.4967) and did not lead to a deterioration of values into critical ranges. CONCLUSION: Mild medical compression therapy appears to be feasible even in patients with advanced PAD. Larger studies are warranted to observe any long-term effects, in particular for the treatment of reperfusion edema after revascularization.

Development and Validation of a Model for Postpancreatectomy Hemorrhage Risk.

Importance: Postpancreatectomy hemorrhage (PPH) due to postoperative pancreatic fistula (POPF) is a life-threatening complication after pancreatoduodenectomy. However, there is no prediction tool for early identification of patients at high risk of late PPH. Objective: To develop and validate a prediction model for PPH. Design, Setting, and Participants: This retrospective prognostic study included consecutive patients with clinically relevant POPF who underwent pancreatoduodenectomy from January 1, 2009, to May 20, 2023, at the University Hospital Mannheim (derivation cohort), and from January 1, 2012, to May 31, 2022, at the University Hospital Dresden (validation cohort). Data analysis was performed from May 30 to July 29, 2023. Exposure: Clinical and radiologic features of PPH. Main Outcomes and Measures: Accuracy of a predictive risk score of PPH. A multivariate prediction model-the hemorrhage risk score (HRS)-was established in the derivation cohort (n = 139) and validated in the validation cohort (n = 154). Results: A total of 293 patients (187 [64%] men; median age, 69 [IQR, 60-76] years) were included. The HRS comprised 4 variables with associations: sentinel bleeding (odds ratio [OR], 35.10; 95% CI, 5.58-221.00; P < .001), drain fluid culture positive for Candida species (OR, 14.40; 95% CI, 2.24-92.20; P < .001), and radiologic proof of rim enhancement of (OR, 12.00; 95% CI, 2.08-69.50; P = .006) or gas within (OR, 12.10; 95% CI, 2.22-65.50; P = .004) a peripancreatic fluid collection. Two risk categories were identified with patients at low risk (0-1 points) and high risk (≥2 points) to develop PPH. Patients with PPH were predicted accurately in the derivation cohort (C index, 0.97) and validation cohort (C index 0.83). The need for more invasive PPH management (74% vs 34%; P < .001) and severe complications (49% vs 23%; P < .001) were more frequent in high-risk patients compared with low-risk patients. Conclusions and Relevance: In this retrospective prognostic study, a robust prediction model for PPH was developed and validated. This tool may facilitate early identification of patients at high risk for PPH.

Ultra-sensitive CTC-based liquid biopsy for pancreatic cancer enabled by large blood volume analysis.

The limited sensitivity of circulating tumor cell (CTC) detection in pancreatic adenocarcinoma (PDAC) stems from their extremely low concentration in the whole circulating blood, necessitating enhanced detection methodologies. This study sought to amplify assay-sensitivity by employing diagnostic leukapheresis (DLA) to screen large blood volumes. Sixty patients were subjected to DLA, with a median processed blood volume of ~ 2.8 L and approximately 5% of the resulting DLA-product analyzed using CellSearch (CS). Notably, DLA significantly increased CS-CTC detection to 44% in M0-patients and 74% in M1-patients, yielding a 60-fold increase in CS-CTC enumeration. DLA also provided sufficient CS-CTCs for genomic profiling, thereby delivering additional genomic information compared to tissue biopsy samples. DLA CS-CTCs exhibited a pronounced negative prognostic impact on overall survival (OS), evidenced by a reduction in OS from 28.6 to 8.5 months (univariate: p = 0.002; multivariable: p = 0.043). Additionally, a marked enhancement in sensitivity was achieved (by around 3-4-times) compared to peripheral blood (PB) samples, with positive predictive values for OS being preserved at around 90%. Prognostic relevance of CS-CTCs in PDAC was further validated in PB-samples from 228 PDAC patients, consolidating the established association between CTC-presence and reduced OS (8.5 vs. 19.0 months, p < 0.001). In conclusion, DLA-derived CS-CTCs may serve as a viable tool for identifying high-risk PDAC-patients and aiding the optimization of multimodal treatment strategies. Moreover, DLA enables comprehensive diagnostic profiling by providing ample CTC material, reinforcing its utility as a reliable liquid-biopsy approach. This high-volume liquid-biopsy strategy presents a potential pathway for enhancing clinical management in this malignancy.

Continuous versus interrupted abdominal wall closure after emergency midline laparotomy: CONTINT: a randomized controlled trial [NCT00544583].

BACKGROUND: High-level evidence regarding the technique of abdominal wall closure for patients undergoing emergency midline laparotomy is sparse. Therefore, we conducted a randomized controlled trial (RCT) to evaluate the efficacy and safety of two commonly applied abdominal wall closure strategies after primary emergency midline laparotomy. METHODS/DESIGN: CONTINT was a multi-center pragmatic open-label exploratory randomized controlled parallel trial. Two different abdominal wall closure strategies in patients undergoing primary midline laparotomy for an emergency surgical intervention with a suspected septic focus in the abdominal cavity were compared: the continuous, all-layer suture and the interrupted suture technique. The primary composite endpoint was burst abdomen within 30 days after surgery or incisional hernia within 12 months. As reliable data on this composite primary endpoint were not available for patients undergoing emergency surgery, it was planned to initially recruit 80 patients and conduct an interim analysis after these had completed the 12 months follow-up. RESULTS: From August 31, 2009, to June 28, 2012, 124 patients were randomized of whom 119 underwent surgery and were analyzed according to the intention-to-treat (ITT) principal. The primary composite endpoint did not differ between the continuous suture (C: 27.1%) and the interrupted suture group (I: 30.0%). None of the individual components of the primary endpoint (reoperation due to burst abdomen after 30 days (C: 13.5%, I: 15.1%) and reoperation due to incisional hernia (C: 3.0%, I:11.1%)) differed between groups. Time needed for fascial closure was longer in the interrupted suture group (C: 12.8 ± 4.5 min, I: 17.4 ± 6.1 min). BMI was associated with burst abdomen during the first 30 days with an OR of 1.17 (95% CI 1.04-1.32). CONCLUSION: This RCT showed no difference between continuous suture with slowly absorbable suture versus interrupted rapidly absorbable sutures after primary emergency midline laparotomy in rates of postoperative burst abdomen and incisional hernia after one year. However, the trial was stopped after the interim analysis due to futility as there was no chance to show superiority of one suture technique.

The Role of Adjuvant Therapy in Duodenal Adenocarcinoma and Intestinal Subtype Ampullary Carcinoma after Curative Resection.

OBJECTIVE: Defining the role of adjuvant therapy in duodenal adenocarcinoma (DAC) and intestinal subtype ampullary carcinoma (iAC). SUMMARY BACKGROUND DATA: DAC and iAC share a similar histological differentiation but the benefit of adjuvant therapy remains unclear. METHODS: Patients undergoing curative-intent surgical resection for DAC and iAC between 2010 and 2021 at five high-volume centers were included. Patient baseline, perioperative and long-term oncological outcomes were evaluated. Statistical testing was performed with SPSS 25 (IBM). RESULTS: A total of 136 patients with DAC and 171 with iAC were identified. Patients with DAC had more advanced tumors than those with iAC. Median overall survival (OS) in DAC patients was 101 months versus 155 months for iAC patients (P=0.098). DAC had a higher rate of local (14.1% vs. 1.2%, P<0.001) and systemic recurrence (30.4% vs. 3.5%, P<0.001). Adjuvant therapy failed to improve overall survival in all patients with DAC and iAC. For DAC, patients with perineural invasion, but not other negative prognostic factors had improved OS rates with adjuvant therapy (72 m vs. 44 m, P=0.044). IAC patients with N+ (190 m vs. 57 m, P=0.003), T3-4 (177 m vs. 59 m, P=0.050) and perineural invasion (150 m vs. 59 m, P=0.019) had improved OS rates with adjuvant therapy. CONCLUSION: While adjuvant therapy fails to improve OS in all patients with DAC and iAC in the current study, it improved overall survival in DAC patients with perineural invasion and in iAC patients with T3-4 tumors, positive lymph nodes, and perineural invasion.

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

Management of Anastomotic Leakage after Colorectal Resection: Survey among the German CHIR-Net Centers.

(1) Background: A widely accepted algorithm for the management of colorectal anastomotic leakage (CAL) is difficult to establish. The present study aimed to evaluate the current clinical practice on the management of CAL among the German CHIR-Net centers. (2) Methods: An online survey of 38 questions was prepared using the International Study Group of Rectal Cancer (ISREC) grading score of CAL combined with both patient- and surgery-related factors. All CHIR-Net centers received a link to the online questionary in February 2020. (3) Results: Most of the answering centers (55%) were academic hospitals (41%). Only half of them use the ISREC definition and grading for the management of CAL. A preference towards grade B management (no surgical intervention) of CAL was observed in both young and fit as well as elderly and/or frail patients with deviating ostomy and non-ischemic anastomosis. Elderly and/or frail patients without fecal diversion are generally treated as grade C leakage (surgical intervention). A grade C management of CAL is preferred in case of ischemic bowel, irrespective of the presence of an ostomy. Within grade C management, the intestinal continuity is preserved in a subgroup of patients with non-ischemic bowel, with or without ostomy, or young and fit patients with ischemic bowel under ostomy protection. (4) Conclusions: There is no generally accepted therapy algorithm for CAL management within CHIR-Net Centers in Germany. Further effort should be made to increase the application of the ISREC definition and grading of CAL in clinical practice.

E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. METHODS: A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. RESULTS: Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2- to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. CONCLUSION: These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.

Liver surgery is an effective treatment for liver tumours. Liver failure is a major problem in patients with a poor liver quality or having large operations. The treatment options for liver failure are limited, with high death rates. To estimate patient risk, assessing liver function before surgery is important. Many methods exist for this purpose, including functional, blood, and imaging tests. This guideline summarizes the available literature and expert opinions, and aids clinicians in planning safe liver surgery.

Proteomics of immune cells from liver tumors reveals immunotherapy targets.

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.

Spatial Omics Imaging of Fresh-Frozen Tissue and Routine FFPE Histopathology of a Single Cancer Needle Core Biopsy: A Freezing Device and Multimodal Workflow.

The complex molecular alterations that underlie cancer pathophysiology are studied in depth with omics methods using bulk tissue extracts. For spatially resolved tissue diagnostics using needle biopsy cores, however, histopathological analysis using stained FFPE tissue and the immunohistochemistry (IHC) of a few marker proteins is currently the main clinical focus. Today, spatial omics imaging using MSI or IRI is an emerging diagnostic technology for the identification and classification of various cancer types. However, to conserve tissue-specific metabolomic states, fast, reliable, and precise methods for the preparation of fresh-frozen (FF) tissue sections are crucial. Such methods are often incompatible with clinical practice, since spatial metabolomics and the routine histopathology of needle biopsies currently require two biopsies for FF and FFPE sampling, respectively. Therefore, we developed a device and corresponding laboratory and computational workflows for the multimodal spatial omics analysis of fresh-frozen, longitudinally sectioned needle biopsies to accompany standard FFPE histopathology of the same biopsy core. As a proof-of-concept, we analyzed surgical human liver cancer specimens using IRI and MSI with precise co-registration and, following FFPE processing, by sequential clinical pathology analysis of the same biopsy core. This workflow allowed for a spatial comparison between different spectral profiles and alterations in tissue histology, as well as a direct comparison for histological diagnosis without the need for an extra biopsy.

Stereotactic Body Radiation Therapy versus Surgical Resection for Stage I/II Hepatocellular Carcinoma.

SBRT is an emerging locoregional treatment modality for hepatocellular carcinoma (HCC). Although local tumor control rates seem encouraging, large-scale survival data comparing SBRT to surgical resection are lacking. We identified patients with stage I/II HCC from the National Cancer Database amenable for potential surgical resection. Patients undergoing hepatectomy were matched by propensity score (1:2) with patients who underwent SBRT as primary treatment. A total of 3787 (91%) and 366 (9%) patients underwent surgical resection or SBRT between 2004 and 2015, respectively. After propensity matching, the 5-year overall survival was 24% (95% CI 19-30%) in the SBRT group versus 48% (95% CI 43-53%) in the surgery group (p < 0.001). The association of surgery with overall survival was consistent in all subgroups. In patients treated with SBRT, a biologic effective dose (BED) of ≥100 Gy (31%, 95% CI 22%-40%) compared with BED < 100 Gy (13%, 95% CI 8-22%) was associated with a higher 5-year overall survival rate (hazard ratio of mortality of 0.58, 95% CI 0.43-0.77; p < 0.001). Surgical resection may be associated with prolonged overall survival compared with SBRT in patients with stage I/II HCC.

Development of a conceptual framework to detect perioperative symptom burden following abdominal surgery for cancer.

BACKGROUND: Abdominal surgery for gastrointestinal malignancies has a significant impact on patients' health-related quality of life. However, there is so far no patient-reported outcome measures (PROM) in the immediate postoperative period to detect the perioperative symptom burden and patients' needs which may precede occult and severe complications. The aim of the study was to create a conceptual framework for the development of a PROM to measure perioperative symptom burden in abdominal cancer patients. METHODS: This mixed method study was performed between March 2021, and July 2021 as part of a multiphase approach to develop a new PROM. A systematic review of the literature was performed health domains were identified. The relevance of the health domains was assessed in a two-round Delphi study with clinical experts. Qualitative interviews were performed in patients who underwent abdominal surgery for cancer. RESULTS: The systematic literature review yielded 12 different PROM with 168 items and 55 health domains. The most common health domains involved the "digestive system" and "pain". In total, 30 patients (median age 66 years, 20 men [60%]) were included for qualitative patient interviews. Of 16 health domains identified by the Delphi study, a total 15 health domains were confirmed during patients' interviews. The final conceptual framework included 20 health domains. CONCLUSION: This study provides the essential groundwork to develop and validate a new PROM for the immediate postoperative period of patients undergoing abdominal surgery for cancer.

Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes.

Bone morphogenetic protein (BMP)-9, a member of the TGFß-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.