Personalized multimodal prehabilitation reduces cardiopulmonary complications after pancreatoduodenectomy:results of a propensity score matching analysis

Background: The purpose of prehabilitation is to improve postoperative outcomes by increasing patients’ resilience against the stress of surgery. This study investigates the effect of personalized multimodal prehabilitation on patients undergoing pancreatoduodenectomy.Methods: Included patients were screened for six modifiable risk factors: (1) low physical fitness, (2) malnutrition, (3) low mental resilience, (4) anemia and hyperglycemia, (5) frailty, and (6) substance abuse. Interventions were performed as needed. Using 1:1 propensity score matching (PSM), patients were compared to a historical cohort.Results: From 120 patients, 77 (64.2%) performed a cardiopulmonary exercise test to assess their physical fitness and provide them with a preoperative training advice. Furthermore, 88 (73.3%) patients received nutritional support, 15 (12.5%) mental support, 17 (14.2%) iron supplementation to correct for iron deficiency, 18 (15%) regulation support for hyperglycemia, 14 (11.7%) a comprehensive geriatric assessment, and 19 (15.8%) substance abuse support. Of all patients, 63% required ≥2 prehabilitation interventions. Fewer cardiopulmonary complications were observed in the prehabilitation cohort (9.2% versus 23.3%; p = 0.002). In surgical outcomes and length of stay no differences were observed.Conclusion: Our prehabilitation program is effective in detecting risk factors in patients; most patients required multiple interventions. Consequently, a reduction in cardiopulmonary complications was observed.</p

Treatment of iron deficiency in patients scheduled for pancreatic surgery:implications for daily prehabilitation practice in pancreatic surgery

BACKGROUND: Preoperative anemia is a frequent complication in pancreatic surgical patients, and it adversely affects morbidity, mortality, and postoperative red blood cell (RBC) transfusion rates. Iron deficiency (ID) is often the underlying cause of anemia and constitutes a modifiable risk factor.METHODS: Single-center, longitudinal prospective cohort study conducted between May 2019 and August 2022 at the University Medical Center Groningen in the Netherlands. Patients scheduled for pancreatic surgery were referred to the outpatient prehabilitation clinic for preoperative optimization of patient-related risk factors. Patients were screened for anemia (&lt; 12.0 g/dL in women and &lt; 13.0 g/dL in men) and ID (either absolute [ferritin &lt; 30 µg/L] or functional [ferritin ≥ 30 µg/L + transferrin saturation &lt; 20% + C-reactive protein &gt; 5 mg/L]). Intravenous iron supplementation (IVIS) (1,000 mg ferric carboxymaltose) was administered to patients with ID at the discretion of the consulting internist. Pre- and postoperative hemoglobin (Hb) levels were assessed, and perioperative outcomes were compared between patients receiving IVIS (IVIS-group) or standard care (SC-group).RESULTS: From 164 screened patients, preoperative anemia was observed in 55 (33.5%) patients, and in 23 (41.8%) of these patients, ID was the underlying cause. In 21 patients, ID was present without concomitant anemia. Preoperative IVIS was administered to 25 patients, out of 44 patients with ID. Initial differences in mean Hb levels (g/dL) between the IVIS-group and SC-group at the outpatient clinic and one day prior to surgery (10.8 versus 13.2, p &lt; 0.001, and 11.8 versus 13.4, p &lt; 0.001, respectively) did not exist at discharge (10.6 versus 11.1, p = 0.13). Preoperative IVIS led to a significant increase in mean Hb levels (from 10.8 to 11.8, p = 0.03). Fewer SSI were observed in the IVIS-group (4% versus 25.9% in the SC-group, p = 0.02), which remained significant in multivariable regression analysis (OR 7.01 (1.68 - 49.75), p = 0.02).CONCLUSION: ID is prevalent in patients scheduled for pancreatic surgery and is amendable to preoperative correction. Preoperative IVIS increased Hb levels effectively and reduced postoperative SSI. Screening and correction of ID is an important element of preoperative care and should be a standard item in daily prehabilitation practice.</p

Exploring transparent reporting and data availability in systematic reviews to identify subgroup evidence:imaging for suspected hepatocellular carcinoma in the non-cirrhotic liver

We aim to illustrate the role of complete and transparent reporting coupled with access to data sourced from published systematic reviews, especially assisting in the identification of evidence for subgroups within the context of a rare disease. To accomplish this principle, we provide a real-world example encountered during the revision of the Dutch clinical practice guideline for hepatocellular carcinoma. Specifically, we retrieved insights from two Cochrane reviews to identify direct evidence concerning the diagnostic test accuracy of computed tomography and magnetic resonance imaging for detecting hepatocellular carcinomas in suspected patients without liver cirrhosis. Through reusing the Cochrane review authors’ efforts already undertaken in their exhaustive literature search and selection, we successfully identified relevant direct evidence for this subgroup of suspected patients without cirrhosis and performed an evidence synthesis within the constraints of limited resources for the guideline revision. This approach holds the potential for replication in other subgroups in the context of rare diseases, contingent on the transparent and complete reporting of systematic reviews, as well as the availability and accessibility of their extracted data. Consequently, we underscore the importance of adhering to established reporting guidelines for systematic reviews, while simultaneously advocating for increased availability and accessibility to data. Such practices would not only increase the transparency and reproducibility of systematic reviews but could also increase reusability of their data. In turn, the increased reusability could result in reduced resource utilization in other sectors such as the guideline developing community as we show in our example.</p

Robot-Assisted Laparoscopic Resection of a Todani Type II Choledochal Malformation

Choledochal malformation (CM) comprise various congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. CM is classified into five different types. Our case describes a 58-year-old man presenting with acute abdominal pain. Further examination showed a Todani type II CM. Treatment for type II is complete cyst excision without the need for an extrahepatic bile duct resection. A robot-assisted laparoscopic resection of the CM was performed and the patient recovered without complications. Pathology results showed a Todani type II malformation in which complete squamous metaplasia has occurred. In this paper, we report, to the best of our knowledge, the first description of a robot-assisted laparoscopic resection of a type II CM

Ex Situ Dual Hypothermic Oxygenated Machine Perfusion for Human Split Liver Transplantation

Liver splitting allows the opportunity to share a deceased graft between 2 recipients but remains underutilized. We hypothesized that liver splitting during continuous dual hypothermic oxygenated machine perfusion (DHOPE) is feasible, with shortened total cold ischemia times and improved logistics. Here, we describe a left lateral segment (LLS) and extended right lobe (ERL) liver split procedure during continuous DHOPE preservation with subsequent transplantation at 2 different centers. Methods: After transport using static cold storage, a 51-year-old brain death donor liver underwent end-ischemic DHOPE. During DHOPE, the donor liver was maintained 106 kPa. An ex situ ERL/LLS split was performed with continuing DHOPE throughout the procedure to avoid additional ischemia time. Results: Total cold ischemia times for the LLS and ERL were 205 minutes and 468 minutes, respectively. Both partial grafts were successfully transplanted at 2 different transplant centers. Peak aspartate aminotransferase and alanine aminotransferase were 172 IU/L and 107 IU/L for the LLS graft, and 839 IU/L and 502 IU/L for the ERL graft, respectively. The recipient of the LLS experienced an episode of acute cellular rejection. The ERL transplantation was complicated by severe acute pancreatitis with jejunum perforation requiring percutaneous drainage and acute cellular rejection. No device-related adverse events were observed. Conclusions: Liver splitting during continuous DHOPE preservation is feasible, has the potential to substantially shorten cold ischemia time and may optimize transplant logistics. Therefore liver splitting with DHOPE can potentially improve utilization of split liver transplantation

Gallbladder Cancer:Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

SIMPLE SUMMARY: Knowledge of genetic alterations in gallbladder cancer (GBC) continues to increase. This systematic review provides an overview of frequently occurring genetic alterations in GBC and describes their possible therapeutic implications. We detected three frequently (>5%) altered genes (ATM, ERBB2 and PIK3CA) for which targeted therapies are available in other cancer types. For solid cancers with microsatellite instability or a high tumor mutational burden pembrolizumab is FDA-approved. Altogether, these five biomarkers might be used in future molecular panels to enable precision medicine for patients with GBC. We found only nine clinical trials evaluating targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials. ABSTRACT: Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials

Risk factors for complications after surgery for pancreatic neuroendocrine tumors

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic neuroendocrine tumors. The choice for the type of procedure is influenced by the expected oncological benefit and the anticipated risk of procedure-specific complications. Few studies have focused on complications in these patients. This cohort study aimed to assess complications and risk factors after resections of pancreatic neuroendocrine tumors. METHODS: Patients undergoing resection of a pancreatic neuroendocrine tumor were identified within 2 centers of excellence. Complications were assessed according to the Clavien-Dindo classification and the comprehensive complication index. Logistic regression was performed to compare surgical procedures with adjustment for potential confounders (Clavien-Dindo ≥3). RESULTS: The cohort comprised 123 patients, including 12 enucleations, 50 distal pancreatectomies, 51 pancreatoduodenectomies, and 10 total/combined pancreatectomies. Mortality was 0.8%, a severe complication occurred in 41.5%, and the failure-to-rescue rate was 2.0%. The median comprehensive complication index was 22.6 (0-100); the comprehensive complication index increased after more extensive resections. After adjustment, a pancreatoduodenectomy, as compared to a distal pancreatectomy, increased the risk for a severe complication (odds ratio 3.13 [95% confidence interval 1.32-7.41]). Of the patients with multiple endocrine neoplasia type 1 or von Hippel-Lindau, 51.9% developed a severe complication vs 38.5% with sporadic disease. After major resections, morbidity was significantly higher in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau (comprehensive complication index 45.1 vs 28.9, P = .029). CONCLUSION: Surgery for pancreatic neuroendocrine tumors is associated with a high rate of complications but low failure-to-rescue in centers of excellence. Complications are procedure-specific. Major resections in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau appear to increase the risk of complications

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol

Background: High dose unilobar radioembolization (also termed ‘radiation lobectomy’)—the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy—has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. Methods: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose–response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. Discussion: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. Trial registration: Netherlands Trial Register NL8902 , registered on 2020–09-15

Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19(+)- liver cells deficient for p53 and Rb

The long term prognosis of liver cancer patients remains unsatisfactory because of cancer recurrence after surgical interventions, particularly in patients with viral infections. Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma (Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis. We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/liver progenitor cell (LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice. We show that liver cancer develops at the necrotic injury site after surgical resection or radiofrequency ablation in p53/Rb deficient livers. Cancer initiation occurs as a result of specific migration, expansion and transformation of cytokeratin-19+-liver (CK-19+) cells. At the injury site migrating CK-19+ cells formed small bile ducts and adjacent cells strongly expressed the transforming growth factor β (TGFβ). Isolated cytokeratin-19+ cells deficient for p53/Rb were resistant against hypoxia and TGFβ-mediated growth inhibition. CK-19+ specific deletion of p53/Rb verified that carcinomas at the injury site originates from cholangiocytes or liver progenitor cells. These findings suggest that human liver patients with hepatitis B and C viral infection or with mutations for p53 and Rb are at high risk to develop tumors at the surgical intervention site

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p