Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Peritoneal metastases of colorectal cancer: Insights from molecular and clinical perspectives

Colorectal cancer (CRC) patients with peritoneal metastases (PM) are currently treated with cytoreductive surgery (CRS) and HIPEC. This thesis primarily focuses on optimizing the preoperative work-up of CRC patients with PM. Part I Molecular insights The first part aims to provide insight in the molecular biology of colorectal PM. Chapter 2 outlines the process of peritoneal dissemination according to two phases, which could help us identify novel candidate biomarkers. Especially tumor cell adhesion to the peritoneum was considered crucial to form PM. Chapter 3 systematically reviews the functional importance of adhesion molecules and their clinical options. For patient selection, especially sLea and MUC16 were found to be of interest. α2β1 integrin antibodies, CD44 antibodies, hyaluronan-bound cytostatic agents, and EpCAM antibodies could target adhesion molecules and theoretically prevent formation of PM. Once a tumor cell has attached to the peritoneal surface, formation of PM depends on angiogenesis. In Chapter 4, we analyzed the expression of the angiogenesis-related markers VCAN, VEGF, and microvessel density in colorectal PM. The PCI, high VEGF expression, age, low epithelial VCAN expression, and lymph node metastases were associated with poor OS after CRS-HIPEC. The expression of the other angiogenesis markers HIF1α, SDF1, CXCR4, and VEGF is described in Chapter 5. The PCI, resection outcome, and VEGF expression had an independent association with OS after CRS-HIPEC. Both studies suggest that additional systemic administration of anti-VEGF agents could enhance survival. Chapter 6 provides a first step towards the clinical use of circulating tumor (ct)DNA analysis by setting out mutation-, copy number alteration- and hypermethylation markers in ctDNA to facilitate early diagnosis, prognostication, and monitoring of CRC patients. For CRC detection, copy number alterations and SEPT9 hypermethylation analysis could be promising. Regarding prognostication, mutation analysis of KRAS and APC could be of value. For monitoring, sequential ctDNA KRAS mutation analysis showed promise. Chapter 7 prospectively assesses ctDNA in CRC patients with PM. Preoperative ctDNA was found in 33% of patients using droplet digital PCR and was associated with a reduced DFS after CRS-HIPEC. In the follow-up, ctDNA was detected in 4/4 patients with a systemic- and 1/8 patients with a local relapse. Thus, sensitivity of single marker ctDNA is currently too low for detection of PM, but it could be used to guide therapy. Part II Insights from a clinical perspective Improved imaging is key to detect PM in an early stage and to optimize patient selection. Chapter 8 prospectively compares the advanced imaging techniques narrow-band imaging (NBI), near-infrared ICG, and spray-dye chromoendoscopy for detection of PM (n=28)15. NBI improved sensitivity for detection of PM from 80.0% to 96.0% (p=0.006), without loss of specificity. Prospective trials are warranted to investigate the clinical value of promising advanced imaging techniques regarding tumor detection, cost-effectiveness, and oncologic outcomes. Chapter 9 aimed to identify prognostic factors that could be assessed prior to surgery in a large prospective cohort of 175 CRC patients with PM treated with CRS-HIPEC. High PCI and peritoneal recurrence within 1 year following adjuvant chemotherapy were associated with worse DFS and OS and should be considered in patient selection prior to CRS-HIPEC. Also tumor subtype could be assessed preoperatively. Patients with PM of GGCs and MANECs might benefit of CRS-HIPEC. However, this is not standard part of care and guidelines. Chapter 10 presents a propensity-matched cohort together with a systematic review to compare outcomes between patients treated with CRS-HIPEC and patients treated with surgery without HIPEC. After matching, CRS-HIPEC was associated with improved median OS accompanied by acceptable morbidity rates, showing that GCC and MANEC patients with PM could benefit from this treatment offered by specialized HIPEC centers

Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic options

Peritoneal dissemination is diagnosed in 10–25 % of colorectal cancer patients. Selected patients are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. For these patients, earlier diagnosis, optimised selection criteria and a personalised approach are warranted. Biomarkers could play a crucial role here. However, little is known about possible candidates. Considering tumour cell adhesion as a key step in peritoneal dissemination, we aim to provide an overview of the functional importance of adhesion molecules in peritoneal dissemination and discuss the prognostic, diagnostic and therapeutic options of these candidate biomarkers. A systematic literature search was conducted according to the PRISMA guidelines. In 132 in vitro, ex vivo and in vivo studies published between 1995 and 2013, we identified twelve possibly relevant adhesion molecules in various cancers that disseminate peritoneally. The most studied molecules in tumour cell adhesion are integrin α2β1, CD44 s and MUC16. Furthermore, L1CAM, EpCAM, MUC1, sLe(x) and Le(x), chemokine receptors, Betaig-H3 and uPAR might be of clinical importance. ICAM1 was found to be less relevant in tumour cell adhesion in the context of peritoneal metastases. Based on currently available data, sLe(a) and MUC16 are the most promising prognostic biomarkers for colorectal peritoneal metastases that may help improve patient selection. Different adhesion molecules appear expressed in haematogenous and transcoelomic spread, indicating two different attachment processes. However, our extensive assessment of available literature reveals that knowledge on metastasis-specific genes and their possible candidates is far from complete

Treatment Options for Weight Regain or Insufficient Weight Loss After Sleeve Gastrectomy: a Systematic Review and Meta-analysis

Weight failure after sleeve gastrectomy (SG) is frequently observed. Consensus on the most effective treatment is lacking. The aim of this meta-analysis was to assess revisional strategies for weight regain (WR) or insufficient weight loss (IWL) following SG. The included studies reported on endoscopic gastroplasty (ESG), re-sleeve gastrectomy (re-SG), Roux-en-Y gastric bypass (RYGB), one-anastomosis gastric bypass (OAGB), single-anastomosis duodeno-ileal bypass (SADI), and duodenal switch (DS). All techniques resulted in clinically relevant weight loss. Although our data suggest that revisional OAGB was the most effective procedure, the lack of direct comparisons precludes strong conclusions. All procedures were feasible but differed regarding complication rates. Choice of procedure is depending on patient’s characteristics and surgeons’ expertise. Graphical abstract: [Figure not available: see fulltext.

Circulating tumor DNA as a preoperative marker of recurrence in patients with peritoneal metastases of colorectal cancer: A clinical feasibility study

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) may be curative for colorectal cancer patients with peritoneal metastases (PMs) but it has a high rate of morbidity. Accurate preoperative patient selection is therefore imperative, but is constrained by the limitations of current imaging techniques. In this pilot study, we explored the feasibility of circulating tumor (ct) DNA analysis to select patients for CRS-HIPEC. Thirty patients eligible for CRS-HIPEC provided blood samples preoperatively and during follow-up if the procedure was completed. Targeted Next-Generation Sequencing (NGS) of DNA from PMs was used to identify bespoke mutations that were subsequently tested in corresponding plasma cell-free (cf) DNA samples using droplet digital (dd) PCR. CtDNA was detected preoperatively in cfDNA samples from 33% of patients and was associated with a reduced disease-free survival (DFS) after CRS-HIPEC (median 6.0 months vs median not reached, p = 0.016). This association could indicate the presence of undiagnosed systemic metastases or an increased metastatic potential of the tumors. We demonstrate the feasibility of ctDNA to serve as a preoperative marker of recurrence in patients with PMs of colorectal cancer using a highly sensitive technique. A more appropriate treatment for patients with preoperative ctDNA detection may be systemic chemotherapy in addition to, or instead of, CRS-HIPEC