Pancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat ...infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood.
Clinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non-pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), rectus abdominus muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) 1H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome.
Muscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis.
Muscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response.
Timely diagnosis and classification of colorectal cancer (CRC) are hindered by unsatisfactory clinical assays. Our aim was to construct a blood-based biomarker series using a single assay, suitable ...for CRC detection, prognostication and staging.
Serum metabolomic profiles of adenoma (N=31), various stages of CRC (N=320) and healthy matched controls (N=254) were analysed by gas chromatography-mass spectrometry (GC-MS). A diagnostic model for CRC was derived by orthogonal partial least squares-discriminant analysis (OPLS-DA) on a training set, and then validated on an independent data set. Metabolomic models suitable for identifying adenoma, poor prognosis stage II CRC and discriminating various stages were generated.
A diagnostic signature for CRC with remarkable multivariate performance (R(2)Y=0.46, Q(2)Y=0.39) was constructed, and then validated (sensitivity 85%; specificity 86%). Area under the receiver-operating characteristic curve was 0.91 (95% CI, 0.87-0.96). Adenomas were also detectable (R(2)Y=0.35, Q(2)Y=0.26, internal AUROC=0.81, 95% CI, 0.70-0.92). Also of particular interest, we identified models that stratified stage II by prognosis, and classified cases by stage.
Using a single assay system, a suite of CRC biomarkers based on circulating metabolites enables early detection, prognostication and preliminary staging information. External population-based studies are required to evaluate the repeatability of our findings and to assess the clinical benefits of these biomarkers.
Excessive muscle loss is commonly observed in cancer patients and its association with poor prognosis has been well-established. Cancer-associated sarcopenia differs from age-related wasting in that ...it is not responsive to nutritional intervention and exercise. This is related to its unique pathogenesis, a result of diverse and interconnected mechanisms including inflammation, disordered metabolism, proteolysis and autophagy. There is a growing body of evidence that suggests that the tumor is the driver of muscle wasting by its elaboration of mediators that influence each of these pro-sarcopenic pathways. In this review, evidence for these tumor-derived factors and putative mechanisms for inducing muscle wasting will be reviewed. Potential targets for future research and therapeutic interventions will also be reviewed.
Objectives
Skeletal muscle mass is a prognostic factor in pancreatic ductal adenocarcinoma (PDAC). However, it remains unclear whether changes in body composition provide an incremental prognostic ...value to established risk factors, especially the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). The aim of this study was to determine the prognostic value of CT-quantified body composition changes in patients with unresectable PDAC starting chemotherapy.
Methods
We retrospectively evaluated 105 patients with unresectable (locally advanced or metastatic) PDAC treated with FOLFIRINOX (
n
= 64) or gemcitabine-based (
n
= 41) first-line chemotherapy within a multicenter prospective trial. Changes (Δ) in skeletal muscle index (SMI), subcutaneous (SATI), and visceral adipose tissue index (VATI) between pre-chemotherapy and first follow-up CT were assessed. Cox regression models and covariate-adjusted survival curves were used to identify predictors of overall survival (OS).
Results
At multivariable analysis, adjusting for RECISTv1.1-response at first follow-up, ΔSMI was prognostic for OS with a hazard ratio (HR) of 1.2 (95% CI: 1.08–1.33,
p
= 0.001). No significant association with OS was observed for ΔSATI (HR: 1, 95% CI: 0.97–1.04,
p
= 0.88) and ΔVATI (HR: 1.01, 95% CI: 0.99–1.04,
p
= 0.33). At an optimal cutoff of 2.8 cm
2
/m
2
per 30 days, the median survival of patients with high versus low ΔSMI was 143 versus 233 days (
p
< 0.001).
Conclusions
Patients with a lower rate of skeletal muscle loss at first follow-up demonstrated improved survival for unresectable PDAC, regardless of their RECISTv1.1-category. Assessing ΔSMI at the first follow-up CT may be useful for prognostication, in addition to routine radiological assessment.
Key Points
• In patients with unresectable pancreatic ductal adenocarcinoma, change of skeletal muscle index (ΔSMI) in the early phase of chemotherapy is prognostic for overall survival, even after adjusting for Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) assessment at first follow-up.
• Changes in adipose tissue compartments at first follow-up demonstrated no significant association with overall survival.
• Integrating ΔSMI into routine radiological assessment may improve prognostic stratification and impact treatment decision-making at the first follow-up.
The primary aim of this study was to evaluate the efficacy of a single preoperative dose of methylprednisolone for preventing postoperative complications after major liver resections.
Hepatic ...resections are associated with a significant acute systemic inflammatory response. This effect subsequently correlates with postoperative morbidity, mortality, and length of recovery. Multiple small trials have proposed that the administration of glucocorticoids may modulate this effect.
This study was a parallel, dual-arm, double-blind randomized controlled trial. Adult patients undergoing elective major hepatic resection (≥3 segments) at a quaternary care institution were included (2013-2019). Patients were randomly assigned to receive a single preoperative 500 mg dose of methylprednisolone versus placebo. The main outcome measure was postoperative complications after liver resection, within 90 days of the index operation. Standard statistical methodology was employed (P < 0.05 = significant).
A total of 151 patients who underwent a major hepatic resection were randomized (mean age = 62.8 years; 57% male; body-mass-index = 27.9). No significant differences were identified between the intervention and control groups (age, sex, body-mass-index, preoperative comorbidities, hepatic function, ASA class, portal vein embolization rate) (P > 0.05). Underlying hepatic diagnoses included colorectal liver metastases (69%), hepatocellular carcinoma (18%), noncolorectal liver metastases (7%), and intrahepatic cholangiocarcinoma (6%). There was a significant reduction in the overall incidence of postoperative complications in the methylprednisolone group (31.2% vs 47.3%; P = 0.042). Patients in the glucocorticoid group also displayed less frequent organ space surgical site infections (6.5% vs 17.6%; P = 0.036), as well as a shorter length of hospital stay (8.9 vs 12.5 days; P = 0.015). Postoperative serum bilirubin and prothrombin timeinternational normalized ratio (PT-INR) levels were also lower in the steroid group (P = 0.03 and 0.04, respectively). Multivariate analysis did not identify any additional significant modifying factor relationships (estimated blood loss, duration of surgery, hepatic vascular occlusion (rate or duration), portal vein embolization, drain use, etc) (P > 0.05).
A single preoperative dose of methylprednisolone significantly reduces the length of hospital stay, postoperative serum bilirubin, and PT-INR, as well as infectious and overall complications following major hepatectomy.
Understanding the contribution of the host’s genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We ...investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.
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•15–20% of intratumoral variation of interferon signaling and cytotoxic cells is heritable•Common variants of IFIH1, STING1, and TMEM108 affect cancer IFN signaling•Common variants of RBL1 are associated with differential T cell infiltration•Rare cancer predisposition variants affect different immunomodulatory pathways
Sayaman, Saad et al. investigate the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA, providing evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment.
We postulated that the abundance of various metabolites in blood would facilitate the diagnosis of pancreatic and biliary lesions, which could potentially prevent unnecessary surgery.
Serum samples ...from patients with benign hepatobiliary disease (n = 43) and from patients with pancreatic cancer (n = 56) were examined by ¹H NMR spectroscopy to quantify 58 unique metabolites. Data were analyzed by "targeted profiling" followed by supervised pattern recognition and orthogonal partial least-squares discriminant analysis (O-PLS-DA) of the most significant metabolites, which enables comparison of the whole sample spectrum between groups.
The metabolomic profile of patients with pancreatic cancer was significantly different from that of patients with benign disease (AUROC, area under the ROC curve, = 0.8372). Overt diabetes mellitus (DM) was identified as a possible confounding factor in the pancreatic cancer group. Thus, diabetics were excluded from further analysis. In this more homogeneous pancreatic cancer group, compared with benign cases, serum concentrations of glutamate and glucose were most elevated on multivariate analysis. In benign cases, creatine and glutamine were most abundant. To examine the usefulness of this test, a comparison was made to age- and gender-matched controls with benign lesions that mimic cancer, controlling also for presence of jaundice and diabetes (n = 14 per group). The metabolic profile in patients with pancreatic cancer remained distinguishable from patients with benign pancreatic lesions (AUROC = 0.8308).
The serum metabolomic profile may be useful for distinguishing benign from malignant pancreatic lesions.
Further studies will be required to study the effects of jaundice and diabetes. A more comprehensive metabolomic profile will be evaluated using mass spectrometry.
Metabolite profiling in complex biological matrices such as serum requires high-throughput technologies capable of accurate and reproducible quantitative analysis and detection of slight differences ...in metabolite concentrations. Gas chromatography-mass spectrometry (GC-MS) is widely used for characterizing the metabolome. This chapter summarizes the necessary preparatory steps required to profile the metabolome using GC-MS. While this chapter focuses on evaluating polar metabolites in serum samples, the methods can be adapted to quantify nonpolar metabolites in other biological matrices.
Surgery represents the main curative therapeutic modality for gastric cancer, and it is occasionally considered for palliation as well as prophylaxis. Most frequently, surgical outcomes are conveyed ...in terms of oncological outcomes such as recurrence and survival. However, quality of life (QoL) is also important and should be considered when making treatment decisions - including the extent of and approach to surgery. Measurement of QoL usually involves the application of questionnaires. While there are multiple QoL questionnaires validated for use in oncology patients, there are very few that have been validated for use in those with gastric cancer. In this review, we discuss and compare the current status of QoL questionnaires in gastric cancer. More importantly, the impact of surgery for treatment, palliation and prophylaxis of gastric cancer on QoL will be described. These data should inform the surgeon on the optimal approach to treating gastric cancer, taking into account oncological outcomes. Knowledge gaps are also identified, providing a roadmap for future studies.
To determine the effect of bile spillage during cholecystectomy on oncological outcomes in incidental gallbladder cancers.
Gallbladder cancer (GBC) is rare, but lethal. Achieving complete resection ...offers the best chance of survival. About 30% of GBCs are discovered incidentally after cholecystectomy for benign pathology. There is an anecdotal association between peritoneal dissemination and bile spillage during the index cholecystectomy. However, no population-based studies are available that measure the consequences of bile spillage on patient outcomes.
We conducted a retrospective cohort comparison of patients with incidental GBC. All cholecystectomies and cases of GBC in Alberta, Canada, from 2001 to 2015, were identified. GBCs discovered incidentally were included. Operative events leading to bile spillage were reviewed. Patient outcomes were compared between cases of bile spillage versus no contamination.
In all, 115,484 cholecystectomies were performed, and a detailed analysis was possible in 82 incidental GBC cases. In 55 cases (67%), there was bile spillage during the index cholecystectomy. Peritoneal carcinomatosis occurred more frequently in those with bile spillage (24% vs 4%; P = 0.0287). Patients with bile spillage were less likely to undergo a radical re-resection (25% vs 56%; P = 0.0131) and were less likely to achieve an R0 resection margin odds ratio 0.19, 95% confidence interval (CI) 0.06-0.55. On Cox regression modeling, bile spillage was an independent predictor of shorter disease-free survival (hazard ratio 1.99, 95% CI 1.07-3.67).
For incidentally discovered GBC, bile spillage at the time of index cholecystectomy has measureable adverse consequences on patient outcomes. Early involvement of a hepatobiliary specialist is recommended where concerning features for GBC exist.
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