Endothelial bound lipoprotein lipase (LpL) depletion in hypoalbuminemia results from decreased endothelial binding, not decreased secretion

Hypertriglyceridemia in nephrotic (NS) and Nagase analbuminemic rats (Analb) results from reduced triglyceride clearance. NS and Analb have reduced or absent albumin, reduced plasma oncotic pressure (π), but Analb lack proteinuria. The heparin releasable lipoprotein lipase (LpL) pool in both models is greatly reduced, suggesting reduced LpL is related to low albumin or π and not proteinuria. To determine the cause of endothelial LpL reduction, we studied effectors of endothelial LpL (eLpL) levels from gene expression, to delivery and endothelial binding. eLpL was measured as heparin releasable activity. eLpL and secretion rate was measured in isolated hearts perfused with heparin. mRNA levels were measured in rat hearts by kinetic RT-PCR. Finally, binding of 125I-LpL by competition assays rat endothelial cells measured serum-induced changes in affinity. eLpL in vivo was reduced in nephrotic and Analb rats. While the eLpL pool was reduced in isolated perfused hearts, neither LpL secretion by isolated hearts nor myocardial mRNA was reduced in NS or Analb. Binding of LpL to RAEC preincubated with serum from either NS or Analb was reduced compared to control. LpL mRNA levels and release rate was not altered in hearts from NS rats, while eLpL is depleted, suggesting that reduced eLpL in NS is not the result of reduced delivery. The finding that NS serum alters LpL binding to RAEC suggests LpL depletion results from decreased binding rather than defective delivery. This in turn is a consequence of reduced serum albumin or π but does not require proteinuria

Value of EUS in Determining Curative Resectability in Reference to CT and FDG-PET: The Optimal Sequence in Preoperative Staging of Esophageal Cancer?

Background: The separate value of endoscopic ultrasonography (EUS), multidetector computed tomography (CT), and18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the optimal sequence in staging esophageal cancer has not been investigated adequately. Methods: The staging records of 216 consecutive operable patients with esophageal cancer were reviewed blindly. Different staging strategies were analyzed, and the likelihood ratio (LR) of each module was calculated conditionally on individual patient characteristics. A logistic regression approach was used to determine the most favorable staging strategy. Results: Initial EUS results were not significantly related to the LRs of initial CT and FDG-PET results. The positive LR (LR+) of EUS-fine-needle aspiration (FNA) was 4, irrespective of CT and FDG-PET outcomes. The LR+ of FDG-PET varied from 13 (negative CT) to 6 (positive CT). The LR+ of CT ranged from 3-4 (negative FDG-PET) to 2-3 (positive FDG-PET). Age, histology, and tumor length had no significant impact on the LRs of the three diagnostic tests. Conclusions: This study argues in favor of PET/CT rather than EUS as a predictor of curative resectability in esophageal cancer. EUS does not correspond with either CT or FDG-PET. LRs of FDG-PET were substantially different between subgroups of negative and positive CT results and vice versa

FDG-PET Parameters as Prognostic Factor in Esophageal Cancer Patients: A Review

Background:18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used extensively to explore whether FDG Uptake can be used to provide prognostic information for esophageal cancer patients. The aim of the present review is to evaluate the literature available to date concerning the potential prognostic value of FDG uptake in esophageal cancer patients, in terms of absolute pretreatment values and of decrease in FDG uptake during or after neoadjuvant therapy. Methods: A computer-aided search of the English language literature concerning esophageal cancer and standardized uptake values was performed. This search focused on clinical studies evaluating the prognostic value of FDG uptake as an absolute value or the decrease in FDG uptake and using overall mortality and/or disease-related mortality as an end point. Results: In total, 31 studies met the predefined criteria. Two main groups were identified based on the tested prognostic parameter: (1) FDG uptake and (2) decrease in FDG uptake. Most studies showed that pretreatment FDG uptake and postneoadjuvant treatment FDG uptake, as absolute values, are predictors for survival in univariate analysis. Moreover, early decrease in FDG uptake during neoadjuvant therapy is predictive for response and survival in most studies described. However, late decrease in FDG uptake after completion of neoadjuvant therapy was predictive for pathological response and survival in only 2 of 6 studies. Conclusions: Measuring decrease in FDG uptake early during neoadjuvant therapy is most appealing, moreover because the observed range of values expressed as relative decrease to discriminate responding from nonresponding patients is very small. At present inter-institutional comparison of results is difficult because several different normalization factors for FDG uptake are in use. Therefore, more research focusing on standardization of protocols and inter-institutional differences should be performed, before a PET-guided algorithm can be universally advocated

Staging investigations for oesophageal cancer: a meta-analysis

The aim of the study was to compare the diagnostic performance of endoscopic ultrasonography (EUS), computed tomography (CT), and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in staging of oesophageal cancer. PubMed was searched to identify English-language articles published before January 2006 and reporting on diagnostic performance of EUS, CT, and/or FDG-PET in oesophageal cancer patients. Articles were included if absolute numbers of true-positive, false-negative, false-positive, and true-negative test results were available or derivable for regional, celiac, and abdominal lymph node metastases and/or distant metastases. Sensitivities and specificities were pooled using a random effects model. Summary receiver operating characteristic analysis was performed to study potential effects of study and patient characteristics. Random effects pooled sensitivities of EUS, CT, and FDG-PET for regional lymph node metastases were 0.80 (95% confidence interval 0.75–0.84), 0.50 (0.41–0.60), and 0.57 (0.43–0.70), respectively, and specificities were 0.70 (0.65–0.75), 0.83 (0.77–0.89), and 0.85 (0.76–0.95), respectively. Diagnostic performance did not differ significantly across these tests. For detection of celiac lymph node metastases by EUS, sensitivity and specificity were 0.85 (0.72–0.99) and 0.96 (0.92–1.00), respectively. For abdominal lymph node metastases by CT, these values were 0.42 (0.29–0.54) and 0.93 (0.86–1.00), respectively. For distant metastases, sensitivity and specificity were 0.71 (0.62–0.79) and 0.93 (0.89–0.97) for FDG-PET and 0.52 (0.33–0.71) and 0.91 (0.86–0.96) for CT, respectively. Diagnostic performance of FDG-PET for distant metastases was significantly higher than that of CT, which was not significantly affected by study and patient characteristics. The results suggest that EUS, CT, and FDG-PET each play a distinctive role in the detection of metastases in oesophageal cancer patients. For the detection of regional lymph node metastases, EUS is most sensitive, whereas CT and FDG-PET are more specific tests. For the evaluation of distant metastases, FDG-PET has probably a higher sensitivity than CT. Its combined use could however be of clinical value, with FDG-PET detecting possible metastases and CT confirming or excluding their presence and precisely determining the location(s)

The 100 most cited articles investigating the radiological staging of oesophageal and junctional cancer: a bibliometric analysis

Objectives Accurate staging of oesophageal cancer (OC) is vital. Bibliometric analysis highlights key topics and publications that have shaped understanding of a subject. The 100 most cited articles investigating radiological staging of OC are identified. Methods The Thomas Reuters Web of Science database with search terms including “CT, PET, EUS, oesophageal and gastro-oesophageal junction cancer” was used to identify all English language, full-script articles. The 100 most cited articles were further analysed by topic, journal, author, year and institution. Results A total of 5,500 eligible papers were returned. The most cited paper was Flamen et al. (n = 306), investigating the utility of positron emission tomography (PET) for the staging of patients with potentially operable OC. The most common research topic was accuracy of staging investigations (n = 63). The article with the highest citation rate (38.00), defined as the number of citations divided by the number of complete years published, was Tixier et al. investigating PET texture analysis to predict treatment response to neo-adjuvant chemo-radiotherapy, cited 114 times since publication in 2011. Conclusion This bibliometric analysis has identified key publications regarded as important in radiological OC staging. Articles with the highest citation rates all investigated PET imaging, suggesting this modality could be the focus of future research

Comparison of CT and PET-CT based planning of radiation therapy in locally advanced pancreatic carcinoma

Abstract Background To compare computed tomography (CT) with co-registered positron emission tomography-computed tomography (PET-CT) as the basis for delineating gross tumor volume (GTV) in unresectable, locally advanced pancreatic carcinoma (LAPC). Methods Fourteen patients with unresectable LAPC had both CT and PET images acquired. For each patient, two three-dimensional conformal plans were made using the CT and PET-CT fusion data sets. We analyzed differences in treatment plans and doses of radiation to primary tumors and critical organs. Results Changes in GTV delineation were necessary in 5 patients based on PET-CT information. In these patients, the average increase in GTV was 29.7%, due to the incorporation of additional lymph node metastases and extension of the primary tumor beyond that defined by CT. For all patients, the GTVCT versus GTVPET-CT was 92.5 ± 32.3 cm3 versus 104.5 ± 32.6 cm3 (p = 0.009). Toxicity analysis revealed no clinically significant differences between two plans with regard to doses to critical organs. Conclusion Co-registration of PET and CT information in unresectable LAPC may improve the delineation of GTV and theoretically reduce the likelihood of geographic misses.</p

Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study

Background: The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry. Methods: Participating centres entered data in the registry through an online, highly secured, and encrypted research data server. Data included baseline characteristics, neoadjuvant therapy, imaging protocols, incidence of local regrowth and distant metastasis, and survival status. All patients with rectal cancer in whom the standard of care (total mesorectal excision surgery) was omitted after neoadjuvant therapy were eligible to be included in the IWWD. For the present analysis, we only selected patients with no signs of residual tumour at reassessment (a cCR). We analysed the proportion of patients with local regrowth, proportion of patients with distant metastases, 5-year overall survival, and 5-year disease-specific survival. Findings: Between April 14, 2015, and June 30, 2017, we identified 1009 patients who received neoadjuvant treatment and were managed by W&W in the database from 47 participating institutes (15 countries). We included 880 (87%) patients with a cCR. Median follow-up time was 3·3 years (95% CI 3·1–3·6). The 2-year cumulative incidence of local regrowth was 25·2% (95% CI 22·2–28·5%), 88% of all local regrowth was diagnosed in the first 2 years, and 97% of local regrowth was located in the bowel wall. Distant metastasis were diagnosed in 71 (8%) of 880 patients. 5-year overall survival was 85% (95% CI 80·9–87·7%), and 5-year disease-specific survival was 94% (91–96%). Interpretation: This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare. Funding: European Registration of Cancer Care financed by European Society of Surgical Oncology, Champalimaud Foundation Lisbon, Bas Mulder Award granted by the Alpe d'Huzes Foundation and Dutch Cancer Society, and European Research Council Advanced Grant

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections