Tissue micro array analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer

Background: Tumor immune escape and angiogenesis contribute to tumor progression, and gangliosides and activation of signal transducer and activator of transcription (STAT)-3 are implicated in these processes. As both are considered as novel therapeutic targets, we assessed the possible association of ganglioside GM3 expression and STAT3 activation with suppression of dendritic cell (DC) activation and angiogenesis in non-small cell lung cancer (NSCLC). Methods: Immunohistochemistry was performed on a tissue array to determine N-glycolyl GM3 (GM3) and phosphorylated STAT3 (pSTAT3) expression in 176 primary NSCLC resections. Median values of GM3 and pSTAT3 expression were used as cut off. Microvessel density (MVD) was determined by CD34 staining and morphology. CD1a and CD83 were used to determine infiltrating immature and mature dendritic cells, respectively. Results: 94% and 71% of the NSCLC samples expressed GM3 and nuclear pSTAT3, respectively. Median overall survival was 40.0 months. Both low GM3 expression and high pSTAT3 expression were associated with a worse survival, which reached near significance for GM3 (P = 0.08). Microvessel density (MVD), determined by CD34 staining and morphology, was lower in NSCLC samples with high GM3 expression. CD1a(+) cells (immature DCs) were more frequent in NSCLC tissues as compared to peritumoral lung tissue, while CD83(+) cells (mature DCs) were more frequent in peritumoral lung tissue. CD83(+) DCs were less frequent in NSCLC tissues with high GM3 expression. Conclusion: GM3 and pSTAT3 are widely expressed in NSCLC. Based on CD83 expression, GM3, but not pSTAT3, appeared to be involved in tumor-induced DC suppression. pSTAT3 expression was not associated with MVD, while GM3 might play an anti-angiogenic rol

Increased numbers of small circulating endothelial cells in renal cell cancer patients treated with sunitinib

Mature circulating endothelial cell (CEC) as well as endothelial progenitor populations may reflect the activity of anti-angiogenic agents on tumor neovasculature or even constitute a target for anti-angiogenic therapy. We investigated the behavior of CECs in parallel with hematopoietic progenitor cells (HPCs) in the blood of renal cell cancer patients during sunitinib treatment. We analyzed the kinetics of a specific population of small VEGFR2-expressing CECs (CD45(neg)/CD34(bright)), HPCs (CD45(dim)/CD34(bright)), and monocytes in the blood of 24 renal cell cancer (RCC) patients receiving 50 mg/day of the multitargeted VEGF inhibitor sunitinib, on a 4-week-on/2-week-off schedule. Blood was taken before treatment (C1D1), on C1D14, C1D28, and on C2D1 before the start of cycle 2. Also plasma VEGF and erythropoietin (EPO) were determined. Remarkably, while CD34(bright) HPCs and monocytes decreased during treatment, CD34(bright) CECs increased from 69 cells/ml (C1D1) to 180 cells/ml (C1D14; P = 0.001) and remained high on C1D28. All cell populations recovered to near pre-treatment levels on C2D1. Plasma VEGF and EPO levels were increased on C1D14 and partly normalized to pre-treatment levels on C2D1. In conclusion, opposite kinetics of two circulating CD34(bright) cell populations, HPCs and small CECs, were observed in sunitinib-treated RCC patients. The increase in CECs is likely caused by sunitinib targeting of immature tumor vessel

The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care

Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the “real-world”. Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug’19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC’s representativeness and its contribution to a learning healthcare system

The use of perfusion CT for the evaluation of therapy combining AZD2171 with gefitinib in cancer patients

The purpose of this study was to determine the feasibility of dynamic contrast-enhanced perfusion CT (CTP) in evaluating the hemodynamic response of tumors in the chest and abdomen treated with a combination of AZD2171 and gefitinib. Thirteen patients were examined just before and every 4-6 weeks after starting therapy. Following intravenous injection of a contrast agent, dynamic image acquisition was obtained at the level of a selected tumor location. To calculate perfusion, the maximum-slope method was used. Pre-treatment average perfusion for extra-hepatic masses was 84 ml/min/100 g, for liver masses arterial perfusion was 25 ml/min/100 g, and a portal perfusion of 30 ml/min/100 g was found. After the administration of AZD2171 and gefitinib, in extra-hepatic masses an initial decrease in perfusion of 18% was followed by a plateau and in liver masses an initial decrease of 39% within the lesions and of 36% within a rim region surrounding the lesions was followed by a tendency to recovery of hepatic artery flow. In conclusion, CTP is feasible in showing changes of perfusion induced by anti-angiogenic therapy

Genetic heterogeneity in patients with multiple neoplastic lung lesions: A report of three cases

INTRODUCTION: It is important to determine the relation among the various lesions in patients presenting with multiple malignant lung tumors to define the best treatment approach. A better understanding of the molecular alterations present in the different lesions may help in defining this relation. METHODS: We performed a detailed molecular analysis of several tumor specimens obtained from three patients presenting with multiple lung lesions. Tumor specimens were analyzed for epidermal growth factor receptor (EGFR) and k-ras mutations by direct DNA sequencing. In addition, a genome-wide chromosomal copy number analysis was performed on DNA extracted from the various lesions using array-based comparative genomic hybridization. RESULTS: In one case, a deletion of 15 base pairs in exon 19 of EGFR was present in all tumor sites analyzed. Furthermore, a similar pattern of chromosomal aberrations was observed among the various lesions, suggesting that they share the same clonal origin. In the other two cases, in contrast, we identified distinct k-ras genotypes among the various lesions from the same patient. These lesions, moreover, showed different chromosomal aberration patterns, indicating that they may have different underlying pathways of tumorigenesis. CONCLUSION: Our results show that EGFR and k-ras mutation analysis, combined with chromosomal copy number profiling, can help in defining the relationship among different tumors in one patient

Genetic heterogeneity in patients with multiple neoplastic lung lesions: A report of three cases

INTRODUCTION: It is important to determine the relation among the various lesions in patients presenting with multiple malignant lung tumors to define the best treatment approach. A better understanding of the molecular alterations present in the different lesions may help in defining this relation. METHODS: We performed a detailed molecular analysis of several tumor specimens obtained from three patients presenting with multiple lung lesions. Tumor specimens were analyzed for epidermal growth factor receptor (EGFR) and k-ras mutations by direct DNA sequencing. In addition, a genome-wide chromosomal copy number analysis was performed on DNA extracted from the various lesions using array-based comparative genomic hybridization. RESULTS: In one case, a deletion of 15 base pairs in exon 19 of EGFR was present in all tumor sites analyzed. Furthermore, a similar pattern of chromosomal aberrations was observed among the various lesions, suggesting that they share the same clonal origin. In the other two cases, in contrast, we identified distinct k-ras genotypes among the various lesions from the same patient. These lesions, moreover, showed different chromosomal aberration patterns, indicating that they may have different underlying pathways of tumorigenesis. CONCLUSION: Our results show that EGFR and k-ras mutation analysis, combined with chromosomal copy number profiling, can help in defining the relationship among different tumors in one patient

Indicators for Enteral Nutrition Use and Prophylactic Percutaneous Endoscopic Gastrostomy Placement in Patients With Head and Neck Cancer Undergoing Chemoradiotherapy

BACKGROUND: Chemoradiotherapy (CRT) is a major risk factor for malnutrition and dehydration in patients with head and neck cancer. Enteral support is often needed, and a percutaneous endoscopic gastrostomy (PEG) is frequently placed. Specific indicators for PEG placement remain unclear. This study retrospectively determined which factors contributed to enteral nutrition (EN) use and PEG placement in a large patient group to gain insight on potential indicators for PEG placement protocol creation. METHODS: A retrospective chart review of 240 patients with head and neck cancer who underwent CRT in 2012-2015 was conducted. Lifestyle, oncological, treatment, and nutrition outcome characteristics were examined and compared between patients who used EN and those who did not, as well as between patients who received a PEG and those who did not. RESULTS: In total, 195 patients used EN (via PEG or nasogastric tube). Multivariate analysis showed that nodal disease presence ( P = .01) and bilateral neck irradiation ( P = .01) were significantly related to EN use while increased age ( P = .01), nodal disease presence ( P = .02), reconstruction extent other than primary closure ( P = .02), bilateral neck irradiation ( P < .01), and an adapted intake consistency prior to treatment ( P = .03) were significantly related to PEG placement. CONCLUSION: Important factors for EN usage and PEG placement consideration include nodal disease and planned bilateral neck irradiation. Results from this study in combination with existing literature can be taken into consideration in the design of a PEG placement protocol. A better understanding of predictive indicators to PEG placement should be explored in further prospective studies

VEGFR2 expressing circulating (progenitor) cell populations in volunteers and cancer patients

Circulating cells of several lineages are thought to participate in angiogenesis and tumor growth. Experimental studies in tumor-bearing mice have pointed to the potential importance of VEGF-responding circulating (endothelial) progenitor cells in tumor growth.We have studied circulating CID31- and/or CD34-positive cell populations with a low to moderate VEGFR2 expression in human volunteers and cancer patients. We recognized four cell populations, which were further characterized by their content of major hematopoetic progenitor, monocytic, endothelial and platelet markers. After establishing the test-retest stability of the measurements in nine patients, we determined the frequencies of the various cell populations in a group of 20 volunteers and 14 cancer patients. Two populations were markedly increased in cancer patients. Small CD45neg/CD34bright/VEGFR2+ cells amounted to 12 and 64 cells/ml (P<0.0001), respectively, and 246/ml and 578/ml VEGFR2+/CD45bright (/CD14+) monocytic cells were present in controls and cancer patients, respectively (P=0.0 17). A third population of CD45dim/CD34bright/VEGFR2low cells amounted to 25 and 30 cells/ml (P=0.38). Unexpectedly, a population of mainly anucleated CD45low/CD31bright/CD41bright cells was present in numbers of 9,076 and 16,697/ml (P=0.04) in volunteers and cancer patients, which contained a VEGFR2low (compared to IgG isotype control) expressing population amounting to 1,142 and 1,642 cells/ml (P=0.12). This fourth population probably reflects large platelets. The role of the herein identified VEGFR2+ circulating cell populations deserve further investigation in cancer patients treated with VEGF(R)-targeted therapies. Quantification of such cell populations in the blood of tumor patients may be valuable to monitor the efficacy of anti-angiogenic treatment

Indicators for Enteral Nutrition Use and Prophylactic Percutaneous Endoscopic Gastrostomy Placement in Patients with Head and Neck Cancer Undergoing Chemoradiotherapy

Background: Chemoradiotherapy (CRT) is a major risk factor for malnutrition and dehydration in patients with head and neck cancer. Enteral support is often needed, and a percutaneous endoscopic gastrostomy (PEG) is frequently placed. Specific indicators for PEG placement remain unclear. This study retrospectively determined which factors contributed to enteral nutrition (EN) use and PEG placement in a large patient group to gain insight on potential indicators for PEG placement protocol creation. Methods: A retrospective chart review of 240 patients with head and neck cancer who underwent CRT in 2012-2015 was conducted. Lifestyle, oncological, treatment, and nutrition outcome characteristics were examined and compared between patients who used EN and those who did not, as well as between patients who received a PEG and those who did not. Results: In total, 195 patients used EN (via PEG or nasogastric tube). Multivariate analysis showed that nodal disease presence (P =.01) and bilateral neck irradiation (P =.01) were significantly related to EN use while increased age (P =.01), nodal disease presence (P =.02), reconstruction extent other than primary closure (P =.02), bilateral neck irradiation (P <.01), and an adapted intake consistency prior to treatment (P =.03) were significantly related to PEG placement. Conclusion: Important factors for EN usage and PEG placement consideration include nodal disease and planned bilateral neck irradiation. Results from this study in combination with existing literature can be taken into consideration in the design of a PEG placement protocol. A better understanding of predictive indicators to PEG placement should be explored in further prospective studies.</p