Random Assay in Radioimmunoassay: Feasibility and Application Compared with Batch Assay

Abstract

Purpose

The batch assay has been conventionally used for radioimmunoassay (RIA) because of its technical robustness and practical convenience. However, it has limitations in terms of the relative lag of report time due to the necessity of multiple assays in a small number of samples compared with the random assay technique. In this study, we aimed to verify whether the random assay technique can be applied in RIA and is feasible in daily practice.

Methods

The coefficients of variation (CVs) of eight standard curves within a single kit were calculated in a CA-125 immunoradiometric assay (IRMA) for the reference of the practically ideal CV of the CA-125 kit. Ten standard curves of 10 kits from 2 prospectively collected lots (pLot) and 85 standard curves of 85 kits from 3 retrospectively collected lots (Lot) were obtained. Additionally, the raw measurement data of both 170 control references and 1123 patients' sera were collected retrospectively between December 2015 and January 2016. A standard curve of the first kit of each lot was used as a master standard curve for a random assay. The CVs of inter-kits were analyzed in each lot, respectively. All raw measurements were normalized by decay and radioactivity. The CA-125 values from control samples and patients' sera were compared using the original batch assay and random assay.

Results

In standard curve analysis, the CVs of inter-kits in pLots and Lots were comparable to those within a single kit. The CVs from the random assay with normalization were similar to those from the batch assay in the control samples (CVs % of low/high concentration; Lot1 2.71/1.91, Lot2 2.35/1.83, Lot3 2.83/2.08 vs. Lot1 2.05/1.21, Lot2 1.66/1.48, Lot3 2.41/2.14). The ICCs between the batch assay and random assay using patients' sera were satisfactory (Lot1 1.00, Lot2 0.999, Lot3 1.00).

Conclusion

The random assay technique could be successfully applied to the conventional CA-125 IRMA kits. The random assay showed strong agreement with the batch assay. The random assay procedure could increase the flexibility and decrease the turnaround time of the radioimmunoassay technique.

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Trial Design and Efficacy Thresholds for Granting Breakthrough Therapy Designation in Oncology [Health Policy]

Breakthrough therapy designation (BTD) is a new approach created by the US Congress and the US Food and Drug Administration (FDA) as part of the FDA Innovation and Safety Act of 2012 to expedite the drug development process for serious illness, including cancer. By law, to qualify for BTD, a new molecular entity must demonstrate substantial clinical improvement over existing therapies. Although the administrative requirements for granting BTD have been made available by the FDA, the actual trial designs, end points, and quantitative therapeutic thresholds involved in the granting process have not been made public. This literature review evaluates nine oncology new molecular entities granted BTD involved in 10 accelerated approvals and summarizes the key factors in clinical trial design leading to successful BTD applications. This information can be used by oncology research teams to set goals for BTD when developing clinical trial designs and thresholds in expedited drug development programs.

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What Is the Real Rate of Surgical Site Infection? [Original Contribution]

Purpose:

Surgical site infections (SSIs) are associated with patient morbidity and increased health care costs. Although several national organizations including the University HealthSystem Consortium (UHC), the National Surgical Quality Improvement Program (NSQIP), and the National Healthcare Safety Network (NHSN) monitor SSI, there is no standard reporting methodology.

Methods:

We queried the UHC, NSQIP, and NHSN databases from July 2012 to June 2014 for SSI after gynecologic surgery at our institution. Each organization uses different definitions and inclusion and exclusion criteria for SSI. The rate of SSI was also obtained from chart review from April 1 to June 30, 2014. SSI was classified as superficial, deep, or organ space infection. The rates reported by the agencies were compared with the rates obtained by chart review using Fisher's exact test.

Results:

Overall SSI rates for the databases were as follows: UHC, 1.5%; NSQIP, 8.8%; and NHSN, 2.8% (P < .001). The individual databases had wide variation in the rate of deep infection (UHC, 0.7%; NSQIP, 4.7%; NHSN, 1.3%; P < .001) and organ space infection (UHC, 0.4%; NSQIP, 4.4%; NHSN, 1.4%; P < .001). In agreement with the variation in reporting methodology, only 19 cases (24.4%) were included in more than one database and only one case was included in all three databases (1.3%).

Conclusion:

There is discordance among national reporting agencies tracking SSI. Adopting standardized metrics across agencies could improve consistency and accuracy in assessing SSI rates.

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Management of Chronic Pain in Survivors of Adult Cancers: ASCO Clinical Practice Guideline Summary [Guideline Summary]

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Patient-Reported Outcome Measures and Integration Into Electronic Health Records [Presentation Summary]

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Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells

Summary

Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF-04449913 (PF-913) is a selective, small-molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof-of-concept and mechanism of action of PF-913 following administration to patients with acute myeloid leukemia are unclear. This study examined the role of the Hedgehog signaling pathway in acute myeloid leukemia cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF-913. In primary acute myeloid leukemia cells, activation of the Hedgehog signaling pathway was more pronounced in CD34⁺ cells than CD34^- cells. In vitro treatment with PF-913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF-913 attenuated the leukemia-initiation potential of acute myeloid leukemia cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF-913 modulated self-renewal signatures and cell cycle progression. Furthermore, PF-913 sensitized acute myeloid leukemia cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in acute myeloid leukemia cells co-cultured with HS-5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia-initiation potential, and also enhanced acute myeloid leukemia therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.

This article is protected by copyright. All rights reserved.

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PODXL, linked to poor prognosis of pancreatic cancers, promotes cell invasion via binding to gelsolin

Summary

The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. Here, we report that high PODXL expression was an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promoted pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin. Suppression of PODXL or gelsolin decreased membrane protrusions with abundant peripheral actin structures, and in turn inhibited cell motility and invasion. Transfection of a PODXL-rescue construct renewed the expression of gelsolin bound to peripheral actin structures in cell protrusions, and abrogated the decreased cell protrusions caused by the knockdown of PODXL. Furthermore, transfection of a PODXL-rescue construct into pancreatic cancer cells in which both PODXL and gelsolin were suppressed failed to increase the formation of the protrusions. PODXL thus enhances motility and invasiveness through an increase in gelsolin-actin interactions in cell protrusions.

This article is protected by copyright. All rights reserved.

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Society and health of migrants

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Differences in mortality by immigrant status in Italy. Results of the Italian Network of Longitudinal Metropolitan Studies

Abstract

Despite a rapid increase in immigration from low-income countries, studies on immigrants' mortality in Italy are scarce. We aimed to describe differences in all and cause-specific mortality among immigrants and Italians residing in Turin and Reggio Emilia (Northern Italy), two cities participating in the Italian Network of Longitudinal Metropolitan Studies (IN-LiMeS). We used individual data from the municipal population registers linked to the cause of death registers. All people aged 1–64 years residing between 2001 and 2010 were enrolled (open cohort) and followed up until 2013. The mortality of citizens from high migratory pressure countries (as a whole, and for each macro-area group) was compared with that of Italians; differences were estimated by Poisson regression adjusted by age and calendar year mortality rate ratios (MRRs), and by age-standardized mortality ratios for the analysis of cause-specific mortality. Compared with Italians, immigrants had lower overall mortality (MRR for men: 0.82, 95 % CI: 0.75–0.90; for women: 0.71, 95 % CI: 0.63–0.81). Sub-Saharan Africans experienced a significant higher mortality than Italians (MRR for men 1.29, 95 % CI: 1.03–1.61; for women: 1.70, 95 % CI: 1.22–2.36). Higher mortality for immigrants compared to Italians was observed for infectious diseases, congenital anomalies, some site-specific tumours and homicide mortality. Our study showed heterogeneity in mortality across the macro-areas of origin, and in particular Sub-Saharan Africans seemed to be a vulnerable population. The extension to other cohorts of IN-LiMeS will allow the health status of immigrants and vulnerable groups to be studied and monitored in more depth.

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Role of BTK in the p53 pathway.

p53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a re-evaluation of the clinical uses of BTK inhibitors in cancer therapy.

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Colorectal Cancer Subtypes by immunohistochemistry

Purpose: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer (CRC) with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles towards widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular CRC subtyping in a multi-center study. Experimental Design: Tissue microarrays from 1076 CRC patients from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1 and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semi-quantitative pathologist scoring of the cores as input, and applied to three independent clinical cohorts. Results: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular CRC subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild type metastatic cancers of the canonical epithelial-like subtypes. Conclusion: This study shows that a practical and robust immunohistochemical-assay can be employed to identify molecular CRC subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of CRC samples, both in the format of an automated image analysis pipeline to score tumour core staining, and as a classifier based on semi-quantitative pathology scoring.

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Complete remission after single agent blinatumomab in a patient with pre-B acute lymphoid leukemia relapsed and refractory to three prior regimens: hyperCVAD, high dose cytarabine mitoxantrone and CLAG

Abstract

Background

The current standard of care for relapsed and refractory acute lymphoblastic leukemia (ALL) is combination chemotherapy.

Case presentation

We report a case of highly refractory ALL who was treated with blinatumomab. The ALL in this patient relapsed within a month after completion of hyperCVAD regimen and was refractory to high dose mitoxantrone/cytarabine and CLAG regimens.

Conclusion

This highly refractory pre-B Ph⁻ ALL was induced to complete remission after one course of single agent blinatumomab.

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DNA methylation of claudin-6 promotes breast cancer cell migration and invasion by recruiting MeCP2 and deacetylating H3Ac and H4Ac

Claudin-6 (CLDN6), a member of claudin transmembrane protein family, has recently been reported to be undetectable or at low levels in human breast cancer cell lines and tissues and plays a role in suppression...

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Telomere structure and maintenance gene variants and risk of five cancer types

Abstract

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level P-value cutoffs ≤3.08x10⁻⁵). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the TERT-CLPTML1 region, rs12655062 was associated positively with prostate cancer, and inversely with colorectal and ovarian cancers, and rs115960372 was associated positively with prostate cancer. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and ovarian cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk. This article is protected by copyright. All rights reserved.

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Leukocyte trafficking is not affected by multikinase inhibitors Sunitinib or Sorafenib in mice

Abstract

Sunitinib and sorafenib are broad-spectrum tyrosine kinase inhibitors (TKI) targeting e.g. VEGF1-3, PDGFRb, RET, FLT3, CD117 (c-KIT), and CSF-1R cell membrane receptors thus suppressing tumor angiogenesis and cancer cell growth. Recently it has been suggested that the kinases targeted by Sunitinib and/or Sorafenib regulate leukocyte transmigration, which might in part be responsible for the often-observed reduction in tumor-associated myeloid derived suppressor cells and regulatory T cells. The aim of the current work was to determine whether sunitinib or sorafenib inhibit leukocyte extravasation. Sunitinib, sorafenib, or vehicle treated animals did not show any difference in leukocyte trafficking either in peritonitis or in vivo homing experiments, although sunitinib treatment effectively inhibited growth of B16 melanoma tumors in WT, SCID, and SCID beige mice. Inhibition of tumor growth was associated with an increased number of infiltrating CD11b+ cells in the tumor, while the numbers of CD8, Gr-1 and F4/80 expressing cells were unchanged. In conclusion, the findings suggest that despite multiple targets with a potential role in leukocyte extravasation, neither sunitinib nor sorafenib effectively inhibits this process in vivo. Thus, the observed specific effect on CD11b cells among tumor infiltrating leukocytes is most likely an indirect effect. This article is protected by copyright. All rights reserved.

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A Prospective Study of Dietary patterns and Cancer mortality among Blacks and Whites in the REGARDS cohort

Abstract

Marked racial differences exist in dietary patterns and obesity, as well as cancer mortality. This study aims to assess whether dietary patterns are associated with cancer mortality overall and by race. We identified 22,041 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Dietary patterns were categorized into: Convenience (Chinese and Mexican foods, pasta, pizza), Plant-based (fruits, vegetables), Southern (added fats, fried foods, sugar-sweetened beverages), Sweets/Fats (sugary foods) and Alcohol/Salads (alcohol, green-leafy vegetables, salad dressing). Using Cox regression, we examined the association between quartiles of dietary patterns and cancer mortality, adjusted for potential confounders, overall among all participants and stratified by race. A total of 873 cancer deaths were observed over the 10-year observation period: 582 (66.7%) in Whites and 291 (33.3%) in Blacks. Greater adherence to the Southern dietary pattern was associated with an increased risk of cancer mortality (4th vs. 1st quartile HR: 1.67; 95% CI: 1.32 - 2.10) overall, especially among Whites (4th vs. 1st quartile HR: 1.59; 95% CI: 1.22 - 2.08). The Convenience (HR: 0.73; 95% CI: 0.56 - 0.94) and Plant-based (HR: 0.72; 95% CI: 0.55 - 0.93) dietary patterns were associated with up to a 28% reduced risk of cancer mortality, but only among Whites. Greater adherence to the Southern dietary pattern increased the risk of cancer mortality, while greater adherence to the Convenience and Plant-based diets reduced the risk of cancer mortality among Whites. Racial differences were observed in the association between dietary patterns and cancer mortality, but warrant further study. This article is protected by copyright. All rights reserved.

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Impaired T cell function in malignant pleural effusion is caused by TGF-β derived predominantly from macrophages

Abstract

Malignant pleural effusion (MPE) is an indication of advanced cancer. Immune dysfunction often occurs in MPE. We aimed to identify the reason for impaired T cell activity in MPE from lung cancer patients and to provide clues towards potential immune therapies for MPE. The surface inhibitory molecules and cytotoxic activity of T cells in MPE and peripheral blood (PB) were analyzed using flow cytometry. Levels of inflammatory cytokines in MPE and PB were tested using ELISA. TGF-β expression in tumor-associated macrophages (TAMs) was also analyzed. The effect of TAMs on T cells was verified in vitro. Lastly, changes in T cells were evaluated following treatment with anti-TGF-β antibody. We found that expression levels of Tim-3, PD-1, and CTLA-4 in T cells from MPE were upregulated compared to those from PB, but levels of IFN-γ and Granzyme B were downregulated (P < 0.05). The amount of TGF-β was significantly higher in MPE than in PB (P < 0.05). TGF-β was mainly produced by TAMs in MPE. When T cells were co-cultured with TAMs, expression levels of Tim-3, PD-1, and CTLA-4 were significantly higher than controls, whereas levels of IFN-γ and Granzyme B were significantly decreased, in a dose-dependent manner (P < 0.05). In vitro treatment with anti-TGF-β antibody restored the impaired T cell cytotoxic activity in MPE. Our results indicate that macrophage-derived TGF-β plays an important role in impaired T cell cytotoxicity. It will therefore be valuable to develop therapeutic strategies against TGF-β pathway for MPE therapy of lung cancer. This article is protected by copyright. All rights reserved.

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Family history and the risk of colorectal cancer: The importance of patients' history of colonoscopy

Abstract

Registry-based studies on the risk of colorectal cancer (CRC) for persons with a family history (FH) typically did not control for important covariates, such as history of colonoscopy. We aimed to quantify the association between FH and CRC risk, carefully accounting for potential confounders. We conducted a population-based case-control study in Germany. A total of 4,313 patients with a first diagnosis of CRC (cases) and 3,153 controls recruited from 2003-2014 were included. We used multiple logistic regression analyses to assess the association between FH and risk of CRC with odds ratios (OR) and the resulting 95% confidence intervals (95% CI). A total of 582 cases (13.5%) and 321 (10.2%) controls reported a history of CRC in a first-degree relative, which was associated with a 41% increase in risk of CRC (OR 1.41, 95% CI 1.22-1.63) after adjustment for sex and age. The OR substantially increased to 1.73 (95% CI, 1.48-2.03) after comprehensive adjustment including previous colonoscopies. Irrespective of their FH status, persons with history of colonoscopies had a lower CRC risk compared to persons without previous colonoscopies and without family history (OR 0.25, 95% CI, 0.22-0.28 for persons without FH and OR 0.45, 95% CI, 0.36-0.56 for persons with FH). In an era of widespread use of colonoscopy, adjusting for previous colonoscopy is therefore crucial for deriving valid estimates of FH-related CRC risk. Colonoscopy reduces the risk of CRC among those with FH far below levels of people with no FH and no colonoscopy. This article is protected by copyright. All rights reserved.

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Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer

Abstract

Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analysed for gene expression, amplification, and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection. This article is protected by copyright. All rights reserved.

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Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort

Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort

British Journal of Cancer 115, 382 (26 July 2016). doi:10.1038/bjc.2016.174

Authors: Mia Persson, Maria Simonsson, Andrea Markkula, Carsten Rose, Christian Ingvar & Helena Jernström

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Tumour-suppressive miRNA-26a-5p and miR-26b-5p inhibit cell aggressiveness by regulating PLOD2 in bladder cancer

Tumour-suppressive miRNA-26a-5p and miR-26b-5p inhibit cell aggressiveness by regulating PLOD2 in bladder cancer

British Journal of Cancer 115, 354 (26 July 2016). doi:10.1038/bjc.2016.179

Authors: K Miyamoto, N Seki, R Matsushita, M Yonemori, H Yoshino, M Nakagawa & H Enokida

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Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP)

Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP)

British Journal of Cancer 115, 281 (26 July 2016). doi:10.1038/bjc.2016.212

Authors: Dewi Vernerey, Florence Huguet, Angélique Vienot, David Goldstein, Sophie Paget-Bailly, Jean-Luc Van Laethem, Bengt Glimelius, Pascal Artru, Malcolm J Moore, Thierry André, Laurent Mineur, Benoist Chibaudel, Magdalena Benetkiewicz, Christophe Louvet, Pascal Hammel & Franck Bonnetain

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Expression of phosphorylated eIF4E-binding protein 1, but not of eIF4E itself, predicts survival in male breast cancer

Expression of phosphorylated eIF4E-binding protein 1, but not of eIF4E itself, predicts survival in male breast cancer

British Journal of Cancer 115, 339 (26 July 2016). doi:10.1038/bjc.2016.178

Authors: Rebecca A Millican-Slater, Craig D Sayers, Andrew M Hanby & Thomas A Hughes

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Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma

Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma

British Journal of Cancer 115, 290 (26 July 2016). doi:10.1038/bjc.2016.209

Authors: Michele Reni, Gianpaolo Balzano, Silvia Zanon, Paolo Passoni, Roberto Nicoletti, Paolo Giorgio Arcidiacono, Gino Pepe, Claudio Doglioni, Clara Fugazza, Domenica Ceraulo, Massimo Falconi & Luca Gianni

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Nut consumption and prostate cancer risk and mortality

Nut consumption and prostate cancer risk and mortality

British Journal of Cancer 115, 371 (26 July 2016). doi:10.1038/bjc.2016.181

Authors: Weike Wang, Meng Yang, Stacey A Kenfield, Frank B Hu, Meir J Stampfer, Walter C Willett, Charles S Fuchs, Edward L Giovannucci & Ying Bao

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Yttrium-90 radioembolization for unresectable/recurrent intrahepatic cholangiocarcinoma: a survival, efficacy and safety study

Yttrium-90 radioembolization for unresectable/recurrent intrahepatic cholangiocarcinoma: a survival, efficacy and safety study

British Journal of Cancer 115, 297 (26 July 2016). doi:10.1038/bjc.2016.191

Authors: Cristina Mosconi, Annagiulia Gramenzi, Salvatore Ascanio, Alberta Cappelli, Matteo Renzulli, Cinzia Pettinato, Giovanni Brandi, Fabio Monari, Alessandro Cucchetti, Franco Trevisani & Rita Golfieri

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Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy

Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy

British Journal of Cancer 115, 273 (26 July 2016). doi:10.1038/bjc.2016.189

Authors: Julia L Drewes, Franck Housseau & Cynthia L Sears

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Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo

Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo

British Journal of Cancer 115, 303 (26 July 2016). doi:10.1038/bjc.2016.198

Authors: Emiliano Cocco, Salvatore Lopez, Jonathan Black, Stefania Bellone, Elena Bonazzoli, Federica Predolini, Francesca Ferrari, Carlton L Schwab, Gulden Menderes, Luca Zammataro, Natalia Buza, Pei Hui, Serena Wong, Siming Zhao, Yalai Bai, David L Rimm, Elena Ratner, Babak Litkouhi, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz & Alessandro D Santin

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Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery

Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery

British Journal of Cancer 115, 346 (26 July 2016). doi:10.1038/bjc.2016.182

Authors: Stéphane Renaud, Joseph Seitlinger, Pierre-Emmanuel Falcoz, Mickaël Schaeffer, Anne-Claire Voegeli, Michèle Legrain, Michèle Beau-Faller & Gilbert Massard

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Repression of the autophagic response sensitises lung cancer cells to radiation and chemotherapy

Repression of the autophagic response sensitises lung cancer cells to radiation and chemotherapy

British Journal of Cancer 115, 312 (26 July 2016). doi:10.1038/bjc.2016.202

Authors: Ilias V Karagounis, Dimitra Kalamida, Achilleas Mitrakas, Stamatia Pouliliou, Maria V Liousia, Alexandra Giatromanolaki & Michael I Koukourakis

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Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching

Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching

British Journal of Cancer 115, 364 (26 July 2016). doi:10.1038/bjc.2016.201

Authors: Chi Huu Nguyen, Serena Stadler, Stefan Brenner, Nicole Huttary, Sigurd Krieger, Walter Jäger, Helmut Dolznig & Georg Krupitza

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Non-canonical NF-κB pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma

Non-canonical NF-κB pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma

British Journal of Cancer 115, 322 (26 July 2016). doi:10.1038/bjc.2016.204

Authors: Federico Rojo, Abel González-Pérez, Jessica Furriol, Ma Jesús Nicolau, Jaime Ferrer, Octavio Burgués, MohammadA Sabbaghi, Irene González-Navarrete, Ion Cristobal, Laia Serrano, Sandra Zazo, Juan Madoz, Sonia Servitja, Ignasi Tusquets, Joan Albanell, Ana Lluch, Ana Rovira & Pilar Eroles

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Endometrial cancer risk factors among Lynch syndrome women: a retrospective cohort study

Endometrial cancer risk factors among Lynch syndrome women: a retrospective cohort study

British Journal of Cancer 115, 375 (26 July 2016). doi:10.1038/bjc.2016.193

Authors: Synnöve Staff, Mari Aaltonen, Heini Huhtala, Kirsi Pylvänäinen, Jukka-Pekka Mecklin & Johanna Mäenpää

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Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis?

Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis?

British Journal of Cancer 115, 332 (26 July 2016). doi:10.1038/bjc.2016.170

Authors: F J Sherida H Woei-A-Jin, Margot E T Tesselaar, Patrica Garcia Rodriguez, Fred P H T M Romijn, Rogier M Bertina & Susanne Osanto

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Deriving stage at diagnosis from multiple population-based sources: colorectal and lung cancer in England

Deriving stage at diagnosis from multiple population-based sources: colorectal and lung cancer in England

British Journal of Cancer 115, 391 (26 July 2016). doi:10.1038/bjc.2016.177

Authors: S Benitez-Majano, H Fowler, C Maringe, C Di Girolamo & B Rachet

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Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis

Abstract

Background

Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model.

Methods

CBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study.

Results

Combination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance.

Conclusions

Combination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.

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Transcriptome analysis of paired primary colorectal carcinoma and liver metastases reveals fusion transcripts and similar gene expression profiles in primary carcinoma and liver metastases

Abstract

Background

Despite the clinical significance of liver metastases, the difference between molecular and cellular changes in primary colorectal cancers (CRC) and matched liver metastases is poorly understood.

Methods

In order to compare gene expression patterns and identify fusion genes in these two types of tumors, we performed high-throughput transcriptome sequencing of five sets of quadruple-matched tissues (primary CRC, liver metastases, normal colon, and liver).

Results

The gene expression patterns in normal colon and liver were successfully distinguished from those in CRCs; however, RNA sequencing revealed that the gene expression between primary CRCs and their matched liver metastases is highly similar. We identified 1895 genes that were differentially expressed in the primary carcinoma and liver metastases, than that in the normal colon tissues. A major proportion of the transcripts, identified by gene expression profiling as significantly enriched in the primary carcinoma and metastases, belonged to gene ontology categories involved in the cell cycle, mitosis, and cell division. Furthermore, we identified gene fusion events in primary carcinoma and metastases, and the fusion transcripts were experimentally confirmed. Among these, a chimeric transcript resulting from the fusion of RNF43 and SUPT4H1 was found to occur frequently in primary colorectal carcinoma. In addition, knockdown of the expression of this RNF43-SUPT4H1 chimeric transcript was found to have a growth-inhibitory effect in colorectal cancer cells.

Conclusions

The present study reports a high concordance of gene expression in the primary carcinoma and liver metastases, and reveals potential new targets, such as fusion genes, against primary and metastatic colorectal carcinoma.

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Rituximab plus chemotherapy as first-line treatment in Chinese patients with diffuse large B-cell lymphoma in routine practice: a prospective, multicentre, non-interventional study

Abstract

Background

The efficacy and safety of rituximab-based chemotherapy (R-chemo), the standard regimen for patients with diffuse large B-cell lymphoma (DLBCL), which is more common in Asia than in Western countries, are well confirmed in randomized controlled trials (RCTs). However, the safety and effectiveness of R-chemo in patients who are largely excluded from RCTs have not been well characterized. This real-world study investigated the safety and effectiveness of R-chemo as first-line treatment in Chinese patients with DLBCL.

Methods

Treatment-naive DLBCL patients who were CD20 positive and eligible to receive R-chemo were enrolled with no specific exclusion criteria. Data collected at baseline included age, gender, disease stage, international prognostic index (IPI), B symptoms, extranodal involvement, performance status, and medical history. In the present study, data on safety, treatment effectiveness, and HBV infection management were collected 120 days after the last R-chemo administration.

Results

Overall, R-chemo was well tolerated. The safety profile of R-chemo in patients with a history of heart or liver disease was well described without any additional unexpected safety concerns. The overall response rate (ORR) in the Chinese patients from this study was 94.2 % (complete response [CR], 55.0 %; CR unconfirmed [CRu] 18.2 %; and partial response [PR], 20.9 %). Compared to patients with no history of disease, the CR and PR rates of patients with a history of heart or liver disease were lower and higher, respectively; this tendency could be in part explained by treatment interruptions in patients with heart or liver diseases. HBsAg positivity and a maximum tumor diameter of ≥7.5 cm negatively correlated with CR + CRu, whereas age and HBsAg positivity negatively correlated with CR.

Conclusions

This study further validated the safety and effectiveness of R-chemo in Chinese patients with DLBCL. Patients with a history of heart or liver disease may further benefit from R-chemo if preventive measures are taken to reduce hepatic and cardiovascular toxicity. In addition to IPI and tumor diameter, HBsAg positivity could also be a poor prognostic factor for CR in Chinese patients with DLBCL.

Trial registration

ClinicalTrials.gov #NCT01340443, April 20, 2011.

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Concepts in glioma immunotherapy

Abstract

Immunotherapeutic concepts in neurooncology have been developed for many decades but have mainly been hampered by poor definition of relevant antigens and selective measures to target the central nervous system. Independent of the recent remarkable successes in clinical immunooncology with checkpoint inhibitors and vaccines, immunotherapy of brain tumors in general and gliomas in particular has evolved with novel neurooncology-specific concepts over the past years providing new phase 1 approaches of individualized immunotherapy to first phase three clinical trials. These concepts are driven by a high medical need in the absence of approved targeted therapies and refute the classic dogma that the central nervous system is immune-privileged and hence inaccessible to potent antitumor immunity. Instead, measures have been taken to improve the odds for successful immunotherapies, including rational targeting of relevant antigens and integration of immunotherapies into standard of care primary radiochemotherapy to increase the efficacy of antitumor immunity in a meaningful time window. This review highlights concepts and challenges associated with epitope discovery and selection and trial design.

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Methodology for analysis and reporting patterns of failure in the Era of IMRT: head and neck cancer applications

Abstract

Background

The aim of this study is to develop a methodology to standardize the analysis and reporting of the patterns of loco-regional failure after IMRT of head and neck cancer.

Material and Methods

Twenty-one patients with evidence of local and/or regional failure following IMRT for head-and-neck cancer were retrospectively reviewed under approved IRB protocol. Manually delineated recurrent gross disease (rGTV) on the diagnostic CT documenting recurrence (rCT) was co-registered with the original planning CT (pCT) using both deformable (DIR) and rigid (RIR) image registration software. Subsequently, mapped rGTVs were compared relative to original planning target volumes (TVs) and dose using a centroid-based approaches. Failures were then classified into five types based on combined spatial and dosimetric criteria; A (central high dose), B (peripheral high dose), C (central elective dose), D (peripheral elective dose), and E (extraneous dose).

Results

A total of 26 recurrences were identified. Using DIR, recurrences were assigned to more central TVs compared to RIR as detected using the spatial centroid-based method (p = 0.0002). rGTVs mapped using DIR had statistically significant higher mean doses when compared to rGTVs mapped rigidly (mean dose 70 vs. 69 Gy, p = 0.03). According to the proposed classification 22 out of 26 failures were of type A (central high dose) as assessed by DIR method compared to 18 out of 26 for the RIR because of the tendencey of RIR to assign failures more peripherally.

Conclusions

RIR tends to assigns failures more peripherally. DIR-based methods showed that the vast majority of failures originated in the high dose target volumes and received full prescribed doses suggesting biological rather than technology-related causes of failure. Validated DIR-based registration is recommended for accurate failure characterization and a novel typology-indicative taxonomy is recommended for failure reporting in the IMRT era.

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Concepts in glioma immunotherapy

Abstract

Immunotherapeutic concepts in neurooncology have been developed for many decades but have mainly been hampered by poor definition of relevant antigens and selective measures to target the central nervous system. Independent of the recent remarkable successes in clinical immunooncology with checkpoint inhibitors and vaccines, immunotherapy of brain tumors in general and gliomas in particular has evolved with novel neurooncology-specific concepts over the past years providing new phase 1 approaches of individualized immunotherapy to first phase three clinical trials. These concepts are driven by a high medical need in the absence of approved targeted therapies and refute the classic dogma that the central nervous system is immune-privileged and hence inaccessible to potent antitumor immunity. Instead, measures have been taken to improve the odds for successful immunotherapies, including rational targeting of relevant antigens and integration of immunotherapies into standard of care primary radiochemotherapy to increase the efficacy of antitumor immunity in a meaningful time window. This review highlights concepts and challenges associated with epitope discovery and selection and trial design.

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Evolution of gastric surgery techniques and outcomes

Abstract

Surgical management of gastric cancer improves survival. However, for some time, surgeons have had diverse opinions about the extent of gastrectomy. Researchers have conducted many clinical studies, making slow but steady progress in determining the optimal surgical approach. The extent of lymph node dissection has been one of the major issues in surgery for gastric cancer. Many trials demonstrated that D2 dissection resulted in greater morbidity and mortality than D1 dissection. However, long-term outcomes demonstrated that D2 dissection resulted in longer survival than D1 dissection. In 2004, the Japan Clinical Oncology Group reported a pivotal trial which was performed to determine whether para-aortic lymph node dissection combined with D2 dissection was superior to D2 dissection alone and found no benefit of the additional surgery. Gastrectomy with pancreatectomy, splenectomy, and bursectomy was initially recommended as part of the D2 dissection. Now, pancreas-preserving total gastrectomy with D2 dissection is standard, and ongoing trials are addressing the role of splenectomy. Furthermore, the feasibility and safety of laparoscopic gastrectomy are well established. Survival and quality of life are increasingly recognized as the most important endpoints. In this review, we present perspectives on surgical techniques and important trials of these techniques in gastric cancer patients.

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Results of a multicenter study investigating the potential impact of the overall treatment time on outcomes of radiotherapy alone with 5x4 Gy for metastatic epidural spinal cord compression

Publication date: Available online 25 July 2016
Source:Practical Radiation Oncology
Author(s): Dirk Rades, Theo Veninga, Antonio J. Conde-Moreno, Jon Cacicedo, Michaela Metz, Barbara Šegedin, Darius Norkus, Volker Rudat, Steven E. Schild
Purpose/Objective.5x4 Gy is commonly used for metastatic epidural spinal cord compression (MESCC). It is unclear whether an overall treatment time (OTT) of five days (five consecutive fractions) results in better outcomes than an OTT of seven days (no irradiation during the weekend).Methods and Materials.A total of 111 patients who received 5x4 Gy over five consecutive days were retrospectively compared to 277 patients treated with 5x4 Gy over seven days (no irradiation during the weekend) for effect on motor function, local control (LC) of MESCC and overall survival (OS). Ten further characteristics were evaluated: age, gender, interval tumor diagnosis to MESCC, visceral metastases, other bone metastases, primary tumor type, time developing motor deficits, walking ability, vertebrae involved, and performance status.ResultsOn multivariate analysis regarding post-RT motor function, primary tumor type (p=0.011) and time developing motor weakness (p<0.001) were significant, whereas the OTT did not even achieve significance on univariate analysis (p=0.99). On multivariate analysis of LC, visceral metastases (p=0.006) were significant. Again, the OTT was not even significant on univariate analysis (p=0.81). On multivariate analysis of OS, interval tumor diagnosis to MESCC (p=0.015), visceral metastases (p<0.001), tumor type (p=0.003), walking ability (p<0.001) and ECOG performance score (p<0.001) achieved significance. Even on univariate analysis, OTT did not have an effect on OS (p=0.79).ConclusionsLonger OTT did not impair outcomes of irradiation with 5x4 Gy for MESCC. Thus, no compensation (for example an additional radiation fraction) is necessary if the radiation treatment is not continued during the weekend.



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Methodology for analysis and reporting patterns of failure in the Era of IMRT: head and neck cancer applications

The aim of this study is to develop a methodology to standardize the analysis and reporting of the patterns of loco-regional failure after IMRT of head and neck cancer.

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The Promise of Molecularly Targeted and Immunotherapy for Advanced Melanoma

Opinion Statement

Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations. Mutational oncogenic "drivers" may be targeted with chronically administered, oral kinase inhibitors, currently consisting of the mitogen-activated protein kinase (MAPK) inhibitor combinations of BRAF plus MEK-targeted drugs. These agents work quickly to relieve symptoms and induce remissions but generally have limited durations of disease control. Immunotherapies include the immune checkpoint inhibitors that block CTLA4 or PD-1-negative immune signaling as well as interleukin-2, a cytokine that stimulates T lymphocytes and natural killer cells. A combination of CTLA4 plus PD-1 blockade has the highest activity ever reported for metastatic melanoma, at the cost of high autoimmune-like toxicities. However, immunotherapies of this type may provide durable responses and even cure a subset of patients. Thus, these immunotherapeutic agents are recommended as first-line therapy for most patients with advanced melanoma. Patients with rapidly progressive, symptomatic melanoma whose tumor carries a BRAF mutation may benefit more from initial therapy with combined MAPK inhibitors.

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Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences

Opinion Statement

At the time of glioblastoma (GBM) recurrence, a sharp analysis of prognostic factors, disease characteristics, response to adjuvant treatment, and clinical conditions should be performed. A prognostic assessment could allow a careful selection between patients that could be proposed to intensified approaches or palliative setting. Participation in clinical trials aims to improve outcome, and should be encouraged due to dismal prognosis of GBM patients after recurrence. Reoperation should be proposed if the tumor is amenable to a complete resection and if prognostic factors suggest that patient could benefit from a second surgery. Second-line chemotherapy should be chosen based on MGMT status, time to disease recurrence, and toxicity profile. If enrollment into a clinical trial is not possible, a nitrosourea-based regimen is the preferred choice, carefully evaluating any previous temozolomide (TMZ)-related toxicity. In MGMT-methylated patients relapsing after TMZ completion, a rechallenge could be proposed. After second progression, the clinical advantage of subsequent lines of chemotherapy still needs to be clarified. However, based on performance status, patients' preference, and disease behavior, a third-line treatment could be considered. Available treatments include nitrosoureas, bevacizumab, or carboplatin plus etoposide. However, more effective therapeutic options are needed.

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Circulating Tumor DNA to Monitor Therapy for Aggressive B-Cell Lymphomas

Opinion statement

The goal of therapy for aggressive B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is to achieve cure. Combination chemotherapy with rituximab cures most patients, but those with recurrent disease have a poor prognosis. Medical imaging scans such as computed tomography (CT) and positron emission tomography (PET) are the principal methods to assess response and monitor for disease relapse after therapy but are fundamentally limited by risks of radiation, cost, and a lack of tumor specificity. Novel sequencing-based DNA monitoring methods are capable of quantifying small amounts of circulating tumor DNA (ctDNA) before, during, and after therapy for mature B-cell lymphomas. Detection of ctDNA encoding clonal rearranged variable-diversity-joining (VDJ) receptor gene sequences has demonstrated improved analytical sensitivity and enhanced tumor specificity compared to imaging scans in DLBCL, offering broad clinical applicability across a range of aggressive B-cell lymphomas. Molecular monitoring of ctDNA has vaulted into the spotlight as a promising non-invasive tool with immediate clinical impact on monitoring for recurrence after therapy prior to clinical symptoms. As these clinical observations are validated, ctDNA monitoring needs to be investigated as a tool for response-adapted therapy and as a marker of minimal residual disease upon completion of therapy in aggressive B-cell lymphomas. Molecular monitoring of ctDNA holds tremendous promise that may ultimately transform our ability to monitor disease in aggressive B-cell lymphomas.

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TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

BACKGROUND

Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML).

METHODS

Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis.

RESULTS

TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53–mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ≤ .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy).

CONCLUSIONS

The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016. © 2016 American Cancer Society.

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