Ranking and rankability of hospital postoperative mortality rates in colorectal cancer surgery.

Objectives: To examine to what extent random variation and variation in case-mix influence hospital rankings on the basis of mortality rates and to determine the suitability of mortality for ranking hospitals in colorectal surgery.

Background: Comparing and ranking postoperative mortality rates between hospitals becomes increasingly popular. Differences in hospital case-mix, and chance variation related to caseload, may influence rankings.

A native chemical ligation handle that enables the synthesis of advanced activity-based probes: diubiquitin as a case study.

We present the development of a native chemical ligation handle that also functions as a masked electrophile that can be liberated during synthesis when required. This handle can thus be used for the synthesis of complex activity-based probes. We describe the use of this handle in the generation of linkage-specific activity-based deubiquitylating enzyme probes that contain substrate context and closely mimic the native ubiquitin isopeptide linkage.

Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma.

Introduction: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit.

Mid-ventilation based PTV margins in Stereotactic Body Radiotherapy (SBRT): a clinical evaluation.

Purpose: Large tumor motion leads to large treatment volumes with an Internal Target Volume (ITV) based approach, whereas mid-ventilation (MidV) based Planning Target Volumes (PTV) margins typically lead to smaller treatment volumes. The purpose of this study was to evaluate the MidV approach on clinical outcome data of Stereotactic Body Radiotherapy (SBRT) in NSCLC.

Methods And Materials: 297 patients with 314 peripheral tumors treated from 2006 to 2012 were retrospectively analyzed.

PIP-box-mediated degradation prohibits re-accumulation of Cdc6 during S phase.

Cdc6 and Cdt1 initiate DNA replication licensing when cells exit mitosis. In cycling cells, Cdc6 is efficiently degraded from anaphase onwards as a result of APC/C-Cdh1 activity. When APC/C-Cdh1 is switched off again, at the end of G1 phase, Cdc6 could thus re-accumulate, risking the re-licensing of DNA as long as Cdt1 is present.

Local recurrence rates after radiofrequency ablation or resection of colorectal liver metastases. Analysis of the European Organisation for Research and Treatment of Cancer #40004 and #40983.

Aim: The aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies.

Background: Only 10-20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM.

TCR repertoires of intratumoral T-cell subsets.

The infiltration of human tumors by T cells is a common phenomenon, and over the past decades, it has become increasingly clear that the nature of such intratumoral T-cell populations can predict disease course. Furthermore, intratumoral T cells have been utilized therapeutically in clinical studies of adoptive T-cell therapy. In this review, we describe how novel methods that are either based on T-cell receptor (TCR) sequencing or on cancer exome analysis allow the analysis of the tumor reactivity and antigen-specificity of the intratumoral TCR repertoire with unprecedented detail.

Excision Repair Cross-Complementation group 1 (ERCC1) C118T SNP does not affect cellular response to oxaliplatin.

Aims: ERCC1 is involved in the repair of oxaliplatin-induced DNA damage. Studies for the association of the C118T SNP with clinical response to treatment with platinum drugs have rendered inconsistent results. We investigated the ERCC1 C118T SNP with respect to overall and progression-free survival in patients with advanced colorectal cancer (ACC) treated with oxaliplatin and in vitro DNA repair capacity after oxaliplatin exposure.

Prospective cost-effectiveness analysis of genomic profiling in breast cancer.

Background: The cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint®) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates.

Methods: Costs and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N-) patients included in the RASTER study (n=427).

Comparison of modified Borg scale and visual analog scale dyspnea scores in predicting re-intervention after drainage of malignant pleural effusion.

Background: Dyspnea is the most common symptom in patients with malignant pleural effusion (MPE). Treatment decisions are primarily based on the perception of dyspnea severity.

Aims: To study dyspnea perception following therapeutic thoracentesis using the visual analog scale (VAS) dyspnea score and modified Borg scale (MBS).

The spindle checkpoint, APC/C(Cdc20), and APC/C(Cdh1) play distinct roles in connecting mitosis to S phase.

DNA replication depends on a preceding licensing event by Cdt1 and Cdc6. In animal cells, relicensing after S phase but before mitosis is prevented by the Cdt1 inhibitor geminin and mitotic cyclin activity. Here, we show that geminin, like cyclin B1 and securin, is a bona fide target of the spindle checkpoint and APC/C(Cdc20).

Synthesis of post-translationally modified proteins.

Post-translational modifications of proteins can have dramatic effect on the function of proteins. Significant research effort has gone into understanding the effect of particular modifications on protein parameters. In the present paper, I review some of the recently developed tools for the synthesis of proteins modified with single post-translational modifications at specific sites in the protein, such as amber codon suppression technologies, tag and modify, and native chemical ligation.

Interplay between N-WASP and CK2 optimizes clathrin-mediated endocytosis of EGFR.

Clathrin-mediated endocytosis (CME) involves spatially and temporally restricted molecular dynamics, to which protein kinases and actin contribute. However, whether and how these two elements merge to properly execute CME remains unknown. Here, we show that neural Wiskott-Aldrich syndrome protein (N-WASP) and casein kinase 2 (CK2) form a complex and localize to clathrin-coated vesicles.

Effect of preservation of the right gastro-epiploic artery on delayed gastric emptying after cytoreductive surgery and HIPEC: a randomized clinical trial.

Background: Delayed gastric emptying (DGE) is a main complication with unknown origin after a cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy (CRS-HIPEC). The aim of this study was to investigate if preservation of the right gastro-epiploic artery (GEA) during standard omentectomy would have a positive effect on gastric emptying after CRS-HIPEC.

Methods: Forty-two patients subjected to a CRS-HIPEC were randomized into two groups perioperatively before performing an omentectomy: in Group I (N = 21) omentectomy was performed with preservation of the GEA; in Group II (N = 21) omentectomy was performed with resection of the GEA.

Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors.

About 10-20% of all breast carcinomas show a basal-like phenotype, while ∼ 90% of breast tumors from BRCA1-mutation carriers are of this subtype. There is growing evidence that BRCA1-mutated tumors are not just a specific subset of the basal-like tumors, but that (the majority of) basal-like tumors show a dysfunctional BRCA1 pathway. This has major treatment implications, because emerging regimens specifically targeting DNA repair mechanisms would then be most effective against these tumors.

Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH.

Germline mutations in BRCA1/2 increase the lifetime risk for breast and ovarian cancer dramatically. Identification of such mutations is important for optimal treatment decisions and pre-symptomatic mutation screening in family members. Although current DNA diagnostics is able to identify many different mutations, it remains unclear, how many BRCA2-associated breast cancer cases remain unidentified as such.

Cyclin A and Nek2A: APC/C-Cdc20 substrates invisible to the mitotic spindle checkpoint.

Active cyclin B1-Cdk1 (cyclin-dependent kinase 1) keeps cells in mitosis, allowing time for spindle microtubules to capture the chromosomes and for incorrect chromosome-spindle attachments to be repaired. Meanwhile, securin, an inhibitor of separase, secures cohesion between sister chromatids, preventing anaphase onset. The spindle checkpoint is a signalling pathway emerging from improperly attached chromosomes that inhibits Cdc20, the mitotic activator of the APC/C (anaphase-promoting complex/cyclosome) ubiquitin ligase.

Mucinous and neuroendocrine breast carcinomas are transcriptionally distinct from invasive ductal carcinomas of no special type.

Mucinous carcinoma is considered a distinct pathological entity. However, mucinous tumours can be divided into a least two groups: mucinous A (or paucicellular) and mucinous B (or hypercellular). Mucinous B cancers display histological features that significantly overlap with those of neuroendocrine carcinomas.

ZNF423 is critically required for retinoic acid-induced differentiation and is a marker of neuroblastoma outcome.

Retinoids play key roles in differentiation, growth arrest, and apoptosis and are increasingly being used in the clinic for the treatment of a variety of cancers, including neuroblastoma. Here, using a large-scale RNA interference-based genetic screen, we identify ZNF423 (also known as Ebfaz, OAZ, or Zfp423) as a component critically required for retinoic acid (RA)-induced differentiation. ZNF423 associates with the RARalpha/RXRalpha nuclear receptor complex and is essential for transactivation in response to retinoids.

Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH.

Background: While new defects in BRCA1 are still being found, it is unclear whether current breast cancer diagnostics misses many BRCA1-associated cases. A reliable test that is able to indicate the involvement of BRCA1 deficiency in cancer genesis could support decision making in genetic counselling and clinical management. To find BRCA1-specific markers and explore the effectiveness of the current diagnostic strategy, we designed a classification method, validated it and examined whether we could find BRCA1-like breast tumours in a group of patients initially diagnosed as non-BRCA1/2 mutation carriers.

Selecting highly affine and well-expressed TCRs for gene therapy of melanoma.

A recent phase 1 trial has demonstrated that the generation of tumor-reactive T lymphocytes by transfer of specific T-cell receptor (TCR) genes into autologous lymphocytes is feasible. However, compared with results obtained by infusion of tumor-infiltrating lymphocytes, the response rate observed in this first TCR gene therapy trial is low. One strategy that is likely to enhance the success rate of TCR gene therapy is the use of tumor-reactive TCRs with a higher capacity for tumor cell recognition.

Active-site directed probes to report enzymatic action in the ubiquitin proteasome system.

Irreversible covalent inhibitors equipped with reporter groups, also termed activity-based probes, allow the study of target enzymes based on catalytic activity instead of expression level, which does not necessarily indicate protein function and subsequent cellular consequences. Activity-based probes offer advantages over traditional techniques: they can be applied to the cell or tissue of choice and molecular imaging and pharmacology applications are possible. Here the design and use of probes directed at enzymatic activities in the ubiquitin proteasome system are discussed.

Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial.

Background: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer.

Methods: We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410).

Array-CGH and breast cancer.

The introduction of comparative genomic hybridization (CGH) in 1992 opened new avenues in genomic investigation; in particular, it advanced analysis of solid tumours, including breast cancer, because it obviated the need to culture cells before their chromosomes could be analyzed. The current generation of CGH analysis uses ordered arrays of genomic DNA sequences and is therefore referred to as array-CGH or matrix-CGH. It was introduced in 1998, and further increased the potential of CGH to provide insight into the fundamental processes of chromosomal instability and cancer.