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Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This landscape reveals distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; we observe relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53 , KRAS , RB1 , CSMD3 , APC , CSMD1 , LRATD2 , TRRAP and MYC as major drivers versus an overall low TMB in neuroendocrine tumors (1.09). Furthermore, we observe distinct drivers which are enriched in somatic aberrations in pancreatic ( MEN1 , ATRX , DAXX , DMD and CREBBP ) and midgut-derived neuroendocrine tumors ( CDKN1B ). Finally, 49% of aNEN patients reveal potential therapeutic targets based upon actionable (and responsive) somatic aberrations within their genome; potentially directing improvements in aNEN treatment strategies. Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) display heterogeneous clinical and genetic characteristics. Here, the authors investigate the mutational landscape of 85 aNEN by whole genome sequencing and identify distinct subpopulations, tumour mutational burden patterns, drivers and actionable somatic alterations.

Background: Treatment of advanced or metastatic esophageal adenocarcinoma (EAC) follows the guidelines for gastroesophageal junction adenocarcinoma (GEJC) and gastric adenocarcinoma (GAC), but patients with EAC are often excluded from clinical studies of GEJC/GAC. Objectives: Here we describe treatment and survival of patients with advanced EAC, GEJC, and GAC to provide population-based evidence on distinctions and similarities between these populations. Design: Retrospective cohort study of patients with unresectable advanced (cT4b) or metastatic (cM1) EAC, GEJC, or GAC (2015–2020) were selected from the Netherlands Cancer Registry. Methods: Overall survival (OS) was assessed using Kaplan–Meier methods, log-rank tests, and multivariable Cox regression. Results: In all, 7391 patients were included (EAC: n = 3346, GEJC: n = 1246, and GAC: n = 2798). Patients with EAC were more often males and more often had ⩾2 metastatic locations. First-line systemic therapy was received by 42%, 47%, and 36% of patients with EAC, GEJC, and GAC, respectively. Median OS was 5.0, 5.1, and 4.0 months for all patients with EAC, GEJC, and GAC, respectively (p < 0.001). Median OS from start of first-line therapy of patients with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinomas was 7.6, 7.8, and 7.5 months (p = 0.12) and of patients with HER2-positive carcinoma receiving first-line trastuzumab-containing therapy was 11.0, 13.3, and 9.5 months (p = 0.37) in EAC, GEJC, and GAC, respectively. After multivariable adjustment, no difference in OS for patients with EAC, GEJC, and GAC was observed. Conclusion: Despite differences in clinical characteristics and treatment strategies, survival between patients with advanced EAC, GEJC, and GAC was similar. We advocate that EAC patients should not be excluded from clinical trials for patients with molecularly similar GEJC/GAC.

Detection of circulating tumor cells (CTCs) in whole blood from metastatic cancer patients by the CellSearch™ CTC Test (Veridex LLC, Warren, NJ, USA) has been shown to have clinical relevance. In addition to enumeration, there is great interest in molecular characterization of these CTCs. We aimed to establish a robust method to perform mRNA expression analysis of multiple genes by a real-time reverse transcriptase (RT)-PCR on small numbers of CTCs enriched from whole blood by the CellSearch™ system. Despite the 4 log depletion of leukocytes after CellSearch enrichment, the CTC-enriched fractions still contained leukocytes, in particular B-lymphocytes, which severely interfered with our CTC-specific gene expression profiling. After extensive washing and leukocyte-specific depletion by anti-CD45 coated magnetic beads prior to CellSearch™ enrichment, the number of leukocytes present in the enriched fraction was still high (range 60-929). However, by using a set of genes with no or minor expression by leukocytes, we succeeded to perform quantitative gene expression profiling specific for as little as one breast cancer CTC present in a CTC-enriched environment typically containing over 800 contaminating leukocytes. Our method allows molecular characterization specific for as little as one CTC, and can be used to expand the understanding of the biology of metastasis and, potentially, to improve patient management.

Multiple prognostic biomarkers, including circulating tumour cell (CTC) counts, exist in metastatic castration‐resistant prostate cancer (mCRPC) patients, but none of them have been implemented into daily clinical care. The modified fast aneuploidy screening test‐sequencing system (mFast‐SeqS), which yields a genome‐wide aneuploidy score, is able to reflect the fraction of cell‐free tumour DNA (ctDNA) within cell‐free DNA (cfDNA) and may be a promising biomarker in mCRPC. In this study, we investigated the prognostic value of dichotomized aneuploidy scores (< 5 vs. ≥ 5) as well as CTC counts (< 5 vs. ≥ 5) in 131 mCRPC patients prior to treatment with cabazitaxel. We validated our findings in an independent cohort of 50 similarly treated mCRPC patients. We observed that, similar to the dichotomized CTC count [HR: 2.92; 95% confidence interval (CI);1.84–4.62], dichotomized aneuploidy scores (HR: 3.24; CI: 2.12–4.94) significantly correlated with overall survival in mCRPC patients. We conclude that a dichotomized aneuploidy score from cfDNA is a prognostic marker for survival in mCRPC patients within our discovery cohort and in an independent mCRPC validation cohort. Therefore, this easy and robust minimally‐invasive assay can be readily implemented as a prognostic marker in mCRPC. A dichotomized aneuploidy score might also be used as a stratification factor in clinical studies to account for tumour load.

Recently, miRNA-expression profiling in primary tumors has yielded promising results. However, establishing miRNA expression in the circulation probably has advantages over determination in primary tumor tissue, further augmenting the potential applications of miRNA determination in oncology. Circulating tumor cells (CTCs) have rapidly developed as important prognostic and therapy-monitoring biomarkers in metastatic breast, colorectal and prostate cancer when enumerated, and their isolation enables subsequent analysis using various molecular applications, including miRNA-expression analysis. In addition to CTC-associated miRNAs, free circulating miRNAs have been identified in whole blood, plasma and serum. Determination of miRNAs in peripheral blood, either cell-free or CTC-associated, is expected to become important in oncology, especially when linked to and interpreted together with epithelial CTCs. In this article, we will discuss miRNA-expression profiling in primary tumors, depict the potential applications of measuring miRNA in the circulation and review the literature on cell-free circulating miRNAs, as well as offering some methodological and technical considerations on the measurement of circulating miRNAs.

IntroductionThe locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC.Methods and analysisThis single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential novel prognostic markers.Ethics and disseminationThe study was approved by the Medical Ethical Committee of Erasmus Medical Center. The main results of the trial will be presented in international meetings and medical journals.Trial registration numberNL8458.

The molecular characterization of circulating tumor cells (CTCs) is a promising tool for the repeated and non-invasive evaluation of predictive and prognostic factors. Challenges associated with CTC characterization using the only FDA approved method for CTC enumeration, the CellSearch technique, include the presence of an excess of leukocytes in CTC-enriched blood fractions. Here we aimed to identify colorectal tumor-specific gene expression levels in the blood of patients with and without detectable CTCs according to CellSearch criteria. Blood of 30 healthy donors (HDs) and 142 metastatic colorectal cancer (mCRC) patients was subjected to CellSearch CTC enumeration and isolation. In all samples, 95 mRNAs were measured by reverse transcriptase quantitative PCR (RT-qPCR). HD blood samples and patient samples with three or more CTCs were compared to identify CTC-specific mRNAs. Patient samples without detectable CTCs were separately analyzed. Thirty-four CTC-specific mRNAs were higher expressed in patients with ≥3 CTCs compared with HDs (Mann–Whitney U-test P < 0.05). Among patients without detectable CTCs, a HD-unlike subgroup was identified which could be distinguished from HDs by the expression of epithelial genes such as KRT19, KRT20 and AGR2. Also, in an independent patient set, a similar HD-unlike group could be identified among the patients without detectable CTCs according to the CellSearch system. Extensive molecular characterization of colorectal CTCs is feasible and a subgroup of patients without detectable CTCs according to CellSearch criteria bears circulating tumor load, which may have clinical consequences. This CTC-specific gene panel for mCRC patients may enable the exploration of CTC characterization as a novel means to further individualize cancer treatment. •We measure the expression of 95 mRNAs in enriched circulating tumor cells (CTCs).•We identify CTC-specific mRNAs based on which three patient clusters are identified.•A subgroup of patients without detectable CTCs differed from healthy donors.•This distinction was driven by the expression of various epithelial genes.•A similar HD-unlike subgroup was identified in an independent patient set.

A substantial proportion of individuals with oesophageal cancer have a pathological complete response after neoadjuvant chemoradiotherapy and oesophagectomy. We aimed to investigate whether active surveillance could be an alternative for individuals with a clinical complete response after neoadjuvant chemoradiotherapy. We performed a multicentre, stepped-wedge, cluster-randomised, non-inferiority, phase 3 trial in 12 Dutch hospitals. Individuals with locally advanced oesophageal cancer and a clinical complete response after neoadjuvant chemoradiotherapy (ie, no tumour detected with endoscopic biopsies, ultrasound, and PET-CT) underwent active surveillance or standard surgery (ie, oesophagectomy within 2 weeks after reaching clinical complete response). There were no inclusion restrictions regarding comorbidities or performance status, but participants had carcinoma, were age 18 years or older, and were treated with curative intent. Randomisation of hospitals was performed using computer-generated sequences without stratification methods, after an initial phase of all hospitals performing standard surgery. The primary endpoint was overall survival, analysed according to a modified intention-to-treat principle (allowing crossover at time of clinical complete response) and an intention-to-treat principle. Non-inferiority was defined as 2-year survival rate for active surveillance of 15% or less below that for standard surgery. The trial was registered within the Netherlands Trial Register, NTR-6803, and the inclusion phase has been completed. Between Nov 8, 2017, and Jan 17, 2021, 1115 individuals were screened, of whom 309 were included. 198 underwent active surveillance and 111 underwent standard surgery. 242 (78%) participants were male and 67 (22%) were female. Median follow-up was 38 months (IQR 32–48). 2-year overall survival for active surveillance (74% [95% CI 69–78]) was non-inferior to standard surgery (71% [62–78]) after modified intention-to-treat analysis (one-sided 95% boundary: 7% lower). It remained non-inferior in the intention-to-treat analysis (75% [68–80] vs 70% [63–77], one-sided 95% boundary: 6% lower). There were no significant differences in overall survival according to modified intention-to-treat analysis (hazard ratio 1·14, two-sided 95% CI 0·74–1·78) or intention-to-treat analysis (0·83, 0·53–1·31). The frequency of postoperative complications and postoperative mortality after standard surgery or postponed surgery after active surveillance was similar between groups. Overall survival after active surveillance for oesophageal cancer was non-inferior compared with standard surgery after 2 years. For the long-term efficacy of active surveillance, extended follow-up is required. The results of the present trial could be used for patient counselling and shared decision making. Dutch Cancer Society (KWF) and Netherlands Organisation for Health Research and Development (ZonMw).

BackgroundPatients with unresectable intrahepatic cholangiocarcinoma (iCCA) have poor survival. This systematic review describes the survival outcomes of hepatic arterial infusion pump (HAIP) chemotherapy with floxuridine for patients with unresectable iCCA.Patients and MethodsA literature search was conducted using the electronic databases PubMed, Medline (Ovid), Embase, Web of Science, Google Scholar, and Cochrane to find studies that reported data on the survival of patients with unresectable iCCA treated with HAIP chemotherapy using floxuridine. The quality of the studies was assessed using the Newcastle–Ottawa quality assessment Scale (NOS). Overall survival (OS) was the primary outcome measure, and progression-free survival (PFS), response rates, resection rates, and toxicity were defined as secondary outcome measures.ResultsAfter removing duplicates, 661 publications were assessed, of which nine studies, representing a total of 478 patients, met the inclusion criteria. Three out of nine studies were phase II clinical trials, one study was a prospective dose-escalation study, and the remaining five studies were retrospective cohort studies. After accounting for overlapping cohorts, 154 unique patients were included for pooled analysis. The weighted median OS of patients with unresectable iCCA treated with HAIP chemotherapy with floxuridine was 29.0 months (range 25.0–39 months). The pooled 1-, 2-, 3-, and 5-year OS were 86.4, 55.5, 39.5, and 9.7%, respectively.ConclusionHAIP chemotherapy with floxuridine for patients with unresectable iCCA was associated with a 3-year OS of 39.5%, which is favorable compared with systemic chemotherapy for which no 3-year survivors were reported in the Advanced Biliary Cancer (ABC) trials.

Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease.