Abstract Background Risk-stratified management of febrile neutropenia (FN) allows intensive management of high-risk cases and early discharge of low-risk cases. Most risk stratification systems predicting severe infection from admission variables have been derived from childhood or adult populations and consequently their value in adolescents/young adults (AYA) may vary. Our objective was to determine their value in this population. Methods Data from the ‘predicting infectious complications in children with cancer’ (PICNICC) individual participant data collaboration were used to evaluate six previously described risk stratification schema in the AYA population. Complete case analyses were undertaken for five ‘paediatric’ rules, with imputation for specific missing variables of the ‘adult’ rule. The predictive performance of the rules or the outcome microbiologically defined infection (sensitivity, specificity and predictive values) were compared. Results Among the 5,127 episodes of FN in 3,504 patients in the PICNICC collaboration data set, 603 episodes of FN from 478 patients in 20 studies were of patients 16–25 years old. The six rules demonstrated variable sensitivity (33–96%) and specificity (13–83%). Their overall discriminatory ability was poor (area under the receiver operator curve estimates 0.514–0.593). Conclusions Both paediatric and adult FN risk stratification schema perform poorly in AYA with cancer. An alternative rule or clinical recognition of their limitations is required.

Abstract Background Primary malignant brain tumours are rare but represent a serious health burden due to their poor survival. This manuscript describes the survival of malignant brain tumours in adults diagnosed 2000–2007 in Europe. Methods For this study we analysed patients archived in 86 European population-based cancer registries, followed up to 31st December 2008. Only primary malignant neuroepithelial brain tumours (with pathological confirmation) and primary malignant unspecified brain tumours without pathological confirmation were included. We estimated 1-year and 5-year relative survival (RS) weighted by age group and country. We also estimated country-specific and age-specific survival, together with survival differences between time periods (for 1999–2001, 2002–2004 and 2005–2007). Results Glioblastoma represents 49% of all brain tumours, followed by other/unspecified astrocytoma (18%), oligodendroglioma/oligoastrocytoma (9%), ependymoma (1.5%) and embryonal tumours (1%). Five-year RS was 20% for all tumours combined, but ranged from 58% for ependymoma to only 6% for glioblastoma and sharply decreased with increasing age. Differences between countries were relatively small, but generally RS in Ireland/United Kingdom (UK) and Eastern Europe was below the average. An increase in 1-year RS (up to 10–12%) was noted over time, being largest in Central and Northern Europe in patients between 45 and 74 years of age. Conclusions Despite an increase in 1-year RS in most European regions, the survival of primary malignant brain tumours is still poor. Disparities between countries were evident, being even larger at the end of the study period than at the beginning, suggesting differences in availability of the latest treatment modalities.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by two major hallmarks. First, insufficient therapeutic treatment options leading to poor prognosis and short survival rates and second, a complex stromal reaction quantitatively exceeding the one found in other tumours. To date, the conflictive interaction of malignant cells with the tumour microenvironment are insufficiently understood and functional model systems are lacking. We investigated the role and interaction of infiltrating lymphocytes as well as myeloid-derived cells in the context of PDAC using genetically engineered mouse (GEM) models which particularly recapitulate human tumourigenesis and desmoplasia. Employing a novel combined Cre/Lox-Flp/Frt approach we were able to activate or abolish canonical Notch-signalling genetically in a myeloid-restricted manner in addition to pancreas-restricted Kras-driven tumourigenesis. While lymphocytes did not influence tumour development markedly, myeloid Notch-activation was found not only to diminish M2-macrophage polarisation but also to perturb recruitment of immature myeloid cells in vivo. By opening an avenue to overcome the immunosuppressive state fostered Notch-signalling in myeloid cells revealed prolonged survival of GEMs. Here we describe a genetic animal model functionally reprogramming tumour-associated myeloid cells. To our knowledge, this provides the first functional proof of the macrophage polarisation concept in an endogenous mouse tumour model.

Abstract Background The aim of this population-based study was to provide insight into the incidence, risk factors and treatment-related survival of patients with peritoneal metastases (PM) of small bowel adenocarcinoma (SBA). Methods Data from the Netherlands Cancer Registry were used. All patients diagnosed with SBA between 2005 and 2014 were included. The influence of patient and tumour characteristics on the odds of developing PM was analysed. Subsequently, for all further analyses, patients without synchronous PM of SBA were excluded. The log-rank test and Kaplan-Meier analyses were conducted to estimate survival, and the Cox proportional hazards model was used to evaluate the risk of death. Results Of the 1428 included patients diagnosed with SBA, 181 (13%) presented with synchronous PM. Synchronous PM was found in 9% of the duodenal tumours and in 17% of the more distal tumours. Median overall survival of all patients with PM was 5.9 months, whereas survival of both 11 months was observed in patients treated with primary tumour resection or palliative chemotherapy and 32 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC). Poor prognostic factors for survival were age ≥70 years (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.1–2.2), systemic metastases other than PM (HR 2.0, 95% CI 1.4–2.9) and an advanced (HR 1.9, 95% CI 1.3–3.0) or unknown T-stage (HR 2.1, 95% CI 1.2–3.5). Conclusions Synchronous PM was frequently encountered in SBA. Without treatment, prognosis was extremely poor. Survival was higher after primary tumour resection, palliative chemotherapy and CRS+HIPEC, but selection bias probably played a significant role calling for further clinical research.

Abstract Ionising radiation (IR) may harm cancer cells through a rare indirect out-of-field phenomenon described as the abscopal effect. Increasing evidence demonstrates that radiotherapy could be capable of generating tumour-specific immune responses. On the other hand, effects of IR also include inhibitory immune signals on the tumour microenvironment. Following these observations, and in the context of newly available immunostimulatory agents in metastatic cancers (anti-cytotoxic T lymphocyte-associated antigen 4 and programmed cell death protein-1 or -ligand 1 [PD1 or PDL-1]), there is a remarkable potential for synergistic combinations of IR with such agents that act through the reactivation of immune surveillance. Here, we present and discuss the pre-clinical and clinical rationale supporting the enhancement of the abscopal effect of IR on the blockade of immune checkpoints and discuss the evolving potential of immunoradiotherapy.

Background DNA methylation in the BRCA1 promotor region is one of the most important epigenetic silencing mechanisms related to tumorigenesis and breast cancer progression, as well as poorer prognosis. Furthermore, it is a potential indicator for chemotherapy response. We measured the BRCA1 methylation level in various stages of breast cancer and adjacent normal breast tissues using the pyrosequencing method, to investigate correlations between BRCA1 methylation and tumour stage, to study BRCA1 methylation level as a prognostic factor related to overall survival, and to prove that pyrosequencing is an effective and efficient method to quantify methylation levels and can be used as a diagnostic, prognostic, adjuvant therapy decision making, and therapy monitoring tool. Methods 30 breast cancer and 30 adjacent normal breast tissue amples from untreated patients were selected for methylation analysis using pyrosequencing assay for DNA methylation analysis. Findings Cancer tissue showed significantly higher levels of BRCA1 methylation (mean 36.5; median 37) than matched normal breast tissues (mean 7.51; median 7.4) (p = 0.0001). There was no significant relationship between BRCA1 methylation level and tumour stage (stage 1: median 32.3; mean 32.1; SD 1.279; stage 2: median 36.45; mean 36.51; SD 1.42; stage 3+4: median 40.55; mean 40.28; SD 1.526). Interpretation Our results suggest that BRCA1 promotor hypermethylation is an early event of breast cancer carcinogenesis. Pyrosequencing generates highly reproducible quantification of methylation frequencies, providing a short read, rapid measurement and good precision.

Abstract Aim To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma. Methods Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented. Results In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached. Conclusion The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated.

Abstract Aim To assess trends in survival and geographic disparities among children (0–14 years) with chronic myeloid leukaemia (CML) before and after the introduction of molecular therapy, namely tyrosine kinase inhibitors (TKIs) in Southern-Eastern European (SEE) countries and the USA. Methods We calculated survival among children with CML, acute lymphoblastic (ALL) and acute myeloid leukaemia (AML) in 14 SEE (1990–2014) cancer registries and the U.S. Surveillance, Epidemiology and End Results Program (SEER, 1990–2012). We used Kaplan–Meier curves and multivariate Cox regression models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Results Among 369 CML cases, substantial improvements were noted in 2-year survival during the post-TKI (range: 81–89%) compared to pre-TKI period (49–66%; HR: 0.37, 95% CI: 0.23–0.60). Risk of death was three times higher for <5-year-old children versus those aged 10–14 years (HR: 3.03, 95% CI: 1.85–4.94) and 56% higher for those living in SEE versus SEER (HR: 1.56, 95% CI: 1.01–2.42). Regardless of geographic area and period of TKI administration, however, age seems to be a significant determinant of CML prognosis (pre-TKI period, HR0–4y: 2.71, 95% CI: 1.53–4.79; post-TKI period, HR0–4y: 3.38, 95% CI: 1.29–8.85). Noticeably, post-TKI survival in CML overall approximates that for ALL, whereas therapeutic advancements for AML remain modest. Conclusion Registry data show that introduction of molecular therapies coincides with revolutionised therapeutic outcomes in childhood CML entailing dramatically improved survival which is now similar to that in ALL. Given that age disparities in survival remain substantial, offering optimal therapy to entire populations is an urgent priority.

Abstract The consideration of the complex interplay between the tumour microenvironment (TME) and the immune response is the key for designing effective immunotherapies. Therapeutic strategies that harness co-stimulatory receptors have recently gained momentum in the clinic. One such strategy with promising clinical applications is the targeting of CD137, a member of the tumour necrosis factor receptor superfamily. Its expression on both innate and adaptive immune cells, coupled with its unique ability to potentiate antitumour responses through modulating the TME and to ameliorate autoimmune responses, has established it as an appealing target. In this review, we will discuss the various CD137-targeted immunotherapeutics that have reached clinical development, with a focus on recent advances and novel modalities such as CD137 chimeric antigen receptors and CD137 bispecific antibodies. We will also highlight the effect of CD137 targeting on the TME and discuss the importance of probing TME changes for predicting and testing the efficacy of CD137-mediated immunotherapy.

Abstract Background Collecting duct carcinoma (CDC) is a rare type of renal cancer with a poor prognosis. As there are no standard guidelines for the management of metastatic CDC (mCDC), we evaluated the efficacy and safety of combined therapies of sorafenib, gemcitabine, plus cisplatin in patients with mCDC. Materials and methods A prospective, multicentre, single-arm, open-label, phase 2 trial (ClinicalTrials.gov identifier NCT01762150) that enrolled 26 mCDC patients with no prior systemic chemotherapy. Patients were treated with sorafenib (400 mg orally, twice daily) combined with chemotherapy (gemcitabine 1000 mg/m2, intravenously for 30–60 min on days 1 and 8, plus cisplatin 25 mg/m2, intravenously on days 1–3, repeated every 28 days for 4 cycles), until disease progression, unacceptable toxicity, or study discontinuation for any other reason. The primary end-points were progression-free survival (PFS) and 6-month PFS rate. Results The 6-month PFS rate was 65%, and the median PFS was 8.8 months (95% confidence interval [CI]: 6.7–10.9) with a median overall survival of about 12.5 months (95% CI: 9.6–15.4). The objective response rate was 30.8%, and the disease control rate was 84.6%. The treatment was generally well tolerated. Major grade 3/4 toxicities included leucopenia (26.9%), thrombocytopenia (23.1%), anaemia (11.5%) and palmar-plantar erythrodysesthesia (7.7%). Conclusions Though the combination of sorafenib and chemotherapy demonstrated a similar outcome as that of the previously reported regimens in patients with mCDC, this combination may be a suitable option for patients who have low Eastern Cooperative Oncology Group performance status or less metastatic sites.