Abstract Background In the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS). Methods Between 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non-teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS. Results A total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40−5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47–0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67–0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06–1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high-frequency referring hospitals (12.6 months, HR 0.82 [0.73−0.91]) and reduced in low-frequency referring hospitals (8.1 months, HR 1.12 [1.01–1.24]). Conclusion Treatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC.

Abstract Fifteen percent of cancers are driven by oncogenic human viruses. Four of those viruses, hepatitis B virus, human papillomavirus, Merkel cell polyomavirus, and human T-cell lymphotropic virus, integrate the host genome. Viral oncogenesis is the result of epigenetic and genetic alterations that happen during viral integration. So far, little data have been available regarding integration mechanisms and modifications in the host genome. However, the emergence of high-throughput sequencing and bioinformatic tools enables researchers to establish the landscape of genomic alterations and predict the events that follow viral integration. Cooperative working groups are currently investigating these factors in large data sets. Herein, we provide novel insights into the initiating events of cancer onset during infection with integrative viruses. Although much remains to be discovered, many improvements are expected from the clinical point of view, from better prognosis classifications to better therapeutic strategies.

Abstract Background Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets.

Abstract Background This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. Methods Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). Results The overall incidence of laboratory events of hypocalcaemia grade ⩾2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; >50 versus ⩽50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; >20.77 μg/L [median] versus ⩽20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had >2 bone metastases at baseline versus those with ⩽2 bone metastases at baseline. Conclusion Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab’s greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia.

Abstract Background The prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use. Patients and methods According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data. Results Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients. Conclusion Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Abstract Background and purpose Advances in magnetic resonance imaging (MRI) and prostate sampling enable early identification of men with low to intermediate risk prostate cancer who are candidates for focal therapies that minimise side effects. We report dosimetry data from a pilot study evaluating the effectiveness of hemi-gland low dose rate (HG-LDR) brachytherapy as a focal therapy approach to control unilateral localised disease. Material and methods Twenty-two men underwent HG-LDR brachytherapy. Multi parametric MRI and transperineal template mapping biopsies were used to identify low volume unilateral disease. Whole gland therapy controls (n = 120) were retrospectively obtained. All implants were performed with 4D Brachytherapy. Results Intraoperative and postimplant dosimetry complied with established brachytherapy parameters. Mean (standard deviation) postoperative D90 for the target hemi-gland was 153.8 (11.3) Gy compared to 47.5 (12.7) Gy for the contralateral hemi-gland (P < 0.001). Mean postoperative V100% was 93.1 (3.9) and 24.6 (10.5) for the target and contralateral hemi-glands respectively (P < 0.001). Urethra D30 was 150.4 (19.8) Gy and 174.2 (15.0) Gy for hemi-gland and whole gland implants respectively (P < 0.001). Significantly reduced dose was also observed for rectum and neurovascular bundles. Conclusions HG-LDR focal brachytherapy is feasible with significant reduction in dose to the contralateral hemi-gland and organs at risk.

Abstract We evaluated the impact of patient-assisted compression (PAC) on image quality, dose, workflow and patient experience of mammography. Patients aged 40–90 years coming for bilateral mammography were included prospectively in the study. After positioning each breast, the technologist performed the compression and exposure of the first breast, initiated the compression of the other until 3 daN and then let the patient complete the compression using a remote control device. Image quality, compression force, breast thickness, average glandular dose and pain value for each breast were assessed for PAC and technologist compression (TC). The compression level was significantly higher with PAC than TC for both craniocaudal (CC; median difference 2.0 daN, p < 0.0001) and mediolateral oblique (MLO) views (median difference 1.5 daN, p < 0.0001). Breast thickness was reduced with PAC (CC, median difference −1.90 cm, p = 0.02), as well as glandular dose (CC, median difference −0.03, p = 0.02). The image quality was rated equivalent for both modes in 85% (85/100) of cases, superior for PAC in 10% (10/100) of cases and inferior in 5% (5/100) of cases. There was no significant difference in discomfort or pain felt between PAC and TC modes. Seventy-four percent of patients reported that the self-compressing device would facilitate their reattendance. PAC may be a suitable technique for mammography examinations, providing an equivalent image quality to TC. Moreover, as the breast compression level is increased, PAC may help reduce breast thickness, hence glandular dose. The fact that patients have control over the procedure may change their perception of mammography and improve uptake and compliance.

Abstract Background Few studies in North America have quantified the risks of second malignant neoplasms (SMNs) among survivors of childhood non-central nervous system (non-CNS) embryonal tumours due to their rarity. We aimed to investigate these risks by combining population-based data from the United States of America and Canada. Methods We evaluated patients with childhood non-CNS embryonal tumours reported to the Surveillance Epidemiology and End Results program and eight Canadian cancer registries from 1969 to 2010. Standardised incidence ratio (SIR) and cumulative incidence of SMNs were calculated. Subgroup analyses were conducted by the type of first primary cancer, age at first primary diagnosis and follow-up duration. Findings Of the 13,107 survivors, 190 SMNs were reported over 134,548 person-years of follow-up. The SIR for all SMNs combined was 6.4 (95% confidence interval [CI]: 5.5–7.4). Most site-specific SIRs were significantly increased, ranging from 36 (95% CI: 26–49) for bone and joint cancer to 3.1 (95% CI: 1.5–5.2) for brain tumour. The risk for second malignancies declined as the time elapsed from the first primary diagnosis and was less prominent for patients first diagnosed at age 1–4 years. Notably, rhabdomyosarcoma survivors had a higher risk for SMNs than those with other first primaries. The overall cumulative incidence of SMNs was 1.0% at 10 years, increasing to 2.2% at 20 years and 4.1% at 30 years. Interpretation Survivors with childhood non-CNS embryonal tumours faced an increased risk for SMNs compared to the general population. The risk variations observed in different patient categories may help target prevention strategies in high-risk subgroups.

Abstract Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.

Abstract Methods French patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic lymph node irradiation (1985–1998) or a wait-and-see strategy (1998–2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases. Results Forty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic lymph nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had lymph node irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with lymph node irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4. Conclusion Dysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.