on behalf of the 100,000 Genomes Project Purpose: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. Methods:We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. Results:We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80°C or 65°C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). Conclusion:We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.Genet Med advance online publication 1 February 2018

Recognition of this rare entity will prevent unnecessary radical surgical resection for presumed carcinoma. It highlights the need for clinical, radiological, endoscopic and histopathological correlation.

The measures to control the COVID-19 outbreak will likely remain a feature of our working lives until a suitable vaccine or treatment is found. The pandemic has had a substantial impact on clinical services, including cancer pathways. Pathologists are working remotely in many circumstances to protect themselves, colleagues, family members and the delivery of clinical services. The effects of COVID-19 on research and clinical trials have also been significant with changes to protocols, suspensions of studies and redeployment of resources to COVID-19. In this article, we explore the specific impact of COVID-19 on clinical and academic pathology and explore how digital pathology and artificial intelligence can play a key role to safeguarding clinical services and pathology-based research in the current climate and in the future.

The role of percutaneous renal tumour biopsy (RTB) in the management of radiological indeterminate renal masses is long established. Patients with small renal masses who have biopsy-proven renal cell carcinoma (RCC) may be offered surgery, ablative therapy, or active surveillance, and RTB can provide diagnostic tissue from patients with metastatic disease who might benefit from systemic therapy. Current guidelines suggest that tumour seeding along the needle tract is anecdotal, but several cases have been reported recently, although some have been associated with lack of a coaxial sheath. We report on seven patients who underwent surgical resection of RCC in our tertiary referral institution following diagnostic RTB between 2014 and 2017 for whom RTB tract seeding by tumour was identified on histological examination of the resection specimen. One of these patients subsequently developed local tumour recurrence at the site of the previous biopsy.

In summary, Dll4 and Jag1 are expressed in glioblastoma vasculature. These data may define subsets of glioblastoma that might be sensitive (Dll4(+) /Jag1(+) ) or resistant (Dll4(+) /Jag1(-) ) to bevacizumab. Our data also suggest that anti-Dll4 therapy should be evaluated experimentally in glioblastoma.

The COVID-19 pandemic has challenged our diagnostic services at a time when many histopathology departments already faced a diminishing workforce and increasing workload. Digital pathology (DP) has been hailed as a potential solution to at least some of the challenges faced. We present a survey of pathologists within a UK National Health Service cellular pathology department with access to DP, in which we ascertain the role of DP in clinical services during this current pandemic and explore challenges encountered. This survey indicates an increase in uptake of diagnostic DP during this period, with increased remote access. Half of respondents agreed that DP had facilitated maintenance of diagnostic practice. While challenges have been encountered, these are remediable, and none have impacted on the uptake of DP during this period. We conclude that in our institution, DP has demonstrated current and future potential to increase resilience in diagnostic practice and have highlighted some of the challenges that need to be considered.

Chordomas are rare primary malignant bone tumors arising from embryonal notochord remnants of the axial skeleton. Chordomas commonly recur following surgery and radiotherapy, and there is no effective systemic therapy. Previous studies implicated receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and type 1 insulin-like growth factor receptor (IGF-1R), in chordoma biology. We report an adult female patient who presented in 2003 with spinal chordoma, treated with surgery and radiotherapy. She underwent further surgery for recurrent chordoma in 2008, with subsequent progression in pelvic deposits. In June 2009, she was recruited onto the Phase I OSI-906-103 trial of EGFR inhibitor erlotinib with linsitinib, a novel inhibitor of IGF-1R/insulin receptor (INSR). Treatment with 100 mg QD erlotinib and 50 mg QD linsitinib was well-tolerated, and after 18 months a partial response was achieved by RECIST criteria. From 43 months, a protocol modification allowed intra-patient linsitinib dose escalation to 50 mg BID. The patient remained stable on trial treatment for a total of 5 years, discontinuing treatment in August 2014. She subsequently experienced further disease progression for which she underwent pelvic surgery in April 2015. Analysis of DNA extracted from 2008 (pre-trial) tissue showed that the tumor harbored wild-type EGFR, and a PIK3CA mutation was detected in plasma, but not tumor DNA. The 2015 (post-trial) tumor harbored a mutation of uncertain significance in ATM, with no detectable mutations in other components of a 50 gene panel, including EGFR, PIK3CA, and TP53. By immunohistochemistry, the tumor was positive for brachyury, the molecular hallmark of chordoma, and showed weak–moderate membrane and cytoplasmic EGFR. IGF-1R was detected in the plasma membrane and cytoplasm and was expressed more strongly in recurrent tumor than the primary. We also noted heterogeneous nuclear IGF-1R, which has been linked with sensitivity to IGF-1R inhibition. Similar variation in IGF-1R expression and subcellular localization was noted in 15 further cases of chordoma. In summary, this exceptionally durable response suggests that there may be merit in evaluating combined IGF-1R/INSR and EGFR inhibition in patients with chordomas that recur following failure of local treatment.

Highlights d p97 interacts with MRE11 and regulates its retention on chromatin after IR d p97 inactivation causes excessive MRE11-mediated DNA end resection d p97-mediated MRE11 chromatin retention causes HR defects but efficient SSA d CB-5083 radiosensitizes cells and suppresses tumor growth in vivo after IR