Circulating cell-free DNA (ccfDNA) sequencing for low-burden cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), the abundance of genomic material within a plasma sample, and pre-analytical error rates due to library preparation, and sequencing errors. Sequencing costs have historically favored the development of deep targeted sequencing approaches for overcoming sparsity in ctDNA detection, but these techniques are limited by the abundance of ccfDNA in samples, which imposes a ceiling on the maximal depth of coverage in targeted panels. Whole genome sequencing (WGS) is an orthogonal approach to ctDNA detection that can overcome the low abundance of ccfDNA by supplanting sequencing depth with breadth, integrating signal across the entire tumor mutation landscape. However, the higher cost of WGS limits the practical depth of coverage and hinders broad adoption. Lower sequencing costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (Ultima Genomics, 1USD/Gb) to plasma samples at ∼120x coverage. Copy number and single nucleotide variation profiles were comparable between matched Ultima and Illumina datasets, and the deeper WGS coverage enabled ctDNA detection at the parts per million range. We further harnessed these lower sequencing costs to implement duplex error-corrected sequencing at the scale of the entire genome, demonstrating a ∼1,500x decrease in errors in the plasma of patient-derived xenograft mouse models, and error rates of ∼10−7 in patient plasma samples. We leveraged this highly de-noised plasma WGS to undertake cancer monitoring in the more challenging context of resectable melanoma without matched tumor sequencing. In this context, duplex-corrected WGS allowed us to harness known mutational signature patterns for disease monitoring without matched tumors, paving the way for de novo cancer monitoring.

Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)‐associated and HPV‐independent types.

Objective To establish optimised diffusion weightings (‘ b -values’) for acquisition of whole-body diffusion-weighted MRI (WB-DWI) for estimation of the apparent diffusion coefficient (ADC) in patients with metastatic melanoma (MM). Existing recommendations for WB-DWI have not been optimised for the tumour properties in MM; therefore, evaluation of acquisition parameters is essential before embarking on larger studies. Methods Retrospective clinical data and phantom experiments were used. Clinical data comprised 125 lesions from 14 examinations in 11 patients with multifocal MM, imaged before and/or after treatment with immunotherapy at a single institution. ADC estimates from these data were applied to a model to estimate the optimum b -value. A large non-diffusing phantom was used to assess eddy current–induced geometric distortion. Results Considering all tumour sites from pre- and post-treatment examinations together, metastases exhibited a large range of mean ADC values, [0.67–1.49] × 10^−3 mm^2/s, and the optimum high b -value ( b _high) for ADC estimation was 1100 (10th–90th percentile: 740–1790) s/mm^2. At higher b -values, geometric distortion increased, and longer echo times were required, leading to reduced signal. Conclusions Theoretical optimisation gave an optimum b _high of 1100 (10th–90th percentile: 740–1790) s/mm^2 for ADC estimation in MM, with the large range of optimum b -values reflecting the wide range of ADC values in these tumours. Geometric distortion and minimum echo time increase at higher b -values and are not included in the theoretical optimisation; b _high in the range 750–1100 s/mm^2 should be adopted to maintain acceptable image quality but performance should be evaluated for a specific scanner. Key Points • Theoretical optimisation gave an optimum high b-value of 1100 (10th–90th percentile: 740–1790) s/mm ^ 2 for ADC estimation in metastatic melanoma. • Considering geometric distortion and minimum echo time (TE), a b-value in the range 750–1100 s/mm ^ 2 is recommended. • Sites should evaluate the performance of specific scanners to assess the effect of geometric distortion and minimum TE.

Introduction Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. Methods We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. Results Twenty-two patients (14 male) with a median age of 64 (range 45–84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. Conclusions Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Checkpoint inhibitor immunotherapy has revolutionised cancer treatment. However, immunotoxicity due to dysregulated immune control can affect a range of non-cancer tissues causing dermatitis, colitis and endocrinopathies in up to 80% of exposed patients. Peripheral nerve neurotoxicity is rare (<5%) and described as GBS-like or CIDP-like in published case series. Here we present two cases of checkpoint inhibitor associated peripheral neuropathy suggesting this neuritis is a novel pathological entity. Case 1 55-year-old man treated with nivolumab and ipilimumab for renal cell carcinoma developed painful sensory predominant neuropathy after cycle 1. Gait impairment led to discontinuation by cycle 3. NCS revealed axonal loss and conduction slowing but no demyelinating features. He was treated with IVIg without response. Case 2 55-year-old woman with metastatic melanoma was treated with pembrolizumab for 16 months without complication. Within weeks of change to nivolumab she developed painful neuropathic symptoms causing difficulty walking. Neurophysiology was similar to case 1 but she improved to normal with high dose corticosteroids over 4 months. Both sural nerve biopsies showed active large fibre degeneration with diffuse, predominantly T cell inflam- matory infiltrate. No malignant cells. No evidence of a primary demyelinating pathology. This novel inflammatory neuropathy warrants recognition due to alternative treatment response.

The fifth edition of the WHO Blue Book on urological tumours, specifically in the bladder chapter, represents a refinement and update in the classification of bladder tumours building on the aggregate major changes made in previous editions. Progress in the molecular underpinnings of urothelial tumours, particularly with promising stratifiers for more precision‐based treatment approaches, have been made. Special attention has been paid to burning questions in bladder pathology, such as grading, heterogeneous lesions, inverted tumours and substaging. The concept of neuroendocrine tumours will be explained precisely.

The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin‐like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of ‘other oncocytic tumours’ with oncocytoma/chRCC‐like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so‐called ‘low‐grade’ oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR002) of the Conference Proceedings. Citation Format: Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, Ellie Carlyle, Alexandra Renn, Christina Messiou, Charlotte Spencer, Andreas M. Schmidt, Zayd Tippu, Aljosja Rogiers, Max Emmerich, Camille Gerard, Husayn Pallikonda, Cristina Naceur-Lombardelli, Floris Foijer, Hilda van den Bos, René Wardenaar, Diana Spierings, Kate Young, Lisa Pickering, Andrew Furness, Elaine Borg, Miriam Mitchison, David Moore, Mary Falzon, Ian Proctor, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Charles Swanton, Mariam Jamal-Hanjani, Kevin Litchfield, Samra Turajlic. Advanced melanoma exhibits a diversity of evolutionary routes to lethality [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A012.