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Understanding oncological and sexual function outcomes with gynaecological organ preserving cystectomy in women with bladder cancer; a systematic review.
No full textINTRODUCTION AND OBJECTIVES: Cystectomy for bladder cancer (BC) in women involves removing gynaecological organs and the anterior vaginal wall, significantly impacting sexual function (SF). Gynaecological organ-preserving cystectomy (GOPC) aims to minimise toxicity, but limited studies assess its impact. We reviewed existing evidence. METHODS: A systematic review was conducted using Ovid (Medline, Embase, PsycINFO, CINAHL) and Cochrane Library. Studies assessing survival and SF outcomes of GOPC and SF outcomes of standard cystectomy were included. RESULTS: Fourteen studies (1049 screened) reported on small cohorts (11-41 patients). Most GOPC patients had ≤T2b N0 M0 disease, while standard cystectomy patients had up to T4/N1. In the GOPC cohort median follow-up was 36 months.Over a 16-70 month period, Disease-Free Survival in GOPC patients was 80-100%. Due to heterogeneity in Patient-Reported Outcome Measures (PROMS), a narrative analysis was performed.GOPC patients reported high levels of sexual activity, reduced dyspareunia and moderate-to-high satisfaction. While SF initially declined, recovery improved over time, with Female Sexual Function Index (FSFI) scores exceeding the 26.2 dysfunction threshold in two studies by 12 months.In standard cystectomy, sexual dysfunction was common, with varying distress levels and inadequate patient counselling. CONCLUSIONS: Understanding the outcomes of GOPC is limited by study design and measurement variability, and meta-analysis was not possible. In this narrative review, oncological outcomes in the GOPC group appears to have equivalent oncological outcomes to a standard radical cystectomy in carefully selected female patients. Sexual recovery outcomes in either complete or partial sexual organ preserving cystectomy appear to be better than a standard female radical cystectomy. Further prospective studies, particularly those involving nerve-sparing surgery, are needed. Women undergoing either standard cystectomy and GOPC commonly experience sexual dysfunction, and there is a need to improve pre- and post-operative counselling
Validating HER3 as a Therapeutic Target for Advanced Prostate Cancer: from Bench to Bedside
No full textThe dysregulation of the ErbB receptor family, particularly HER2 and HER3, has long been implicated in the pathogenesis of prostate cancer. Despite numerous clinical attempts, targeting ErbB receptors has largely been unsuccessful. However, recent advances in targeted therapies, such as antibody-drug conjugates, have revitalised the potential of these receptors as therapeutic targets.This thesis investigated the clinical significance of the ErbB receptor family in advanced prostate cancer and evaluated their potential as drug targets. The data demonstrated that membranous HER3 protein was commonly expressed in lethal prostate cancer, associating with reduced time to castration resistance and worse overall survival. In vitro studies in murine transgenic prostate cancer models, single cell RNAseq of human prostate cancer biopsies and multiplex immunofluorescence assays indicated that the HER3 ligand NRG1 was detectable primarily in tumour-infiltrating myelomonocytic cells. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids (PDX-O), recombinant NRG1 enhanced proliferation, when HER3 expression was present. The anti-HER3 antibody-drug conjugate U3-1402 demonstrated significant antitumour activity in vitro and in vivo in HER3 positive metastatic CRPC patient models. A clinical trial of an anti-HER3 antibody, HMBD-001, is ongoing as a single agent and in combination with an AR antagonist; HER3 biomarker-driven patient selection is being pursued. Trials of anti-HER3 immunoconjugates and radioimmunoconjugates are also ongoing. It is envisioned that these trials will bring ErbB targeting therapies to prostate cancer care
Enabling in vivo comparisons of different four-dimensional magnetic resonance imaging sequences for radiotherapy guidance using visual biofeedback.
No full textBACKGROUND AND PURPOSE: Managing respiratory motion is essential for effective radiotherapy in the abdominothoracic regions. Respiratory-correlated four-dimensional magnetic resonance imaging (4D-MRI) can provide accurate motion estimation to help define treatment volumes for adaptive radiotherapy. However, validating and comparing 4D-MRI sequences in vivo is challenging due to the presence of breathing variability. This study combines visual biofeedback (VBF) with 4D-MRI sequences to facilitate in vivo comparisons. MATERIALS AND METHODS: Fourteen healthy volunteers and one patient were scanned on a 1.5 T Unity MR-linear accelerator (Elekta AB, Stockholm, Sweden) at two institutions. A radial stack-of-stars (SoS), a simultaneous multi-slice (SMS), and a Cartesian acquisition with spiral ordering (CASPR) 4D-MRI sequence were acquired. These acquisitions were performed without and with VBF based on an interleaved one-dimensional respiratory navigator (1D-RNAV) acquisition. Breathing variability across sequences was quantified using 1D-RNAV-derived breathing waveforms. Reconstructed 4D-MRI data were used to extract the motion amplitude, which was compared intra-volunteer across sequences and to the amplitudes of the breathing waveforms. RESULTS: Breathing variability across sequences decreased by 37% (amplitude, p = 0.039) and 64% (period, p < 0.003), and the median intra-volunteer 4D-MRI-derived motion amplitude agreement improved from 3.5 mm to 1.8 mm (p = 0.064) across sequences due to VBF guidance. Four-dimensional MRI-derived amplitudes were smaller than breathing waveform amplitudes, with median differences of -31% (SoS), -17% (SMS), and -9% (CASPR). The average breathing waveform amplitude was 8% larger than instructed. CONCLUSIONS: This methodology enables in vivo comparisons of 4D-MRI sequences for adaptive radiotherapy, with guidance improving anatomical consistency and ensuring more reliable comparisons
UK guidelines for the management of soft tissue sarcomas.
No full textSoft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location, means that developing evidence-based guidelines is complicated by the limitations of the data available. This makes it more important that STS are managed by expert multidisciplinary teams, to ensure consistent and optimal treatment, recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous versions published in 2010 and 2016 [1, 2]. The original guidelines were drawn up by a panel of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This iteration of the guidance, as well as updating the general multidisciplinary management of soft tissue sarcoma, includes specific sections relating to the management of sarcomas at defined anatomical sites: gynaecological sarcomas, retroperitoneal sarcomas, breast sarcomas, and skin sarcomas. These are generally managed collaboratively by site specific multidisciplinary teams linked to the regional sarcoma specialist team, as stipulated in the recently published sarcoma service specification [3]. In the UK, any patient with a suspected soft tissue sarcoma should be referred to a specialist regional soft tissues sarcoma service, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging and a tissue biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon, combined with pre- or post-operative radiotherapy for tumours at higher risk for local recurrence. Systemic anti-cancer therapy (SACT) may be utilised in cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late effects of treatment
CONSORT-DEFINE explanation and elaboration: recommendations for enhancing reporting quality and impact of early phase dose-finding clinical trials.
No full textUNLABELLED: Early phase dose-finding (EPDF) trials are key in the development of novel therapies, with their findings directly informing subsequent clinical development phases and providing valuable insights for reverse translation. Comprehensive and transparent reporting of these studies is critical for their accurate and critical interpretation, which may improve and expedite therapeutic development. However, quality of reporting of design characteristics and results from EPDF trials is often variable and incomplete. The international consensus-based CONSORT-DEFINE (Consolidated Standards for Reporting Trials Dose-finding Extension) statement, an extension of the CONSORT statement for randomised trials, was developed to improve the reporting of EPDF trials. The CONSORT-DEFINE statement introduced 21 new items and modified 19 existing CONSORT items.This CONSORT-DEFINE Explanation and Elaboration (E&E) document provides important information to enhance understanding and facilitate the implementation of the CONSORT-DEFINE checklist. For each new or modified checklist item, we provide a detailed description and its rationale with supporting evidence, and present examples from EPDF trial reports published in peer-reviewed scientific journals. When reporting the results of EPDF trials, authors are encouraged to consult the CONSORT-DEFINE E&E document, together with the CONSORT and CONSORT-DEFINE statement papers, and adhere to their recommendations. Widespread adoption of the CONSORT-DEFINE statement is likely to enhance the reporting quality of EPDF trials, thus facilitating the peer review of such studies and their appraisal by researchers, regulators, ethics committee members, and funders. FUNDING: This work is a further extension of the CONSORT-DEFINE study, which was funded by the UK Medical Research Council (MRC)-National Institute for Health and Care Research (NIHR) Methodology Research Programme (MR/T044934/1). The Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU) receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec 22/100 004), which has contributed to accelerating the advancement and successful completion of this work
Hypofractionated radiotherapy for prostate cancer (HYDRA): an individual patient data meta-analysis of randomised trials in the MARCAP consortium.
No full textBACKGROUND: Trials comparing moderately hypofractionated radiotherapy (MHFRT) to conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs superiority) and MHFRT dose. We compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT. METHODS: This was an individual patient data meta-analysis that identified randomised phase 3 trials of CFRT versus MHFRT that had published individual patient-level data on efficacy and late toxicity. A systematic literature search using MEDLINE, Embase, trial registries, the Web of Science, Scopus, and relevant conference proceedings was initially conducted on Dec 15, 2023, and was re-conducted on Jan 8, 2025. Trials that did not publish efficacy data, did not publish late toxicity data, or did not use modern dose radiotherapy (≥70 Gy in 2 Gy equivalents) in the CFRT group were excluded. Individual patient data were provided to MARCAP by study investigators. Three separate meta-analyses were designed to compare efficacy (primary endpoint was progression-free survival), physician-scored late toxicity (co-primary endpoints were late grade 2 or higher genitourinary and late grade 2 or higher gastrointestinal toxic effects), and patient-reported outcomes (co-primary endpoints were clinically-significant decrements in patient-reported urinary or bowel quality of life) between patients receiving CFRT versus MHFRT. FINDINGS: We identified 1696 records for review. Seven phase 3 trials comparing MHFRT with CFRT were eligible for inclusion in our analysis. Individual patient data were obtained from these seven studies (3454 patients from three trials comparing CFRT with isodose MHFRT and 2426 patients from four trials comparing CFRT with dose-escalated MHFRT). At a median follow-up of 5·4 years (IQR 4·6-7·2) for isodose MHFRT and 7·1 years (5·7-8·4) for dose-escalated MHFRT, no differences in progression-free survival were detected (hazard ratio 0·92, 95% CI 0·81-1·05; p=0·21 and 0·94, 0·82-1·09; p=0·43 respectively). No increased odds of grade 2 or higher genitourinary toxic effects were identified for either isodose (odds ratio [OR] 1·16, 95 CI% 0·86-1·57; p=0·32) or dose-escalated MHFRT (1·20, 0·95-1·51; p=0·13). The odds of grade 2 or higher gastrointestinal toxic effects were significantly higher with dose-escalated (OR 1·48, 95% CI 1·14-1·92; p=0·0035) but not isodose MHFRT (1·30, 0·59-2·87; p=0·51). Isodose MHFRT was not found to show different odds of urinary quality-of-life decrement (OR 1·03, 95% CI 0·51-2·09; p=0·93) or bowel quality-of-life decrement (0·76, 0·40-1·43; p=0·39). Dose-escalated MHFRT was associated with greater odds of bowel quality-of-life decrement (OR 1·68, 95% CI 1·07-2·61; p=0·023), but no evidence of greater urinary quality-of-life decrement was found (1·57, 0·87-2·85; p=0·13). INTERPRETATION: Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel toxicity. Isodose regimens, eg, 60 Gy in 20 fractions, should be the standard MHFRT regimen for localised prostate cancer. FUNDING: None
The Integration of Stereotactic Body Radiotherapy for the Treatment of Localised Prostate Cancer of a 1.5 Tesla Magnetic Resonance Linear Accelerator
No full textThe MR-linear accelerator (MRL) delivers adaptive radiotherapy under MRI guidance thereby offering the potential to mitigate the errors introduced on other platforms and provide a promising modality for the delivery of prostate radiotherapy in the era of prostate Stereotactic Body Radiotherapy (SBRT). However, as with any new technology ongoing studies examining the clinical and technical data are required to ensure its full potential is reached.
The MOMENTUM repository is an extensive source of real-world data of patients imaged and treated on 1.5T MRL. Interrogation of this data supports the delivery of SBRT to localised prostate cancer on the MRL with low levels of clinician reported toxicities and good patient reported outcomes (PRO). Furthermore, when examining whether overall treatment time (OTT) can be adapted to further decrease toxicity, there is no evidence to support such a concept.
Reducing planning target volumes (PTVs) is an important concept when aiming to decrease the dose to the associated organs at risk (OARs) and potentiate dose escalation to the primary tumour. Cine images taken during the delivery of five fraction SBRT show that PTV margins can be reduced to 3 mm when treating on a 1.5T MRL using the workflow adopted in my centre.
The interim analysis of HERMES, examining the delivery of 2-fraction and 5-fraction SBRT to localise prostate cancer shows that such regimes can successfully be delivered by utilising the MRL. This thesis finds that acute genitourinary toxicity was no worse than that measured in PACE, allowing for recruitment to continue. Analysis of the dose deliver to the targets and OARS in both the 2-fraction and 5-fraction cohort is reassuring suggesting that both schedules are effectively and safely delivered on the MRL.
Finally, the role of MRI guided adapted radiotherapy in the setting of locally relapsed prostate cancer is explored. The literature to data and a detailed case report suggests that re-irradiation with SBRT on the MRL is safe treatment. The resulting guidelines should help to guide future practice
Treatment of Pediatric, Adolescent, and Young Adult Patients With Fusion-Positive Alveolar Rhabdomyosarcoma Infiltrating Regional Lymph Nodes in the European CWS-2002P and RMS 2005 Studies and the Soft Tissue Sarcoma Registry.
No full textBACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) with regional lymph node involvement (N1) are defined as "very-high-risk rhabdomyosarcoma" in Europe. Different chemotherapy regimens were used in European study protocols. METHODS: Patients with FOXO1 fusion-positive N1 ARMS registered in the CWS-2002P study, the EpSSG RMS 2005 study, and SoTiSaR were retrospectively investigated. Patients received systemic treatment with chemotherapy (CHT) and local treatment of primary tumor (PT) and involved lymph nodes (LN) with radiotherapy (RT) and/or surgery. Kaplan-Meier estimators and Cox regression were used to examine event-free survival (EFS) and overall survival (OS) according to prognostic factors and treatment. RESULTS: A total of 156 patients registered in RMS 2005 (n = 99), CWS-2002P (n = 20), and SoTiSaR (n = 37) between 2003 and 2020 were eligible for this analysis. Median age at diagnosis was 10.2 years [0.1-21.9]. Treatment comprised CHT with IVADo (ifosfamide, vincristine, actinomycin-D, doxorubicin, n = 93; 60%), VAIA (vincristine, actinomycin-D, ifosfamide, adriamycin/doxorubicin, n = 53; 34%) or other regimens (n = 10; 6%); resection of the PT (n = 89; 57%), LN sampling or dissection (n = 92; 59%), and/or RT (n = 139; 89%). Maintenance treatment (MT) was added in n = 99/135 (73%) patients who achieved complete remission. Five-year EFS and OS of the cohort were 45% and 47%, respectively. Age and tumor size were independent prognostic factors for EFS. Local treatment applied to the LN with surgery, RT or both significantly improved EFS (p = 0.02) and OS (p = 0.04), with no difference between the modalities (p = 0.7). CONCLUSIONS: Patients with fusion-positive N1 ARMS carry a poor prognosis. Adequate local treatment of LN improved survival
A CRISPR based approach to identifying target genes and causal variants at breast cancer risk loci
No full textGenome wide association studies (GWAS) and fine mapping analysis have identified 196
independent signals associated with breast cancer risk. Deciphering the functional basis
of these associations has the potential to further our understanding of the biology of breast
cancer risk and inform future prevention strategies. Most GWAS variants map to noncoding
regions which makes identifying causal (as opposed to correlated) variants and
their target genes challenging. As a result, causal variants and target genes at most of
these regions remain unknown. Transcription of genes and activity of regulatory elements
can be perturbed without making permanent changes to the genome using a catalytically
inactive dCas9 fused to a transcriptional activator (CRISPRa) or repressor (CRISPRi). This
project uses these techniques to evaluate the probability that one or more credible causal
variants (CCVs), defined as variants that cannot be excluded as causal on statistical
grounds alone, is truly functional and to identify the gene(s) that the functional variant
impacts. sgRNAs targeting each CCV at each of two loci mapping to gene-rich regions at
19q13.3 were transduced into CRISPRa/CRISPRi modified normal breast epithelial cells
(MCF-10A) and changes in gene expression were measured using NanoString nCounter.
This identified rs1685191 and rs4399645 as potentially causal variants with KCNN4 and
GIPR as their target genes respectively. KCNN4 and GIPR show cell type-specific
expression in normal breast and breast cancer, with KCNN4 preferentially expressed in
basal-like breast cancer cells and estrogen receptor-negative breast cancers and GIPR in
luminal breast cancer cells and estrogen receptor-positive breast cancers. Follow-up
experiments demonstrate that GIPR expressed on normal breast and breast cancer cells
can signal in response to both the GIPR ligand (GIP) and agonist (tirzepatide) to regulate
cellular functional responses. These findings demonstrate that GWAS have the potential
to identify genes that may be new targets for breast cancer preventio
Preoperative Magnetic Resonance Guided Single-Dose Partial Breast Irradiation: 5-Year Results of the Prospective Single-Arm ABLATIVE Trial.
No full textPURPOSE: Preoperative partial breast irradiation (PBI) can increase accuracy of target volume definition and decrease irradiated volumes compared with postoperative PBI. In the ABLATIVE trial (NCT02316561), 15 of 36 patients achieved pathologic complete response 6 to 8 months after preoperative PBI and breast-conserving surgery (BCS). We now present the 5-year results. METHODS AND MATERIALS: The ABLATIVE trial is a Dutch prospective cohort study conducted in 4 hospitals. Women aged ≥50 years with unifocal, nonlobular breast cancer, estrogen receptor-positive, HER2-negative, and a tumor negative sentinel node were treated between 2015 and 2018 with preoperative single-dose PBI followed by BCS after 6 or 8 months. The primary endpoint was pathologic complete response. Secondary endpoints were annually evaluated oncological outcomes, toxicity, cosmetic outcome (assessed by patients and physicians), and quality of life. RESULTS: Thirty-six patients were treated with BCS 6 (n = 15) and 8 (n = 21) months following PBI. Median tumor size was 13 mm (IQR 9-16 mm). After a median follow-up of 5.5 years (IQR, 5.1-6.0), 2 (6%) patients had ipsilateral breast events and 2 (6%) distant metastases. The 5-year overall survival was 94% (95% CI, 87-100). The 5-year cumulative incidence of clinician-reported grade 1/2 breast fibrosis and breast discomfort/pain were 94%/6% and 75%/6%, respectively. The proportion of patients (very) satisfied with the cosmetic results was 89% at baseline and 78% at 5 years. Cosmetic results evaluated using the BCCT.core software were excellent or good in all patients. The 4-year median global quality of life score was 83 (IQR, 67-92), similar to baseline (83; IQR, 75-83; P = .42). CONCLUSIONS: Preoperative single-dose PBI and BCS may be an oncologically safe treatment with mild late toxicity and no decline in cosmetic results and quality of life during 5 years of follow-up. This means that preoperative instead of standard postoperative irradiation has the potential to challenge the current clinical practice