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Aims: Prognosis of locally advanced pancreatic cancer (LAPC) remains poor with limited therapeutic options. Radiation therapy in pancreatic cancer has been restricted by the disease's proximity to radiosensitive organs at risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has demonstrated promise in delivering ablative doses safely. We sought to report clinical outcomes from a UK-based Compassionate Access Programme that provided access to SMART to patients with LAPC., Materials and Methods: This was a registry retrospective study conducted at a single centre with access to SMART. Patients with LAPC were treated with prescription dose of 40 Gy in 5 fractions. The planning objective was that 98% of PTV received ≥95% of the prescribed dose, prioritising duodenal, stomach and bowel UK SABR consortium constraints. Daily online adaptation was performed using magnetic resonance guidance and on-table re-optimisation. 0-3 months and > 3-month post-treatment-related toxicities, local progression-free survival, metastatic-free survival and overall survival were evaluated., Results: 55 patients were treated with SMART at our institution from 2020 to 2022. Median follow-up from date of diagnosis was 17 months (range 5-37 months). Median age was 69.87% of patients underwent induction chemotherapy. 71% of patients reported 0-1 grade acute toxicity only. No grade >3 acute toxicity was reported. 5 patients (9%) reported a grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal stricture). No grade >3 toxicity after 3 months was reported. 6 (10%) of patients had grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal haemorrhage). Median local PFS post diagnosis was 17 months (95% CI 15.3-18.7). Median OS post diagnosis was 19 months (95% CI 15.9-22.1). One-year local control post SMART was 65%., Conclusion: This is the first UK-reported experience of MR-guided daily adaptive pancreatic SABR. SMART shows promise in delivering ablative doses with acceptable toxicity rates and good clinical outcomes., (Copyright © 2024. Published by Elsevier Ltd.)

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by advanced disease stage at presentation, aggressive disease biology, and resistance to therapy, resulting in an extremely poor 5-year survival rate of <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression, but exactly why is unclear and is hindered by the technical limitations of analyzing clinical samples., Methods: We performed genome-wide epigenetic mapping of DNA modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmc) using oxidative bisulfite sequencing from formalin-embedded sections. We identified overlap with transcriptional signatures in formalin-fixed, paraffin-embedded tissue from resected patients, via bioinformatics using iCluster and mutational profiling and confirmed them in vivo., Results: We found that aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci, including GATA6, which promote differentiated classical pancreatic subtypes. We showed that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5-methylcytosine hydroxylase TET2. Furthermore, we found that SMAD4 directly supports TET2 levels in classical pancreatic tumors, and loss of SMAD4 expression was associated with reduced 5hmc, GATA6, and squamous-like tumors. Importantly, enhancing TET2 stability using metformin and vitamin C/ascorbic acid restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo., Conclusions: We identified epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data showed that restoring epigenetic control increases biomarkers of classical pancreatic tumors that are associated with improved therapeutic responses and survival., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Over the last 5 years there has been a surge in interest in the molecular classification of colorectal cancer. The effect of molecular subtyping on current treatment decisions is limited to avoidance of adjuvant 5-fluorouracil chemotherapy in stage II microsatellite unstable-high disease and avoidance of epidermal growth factor receptor-targeted antibodies in extended RAS mutant tumours. The emergence of specific novel combination therapy for the BRAF-mutant cohort and of the microsatellite unstable-high cohort as a responsive group to immune checkpoint inhibition shows the growing importance of a clinically relevant molecular taxonomy. Clinical trials such as the Medical Research Council FOCUS4 trial using biomarkers to select patients for specific therapies are currently open and testing such approaches. The integration of mutation, gene expression and pathological analyses is refining our understanding of the biological subtypes within colorectal cancer. Sharing of data sets of parallel sequencing and gene expression of thousands of cancers among independent groups has allowed the description of disease subsets and the need for a validated consensus classification has become apparent. This biological understanding of the disease is a key step forward in developing a stratified approach to patient management. The discovery of stratifiers that predict a response to existing and emerging therapies will enable better use of these treatments. Improved scientific understanding of the biological characteristics of poorly responsive subgroups will facilitate the design of novel biologically rational combinations. Novel treatment regimens, including the combination of new drugs with radiation, and the discovery and validation of their associated predictive biomarkers will gradually lead to improved outcomes from therapy., (Copyright © 2015. Published by Elsevier Ltd.)

Aims: The outcome of patients with pancreatic cancer from an unselected population within a UK region has not previously been reported. We undertook a review of pancreatic cancer in southeast Wales, with an emphasis on locally advanced non-metastatic pancreatic cancer (LANPC) in an attempt to define a subgroup of patients who would probably benefit from multi-modality treatment., Materials and Methods: Case notes of patients referred to Velindre Hospital between 1 January 2002 and 31 December 2005 were reviewed. Data on patient demographics, tumour characteristics, treatment, treatment response and overall survival were collected. The Log-rank test was used to compare survival between groups and Cox regression was used to evaluate whether age, gender, tumour site and treatment response correlated with overall survival in LANPC., Results: Of the 354 referrals (complete data on 315 patients), 93% were inoperable and 51% of inoperable patients received active treatment (149/294). One hundred and fourteen patients out of 315 (36%) had LANPC and 72/114 (64%) were fit for active treatment, including chemotherapy (n=66) and chemoradiotherapy (CRT) (n=6). The median survival of patients with LANPC was 7.4 months (95% confidence interval 6.4-8.5). Survival for patients receiving chemotherapy, CRT and no treatment was 9.2 (7.5-10.7), 12.6 (6.1-19.1) and 4.5 (3.7-5.3) months, respectively. Overall survival of patients who had non-progressive disease after initial chemotherapy was significantly better than those who progressed (11.8 vs 6.6 months, P=0.01). Of the 180/315 (57%) patients presenting with metastatic disease, 43% received active treatment. Overall survival of metastatic patients was 2.8 months (2.3-3.2 months); for those receiving active treatment, this was 5.6 months (5.1-6.1 months) and for those receiving active supportive care 1.8 months (1.6-2.0 months)., Conclusions: In this UK network, about half of the patients received active treatment. Although the overall outcome was poor, that of treated patients was comparable with published studies. For patients with LANPC, the initial response or disease stabilisation on chemotherapy defined a subset of patients who had better outcome. The role of CRT over and above chemotherapy needs to be defined through trials that should include a neoadjuvant 'chemotherapy-only' phase to select out patients who benefit from multi-modality treatment.

Involved field (IF) radiation was compared with extended field (EF) radiation in Hodgkin lymphoma (HL) to ascertain whether reduced radiation fields would reduce the late sequelae of radiation without compromising disease control and survival. A total of 603 patients with stage I or II HL were entered into this trial; laparotomy was carried out in 380 (63%) patients. Stage I or IIA disease patients were randomised to receive IF or EF comprising a mantle or inverted Y fields alone. Stage I and IIB patients were randomised between mantle or inverted Y fields and total nodal irradiation (TNI). The dose was 35 Gy to uninvolved sites and 40 Gy to involved sites. The median followup of surviving patients was 25.2 years with only 3.3% lost to follow-up. The treatment failure rate at 25 years in stage IA and IIA was 44% after EF and 54% after IF (P = 0.01); in stage I and IIB this was 80% (EF) and 82% (TNI) at 25 years. No difference in overall survival between the randomised groups was seen. The incidence of second malignancies was 21% after IF and 20% after EF with a slight excess of lung cancer in the EF group. No significant differences in the causes of death between the randomised arms have emerged. In conclusion, IF radiotherapy for stage I and IIA HL results in a 11% greater risk of relapse compared with EF but has no effect on overall survival, risk of second malignancy or cause of death at 25 years.

A model of undergraduate education based on a one to one relationship between a student and a patient with cancer has become a core module within the University of Wales College of Medicine undergraduate curriculum. The project combines the powerful impact of a one to one interaction with an active investigative and reflective approach to issues triggered from that patient's cancer journey. The aim is to provide each medical student with an understanding of the impact of a malignant disease and its treatment on patients and their families through the experience of one patient with cancer. The benefits of the project cover the areas of attitudes, skills and knowledge. Students are assessed on their involvement with the patient, in tutorials and on their portfolio, in which they record all aspects of the project. Student evaluations indicate high levels of appreciation of the project, despite its potentially strong emotional content.

A total of 25 patients with small cell lung cancer (SCLC) were treated with carboplatin and Adriamycin (CA) following symptomatic relapse after initial therapy, or because of static or progressive disease during primary treatment. Nine patients had disease within the thorax, and 16 had extensive metastases at relapse. The overall response rate to CA was 64% (20% complete response: CR; 44% partial response: PR). Survival from presentation in 22 of the patients who have died was 6-36 months (median 13 months), and the median survival from the commencement of CA was 23 weeks (range 1 week-11.5 months). The duration of CR was 4-8 months, and of PR 2-7 months. Hospital admission was required following 12% of cycles for management of the complications of treatment. The increasing use of first line regimens of short duration means that reassessment should be made of the activity of further therapy at relapse.

The membrane bound, tumour associated antigen CA125 is recognized by the monoclonal antibody OC125 and may be detected in tumour tissue and serum in over 80% of patients with epithelial ovarian carcinomas. A total of 13 immunoscintigrams using 111 MBq 131I-OC125 have been performed in 11 patients. The results have been compared with clinical examination, CT and ultrasound scans, surgical findings and serum CA125 concentrations. Macroscopic disease was present at the time of scanning in 11 patients (less than 2 cm, eight patients, greater than 2 cm, three patients). Clinical examination and ultrasound were positive in three, CT scanning in four, immunoscintography in seven and serum CA125 in eight patients. This pilot study suggest that serum CA125 estimation is the most sensitive indicator of disease activity. However, immunoscintigraphy using this agent may localize residual disease when clinical examination and other radiological investigations fail.