Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer.

Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043-1.1, p = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024-0.55, p = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013-0.42, p = 0.003). Overall, the survival time increased with reduced dose for both single drugs (p < 0.01) and combined drugs (p < 0.001), resulting in tumors with fewer proliferation cells (p = 0.0026) and more apoptotic cells (p = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined.

BSHI and BTS UK guideline on the detection of alloantibodies in solid organ (and islet) transplantation.

Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.

Testing Adaptive Therapy Protocols using Gemcitabine and Capecitabine on a Mouse Model of Endocrine-Resistant Breast Cancer.

Highly effective cancer therapies often face limitations due to acquired resistance and toxicity. Adaptive therapy, an ecologically inspired approach, seeks to control therapeutic resistance and minimize toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life over maximum cell kill. In preparation for a clinical trial in breast cancer, we used large populations of MCF7 cells to rapidly generate endocrine-resistance breast cancer cell line. We then mimicked second line therapy in ER+ breast cancers by treating the endocrine-resistant MCF7 cells in a mouse xenograft model to test adaptive therapy with capecitabine, gemcitabine, or the combination of those two drugs. Dose-modulation adaptive therapy with capecitabine alone increased survival time relative to MTD, but not statistically significant (HR: 0.22, 95% CI 0.043- 1.1 P = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI: 0.024 - 0.55, P = 0.007) and intermittent adaptive therapies significantly increased survival time compared to high dose combination therapy (HR = 0.07, 95% CI: 0.013 - 0.42; P = 0.003). Overall, survival time increased with reduced dose for both single drugs (P < 0.01) and combined drugs (P < 0.001). Adaptive therapy protocols resulted in tumors with lower proportions of proliferating cells (P = 0.0026) and more apoptotic cells (P = 0.045). The results show that Adaptive therapy outperforms high-dose therapy in controlling endocrine-resistant breast cancer, favoring slower-growing tumors, and showing promise in two-drug alternating regimens.

HLA-DPB1 allele frequencies in the West Midlands region of the United Kingdom: A critical evaluation against the common, intermediate and well-documented allele catalogues CWD 2.0.0, EFI CWD and CIWD 3.0.0.

The Birmingham H&I laboratory performed HLA typing on 456 potential deceased solid organ donors in the UK between 2014 and 2016. Accurate DPB1 typing is essential for determining HLA compatibility in transplantation, thus we report HLA-DPB1 for potential deceased solid organ donors. To correctly interpret HLA typing data, laboratories must understand both international and local HLA allele frequencies. In this analysis, we determined HLA-DPB1 allele and genotype frequencies for these 456 donors. HLA-DPB1 diversity was evaluated against the common and well-documented (CWD) alleles 2.0.0 catalogue, the European Federation for Immunogenetics (EFI) CWD catalogue and the common, intermediate and well-documented (CIWD) 3.0.0 catalogue. Additionally, we determined which alleles are common in our local deceased donor population. We observed 27 HLA-DPB1 alleles with DPB1*04:01 being the most frequently observed (allele frequency = 0.4342). All alleles detected locally were present in CIWD 3.0.0, however, DPB1*124:01 and *135:01 were not present in CWD 2.0.0 and DPB1*104:01 and *135:01 were not present in EFI CWD. Twenty of 27 DPB1 alleles identified were defined as locally common and also listed as common in CIWD 3.0.0 representing 62.5% of common alleles in the subset of CIWD 3.0.0 from individuals of a European geographic, ancestral or ethnic background. The alleles HLA-DPB1*16:01 and *20:01 are locally common but not listed as common in EFI CWD and DPB1*104:01 is not listed as common in CWD 2.0.0 catalogue. Our analysis showed that the detected alleles and locally common alleles within our population were aligned with the CIWD 3.0.0 catalogue.

Sclerotherapy treatment of a large venous malformation invading the bladder wall related to Klippel-Trenaunay syndrome.

We report the case of a 35-year-old woman who presented with recurrent macroscopic haematuria and known diagnosis of Klippel-Trenaunay syndrome. Imaging and cystoscopy identified an extensive venous malformation involving a large area of the bladder wall. Holmium laser therapy was ineffective at obtaining symptom control. Following a multidisciplinary team meeting, transvenous sclerotherapy with sodium tetradecyl sulphate was performed under image guidance. A reduction in venous density was observed on cystoscopy and the patient has had complete resolution of symptoms within 6 weeks and continued to be asymptomatic up to 24-month follow-up. We propose that transvenous sclerotherapy is considered first-line treatment in this clinical setting.