Estimated Doses to the Heart, Lungs and Oesophagus and Risks From Typical UK Radiotherapy for Early Breast Cancer During 2015-2023.

PURPOSE: Breast cancer radiotherapy can increase the risks of heart disease, lung cancer and oesophageal cancer. At present, the best dosimetric predictors of these risks are mean doses to the whole heart, lungs and oesophagus, respectively. We aimed to estimate typical doses to these organs and resulting risks from UK breast cancer radiotherapy. METHODS: A systematic review and meta-analysis was conducted of planned or delivered mean doses to the whole heart, lungs or oesophagus from UK breast cancer radiotherapy in studies published during 2015-2023. Average mean doses were summarised for combinations of laterality and clinical targets. Heart disease and lung cancer mortality risks were then estimated using established models. RESULTS: For whole heart, thirteen studies reported 2893 doses. Average mean doses were higher in left than in right-sided radiotherapy and increased with extent of clinical targets. For left-sided radiotherapy, average mean heart doses were: 2.0 Gy (range 1.2-8.0 Gy) breast/chest wall, 2.7 Gy (range 0.6-5.6 Gy) breast/chest wall with either axilla or supraclavicular nodes and 2.9 Gy (range 1.3-4.7 Gy) breast/chest wall with nodes including internal mammary. For right-sided radiotherapy, average mean heart doses were: 1.0 Gy (range 0.3-1.0 Gy) breast/chest wall and 1.2 Gy (range 1.0-1.4 Gy) breast/chest wall with either axilla or supraclavicular nodes. There were no whole heart dose estimates from right internal mammary radiotherapy. For whole lung, six studies reported 2230 doses. Average mean lung doses increased with extent of targets irradiated: 2.6 Gy (range 1.4-3.0 Gy) breast/chest wall, 3.0 Gy (range 0.9-5.1 Gy) breast/chest wall with either axilla or supraclavicular nodes and 7.1 Gy (range 6.7-10.0 Gy) breast/chest wall with nodes including internal mammary. For whole oesophagus, two studies reported 76 doses. Average mean oesophagus doses increased with extent of targets irradiated: 1.4 Gy (range 1.0-2.0 Gy) breast/chest wall with either axilla or supraclavicular nodes and 5.8 Gy (range 1.9-10.0 Gy) breast/chest wall with nodes including internal mammary. CONCLUSIONS: The typical doses to these organs may be combined with dose-response relationships to estimate radiation risks. Estimated 30-year absolute lung cancer mortality risks from modern UK breast cancer radiotherapy for patients irradiated when aged 50 years were 2-6% for long-term continuing smokers, and <1% for non-smokers. Estimated 30-year mortality risks for heart disease were <1%.

CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.

BACKGROUND: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. METHODS: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation. RESULTS: Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival. CONCLUSION: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

Dihydroquercetin as a means of antioxidative defence in rats with tetrachloromethane hepatitis.

The antioxidant effect of dihydroquercetin (DHQ) was studied in Wistar rats with experimental hepatitis, caused by tetrachloromethane (CCl(4)). Animals were divided into three groups: intact (n = 9); control (n = 9) which received CCl(4) subcutaneously for 4 days (4 mL/kg); and experimental (n = 9) which received DHQ (100 mg/kg) for 4 days prior to the first administration of CCl(4) and during the course of the subsequent 14 days. DHQ was intubated per os, using a water crystalline suspension. The content of products of lipid peroxidation, reacting with thiobarbituric acid in the serum and liver of the control animals, was increased by more than 1.5 fold compared with the intact and experimental animals (p < 0.01). The blood plasma antioxidant activity of the control animals was 1.8 to 2 times lower than that of experimental and intact animals (p < 0.01) It is suggested that the data obtained are dependent on the anti-oxidant properties of DHQ.

Organ-specific effects of 1,2-dimethylhydrazine in hamster.

Uptake and metabolism of the carcinogen 1,2-dimethylhydrazine (DMH) were compared in isolated epithelial cells from the colon and the small intestine. A new method was developed to separate colonic epithelial cells into surface columnar cells and crypt cells without the use of any proteolytic enzymes. Colonic columnar cell-enriched fraction exhibited DMH metabolism two to three times higher than that of crypt cells. The carcinogen binding was much lower in the small intestine as compared to the colon. In the small intestine, the crypt cell-enriched fraction showed higher carcinogen binding as compared to villus cells. Pyrazole was found to inhibit DMH binding by isolated small intestinal and colonic epithelial cells. The extent of inhibition was maximum in cells showing the greatest ability to incorporate DMH.

Characterization of a photosensitive glucose derivative. A photoaffinity reagent for the erythrocyte hexose transporter.

The photosensitive reagent 6-N-(4-azido-2-hydroxy-3,5-diiodobenzoyl)-D-glucosamine has been assessed as a potential photoaffinity label for the hexose transporter. Under zero-trans conditions, transport experiments performed in the dark reveal that the reagent inhibits the uptake of D-glucose in resealed human erythrocyte ghosts. Increasing the concentration of glucose in the transport medium has a protective effect, reducing the inhibition. Kinetic analysis indicates that the probe acts as a competitive inhibitor with high affinity for the erythrocyte hexose transporter (Ki between 0.07 and 0.2 microM). Exposure to a 280 nm filtered high intensity mercury-vapor lamp results in a rapid and efficient photolysis. At low concentrations of the probe, specific labeling of membrane preparations was observed. Autoradiograms of 10% SDS gels revealed the specific labeling of bands 4.51 and 6. This labeling was concentration-dependent and protected by D-glucose (not the L-isomer) and phloretin in the medium. When subjected to multiple exposures of low concentration of the photoaffinity reagent, apparent saturation was achieved.

Separation of isolated hamster intestinal epithelial cells by velocity sedimentation on Ficoll Gradients.

Isolated hamster intestinal epithelial cells can be separated by velocity sedimentationion on 2-10% Ficoll gradients into three subpopulations of cells which differ in morphology, biochemistry, physiology, and membrane components. These subpopulations are not pure but are enriched in a single cell type to the extent that differences in cell function can be observed. The proliferative crypt cells are separated from the digestive-absorptive villus cells. A third subpopulation with a distinctive morphology is also obtained. Quantitation of DNA recoveries from the gradients indicates that this population constitutes approximately one-third of the epithelial cell population. These carrot-shaped cells are found adjacent to the digestive-absorptive columnar epithelial cells on the villus. The two types of villus cells differ in glycolipid or glycoprotein components of the brush border as shown by lectin binding experiments with the isolated cells. The gradient data also suggest that only one-third of the intestinal epithelial cell population is responsible for most monosaccharide absorption in hamster small intestine.

Isolation of hamster intestinal epithelial cells using hypoosmotic media and PVP.

Vibration of hamster small intestinal segments in hypotonic media containing PVP is a rapid method for obtaining quantitative yields of viable intestinal epithelial cells. This preparation of epithelial cells offers a unique system for the study of epithelial cell function in vitro. The method for cell separation combines hypoosmotic swelling of cells, which separates them at the desmosomes, with mechanical agitation which releases the cells from the lamina propria. No chemical agents known to affect cell proteins and cell surfaces are employed in this procedure. Only a short time is elapsed between in vivo and in vitro conditions, i.e., a preparation time of approximately 75 minutes. Although the technique yields a pure population of epithelial cells, the cells are of different morphologies, are removed from different areas of the crypts and villi, and therefore presumably have different functions. Examination of the intestinal tissue remaining after several vibration intervals by light and scanning electron microscopy indicates that the sequence of release of cells is removal of: (1) cells from the villus bases, (2) cells from the lower one-half to two-thirds of the villi, (3) cells from the villus tips (and some crypts), and (4) cells from the crypts. When pools of a+b cells are compared to pools of c+d cells, it is found that villus cells can be characterized by: (1) processes, such as monosaccharide absorption, associated with the brush border, and (2) synthesis of components (e.g., glycoproteins) of the brush border. Surprisingly, disaccharide hydrolytic activity is found in cells which transport monosaccharides poorly. The subpopulations of cells synthesize proteins equally.

Binding of aminocyclitol antibiotics to kidney and intestinal brush border membranes.

Binding of aminocyclitol antibiotics to intestinal and kidney brush border membranes has been studied in vitro by means of vesicular preparations. The binding is rapid, reversible, specific, saturable and has a high affinity. To both tissues, gentamicin and sisomicin bind to a single binding site or receptor. These antibiotics demonstrate increased binding under conditions of increasing pH. Membrane binding disappears when the vesicle proteins are denatured with TCA. A significant reduction in aminocyclitol binding after treatment of vesicles with papain indicates that a portion of the binding receptor protein is exposed to the outer surface of the brush border membrane. The accumulated evidence suggests that the nature of the binding mechanism is not a simple electrostatic interaction between the antibiotic's charged amino groups and the polyanions of the membrane. Alternatively, a specific membrane structure is required for binding whose characteristics reflect a drug-receptor interaction. Receptor binding is characterized as being saturable, reversible, and specific; all of which have been demonstrated for aminocyclitols and brush border membranes.

Solubilization of brush borders of hamster small intestine and fractionation of some of the components.

About 90% of the protein of hamster intestinal brush borders was solubilised in 0.25% (w/v) sodium dodecyl sulphate without total loss of biological activity. Detergent-polyacrylamide gel electrophoresis of the solubilised proteins separated 10-15 bands and partially resolved maltase, lactase, sucrase-maltase, trehalase and alkaline phosphatase activities. The disaccharidases, which were associated with the higher molecular weight proteins, were preferentially solubilised with 0.1%. (w/v) Triton X-100, butanol or papain, whereas Tris and NaI extracted only the lower molecular weight proteins, possible derived from the core filaments. Electrophoresis of brush border proteins metabolically labelled with [14-C] glucosamine suggested that many of the membrane-bound enzymes are glycoproteins. However, chromatography of a papain digest on Sephadex G-200 showed that the sucrase-maltase complex can be separated nearly free of carbohydrate without total loss of activity. The importance of characterizing membrane proteins solubilised by a number of techniques is discussed.