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PurposeThis work aims to characterize a proton pencil beam scanning (PBS) and passive double scattering (DS) systems as well as to measure parameters relevant to the relative biological effectiveness (RBE) of the beam using a silicon on insulator (SOI) microdosimeter with well‐defined 3D sensitive volumes (SV). The dose equivalent downstream and laterally outside of a clinical PBS treatment field was assessed and compared to that of a DS beam.MethodsA novel silicon microdosimeter with well‐defined 3D SVs was used in this study. It was connected to low noise electronics, allowing for detection of lineal energies as low as 0.15 keV/μm. The microdosimeter was placed at various depths in a water phantom along the central axis of the proton beam, and at the distal part of the spread‐out Bragg peak (SOBP) in 0.5 mm increments. The RBE values of the pristine Bragg peak (BP) and SOBP were derived using the measured microdosimetric lineal energy spectra as inputs to the modified microdosimetric kinetic model (MKM). Geant4 simulations were performed in order to verify the calculated depth‐dose distribution from the treatment planning system (TPS) and to compare the simulated dose‐mean lineal energy to the experimental results.ResultsFor a 131 MeV PBS spot (124.6 mm R90 range in water), the measured dose‐mean lineal energy increased from 2 keV/μm at the entrance to 8 keV/μm in the BP, with a maximum value of 10 keV/μm at the distal edge. The derived RBE distribution for the PBS beam slowly increased from 0.97 ± 0.14 at the entrance to 1.04 ± 0.09 proximal to the BP, then to 1.1 ± 0.08 in the BP, and steeply rose to 1.57 ± 0.19 at the distal part of the BP. The RBE distribution for the DS SOBP beam was approximately 0.96 ± 0.16 to 1.01 ± 0.16 at shallow depths, and 1.01 ± 0.16 to 1.28 ± 0.17 within the SOBP. The RBE significantly increased from 1.29 ± 0.17 to 1.43 ± 0.18 at the distal edge of the SOBP.ConclusionsThe SOI microdosimeter with its well‐defined 3D SV has applicability in characterizing proton radiation fields and can measure relevant physical parameters to model the RBE with submillimeter spatial resolution. It has been shown that for a physical dose of 1.82 Gy at the BP, the derived RBE based on the MKM model increased from 1.14 to 1.6 in the BP and its distal part. Good agreement was observed between the experimental and simulation results, confirming the potential application of SOI microdosimeter with 3D SV for quality assurance in proton therapy.

Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (125I) measurement of cardiac iodine uptake allowed calculation of the 131I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak +dP/d t. Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. NEW & NOTEWORTHY Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.

Abstract The American Joint Committee on Cancer/Union Internationale Contre le Cancer ( AJCC / UICC ) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression‐based stratification. These parameters rely on tumour‐cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC / UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC / UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM ‐I ( TNM ‐Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Cholangiocytes line the intrahepatic bile ducts and regulate salt and water secretion during bile formation, but the mechanism(s) regulating ductal water movement remains obscure. A water-selective channel, the aquaporin CHIP, was recently described in several epithelia, so we tested the hypothesis that osmotic water movement by cholangiocytes is mediated by CHIP. Isolated rodent cholangiocytes showed a rapid increase in volume in the presence of hypotonic extracellular buffers; the ratio of osmotic to diffusional permeability coefficients was > 10. The osmotically induced increase in cholangiocyte volume was inversely proportional to buffer osmolality, independent of temperature, and reversibly blocked by HgCl2. Also, the luminal area of isolated, enclosed bile duct units increased after exposure to hypotonic buffer and was reversibly inhibited by HgCl2. RNase protection assays, anti-CHIP immunoblots, and immunocytochemistry confirmed that CHIP transcript and protein were present in isolated cholangiocytes but not in hepatocytes. These results demonstrate that (i) isolated cholangiocytes and intact, polarized bile duct units manifest rapid, mercury-sensitive increases in cell size and luminal area, respectively, in response to osmotic gradients and (ii) isolated cholangiocytes express aquaporin CHIP at both the mRNA and the protein level. The data implicate aquaporin water channels in the transcellular movement of water across cholangiocytes lining intrahepatic bile ducts and provide a plausible molecular explanation for ductal water secretion.

Abstract Purpose: MV-CEA is an oncolytic measles virus currently being tested in patients with ovarian cancer and whose propagation can be monitored by measuring blood carcinoembryonic antigen (CEA) levels. MV-NIS is an oncolytic measles virus coding for the thyroidal sodium iodide symporter (NIS) whose propagation can be mapped by serial radioiodine imaging. Expression of both CEA and NIS genes from a single virus would combine sensitive, quantitative expression monitoring (CEA) with radioisotopic expression mapping (NIS). Because of the unfavorable replication kinetics of measles viruses expressing both CEA and NIS, we explored the feasibility of combining MV-CEA with MV-NIS for comprehensive virotherapy monitoring in ovarian cancer. Experimental Design and Results: Mice implanted with i.p. SKOV3ip.1 ovarian cancer xenografts received MV-CEA alone, MV-NIS alone, or a combination of MV-CEA plus MV-NIS. Viral gene expression was monitored by measuring blood CEA levels, and the location of virus-infected cells was monitored by gamma camera imaging. Surprisingly, mice receiving the combination of MV-CEA plus MV-NIS showed greatly superior responses to therapy, but this was associated with 10-fold lower plasma levels of CEA compared with mice treated with MV-CEA alone. In vitro studies showed superior replication kinetics of MV-NIS relative to MV-CEA. The gamma camera scans were considerably less sensitive than the plasma CEA marker for monitoring virus infection. Conclusions: Dual therapy with MV-CEA and MV-NIS is superior to treatment with either virus alone, and it allows noninvasive monitoring of virotherapy via soluble marker peptide and gamma camera imaging. This has important implications for the clinical development of oncolytic measles viruses.