In vivo generation of decidual natural killer cells from resident hematopoietic progenitors

Decidual natural killer cells accumulate at the fetal-maternal interface and play a key role in a successful pregnancy. However, their origin is still unknown. Do they derive from peripheral natural killer cells recruited in decidua or do they represent a distinct population that originates in situ? Here, we identified natural killer precursors in decidua and uterus of pregnant mice. These precursors underwent rapid in situ differentiation and large proportions of proliferating immature natural killer cells were present in decidua and uterus as early as gestation day 4.5. Here, we investigated the origin of decidua- and uterus-natural killer cells by performing transfer experiments of peripheral mature natural killer cells or precursors from EGFP⁺ mice. Results showed that mature natural killer cells did not migrate into decidua and uterus, while precursors were recruited in these organs and differentiated towards natural killer cells. Moreover, decidua- and uterus-natural killer cells displayed unique phenotypic and functional features. They expressed high levels of the activating Ly49D receptor in spite of their immature phenotype. In addition, decidua- and uterus-natural killer cells were poorly cytolytic and produced low amounts of IFN-γ, while they released factors (GM-CSF, VEGF, IP-10) involved in neo-angiogenesis and tissue remodeling. Our data reveal in situ generation of decidual natural killer cells and provide an important correlation between mouse and human decidual natural killer cells, allowing further studies to be carried out on their role in pregnancy-related diseases.     

Stereotactic body radiotherapy for castration-sensitive prostate cancer bone oligometastases

To evaluate outcome in patients treated with stereotactic body radiotherapy (SBRT) on bone oligometastases from castration-sensitive prostate cancer after primary treatment. We retrospectively collected data of patients with less than five lesions at time of SBRT and hormone-naïve disease at the first extra-regional localization, treated between 03/2012 and 11/2016. Prostate-specific antigen (PSA) was measured every 3 months after SBRT. Imaging was performed in case of progression. Survival analysis was performed with Kaplan–Meier (log-rank test) approach. Fifty-five patients were treated on 77 bone oligometastases. Median age, initial PSA and pre-SBRT PSA were 72 years, 9.12 and 3.5 ng/mL, respectively. Twenty-five patients (45%) received SBRT alone while the remaining 30 patients (55%) received concomitant ADT. Median follow-up was 24.6 months (range 3.0–67.2 months). No acute or late toxicity of grade?>?1 was reported. Clinical progression was observed in 38 (69%) patients. 1-year biochemical progression-free survival (b-PFS), clinical progression-free survival (c-PFS), prostate-specific survival (PCSS) and local control (LC) rates were 51, 56, 100 and 83%, respectively. Comparing patients treated with SBRT alone and with concomitant ADT, no significant differences were found for those outcomes. SBRT is safe and allows high 1-year LC rate (83%) with low toxicity profile. No significant improvement in outcomes was registered with the addition of ADT to SBRT.     

A relaxometric method for the assessment of intestinal permeability based on the oral administration of gadolinium‐based MRI contrast agents

Herein, a new relaxometric method for the assessment of intestinal permeability based on the oral administration of clinically approved gadolinium (Gd)‐based MRI contrast agents (CAs) is proposed. The fast, easily performed and cheap measurement of the longitudinal water proton relaxation rate (R₁) in urine reports the amount of paramagnetic probe that has escaped the gastrointestinal tract. The proposed method appears to be a compelling alternative to the available methods for the assessment of intestinal permeability. The method was tested on the murine model of dextran sulfate sodium (DSS)‐induced colitis in comparison with healthy mice. Three CAs were tested, namely ProHance®, MultiHance® and Magnevist®. Urine was collected for 24 h after the oral ingestion of the Gd‐containing CA at day 3–4 (severe damage stage) and day 8–9 (recovery stage) after treatment with DSS. The Gd content in urine measured by ¹H relaxometry was confirmed by inductively coupled plasma‐mass spectrometry (ICP‐MS). The extent of urinary excretion was given as a percentage of excreted Gd over the total ingested dose. The method was validated by comparing the results obtained with the established methodology based on the lactulose/mannitol and sucralose tests. For ProHance and Magnevist, the excreted amounts in the severe stage of damage were 2.5–3 times higher than in control mice. At the recovery stage, no significant differences were observed with respect to healthy mice. Overall, a very good correlation with the lactulose/mannitol and sucralose results was obtained. In the case of MultiHance, the percentage of excreted Gd complex was not significantly different from that of control mice in either the severe or recovery stages. The difference from ProHance and Magnevist was explained on the basis of the (known) partial biliary excretion of MultiHance in mice. Copyright © 2016 John Wiley & Sons, Ltd.     

Quality assurance of 3D-CRT: indications and difficulties in their applications

Although more advanced techniques such as intensity-modulated radiotherapy are rapidly spreading, 3D conformal radiotherapy (3D-CRT) remains the standard of treatment for many diseases. The authors outline essential indications to guarantee the quality of 3D-CRT treatments. Criteria for clinical indications and potential clinical advantages and disadvantages of 3D-CRT technology are presented. After briefly listing human and technological resources requirements, procedures for 3D-CRT and physical aspects peculiar to 3D-CRT are described. Medical physics support activities are also considered, including suggestions concerning quality control protocols. Difficulties in the application of correct quality procedures, particularly related to human and technological resources, procedures for patient positioning, imaging, contouring, treatment planning, in vivo dosimetry, set-up verification, follow-up, dose delivery are then discussed.     

Pharmacological and Dietary Prophylaxis and Treatment of Acute Actinic Esophagitis During Mediastinal Radiotherapy

Our purpose was to evaluate a pharmacological and dietary protocol of prophylaxis and treatment of acute actinic esophagitis during mediastinal radiotherapy. This phase II study was conducted on 29 patients affected by cancer not directly involving the esophagus. The irradiated volume included at least 10 cm of esophagus with a median dose of 46 Gy and the incidence of clinical acute esophagitis was scored with RTOG-EORTC tables. During the entire course of radiation therapy all patients were subjected to prophylaxis pharmacological therapy in addition to dietetic rules commonly used. All patients were evaluable, 9 (31%) had no acute esophageal toxicity, 20 (69%) had toxicity of degree 1, and no patient showed a toxicity of degree 2, 3, or 4, there were no toxicity-related related interruptions of the radiotherapy course. In conclusion, this low cost protocol seems to reduce the incidence and degree of acute radiation esophagitis (without added morbidity), compared with literature reports.     

Locoregional recurrence in patients with HER2 positive breast cancer

Literature shows that HER2/neu positive breast cancer cells are more sensitive to radiation-induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase. We selected 466 patients with pT1-2 HER2/neu positive tumors who received adjuvant trastuzumab for primary invasive breast cancer. Patients were divided into three groups [Quadrantectomy followed by conventional radiotherapy vs Quadrantectomy followed by Intra-operative radiotherapy with electrons vs Mastectomy without radiotherapy]. After a median follow-up of 52 months, the 5-year cumulative incidence of locoregional recurrence (LRR) was 1.9%, 11.5% and 5.0% respectively (p < 0.01). At the multivariate analysis, extensive perivascular invasion, Luminal B HER2/Progesterone Receptor (PgR) negative status and Quadrantectomy followed by Intra-operative radiotherapy with electrons have significantly increased the risk of LRR. Our results suggest that HER2/neu positive breast cancer might have better outcomes when treated simultaneously with external radiotherapy and trastuzumab. Moreover, we underline the importance of PgR and further new stratification of risk among luminal subtypes.