Niemann-Pick disease type C in monozygotic twins]

The Authors describe two monochorionic twins affected by Niemann-Pick disease type C with a clinical picture beginning in the neonatal age and with a progressive mental deterioration, loss of speech and spasticity started at 30 months. The importance of cultured skin fibroblasts is emphasized. The evidence of a defective intracellular cholesterol esterification is established as an intrinsic feature of Niemann-Pick disease type C.     

Can Ki67 immunostaining predict response to radiotherapy in oral squamous cell carcinoma?

AIMS--To determine whether immunohistochemical evaluation of the abatement of proliferating cells after a first course of radiotherapy could predict the final response to treatment in oral squamous cell carcinoma (SCC). METHODS--Frozen sections from 31 cases of histologically confirmed oral SCC were stained with the monoclonal antibody Ki67 at diagnosis and after 10 Gy of radiotherapy. The percentage difference of Ki67 positive cells among the biopsy specimens taken at the beginning and after 10 Gy was correlated with the clinical response obtained at the end of the treatment and its significance determined. RESULTS--The percentage of Ki67 positive cells at diagnosis had no significant correlation with the final therapeutic result of radiotherapy. By contrast, the 32% difference of proliferating cells after 10 Gy of radiotherapy significantly differentiated responders from non-responders (p < 0.05). Furthermore, the abatement of the growth fraction after 10 Gy of radiotherapy was significantly correlated with the complete response (p < 0.01). CONCLUSIONS--These data show that the immunohistochemical evaluation of the abatement of Ki67 positive cells after 10 Gy of radiotherapy provides an independent variable of responsiveness to radiotherapy, allowing a reliable prediction of the final therapeutic result to be made.     

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.     

Selective targeted delivery of TNFalpha to tumor blood vessels

We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFalpha) composed of mouse TNFalpha and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFalpha was expressed in mammalian cells, purified, and characterized. L19mTNFalpha was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFalpha selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFalpha showed a greater anticancer therapeutic activity than both mTNFalpha and TN11mTNFalpha, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFalpha allows concentrating therapeutically active doses of TNFalpha at the tumor level, thus opening new possibilities for the systemic use of TNFalpha in cancer therapy.     

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.     

STRA-MI-VT (STereotactic RadioAblation by Multimodal Imaging for Ventricular Tachycardia): rationale and design of an Italian experimental prospective study

Background

Ventricular tachycardia (VT) is a life-threatening condition, which usually implies the need of an implantable cardioverter defibrillator in combination with antiarrhythmic drugs and catheter ablation. Stereotactic body radiotherapy (SBRT) represents a common form of therapy in oncology, which has emerged as a well-tolerated and promising alternative option for the treatment of refractory VT in patients with structural heart disease.

Objective

In the STRA-MI-VT trial, we will investigate as primary endpoints safety and efficacy of SBRT for the treatment of recurrent VT in patients not eligible for catheter ablation. Secondary aim will be to evaluate SBRT effects on global mortality, changes in heart function, and in the quality of life during follow-up.

Methods

This is a spontaneous, prospective, experimental (phase Ib/II), open-label study (NCT04066517); 15 patients with structural heart disease and intractable VT will be enrolled within a 2-year period. Advanced multimodal cardiac imaging preceding chest CT-simulation will serve to elaborate the treatment plan on different linear accelerators with target and organs-at-risk definition. SBRT will consist in a single radioablation session of 25 Gy. Follow-up will last up to 12 months.

Conclusions

We test the hypothesis that SBRT reduces the VT burden in a safe and effective way, leading to an improvement in quality of life and survival. If the results will be favorable, radioablation will turn into a potential alternative option for selected patients with an indication to VT ablation, based on the opportunity to treat ventricular arrhythmogenic substrates in a convenient and less-invasive manner.

     

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.