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Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) have recently revolutionized anti-cancer therapy and are nowadays used in different metastatic cancers. These treatments may induce immune-related adverse events which frequently involve the digestive tract and, to a less extent the liver. The tissular injuries, which are still poorly characterized from a morphological and physiopathological point of view, may lead on one side to the interruption of a life-saving treatment and on the other side to the development of severe complications, if not death. Therefore, it is crucial to diagnose as early as possible and treat these digestive and hepatic adverse effects in an optimal way. This article aims to describe the clinical and pathological presentations of digestive and hepatic adverse events induced by these immunotherapies., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Programmed death receptor-1 blocking antibodies (anti-PD1) are a new standard of care in many cancer types. Patients benefit from improved survival but have the risk of immune-related adverse events (irAE). We evaluated if medical imaging procedures, used for anti-tumour response assessment, can detect irAEs., Materials and Methods: All consecutive patients treated with anti-PD1 and with a medical imaging acquisition performed within 2 weeks with irAEs ≥2 were retrospectively included. Data were gathered from June 2014 to February 2017, and a central review was performed. The primary and secondary end-points were i) to evaluate the overall detection rate of irAEs by medical imaging and ii) to provide a comprehensive radiological description of irAEs., Results: Fifty-three patients (31 women, 22 men; average age: 61 years) were included. The primary tumour was melanoma (n = 32), lung cancer (n = 18) and other (n = 3). Patients were treated with nivolumab (n = 27) or pembrolizumab (n = 26). Of 74 medical imaging procedures analysed (ratio = 1.4 medical imaging per patient), 55 irAE were detected. The detection rate was overall: 74% (95 confidence interval: 63-84%), positron emission tomography with 18F-fludeoxyglucose integrated with computed tomography (18F-FDG PET/CT): 83% (n = 10/12), magnetic resonance imaging: 83% (n = 5/6), computed tomography scan: 79% (n = 19/24), ultrasonography: 70% (n = 19/27), standard X-rays: 40% (n = 2/5), lung/mediastinum: 100% (n = 7/7), enterocolitis: 100% (n = 8/8), hypophysitis: 100% (n = 3/3), thyroiditis: 75% (n = 15/20), hepatitis: 67% (n = 2/3), arthralgia or arthritis: 40% (n = 2/5) and pancreas: 28% (n = 2/7)., Conclusion: Medical imaging detected 74% of irAE in patients treated with anti-PD1. Beyond response assessment, medical imaging can detect irAE and guide towards specific management. We described the most frequent sites and patterns of imaging findings., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background & Aims: Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs)., Methods: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens., Results: In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction., Conclusions: Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration., Lay Summary: Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer., Methods: This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result., Results: Mean pathological tumor size was 10.5 mm (±4.3, range 3-18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107-213; range:56-325) with a median PTV isodose prescription of 86.0% (IQR 85.0-88.5; range:82-94). The median PTV was 88.1 cm3 (IQR 63.8-108.6; range:32.3-238.8). The median breast V100 and V50 was 0.6 (IQR 0.1-1.5; range:0-13) and 18.6 (IQR 13.1-21.7; range:7.5-37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7-27.6; range 22.3-29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer., Conclusions: These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results., Trial Registration: The present study is registered at Clinicaltrial.gov ( NCT02896322 ). Retrospectively egistered August 4, 2016.

Introduction: The aim of this article was to evaluate the influence of applying filters in cone-beam computed tomography (CBCT) images at different resolutions. These CBCT images were obtained for diagnosing mesiodistal vertical root fractures (VRFs) in teeth with metal posts., Methods: Forty teeth were treated endodontically, and 20 received metal posts. Ten teeth without posts and 10 teeth with posts were subjected to VRF in the mesiodistal direction. The sample was submitted to periapical radiographs and CBCT exams with a voxel of 0.25 and 0.30 mm. To reduce the influence of the metal artifact in the CT images, the teeth were evaluated with and without the application of filters ("Sharpen" and "Hard"). The images were evaluated by 2 radiologists who identified the presence of VRF. Accuracy values (receiver operating characteristic curves) for the different variables were compared by using analysis of variance and t test., Results: No difference was observed between images with and without filter application (P > .05). Images obtained with a 0.25-mm voxel were more accurate (P < .05). The presence of the metal post reduced the accuracy of the diagnosis of VRF (P < .05), and the CBCT images showed superior results compared with periapical radiographs (P < .05)., Conclusions: The presence of a metal post and the voxel size significantly interfere with the diagnosis of VRF. Despite the formation of metal artifacts associated with metallic cores, applying filters did not improve the diagnosis. For mesiodistal VRF, the CBCT images are superior to the periapical radiographs., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Objective: Magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) provide noninvasive localization of eloquent brain areas for presurgical planning. The aim of this study is the integration of MEG and fMRI maps into a CyberKnife (CK) system to optimize dose planning., Methods: Four patients with brain metastases in the motor area underwent functional imaging study of the hand motor cortex before radiosurgery. MEG data were acquired during a visually cued hand motor task. Motor activations were identified also using an fMRI block-designed paradigm. MEG and fMRI maps were then integrated into a CK system and contoured as organs at risk for treatment planning optimization., Results: The integration of fMRI data into the CK system was achieved for all patients by means of a standardized protocol. We also implemented an ad hoc pipeline to convert the MEG signal into a DICOM standard, to make sure that it was readable by our CK treatment planning system. Inclusion of the activation areas into the optimization plan allowed the creation of treatment plans that reduced the irradiation of the motor cortex yet not affecting the brain peripheral dose., Conclusions: The availability of advanced neuroimaging techniques is playing an increasingly important role in radiosurgical planning strategy. We successfully imported MEG and fMRI activations into a CK system. This additional information can improve dose sparing of eloquent areas, allowing a more comprehensive investigation of the related dose-volume constraints that in theory could translate into a gain in tumor local control, and a reduction of neurological complications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background & Aims: Liver transplantation (LT) for the most severely ill patients with cirrhosis, with multiple organ dysfunction (accurately assessed by the acute-on-chronic liver failure [ACLF] classification) remains controversial. We aimed to report the results of LT in patients with ACLF grade 3 and to compare these patients to non-transplanted patients with cirrhosis and multiple organ dysfunction as well as to patients transplanted with lower ACLF grade., Methods: All patients with ACLF-3 transplanted in three liver intensive care units (ICUs) were retrospectively included. Each patient with ACLF-3 was matched to a) non-transplanted patients hospitalized in the ICU with multiple organ dysfunction, or b) control patients transplanted with each of the lower ACLF grades (three groups)., Results: Seventy-three patients were included. These severely ill patients were transplanted following management to stabilize their condition with a median of nine days after admission (progression of mean organ failure from 4.03 to 3.67, p=0.009). One-year survival of transplanted patients with ACLF-3 was higher than that of non-transplanted controls: 83.9 vs. 7.9%, p<0.0001. This high survival rate was not different from that of matched control patients with no ACLF (90%), ACLF-1 (82.3%) or ACLF-2 (86.2%). However, a higher rate of complications was observed (100 vs. 51.2 vs. 76.5 vs. 74.3%, respectively), with a longer hospital stay. The notion of a "transplantation window" is discussed., Conclusions: LT strongly influences the survival of patients with cirrhosis and ACLF-3 with a 1-year survival similar to that of patients with a lower grade of ACLF. A rapid decision-making process is needed because of the short "transplantation window" suggesting that patients with ACLF-3 should be rapidly referred to a specific liver ICU. Lay summary: Liver transplantation improves survival of patients with very severe cirrhosis. These patients must be carefully monitored and managed in a specialized unit. The decision to transplant a patient must be quick to avoid a high risk of mortality., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Gafchromic EBT3 film dosimetry in radiosurgery (RS) and hypofractionated radiotherapy (HRT) is complicated by the limited film accuracy at high fractional doses. The aim of this study is to develop and evaluate sum signal (SS) film dosimetry to increase dose resolution at high fractional doses, thus allowing for use of EBT3 for dose distribution verification of RS/HRT treatments. To characterize EBT3 dose-response, a calibration was performed in the dose range 0.44-26.43 Gy. Red (RC) and green (GC) channel net optical densities were linearly added to produce the SS. Dose resolution and overall accuracy of the dosimetric protocol were estimated and compared for SS,RC, and GC. A homemade Matlab software was developed to compare, in terms of gamma analysis, dose distributions delivered by a Cyberknife on EBT3 films to dose distributions calculated by the treatment planning system. The new SS and conventional single channel (SC) methods were compared, using 3%/1 and 4%/1 mm acceptance criteria, for 20 patient plans. Our analysis shows that the SS dose-response curve is characterized by a steeper trend in comparison with SC, with SS providing a higher dose resolution in the whole dose range investigated. Gamma analysis confirms that the percentage of points satisfying the agreement criteria is significantly higher for SS compared to SC: 95.03% vs. 88.41% (P = 0.014) for 3%/1 mm acceptance criteria and 97.24% vs. 93.58% (P = 0.048) for 4%/1 mm acceptance criteria. This study demonstrates that the SS approach is a new and effective method to improve dosimetric accuracy in the framework of the RS-HRT patient-specific quality assurance protocol., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice., (© 2015 Steunstichting ESOT.)

Background: The challenging diagnosis and poor prognosis of cholangiocarcinoma require the determination of biomarkers. Autoantibodies could be used in the clinic as diagnostic markers for the early detection of tumours. By proteomic approaches, several autoantibodies were proposed as potential markers. We tried in this study, to perform a serological proteome analysis, using various antigenic substrates, including tumours and human liver., Methods: Sera from patients (n = 13) and healthy donors (n = 10) were probed on immunoblots performed using 2-dimensionally separated proteins from cholangiocarcinoma cell lines (CCLP1 and CCSW1), from the liver of healthy subject and interestingly, from tumour and adjacent non-tumour liver tissues from five patients with cholangiocarcinoma and tested with their corresponding serum. Spots of interest were identified using mass spectrometry and classified according gene ontology analysis., Results: A comparison of the whole immunoblotting patterns given by cholangiocarcinoma sera against those obtained with normal control sera enabled the definition of 862 spots. Forty-five different proteins were further analysed, corresponding to (1) spots stained with more than four of 13 (30 %) sera tested with the CCLP1 or the CCSW1 cell line and with the normal liver, and (2) to spots immunoreactive with at least two of the five sera probed with their tumour and non-tumour counter-part of cholangiocarcinoma. Immunoreactive proteins with catalytic activity as molecular function were detected at rates of 93 and 64 % in liver from healthy subjects or cholangiocarcinoma non-tumour tissues respectively, compared to 43, 33, 33 % in tumour tissues, or CCSW1 and CCLP1 cell lines. A second pattern was represented by structural proteins with rates of 7 and 7 % in normal liver or non-tumour tissues compared to 14, 33 and 67 % in tumour tissue, CCSW1 or CCLP1 cell lines. Proteins with a binding function were detected at rates of 7 % in non-tumour tissue and 14 % in tumour tissue. Using the extracted tumour tissue, serotransferrin was targeted by all cholangiocarcinoma-related sera., Conclusions: Immunological patterns depended on the type of antigen substrate used; i.e. tumour versus non tumour specimens. Nevertheless, a combination of multiple autoantibodies tested with the most appropriate substrate might be more sensitive and specific for the diagnosis of cholangiocarcinoma.

Aim of this study is to examine the feasibility of using the new Gafchromic EBT3 film in a high-dose stereotactic radiosurgery and radiotherapy quality assurance procedure. Owing to the reduced dimensions of the involved lesions, the feasibility of scanning plan verification films on the scanner plate area with the best uniformity rather than using a correction mask was evaluated. For this purpose, signal values dispersion and reproducibility of film scans were investigated. Uniformity was then quantified in the selected area and was found to be within 1.5% for doses up to 8 Gy. A high-dose threshold level for analyses using this procedure was established evaluating the sensitivity of the irradiated films. Sensitivity was found to be of the order of centiGray for doses up to 6.2 Gy and decreasing for higher doses. The obtained results were used to implement a procedure comparing dose distributions delivered with a CyberKnife system to planned ones. The procedure was validated through single beam irradiation on a Gafchromic film. The agreement between dose distributions was then evaluated for 13 patients (brain lesions, 5 Gy/die prescription isodose ~80%) using gamma analysis. Results obtained using Gamma test criteria of 5%/1 mm show a pass rate of 94.3%. Gamma frequency parameters calculation for EBT3 films showed to strongly depend on subtraction of unexposed film pixel values from irradiated ones. In the framework of the described dosimetric procedure, EBT3 films proved to be effective in the verification of high doses delivered to lesions with complex shapes and adjacent to organs at risk., (Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Background: Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies., Aims: To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome., Methods: We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included., Results: Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence., Conclusions: This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: A multidisciplinary and multi-institutional working group applied the Failure Mode and Effects Analysis (FMEA) approach to assess the risks for patients undergoing Stereotactic Body Radiation Therapy (SBRT) treatments for lesions located in spine and liver in two CyberKnife® Centres., Methods: The various sub-processes characterizing the SBRT treatment were identified to generate the process trees of both the treatment planning and delivery phases. This analysis drove to the identification and subsequent scoring of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system. Novel solutions aimed to increase patient safety were accordingly considered., Results: The process-tree characterising the SBRT treatment planning stage was composed with a total of 48 sub-processes. Similarly, 42 sub-processes were identified in the stage of delivery to liver tumours and 30 in the stage of delivery to spine lesions. All the sub-processes were judged to be potentially prone to one or more failure modes. Nineteen failures (i.e. 5 in treatment planning stage, 5 in the delivery to liver lesions and 9 in the delivery to spine lesions) were considered of high concern in view of the high RPN and/or severity index value., Conclusions: The analysis of the potential failures, their causes and effects allowed to improve the safety strategies already adopted in the clinical practice with additional measures for optimizing quality management workflow and increasing patient safety.

The evolution of liver diseases to end-stage liver disease or to acute hepatic failure, the evaluation process for liver transplantation, the organ allocation decision-making, as well as the post-transplant outcomes are different between female and male genders. Women's access to liver transplantation is hampered by the use of model for end-stage liver disease (MELD) score, in which creatinine values exert a systematic bias against women due to their lower values even in the presence of variable degrees of renal dysfunction. Furthermore, even when correcting MELD score for gender-appropriate creatinine determination, a quantifiable uneven access to transplant prevails, demonstrating that other factors are also involved. While some of the differences can be explained from the epidemiological point of view, hormonal status plays an important role. Moreover, the pre-menopausal and post-menopausal stages imply profound differences in a woman's physiology, including not only the passage from the fertile age to the non-fertile stage, but also the loss of estrogens and their potentially protective role in delaying liver fibrosis progression, amongst others. With menopause, the tendency to gain weight may contribute to the development of or worsening of pre-existing metabolic syndrome. As an increasing number of patients are transplanted for non-alcoholic steatohepatitis, and as the average age at transplant increases, clinicians must be prepared for the management of this particular condition, especially in post-menopausal women, who are at particular risk of developing metabolic complications after menopause.

Background: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival., Aim: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence., Methods: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated., Results: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008)., Conclusions: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 is a target for antinuclear autoantibodies in systemic Lupus erythematosus (SLE), rheumatoid arthritis (RA), and autoimmune hepatitis (AIH)., Aim: To monitor molecular interactions between peptides spanning the entire sequence of hnRNP A2/B1 and sera from patients and healthy controls., Methods: Sera from 8 patients from each pathology and controls were passed across a surface plasmon resonance Imagery (SPRi) surface containing 39 overlapping peptides of 17 mers covering the human hnRNP B1. Interactions involving the immobilised peptides were followed in real time and dissociation rate constants k(off) for each interaction were calculated., Results: Several significant interactions were observed: i) high stability (lower k(off) values) between P₅₅₋₇₀ and the AIH sera compared to controls (p= 0.003); ii) lower stability (higher k(off) values) between P₁₁₈₋₁₃₃ and P₂₆₂₋₂₇₇ and SLE sera, P₁₄₅₋₁₆₀ and RA sera compared to controls (p=0.006, p=0.002, p=0.007). The binding curves and k(off) values observed after the formation of complexes with anti-IgM and anti-IgG antibodies and after nuclease treatment of the serum indicate that i) IgM isotypes are prevalent and ii) nucleic acids participate in the interaction between anti-hnRNAP B1 and P₅₅₋₇₀ and also between controls and the peptides studied., Conclusions: These results indicate that P₅₅₋₇₀ of hnRNP B1 is a potential biomarker for AIH in immunological tests and suggest the role of circulating nucleic acids, (eg miRNA), present or absent according to the autoimmune disorders and involved in antigen-antibody stability.

Background: The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response., Methods: Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients., Results: Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤ 1 T allele (56.1%) to tacrolimus-treated patients carrying ≤ 1 T allele (44.7%) to patients carrying ≥ 2 T alleles (25.0%, p=0.0009)., Conclusions: Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying <2 T alleles cyclosporine favours a better response than tacrolimus, while no difference was found in the presence of ≥ 2 T alleles., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Surgery represents the first-choice treatment for spinal intradural tumours. On the other hand, whether it is most appropriate in the setting of recurrences, residual or multiple lesions remains an open question. Moreover, some patients are less than ideal candidates for surgery. In this study we report about our own radiosurgery experience in the treatment of benign intradural extramedullary tumours of the spine., Methods: In our study we analyzed the outcomes for 18 patients (21 lesions) treated for benign intradural extramedullary lesions, with a minimum follow-up period of 32 months. The lesions included 11 meningiomas, 9 schwannomas and 1 neurofibroma., Results: The mean follow-up was 43 months (32-73 months). The median tumour volume was 2 cc (0.2-17.7 cc). Eleven lesions underwent single-fraction treatment (mean prescribed dose ranging from 10 to 13 Gy). The others received a multisession radiosurgery treatment (4-6 fractions) with a mean prescription dose ranging from 18.5 to 25 Gy. The maximum dose to the spinal cord ranged from 9.2 to 26 Gy. During the follow-up period, none of the lesions showed radiological evidence of progression. Neurological status was preserved or improved and no permanent sequelae were observed. Significant and durable pain relief was observed., Conclusions: Although surgical excision remains the primary treatment option for most intradural tumours, radiosurgery offers a real alternative therapeutic modality, especially in case of recurrent and residual lesions or when surgery is contraindicated.

Women constitute a particular group among patients with chronic liver disease and in the post-liver transplantation (LT) setting: they are set apart not only by traditional differences with respect to men (ie, body mass index, different etiologies of liver disease, and accessibility to transplantation) but also in increasingly evident ways related to hormonal changes that characterize first the fertile age and subsequently the postmenopausal period (eg, disease course variability and responses to therapy). The aim of this review is, therefore, to evaluate the role of the interplay of factors such as age, gender, and hormones in influencing the natural history of chronic liver disease before and after LT and their importance in determining outcomes after LT. As the population requiring LT ages and the mean age at transplantation increases, older females are being considered for transplantation. Older patients are at greater risk for nonalcoholic steatohepatitis, osteoporosis, and a worse response to antiviral therapy. Female gender per se is associated with a greater risk for osteoporosis because of metabolic changes after menopause, the bodily structure of females, and, in the population of patients with chronic liver disease, the greater prevalence of cholestatic and autoimmune liver diseases. With menopause, the fall of protective estrogen levels can lead to increased fibrosis progression, and this represents a negative turning point for women with chronic liver disease and especially for patients with hepatitis C. Therefore, the notion of gender as a binary female/male factor is now giving way to the awareness of more complex disease processes within the female gender that follow hormonal, social, and age patterns and need to be addressed directly and specifically., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Backgrounds/aims: We evaluated the effect of antiviral therapy on fibrosis progression in patients with histological features of mild/moderate HCV disease recurrence defined by a Grading score≥4 and Staging score up to 3 (Ishak) at 1 year after liver transplantation., Methods: Seventy-three consecutive patients with mild/moderate recurrence were randomized either to no treatment or to receive Pegilated-Interferon-alfa-2b and ribavirin for 52 weeks. Liver biopsies obtained at baseline (1 year after transplantation) and 2 years afterwards were evaluated for assessment of disease progression, defined as worsening of at least 2 staging points or progression to stage 4 or higher., Results: As for these two major histological end points there were no statistically significant differences between the 2 groups (36.1% vs. 50%, p=0.34 and 36.1% vs. 38.9%, p=1). Fifteen treated patients (41%) achieved a sustained virological response which was associated with a reduced risk of fibrosis worsening for both endpoints when compared to viremic patients (p=0.04)., Conclusions: Although antiviral-therapy was beneficial in preventing fibrosis progression in patients achieving a sustained virological response, the majority of the overall population of our patients with mild-moderate disease recurrence could not benefit from antiviral therapy either because they either could not be treated or did not respond to treatment (EudraCT number: 2005-005760)., (Copyright © 2012. Published by Elsevier Ltd.)

It has been recently suggested that the risk of graft loss after liver transplantation (LT) may increase in female HCV patients. The aim of the study was to examine gender differences in HCV therapy tolerance and outcome in LT patients treated for HCV recurrence. A retrospective study was conducted on liver recipients with HCV recurrence, who were given antiviral therapy from 2001 to 2009 in 12 transplant centers in Italy. Sustained virological response (SVR), adherence-to-therapy, and side effects were evaluated. A multivariate logistic regression model was used after adjusting for possible confounders. The data regarding 342 treated patients were analyzed. SVR was reported in 38.8% of patients. At baseline, male and female did not differ in HCV viral load, histology, or rate of diabetes. SVR was lower in females than in males (29.5% vs. 42.1%; P=0.03). Adherence-to-therapy was also lower in females than in males 43.4% vs. 23.8%; P=0.001); anemia was the main reason for lower adherence. In a multivariate analysis in patients Genotype1, female gender (P<0.04), early virological response (P<0.0001), and adherence to therapy (P<0.0001) were independent predictors for SVR. In conclusion, female gender represents an independent negative prognostic factor for the outcome of HCV antiviral therapy after LT., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

The goal of liver transplantation is not only to ensure patient long-term survival but also to offer the opportunity to achieve psychologic and physical integrity. Quality of life after liver transplantation may be affected by unsatisfactory sexual function. Before liver transplantation, sexual dysfunction and sex hormone disturbances are reported in men and women mainly due to abnormality of physiology of the hypothalamic-pituitary-gonadal axis and, in some cases, origin of liver disease. Successful liver transplantation should theoretically restore hormonal balance and improve sexual function both in men and women, thus improving the reproductive performance. However, after transplantation, up to 25% of patients report persistent sexual dysfunction, and approximately one third of patients describe the appearance of de novo sexual dysfunction. Despite the described high prevalence of this condition, epidemiologic data are relatively scant. Further studies on pathophysiology and risk factors in the field of sexual function after liver transplantation along with new strategies to support and inform patients on the waiting list and after surgery are needed.

Primary cutaneous mucinous carcinomas originating from sweat glands are rare tumors with patterns of spread that are difficult to predict. We present a case of a five times recurring eccrine mucinous adenocarcinoma of the scalp, previously treated with surgery and adjuvant radiation therapy. After magnetic resonance imaging (MRI) and 18F-fluoro-2-deoxyglucose positron-emission tomography/computed tomography (18FDG-PET/CT), which documented local recurrence, the patient was considered eligible for salvage irradiation of the scalp. We decided to use helical tomotherapy, which combines conformity of dose delivery with the possibility of daily control of the setup accuracy. Forty gray (2Gy/fraction) to the planning target volume and 50 Gy (2.5Gy/fraction) to the biological target volume defined on the basis of 18FDG-PET/CT was prescribed with a simultaneous integrated boost technique. After 12 fractions the patient was submitted to intermediate evaluation by 18FDG-PET/CT, which showed a partial response to the treatment. After 2, 4, 8, and 12 months, 18FDG-PET/CT showed a complete metabolic local response. This experience suggests a possible role of 18FDG-PET/CT-guided helical tomotherapy as an alternative to repeated and frequently demolitive surgery approaches.

Recurrent hepatitis C (HCV) and biliary complications (BC) are major causes of post liver transplant morbidity and mortality. The impact of these complications may be additive or synergistic. We performed a retrospective cohort study to analyze the effects of HCV and BC on all patients transplanted at two institutions over 6 years. BC was defined by imaging findings in the setting of abnormal liver function tests that required intervention. The primary outcomes were graft and patient survival over a mean 3.4 years. 709 patients (619 deceased, 90 living donor) were included, 337 with HCV and 372 without. BC was diagnosed more frequently in patients with HCV, 26% versus 18% (p = 0.008). One-year and overall patient and graft survival were significantly lower in patients with HCV, but BC impacted only 1-year graft survival. The combination of BC and HCV had no additional impact on survival or fibrosis rates on 1-year protocol biopsies. Multivariate analysis revealed HCV (HR 2.1) and HCC (HR 1.9) to be independent predictors of mortality. Since BC are diagnosed more frequently in HCV patients and only affect early graft loss, it is likely that recurrent HCV rather than BC accounts for the majority of adverse graft outcomes.

Background and Aim: Hepatitis C virus (HCV)-related cirrhosis is one of the leading indication for liver transplantation (LT) and a major risk factor for the development of hepatocellular carcinoma (HCC). HCV recurrence after LT is universal. This study evaluated HCV recurrence and survival in patients transplanted for HCV and HCC., Methods: We evaluated all adults transplanted for HCV cirrhosis between January 1999 and December 2006, HCC was diagnosed on the explant and HCV recurrence confirmed on protocol liver biopsies performed at 6 months and yearly after LT. The sustained viral response (SVR) was defined as HCV-RNA undetectable at 6 months after therapy discontinuation. The patient survival rates were assessed with Kaplan-Meier curves and the chi-square test was used when appropriate., Results: Two hundred sixteen patients underwent LT for HCV including 153 men and 63 women of mean age 54 years with a mean follow-up of 35 months. There were 71 (33%) HCC(+) patients. At 1, 3, and 5 years from LT severe fibrosis (Scheuer 3-4) due to the HCV recurrence was reported in 18%, 14%, and 11% for HCC(+) and 14%, 16%, and 28% for HCC(-) patients respectively (P=NS). HCC recurred only in 3 (4%) patients at a mean follow-up of 3 years. Patients who received antiviral treatment after LT were 10% HCC(+) and 12% HCC(-) patients (P=NS). SVR was seen in 3/7 (43%) of HCC(+) and in 10/18 (55%) of HCC(-) patients (P=NS). At 1, 3, and 5 years the patient survivals was 91%, 86%, and 86% for HCC(+) and 94%, 86%, and 83% for HCC(-) patients, respectively (P=NS)., Conclusions: Severe fibrosis due to HCV recurrence, which increases over time, involves one third of transplanted patients at 5 years after LT. The long-term survival was identical among HCC(+) compared to HCC(-) recipients. The recurrence of HCC was negligible and did not affect patient survival.

Adenoid cystic carcinoma, also called cylindroma, is the second most common histological type of tracheal malignancy but represents 1% of all respiratory tract cancers. We report a case of a 59-year-old patient submitted to an incomplete resection of the trachea and subsequently treated with adjuvant tomotherapy. There have been no reports in the literature regarding intensity-modulated radiation therapy with linac or tomotherapy systems in adenoid cystic carcinoma of the trachea. The present clinical case demonstrates the feasibility of adjuvant intensity-modulated radiation therapy techniques for optimizing the dose coverage of the tumor bed while sparing surrounding normal tissues. A dosimetric comparison between the tomotherapy plan and a 3-dimensional conformal radiotherapy plan is also reported. We demonstrate that tomotherapy permits an increase in the dose per fraction without important acute adverse effects. At 24 months' follow-up, our patient shows no evidence of disease with negative histological findings.

Background and Purpose: The aim of this study was to analyse our pre-treatment QA data in order to establish uniquely defined agreement criteria between planned and delivered dose distribution for clinical QA practice in IMRT of head and neck (HN) patients., Materials and Methods: Pre-treatment QA dosimetry using films in combination with ionisation chambers is routinely evaluated for each patient. This evaluation is performed by comparing planned and measured dose distributions in terms of absolute point dose measurements, planar dose verification and gamma function analysis using 4%/3mm values as acceptance criteria. In the current investigation, gamma histograms, calculated on dose levels higher than 10% of the prescription dose (1.8Gy/fraction), were further analysed by considering mean values, gamma values corresponding to Delta=mean+1.5 SD (named as gamma(Delta)) and the % of points with gamma<1, gamma<1.5 and gamma>2. When considering the patient population, the average values of all these parameters and their confidence limits (mean value+1.5 SD) were calculated. The results here presented refer to 57 HN patients treated in the period September 04-April 06., Results: Better results were found for treatments performed with our newly installed linac (e.g. average gamma(Delta): 0.8 vs. 1.1 for the preexisting one, p<0.001), due to a more accurate dosimetric configuration. Also, confidence limits for the percentage of points with gamma<1, gamma<1.5 and gamma>2 were found to be quite different for the two linacs (95.3%, 98.9% and 0.4% for the newly installed unit, 87.6%, 95.2% and 2.0% for the preexisting one)., Conclusions: Statistical analyses of gamma evaluation of QA pre-treatment dosimetry are useful to properly define confidence limits of the agreement between expected and measured fluences based on our institutional experience. Our results confirm that the dosimetry configuration of the beam may significantly affect the agreement between planned and measured IMRT beam fluences.

Purpose: To explore the potential of helical tomotherapy (HT) in the treatment of nasopharynx cancer., Patients and Methods: Six T1-4 N1-3 patients were considered. A simultaneous integrated boost (SIB) technique was planned with inversely optimized conventional intensity-modulated radiotherapy (IMRT; dynamic multileaf collimator using the Eclipse-Helios Varian system) and HT. The prescribed (median) doses were 54 Gy, 61.5 Gy, and 64.5 Gy delivered in 30 fractions to PTV1 (planning target volume), PTV2, and PTV3, respectively. The same constraints for PTV coverage and for parotids, spinal cord, mandible, optic structures, and brain stem were followed in both modalities. The planner also tried to reduce the dose to other structures (mucosae outside PTV1, larynx, esophagus, inner ear, thyroid, brain, lungs, submental connective tissue, bony structures) as much as possible., Results: The fraction of PTV receiving >95% of the prescribed dose (V95%) increased from 97.6% and 94.3% (IMRT) to 99.6% and 97% (HT) for PTV1 and PTV3, respectively (p<0.05); median dose to parotids decreased from 30.1 Gy for IMRT to 25.0 Gy for HT (p<0.05). Significant gains (p<0.05) were found for most organs at risk (OARs): mucosae (V30 decreased from 44 cm(3) [IMRT] to 18 cm(3) [HT]); larynx (V30: 25 cm(3) vs. 11 cm(3)); thyroid (mean dose: 48.7 Gy vs. 41.5 Gy); esophagus (V45: 4 cm(3) vs. 1 cm(3)); brain stem (D1%: 45.1 Gy vs. 37.7 Gy)., Conclusion: HT improves the homogeneity of dose distribution within PTV and PTV coverage together with a significantly greater sparing of OARs compared to linac five-field IMRT.

Purpose: In order to explore the potential of helical Tomotherapy in the treatment of head and neck cancers (HNC), a planning study comparing our routinely delivered IMRT technique (dynamic MLC Varian 600CD Linac, inversely optimised by the Helios/Eclipse system) against two different Tomotherapy planning approaches was performed., Materials and Methods: In the first Tomotherapy plan (TOMO-a), we merely applied the same constraints used for the IMRT-Linac technique; in the second one (TOMO-b), we tried to stress the sparing of parotids and mandible while keeping PTV coverage and spinal cord Dmax similar to their values in the TOMO-a plan. Five patients with locally advanced oropharinx (n=3), hypopharinx (n=1) and larynx (n=1) cancer were considered. For each patient, CTV1 including neck nodes and the tumour was defined and was expanded with a margin of 0.5 cm (PTV1); then, CTV2 including high risk nodes and CTV3 including only T were defined and the corresponding PTV2/PTV3 were defined by a 0.5 cm expansion. IMRT and Tomotherapy planning were optimised to deliver 54 Gy in 30 fractions on PTV1 and 16.2 Gy in 9 fractions on PTV3; in the case a PTV2 was defined, 15 Gy were concomitantly delivered while delivering 16.2 Gy on PTV3. Separated plans for the two phases (Phase 1: first 30 fractions; Phase 2: last 9 fractions) were compared in terms of dose-volume histograms (DVH) and dose statistics on PTVs and OARs., Results: When considering Phase 1, Tomotherapy improved the homogeneity of the dose distribution within PTV1 while delivering the same prescribed dose (assessed to be the median dose to PTV): the fraction of PTV1 receiving more than 95% of the prescribed dose (V95%) increased from 90% (IMRT) to 96-97% for Tomotherapy plans. Dmax within PTV1 decreased from 60.3 Gy (IMRT) to 57.4 Gy (TOMO-a) and 58.7 Gy (TOMO-b). Spinal cord Dmax decreased from 31.6 Gy (IMRT) to 26.5 Gy (TOMO-a) and 24.6 Gy (TOMO-b). No attempts to further reduce spinal cord Dmax were done. Mean dose to the parotids decreased from 26.1 Gy (IMRT) to 25.1 Gy (TOMO-a) and 20.8 Gy (TOMO-b). Mandible was significantly better spared with Tomotherapy: mean dose decreased from 34.9 Gy (IMRT) to 34.0 Gy (TOMO-a) and 30.7 Gy (TOMO-b). When considering phase 2, the average gains (TOMO-b vs IMRT) were more modest and depended on the location of PTV2/PTV3., Conclusions: Preliminary findings obtained in a sequential approach for HNC suggest that Tomotherapy has the potential to significantly improve the therapeutic ratio with respect to a conventional IMRT delivery method.

Background and Purpose: To investigate the feasibility and the advantages of using Intensity-Modulated Radiotherapy (IMRT) for the treatment of head-and-neck cancer. Comparing different methods to deliver IMRT in this clinical setting., Materials and Methods: Seven patients (four radical; three post-operative), treated on a 6MV Varian Linac (equipped with an 80 leaves MLC) in accordance with a routine 3DCRT plan, were replanned. Original treatment plans were computed to irradiate a primary Planning Target Volume (PTV1, 54 Gy) and then to perform a boost on a PTV2 (radical: 70.2 Gy; post-operative: 64.8 Gy). IMRT dose plans were inversely-optimized using appropriate constraints with the Helios tool on a Varian Eclipse system. Once the optimal fluences were calculated, different modalities to deliver IMRT were considered: Sliding Window (SW) and Step and Shoot (SS) techniques using a different number of intensity levels to approximate the optimal fluences (e.g. 5, 10 and 20). Mean dose, maximum dose and a number of dose-volume parameters regarding CTV1, CTV2, PTV1, PTV2, OARs (spinal and planning spinal cord, parotids, optical structures, brain and temporal mandibular joint) were considered to compare the five modalities (3DCRT, SW, SS5, SS10, SS20); the Conformity Index (CI), the Irradiated Volume (IV) and the Treated Volume (TV) were also considered in the comparison., Results: A more uniform coverage of the PTV in the IMRT dose plans with respect to the 3DCRT plan was found (for PTV2: V90% = 94.3 for 3DCRT, 97.6 for SS5, 98 for SS10 and 98.1 for SW; V107% = 20.7 for 3DCRT, 5.9 for SS5, 2 for SS10 and 1.3 for SW). Concerning OARs, they all present a significant reduction of mean and/or maximum dose and dose-volume patterns assessed from DVHs: in particular the mean dose of parotids decrease on average of about 13.5Gy passing from 3DCRT to IMRT with an average reduction of NTCP ranging from about 20% to more than 40% for radically treated patients, depending on the chosen end-point. IV and TV are also slightly smaller with IMRT. The results obtained with SS techniques employing 10 or more intensity levels are comparable with those obtained with SW; no differences between SS10 and SW may be appreciated when considering the DVHs of PTV, CTV and OARs. On the other hand, in some cases SS5 may be slightly sub-effective with respect to SS10-SW when considering PTV coverage and Dmax of the spinal cord., Conclusions: With the Varian planning and delivery system, Step-and-shoot approximations of inversely optimised fluences in head-neck IMRT compare well with SW delivery, even with only five intensity levels. With a number of intensity level of 10 or more, no differences can be appreciated in PTV coverage/OAR sparing with respect to SW.