Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer

IntroductionWe hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). MethodsThe study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in >= 2 (WS2) or >= 3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. ResultsIn REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L center dot Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L center dot Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58, ConclusionIncreasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT

Litiasi biliare e renale in paziente con coinfezione HIV e HCV genotipo 4 in corso di terapia con daclatasvir/sofosbuvir + ribavirina e atazanavir/ritonavir + abacavir/lamivudina: caso clinico

ew Direct-acting Antiviral Agents (DAA)-based anti-HCV therapies currently provide extraordinary opportunities to cure patients. Drug-drug interactions are however a real challenge during treatment. In particular, in HIV-infected patients in cART, DAA choice is limited by such interactions, which can result both in reduced efficacy and toxicity. We report the case of a HIV-infected patient on cART with atazanavir/ritonavir/abacavir/lamivudine, who presented kidney and biliary lithiasis, the latter treated with endoscopic retrograde cholangiopancreatography and endoscopic biliary sphincterotomy, after beginning anti-HCV treatment with daclatasvir/sofosbuvir/ribavirin. Hyperbilirubinemia with or without jaundice is a well known side effect of atazanavir, because of its inhibition of uridine diphosphate-glucuronosyl transferase. We speculate that in this case hyperbilirubinemia worsening was due to atazanavir/ribavirin co-administration. However, pharmacokinetic data are lacking about atazanavir/daclatasvir concomitant administration in real life setting

Hepatitis B virus reactivation after effective sofosbuvir and ribavirin treatment in a patient with occult hepatitis B virus infection

Reactivation of the hepatitis B virus (HBV) has been reported in patients with occult infection (OBI), i.e. HBV surface antigen (HBsAg) negative, HBV core antibody (anti-HBc) positive ± antibodies against HBsAg (anti-HBs) and detectable HBV DNA in serum or liver, receiving immunosuppressive or cytotoxic therapies. Recently, concerns have been raised regarding the risk of HBV reactivation in OBI patients treated with direct acting antiviral agents (DAAs) for chronic hepatitis C (CHC). Here we describe a case of HBV reactivation in a 72-year-old woman with OBI as a possible consequence of effective treatment with sofosbuvir (SOF) and ribavirin (Rbv) for genotype 2a/2c CHC

Analisi del rischio clinico del percorso del paziente in un centro di radioterapia avanzata mediante metodologia F.M.E.A.

Starting from the increasing requirement of efficient access to healthcare, the study aims to assess the current standard procedures in order to optimize safety and quality.The decision to study the patient's process in Radiotherapy (RT) by FMEA methodology (Failure Mode and Effect Analysis), in order to identify and manage the risks for patients, arose from an interest of both the Radiotherapy Division and the Management of the European Institute of Oncology (IEO) IRCSS of Milan (Italy) in consideration of its high activity and of the volume of patients treated. The department has undergone a remarkable change in the last seven years, by increasing the number of accelerators and the number of patients treated, which rose from 2.197 (2011) to 3.194 (2017).Treatment modalities and timing of each session have changed: nowadays the majority of the patients receive highly complex treatments (intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic radiotherapy, etc.).PurposeThe purpose of this study is to define an instrument of practical use and maintenance, for the proactive management of clinical risk by analysing the patient’s care path in RT: from his medical examination to the discharge and the next follow-up visits.The instrument was tested by handing it out to employees in the form of a questionnaire, trying to involve a significant pool of professionals.Materials and methodsStarting from previous Institutional experiences of FMEA studies in other clinical areas, we decided to:make-up several multidisciplinary working groups (with one or two members of each professional level) in order to define the sub-processes, the failure mode and the impact of potential damage.propose the participation of radiotherapy professionals in defining the frequency of the failure mode in their experience, using questionnaires and scales of predefined values.To define the value "potential damage" and the attribution of the frequency of occurrence of the various failure modes, we sought to minimize a potentially non-voluntary effect of mitigating the risk due to the awareness of the correlations between frequency of occurrence and damage.Therefore, the professionals involved were not aware of the results.ResultsThe study was carried out with great participation from the professionals involved in the patient's path (88,6% of the staff involved in the study responded to the questionnaires administered in the first part of the study; 69,7% was the rate of participation in the second part). This result allowed to overcome the subjective limitations due to the low numerical representation and the lack of objective epidemiological data concerning the near miss. Forty-four criticalities were found (14% of all the failure) and required intervention planning.ConclusionThis work led to the definition of a model with analytical description and quantification of the clinical risk for all the failure modes by "Risk Priority Number" (RPN) of all the sub-processes of the patient's path. Starting from the significant result of the areas requiring intervention, we could identify several improvement actions to reduce clinical risk. The model allows a dynamic management of clinical risk linked to a specific process and it could be exported to other Radiotherapy Centers.Lo studio nasce dalla volontà di garantire costantemente elevati standard di sicurezza e qualità delle cure in uno scenario di incremento della domanda sanitaria che richiede, anche, mantenimento di processi produttivi efficienti.La decisione di studiare il processo del paziente in Radioterapia mediante la metodologia FMEA (Failure Mode and Effect Analysis) al fine di identificare e gestire i rischi per i pazienti è scaturita da un interesse della Divisione di Radioterapia e del Management dell’Istituto Europeo di Oncologia (IEO) IRCCS di Milano in considerazione degli alti volumi di attività: il reparto ha subito una notevole trasformazione nel corso degli ultimi sette anni, aumentando il numero di acceleratori ed il numero di pazienti trattati, passando da 2.197 (2011) a 3.194 (2017).Sono cambiate le modalità di terapia e le tempistiche di ogni seduta, infatti la maggior parte dei pazienti attuali riceve trattamenti di alta complessità (radioterapia a intensità modulata, radioterapia guidata dalle immagini, radioterapia stereotassica, etc.).Obiettivo dello studioLo scopo di questo lavoro è definire uno strumento di pratico utilizzo e manutenzione per la gestione proattiva del rischio clinico, mediante l’analisi dell’intero percorso radioterapico del paziente: dalla sua prima visita medica sino alla dimissione e successivi follow-up; e testarlo somministrandolo, sotto forma di questionario, ai dipendenti, cercando di coinvolgere rappresentanze numericamente significative di professionisti.Materiali e metodiFacendo tesoro di altre esperienze di studi FMEA già condotti in Istituto in altri ambiti, si è deciso di:costituire più gruppi di lavoro multidisciplinare (con uno o due componenti di ogni professione) al fine di definire i sotto-processi, i modi di errore e l’entità del danno potenziale.proporre a tutti i professionisti sanitari della radioterapia la partecipazione alla definizione della frequenza dei modi di errore nel loro vissuto, utilizzando questionari e scale di valori predefinite.Per la definizione del valore “danno” e l’attribuzione della frequenza ponderata di accadimento dei vari Failure mode si è voluto evitare l’effetto, potenzialmente involontario, di mitigazione del rischio dovuto alla presa di consapevolezza delle correlazioni tra frequenza di accadimento e danno.I professionisti coinvolti non erano a conoscenza dei risultati ottenuti.RisultatiLo studio è stato effettuato con una partecipazione ampia dei professionisti coinvolti nel percorso del paziente (88,6% del personale coinvolto nello studio ha risposto ai questionari somministrati nella prima parte dello studio; il 69,7%, invece, è stato il tasso di partecipazione nella seconda parte dello studio), consentendo quindi di superare i limiti soggettivi dovuti alla scarsa rappresentatività numerica dei professionisti solitamente coinvolti ed alla mancanza di dati statistici oggettivi sui near miss. Sono state individuate 44 criticità (14% di tutti i Failure studiati) che richiedono la pianificazione di intervento.ConclusioniIl lavoro ha portato alla definizione di un modello con analitica descrizione e quantificazione del rischio clinico per tutti i modi di errore mediante un “Risk Priority Number” (RPN) di tutti i sotto-processi del percorso del paziente, dal quale emerge che le aree di criticità che necessitano di un intervento sono ridotte. Sono state individuate diverse azioni di miglioramento per ridurre il rischio clinico. Il modello consente una gestione dinamica nel tempo del rischio clinico legato ad un determinato processo e trasferibile presso altre radioterapie

Clinical risk analysis of the patient’s path in an Advanced Radiotherapy Center (A.R.C.) through F.M.E.A. method

Starting from the increasing requirement of efficient access to healthcare, the study aims to assess the current standard procedures in order to optimize safety and quality.The decision to study the patient's process in Radiotherapy (RT) by FMEA methodology (Failure Mode and Effect Analysis), in order to identify and manage the risks for patients, arose from an interest of both the Radiotherapy Division and the Management of the European Institute of Oncology (IEO) IRCSS of Milan (Italy) in consideration of its high activity and of the volume of patients treated. The department has undergone a remarkable change in the last seven years, by increasing the number of accelerators and the number of patients treated, which rose from 2.197 (2011) to 3.194 (2017).Treatment modalities and timing of each session have changed: nowadays the majority of the patients receive highly complex treatments (intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic radiotherapy, etc.).PurposeThe purpose of this study is to define an instrument of practical use and maintenance, for the proactive management of clinical risk by analysing the patient’s care path in RT: from his medical examination to the discharge and the next follow-up visits.The instrument was tested by handing it out to employees in the form of a questionnaire, trying to involve a significant pool of professionals.Materials and methodsStarting from previous Institutional experiences of FMEA studies in other clinical areas, we decided to:make-up several multidisciplinary working groups (with one or two members of each professional level) in order to define the sub-processes, the failure mode and the impact of potential damage.propose the participation of radiotherapy professionals in defining the frequency of the failure mode in their experience, using questionnaires and scales of predefined values.To define the value "potential damage" and the attribution of the frequency of occurrence of the various failure modes, we sought to minimize a potentially non-voluntary effect of mitigating the risk due to the awareness of the correlations between frequency of occurrence and damage.Therefore, the professionals involved were not aware of the results.ResultsThe study was carried out with great participation from the professionals involved in the patient's path (88,6% of the staff involved in the study responded to the questionnaires administered in the first part of the study; 69,7% was the rate of participation in the second part). This result allowed to overcome the subjective limitations due to the low numerical representation and the lack of objective epidemiological data concerning the near miss. Forty-four criticalities were found (14% of all the failure) and required intervention planning.ConclusionThis work led to the definition of a model with analytical description and quantification of the clinical risk for all the failure modes by "Risk Priority Number" (RPN) of all the sub-processes of the patient's path. Starting from the significant result of the areas requiring intervention, we could identify several improvement actions to reduce clinical risk. The model allows a dynamic management of clinical risk linked to a specific process and it could be exported to other Radiotherapy Centers.Starting from the increasing requirement of efficient access to healthcare, the study aims to assess the current standard procedures in order to optimize safety and quality.The decision to study the patient's process in Radiotherapy (RT) by FMEA methodology (Failure Mode and Effect Analysis), in order to identify and manage the risks for patients, arose from an interest of both the Radiotherapy Division and the Management of the European Institute of Oncology (IEO) IRCSS of Milan (Italy) in consideration of its high activity and of the volume of patients treated. The department has undergone a remarkable change in the last seven years, by increasing the number of accelerators and the number of patients treated, which rose from 2.197 (2011) to 3.194 (2017).Treatment modalities and timing of each session have changed: nowadays the majority of the patients receive highly complex treatments (intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic radiotherapy, etc.).PurposeThe purpose of this study is to define an instrument of practical use and maintenance, for the proactive management of clinical risk by analysing the patient’s care path in RT: from his medical examination to the discharge and the next follow-up visits.The instrument was tested by handing it out to employees in the form of a questionnaire, trying to involve a significant pool of professionals.Materials and methodsStarting from previous Institutional experiences of FMEA studies in other clinical areas, we decided to:make-up several multidisciplinary working groups (with one or two members of each professional level) in order to define the sub-processes, the failure mode and the impact of potential damage.propose the participation of radiotherapy professionals in defining the frequency of the failure mode in their experience, using questionnaires and scales of predefined values.To define the value "potential damage" and the attribution of the frequency of occurrence of the various failure modes, we sought to minimize a potentially non-voluntary effect of mitigating the risk due to the awareness of the correlations between frequency of occurrence and damage.Therefore, the professionals involved were not aware of the results.ResultsThe study was carried out with great participation from the professionals involved in the patient's path (88,6% of the staff involved in the study responded to the questionnaires administered in the first part of the study; 69,7% was the rate of participation in the second part). This result allowed to overcome the subjective limitations due to the low numerical representation and the lack of objective epidemiological data concerning the near miss. Forty-four criticalities were found (14% of all the failure) and required intervention planning.ConclusionThis work led to the definition of a model with analytical description and quantification of the clinical risk for all the failure modes by "Risk Priority Number" (RPN) of all the sub-processes of the patient's path. Starting from the significant result of the areas requiring intervention, we could identify several improvement actions to reduce clinical risk. The model allows a dynamic management of clinical risk linked to a specific process and it could be exported to other Radiotherapy Centers

Cyberknife Radiosurgery for Prostate Cancer after Abdominoperineal Resection (CYRANO): The Combined Computer Tomography and Electromagnetic Navigation Guided Transperineal Fiducial Markers Implantation Technique

In this technical development report, we present the strategic placement of fiducial markers within the prostate under the guidance of computed tomography (CT) and electromagnetic navigation (EMN) for the delivery of ultra-hypofractionated cyberknife (CK) therapy in a patient with localized prostate cancer (PCa) who had previously undergone chemo-radiotherapy for rectal cancer and subsequent abdominoperineal resection due to local recurrence. The patient was positioned in a prone position with a pillow under the pelvis to facilitate access, and an electromagnetic fiducial marker was placed on the patient’s skin to establish a stable position. CT scans were performed to plan the procedure, mark virtual points, and simulate the needle trajectory using the navigation system. Local anesthesia was administered, and a 21G needle was used to place the fiducial markers according to the navigation system information. A confirmatory CT scan was obtained to ensure proper positioning. The implantation procedure was safe, without any acute side effects such as pain, hematuria, dysuria, or hematospermia. Our report highlights the ability to use EMN systems to virtually navigate within a pre-acquired imaging dataset in the interventional room, allowing for non-conventional approaches and potentially revolutionizing fiducial marker positioning, offering new perspectives for PCa treatment in selected cases

Intraoperative radiotherapy for locally advanced prostate cancer: The experience of the European institute of oncology

INTRODUCTION AND OBJECTIVE: To present the technique adopted for intraoperative radiotherapy (IORT) for locally advanced prostate cancer. METHODS: Between June 2005 and February 2007, 24 patients (pts) with non-metastatic prostate cancer were treated with IORT before prostatectomy as part of their surgical procedure. Median DJHZDV\HDUVUDQJH7HQSWVZHUHFODVVL\ubfHGDV 7FSWVDV\u9577KHPHGLDQL36$ZDVQJPODQGWKH median bioptic Gleason Score was 7. According to NCCN 2007, risk group distribution was as follows: intermediate risk 2 pts (8.33%) and high risk 22 pts (91.67%). A total of 11 pts (45.83%) were treated with neoadjuvant hormones. Immediately before IORT prostate dimensions and rectum depth were measured with intraoperative ultrasound. IORT was delivered by a mobile linear accelerator in the operating room. The prescribed dose was 12 Gy at the 90% isodose. In vivo dosimetry was performed. Three months later, postoperative external beam radiotherapy (EBRT) of 45-50,4 Gy in 25-28 fractions was prescribed to the prostatic bed alone and whole pelvis in case of pT3-4 pN0 and pN1, respectively. RESULTS: According to the MSKCC nomograms, the mean SUHRSHUDWLYHSUREDELOLW\RIRUJDQFRQ\ubfQHGGLVHDVHH[WUDFDSVXODUGLVHDVH and lymph node involvement were 8%, 40% and 25% respectively. 3RVWRSHUDWLYHKLVWRORJLFDO\ubfQGLQJVZHUHDVIROORZVPHGLDQ*6UDQJH 6-9), pT2 7 pts (29,2%), pT3 14 pts (58,3), pT4 3 (12,5%), pN0 12 pts, S1SWV2UJDQFRQ\ubfQHGGLVHDVHS7S15ZDVGLDJQRVHGLQ pts (16.6%) and no further radiation treatment was prescribed. Based RQWKHGH\ubfQLWLYHKLVWRORJLFDOUHSRUWVSRVWRSHUDWLYHSHOYLFDQGSURVWDWLF bed EBRT is planned in 12 and 8 pts, respectively. After a median follow up of 9.2 months (range 3.3-15.7) only 1 patient had evidence of biochemical relapse. No patients had major acute rectal toxicity. No acute urinary toxicity was observed in 6 patients, 17 patients had G1 toxicity. No increased risk of urinary incontinence was recorded. CONCLUSIONS: IORT delivered before prostatectomy appeared a feasible and safe approach for prostate cancer, showing a satisfactory dose coverage to the prostate bed with relatively low rectal wall dose. Longer follow-up is needed to evaluate late toxicity and clinical control

CyberKnife Ultra-Hypofractionated SBRT for Localized Prostate Cancer with Dose Escalation to the Dominant Intraprostatic Lesion: In Silico Planning Study

The aim is to evaluate the feasibility of ultra-hypofractionated (UH) SBRT with CyberKnife® (CK) radiosurgery (Accuray Inc., Sunnyvale, California, USA) for localized prostate cancer (PCa) with a concomitant focal boost to the dominant intraprostatic lesion (DIL). Patients with intermediate/high-risk PCa, with at least one visible DIL on multi-parametric MRI, were included. For each, two CK-SBRT in silico plans were calculated using 95% and 85% isodose lines (CK-95%, CK-85%) and compared with the UH-DWA plan delivered with VERO®. All plans simulated a SIB prescription of 40 Gy to PTV-DIL and 36.25 Gy to the whole prostate (PTV-prostate) in five fractions every other day. Fifteen patients were considered. All plans reached the primary planning goal (D95% > 95%) and compliance with organs at risk (OARs) constraints. DVH metrics median values increased (p < 0.05) from UH-DWA to CK-85%. The conformity index of PTV-DIL was 1.00 for all techniques, while for PTV-prostate was 0.978, 0.984, and 0.991 for UH-DWA, CK-95%, and CK-85%, respectively. The CK-85% plans were able to reach a maximum dose of 47 Gy to the DIL while respecting OARs constraints. CK-SBRT plus a focal boost to the DIL for localized PCa appears to be feasible. These encouraging dosimetric results are to be confirmed in upcoming clinical trials such as the phase-II “PRO-SPEED” IEO trial

Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper‐IgM syndrome

Abstract Precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) holds promise for treating X‐linked hyper‐IgM Syndrome (HIGM1), but its actual therapeutic potential remains elusive. Here, we developed a one‐size‐fits‐all editing strategy for effective T‐cell correction, selection, and depletion and investigated the therapeutic potential of T‐cell and HSPC therapies in the HIGM1 mouse model. Edited patients’ derived CD4 T cells restored physiologically regulated CD40L expression and contact‐dependent B‐cell helper function. Adoptive transfer of wild‐type T cells into conditioned HIGM1 mice rescued antigen‐specific IgG responses and protected mice from a disease‐relevant pathogen. We then obtained ~ 25% CD40LG editing in long‐term repopulating human HSPC. Transplanting such proportion of wild‐type HSPC in HIGM1 mice rescued immune functions similarly to T‐cell therapy. Overall, our findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T‐cell ahead of HSPC gene therapy because of easier translation, lower safety concerns and potentially comparable clinical benefits