Search

Background: Biliary tract cancer (BTC) encompasses a group of rare and heterogeneous malignancies with poor prognosis, including gallbladder cancer, ampulla of Vater cancer, intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma (eCCA), with the latter further subdivided into perihilar (pCCA) and distal (dCCA). Unfortunately, potentially curative surgical resection is possible in approximately the 25% of BTC patients at diagnosis, and even following radical surgery, relapse rates remain high. The aim of this research was to evaluate the impact of an intensive follow-up program in BTC patients who had received surgical resection with curative intent at a tertiary referral hospital. Methods: Medical records of all consecutive BTC patients treated with curative intent surgery at S. Orsola Malpighi Hospital, Bologna, Italy, from January 2000 to November 2020, were retrospectively reviewed. The BTC-specific overall survival (OS) and disease-free survival (DFS) status were determined by the Kaplan-Meier method; univariate and multivariate analysis were performed to assess the impact of covariates on survival. Results: A total of 398 BTC patients receiving surgery with curative intent were included in the analysis. Macroscopic residual tumor was observed in 29 patients, while 329 BTCs underwent R0 (n¼222; 67%) or R1 (n¼107; 33%) surgery. Among these, 278 patients started a follow-up program at our institution based on physical examination, serum CEA and CA19-9 and abdominal/chest CT scan every 3-4 months in the first two years and every 6 months from the third to the fifth year; 80% of this group (222/278) started follow-up after adjuvant chemotherapy (in case of R0 surgery) or chemoradiotherapy (in R1 resection). The median age of the follow-up group was 63 years (range 31-85 years) and 164 (49.5%) were females. Overall, 116 (32.5%) and 126 (38.6%) patients had iCCA and eCCA (78 pCCAs and 48 dCCAs), respectively. At a median follow-up of 37.4 months, median OS was 50.8 and 35 months in R0 and R1 patients, respectively (p¼0.04); similarly, median DFS was 16.4 and 12.3 months in the same groups (p¼0.02). No relapse was observed in 129 out of 329 BTCs (39%), while the 61% of R0/R1 patients (200/329) experienced disease relapse, including 39% of iCCA and 38% of eCCA; liver was the most frequent site of relapse (78%) followed by peritoneum and locoregional lymph nodes. In terms of treatment at the relapse, 15% (30/200) of patients underwent second surgery (R0¼14, R1¼6, R2¼3, exploratory laparotomy¼7) while 20% (40/200) received a locoregional approach, the most frequent of which was radiofrequency ablation (n¼22). None of the 14 BTC patients receiving second surgery with R0 experienced disease relapse. Overall, 127 BTCs received first-line chemotherapy following relapse, with gemcitabine-cisplatin as the most commonly used regimen (52%). Conclusions: Based on the results of our 20-year, single-center experience of 278 BTC patients, an intensive follow-up after surgical resection with curative intent could help in the identification of disease relapse, leading to early treatment and prolonged survival in selected cases, as reported in BTCs treated with second surgical resection with negative margins.

Biliary tract cancer (BTC) patients usually have poor prognosis. Whereas combination chemotherapy has been shown to improve survival in the frontline setting, second-line treatment is subject to a lot of debate in the scientific community. Recent data of the ABC-06 trial has provided slight evidence for the use of second-line chemotherapy after progression on cisplatin plus gemcitabine combination. In this study, mFOLFOX plus active symptom control (ASC) improved overall survival (OS) after progression on cisplatin-gemcitabine combination compared with ASC alone, with an increase in 6- and 12-month OS rate. Although genomic studies have paved the way for a new age in cancer management, the “Precision Medicine Era” in BTC is still limited to intrahepatic cholangiocarcinoma and primarily focused on isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) targeted therapies. We herein review recent published data regarding the use of second-line treatment after failure of standard first-line therapies in BTC patients, with a particular focus on ongoing active and recruiting clinical trials.

Background The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology. Design and Methods We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios. Results During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51-0.61) and 0.70 (95% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53-0.62) overall, and 1.08 (95% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women Conclusions Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood. ©2011 Ferrata Storti Foundation.

Hernia repair is the most common surgical procedure in general surgery in Italy and in the Lombardy region. In the last decade, the use of mesh, the concept of a tension-free technique, and the postoperative rate of recurrences after Bassini or Shouldice operations have completely changed the surgical approach to hernia repair. For this reason, we sent a questionnaire to 148 surgical departments in the Lombardy region to investigate about total hernia operations performed in 2000 in Lombardy, the surgical approach, the surgical techniques used, the type of anesthesia and the hospital stay. One hundred five out of 148 surgical departments returned the questionnaire, and we collected information on a total of 16,935 surgical operations for hernia: 16,494 were performed using tension-free techniques. The inguinal anterior approach is the one of choice for primary and recurrent inguinal hernia, whereas the open preperitoneal and laparoscopic approaches are limited to bilateral and recurrent hernias. The majority of cases were treated under locoregional anesthesia and with a hospital stay of two nights.

Dottorato di Ricerca in Ingegneria Idraulica per l’Ambiente e il Territorio, Ciclo XXV, a.a. 2012 Università degli Studi della Calabria

Soil erosion varies greally over space and neglecting information about estimation uncertainty may lead to inappropriate decision-making. One geostatistical approach to spatial analysis is joint stochastic simulation. Differences between the realilizations provide a measure of spatial uncertainty and allow to carry out an error propagation analysis. The objective of this study was lo assess the model output error of soil erodibility resulting from the uncertainties in the Input parameters. The study area (about 1.4 km2) was a forest watershed (South Italy). From superficial soil horizon 110 soil samples were collected and analyzed for soil texture and organic matter content. A Monle Carlo analysis was performed, which consisted of drawing a large number of identical1y distributed inputparameters from the multivariable joint probability distribution function. Spatial cross-correlation information was incorporated through joint turning bands simulation. A linear coregionalization model was fitted to all simple and cross- variograms of the input variables including a nugget effect and spherical structure with a range of 129 m. The erodibility model was estimated for each set of the 500 joint realizations of the input variables and the ensemb1e of the model outputs was used to infer the erodibility probability distribution function. thus providing a confidence interval at each simulated point. This approach has also allowed to delineate the areas characterized by greater uncertainty and then to suggest efficient strategies for funther improving the accuracy of soil erodibility value predictions, in the contest to identify potential erosion risk area with accuracy and precision.

Spatially distributed models coupled with Geographic Information System allow to identify areas sensitive or susceptible of soil loss.The objective of this study was mapping areas more prone to soil erosion in a forest catchment using the Revised Universal Soil Loss Equation. Patterns of spatial variability of RUSLE parameters were evaluated through geostatistical methods. The study area (about 1.4 km2) was a forest watershed (South Italy). To calculate the soil erodibility factor (K), 110 soil samples were collected from superficial pedological horizon and were analyzed for soil texture and organic matter content. Three raingauges, located inside the watershed, were used to compute the rainfall-runoff erosivity factor (R). Coupling a geostatistical approach with a spatial distributed model in a GIS, produced a good representation of the erosion process. The annual soil loss was in accordance with field measurements and other studies carried out using different approaches

Gli Aulori analizzano il rilascio di nutrienti nelle acque di deflusso in un piccolo bacino sperimentale, quota medio 1131 ms.l.m., ubicoto nella Sila Greca Cosentino in Calabria. IL bacino boscato per circa il 95% dello superficie e privo di insediamenti umani stabili, è attrezzoto sin dal 1986 per il monitoraggio dei processi idrologici. Lo memoria, quindi, può fornire un contributo sperimentale per lo comprensione dei processi che determinano lo qualità delle acque superficiali in assenza di sorgenti puntuali antropiche.

The objective of this paper is to spread a optimized statistical sampling distribution in a representative river basin to evaluate the soil parameters in researching activities. The proposed approach was applied to starting two researching activities about interrill and rill soil erosion. In both researches is needed an optimized sampling distribution, which minimizes the spatial uncertainty in soil proprieties mapping to have a soil characteristic map which is the most accurate feasible. The sampling procedure uses an algorithm named Spatial Simulated Annealing (SSA) that was designed for optimization of spatial sampling schemes. This is done by minimizing the expectation of the distance between an arbitrarily chosen location, and its nearest observation point. This criterion is named Minimization of the Mean of the Shortest Distances. The elaboration was done using a Van Groenigen and Stein application named SANOS, using the sampling field GRID file and the list of the geographic coordinate of the first 55 samples points used as earlier observations. The result consist of 110 samples points to locate on the landscape. This sampling distribution will have advantages in accuracy of final soil properties mapping.

Gli Autori analizzano il ruolo della copertura forestale nei processi idrici e nell'apporto areale di alcune sostanze (N-NH4,N-NO3,P-PO4,S-SO4,Cl nonchè Ph e conducibilità) In popolamenti di pino lurido (Pinus larricio ssp calabrica) a diversa densità in un bacino campione in Calabria ncll. nella Sila Greca Cosentina appositamente attrezzato dal 1986.I risultati ottenuti evidenziano che a livello quantitativo gli interventi selvicolturali non modificano, anche a distanza di dieci anni dal diradamento, l'entità del'intercettazione.L'indagine ha permesso di ottenere le concentrazioni delle sostanze presenti nelle deposizioni atmosferiche nelle diverse situazioni, a ciclo aperto(soprachioma, throughfall,stemflow e di evidenziare il ruolo svolto dalla vegetazione quale fattore di cambiamento del contenuto di soluti in soluzione acquosa.I risultati ottenuti, nelle diverse situazioni considerate, consentono di confermare l'efficacia del bosco nei confronti del miglioramentodelle caratteristiche chimiche delle precipitazioni, riducendo quindi il rischio di contaminazione delle acque superficiali e profonde da nitrati.Si può altresì valutare positivamente l'influenza dei diradamenti sulla gestione delle risorse idriche in ambiente mediterraneo.

L'indagine iniziata nel 1995, tutt'ora in corso ha prodotto un numero elevato di informazioni sulla chimica delle deposizioni e sulle condizioni meteorologiche e climatiche dalle quali sono influenzate.Sono state attrezzate, nel corso degli anni numerose stazioni di misura sia per il controllo delle deposizioni(bulk)sia per valutare il bilancio complessivo delle quantità sottratte o apportate dalle piante e quelle perse per il deflusso superficiale. Nel presente lavorosono riportati i risultati relativi alla valle del Fiume Crati in Calabria, dove sono operanti due siti posti in area collinare in località Settimo di Mintalto Uffugo,con soprasuolo misto di ceduo composto a roverella(Q. pubescens Wild.) Farnetto (Q.Farnetto Ten) e ceduo matricinato.Sui campioni prelevati al termine di ogni evento piovoso sono state effettuate in laboratorio le determinazioni chimiche. Oltre alla valutazione qualitativa si è effettuata anche l'analisi della evoluzione quantitativa che le precipitazioni subiscono quando giungono a contatto con i soprasuoli boscati a latifoglie con diversa età e densità e quando invece giungono direttamente al suolo,mettendo in evidenza l'effetto della vegetazionesulla correzione dell'acidità e sulla trasformazione dell'azoto. L'analisi dei dati termometrici ha evidenziato come nella Valle del Fiume Crati si istaurino condizioni meteorologiche di stabilità (inversione termica).Tale fenomeno influenza oltre che la chimica delle deposizioni anche l'attività vegetativa (termoperiodismo) e in particolare la fioritura a diverse quote lungo una sezione (Est-Ovest) della Valle.

Nel presente lavoro sono analizzate alcune sostanze presenti nelle precipitazioni atmosferiche, quale fonte non puntuale d'inquinamento, e l'evoluzione quantitativa che subiscono quando giungono a contatto con soprassuoli boscati a latifoglie con diversa età e densità e quando invece giungono direttamente sul suolo. L'indagine condotta per quattro anni (1995-1998) in due stazioni appositamente attrezzate della valle del F. Crati in Calabria ha permesso di ottenere le concentrazioni e gli apporti per unità di superficie delle sostanze presenti nelle deposizioni (radicali acidi d'azoto e zolfo, cloruri, sodio, magnesio e calcio nonché pH, conducibilità elettrica) nelle diverse situazioni analizzate. E' stato valutato nel bilancio complessivo la quantità sottratta o apportata dalle piante e quella persa per deflusso superficiale. Sono state inoltre ricercate le relazioni esistenti tra alcune sostanze analizzate.

La città di Cosenza, posta storicamentc all'inizio della valle del fiume Crati in particolare alla confluenza tra il F. Crati c F. Busento, a partire dai primi anni del 1900, è uscita da detti confini fisici e iniziato ad estendersi lungo la valle secondo la direttrice Sud-Nord.La situazione orografica determina uno scarso ricambio di aria nella valle e quindi l'instaurarsi di condizioni di stabilità atmosferica e in particolare di inversione termica i cui limiti variabili durante l'arco dell'anno, sono nettamente individuabili cd interessano l'intera area urbana. L'analisi dei dati termometrici rilevati su numerose stazioni nel periodo 1996-1998 ha consentito di determinare come la valle sia caratterizzata mediamente da uno strato atmosferico a stabilità debole e quindi di inversione.Gli inquinanti gassosi prodotti dalle attività antropiche e intrappolati nella valle determinano la presenza di deposizioni di inquinanti secondari prodotti nella troposfera e l'insorgenza periodica di precipitazione a carattere acido. Durante la sperimentazione si sono registrati nel periodo autunno-inverno degli eventi acidi Durante tali eventi le concentrazioni medie di N-NO in tutte le stazioni presentano un andamento lineare con la quota: ciò dimostra come le condizioni di stabilità atmosferiche abbiano influenza sulla· formazione e diffusione di questo composto.

OBJECTIVES: This study describes up-to-date cancer incidence and survival in Italian paediatric and adolescent patients, based on data collected by the network of Italian cancer registries (AIRTUM). It updates the monograph published on the same topic in 2008. The main objective of this monograph is to present the statistics according to standard rigorous epidemiological methods and disseminate them to a wide range of readers, including the lay public. Given the deep impact of the 2008 monograph on the general public, in this update we complement descriptive statistics with additional data and commentaries on issues of importance for public health, in order to provide unambiguous criteria on how to interpret the statistics. The study is the result of the collaboration between AIRTUM and AIEOP (Italian Association of Paediatric Haematology and Oncology) with contributions from interested parties, including representatives of parent associations. The monograph is divided into three parts. The first part presents incidence rates, survival probabilities, and time trends, by sex, age, geographical area, and cancer site or type, by means of tables and graphs as in the previous monograph, to facilitate direct comparisons. Four articles summarize and comment the results. The second part uses data from AIRTUM and AIEOP to outline patient management and health care issues; it includes estimates of the number of new cases in the next decade and of young adults living after a paediatric cancer diagnosis. Health organizational aspects of treatment services for paediatric patients, based on the AIEOP database, are also discussed, along with long-term complications in cured patients. The third section describes the changes in mortality trends due to improving therapies and healthcare services, and discusses risk factors and prevention of childhood cancer, late adverse events in cured patients, and other related issues. MATERIAL AND METHODS: Data herein presented were provided by AIRTUM population-based cancer registries, covering 47%of the Italian population below age 20 years, in the period 2003-2008. Quality of cancer registration in Italy is elevated, with high proportions of microscopically verified diagnoses (91%in the 0-14 years age group and 96% between 15 and 19 years of age) and a very small proportion of cases collected through death certificate only (0.1%).The proportion of cases in diagnostic groups XI (other malignant epithelial neoplasms) and XII (other and unspecified neoplasms) of the International Classification for Childhood Cancer (ICCC), based on the third revision of the International Classification of Diseases for Oncology (ICD-O-3), were 7.0% in the 0-14 years age group and 26.0%in the 15-19 years age group.The ratio between mortality and incidence was 17.7% in both children and adolescents. Detailed results are presented in 24 fact sheets for the 12 major ICCC-3 diagnostic groups and 10 sub-groups of special interest; the series is completed by a sheet on all malignant tumours and one on all tumours including non-malignant neoplasms of the central nervous system. All sheets include results for three age groups (0-14, 15-19, and 0-19 years) and are followed by two commentaries on incidence in the recent period, one on trends and the other on survival. Incidence rates were age-standardized on the European population and presented per million children. Incidence rates are also presented by age group, sex, and geographical area. Incidence trends were evaluated for two periods, 1988-2008 and 1998-2008, using estimated annual percent changes, and survival estimates were calculated by age and period. Indicators and corresponding 95% confidence intervals are shown in forms of graphics and tables at the end of the monograph and online at http://www.registri-tumori.it. Geographical analyses were conducted rearranging cancer registries into four macroareas (North-West, North-East, Centre, and South and Islands). Age groups were the same used in descriptive studies on children worldwide (0, 1-4, 5-9, 10- 14 years for paediatric tumours and 15-19 years for adolescents). Incidence trend analyses included cancer registries with three or more years of registration in the 5-year period, using Poisson regression models. Observed survival was computed according to the Kaplan-Meier method. The estimate of expected cases in the next decade was based on observed incidence rates in the most recent period, extended to the Italian estimated population of children and adolescents in the periods 2011-2015 and 2016-2020. The AIEOP database (Modello 1.01) allowed us to compare the number of patients treated and followed-up in specialized centres with expected cases based on AIRTUM estimates. The AIEOP database also provided information regarding health care migration throughout Italian regions and the number of foreign (immigrated) children treated in Italian AIEOP centres. RESULTS: In the period 2003-2008, 31 cancer registries reported 4,473 incident malignant neoplasms, 2,855 in children and 1,618 in adolescents. Cancer incidence rates were 164 cases per million in children aged 14 years or below and 269 cases per million in patients aged 15-19 years. Limited geographical variations emerged. In children (0-14 years) a significant increase in malignant cancer incidence was observed until 1997 (APC: +3.2%), followed by a plateau (APC: -1.1%not statistically significant).Until the late Nineties, a statistically significant increase was also observed in the incidence of all leukaemias in males (APC: +5.7%), lymphoid leukaemias (APC: +5.6%), representing 80% of all leukaemias, Hodgkin and non- Hodgkin lymphomas (APC: +6.3%). A significant decrease emerged for lymphoid leukaemia starting in 1995 (APC: -1.9%), while no substantial change in cancer incidence rates was observed in the last decade of observation for all malignant neoplasms and lymphomas. In addition, no variation emerged for malignant (according to the most recent classification) central nervous system (CNS) neoplasms, while an annual increase of 1.8% (significant) was observed in the period 1988-2008, when non-malignant tumours were included. Increases in cancer incidence were observed throughout the study period for neuroblastoma (APC: +1.9%) and epithelial tumours or melanoma (APC: +4.1%). In the period 1998-2008, in addition to lymphoid leukaemias, a significant decrease was observed for all malignant neoplasms, lymphomas in girls, CNS tumours (males and females), and renal tumours in girls, while no increases were observed in this age group. In adolescents (15-19 years) between 1988 and 2008, a significant increase in incidence rates was observed (APC: +2.0%) for all malignant neoplasms, all lymphomas (APC: +2.9%; in particular Hodgkin lymphoma, APC: +3.6%), thyroid cancer (APC: +6.1%), and melanoma (APC: +8.1%). Conversely, lymphoid leukaemia is the only neoplasm showing a long-term decrease in adolescents. Recent trends (1998-2008) confirm the long-term increases only for all malignant neoplasms in girls and thyroid cancer (APC: +7.9%, boys and girls), while a decrease in bone tumour incidence emerged in girls, albeit based only on 46 cases. Cancer mortality in children showed a persistent decrease for all neoplasms and even for more frequent cancer sites or types, and mortality rates for cancer were three-fold higher in the early Seventies than in 2008. In addition, five-year survival after cancer diagnosis increased in the last three decades and was still increasing in the period 2003- 2008, reaching 82% in children and 86% in adolescents. In the period 2008-2010, 4,488 children (0-14 years) were treated in one of the AIEOP clinical centres and we estimate, based on the above-presented incidence rates, that they represented 92% of all cancer cases in Italy. However, in adolescents, the proportion of patients treated in AIEOP centres was only 25%. A migration of patients living in the South of Italy to Central and Northern Italy emerged from AIEOP information. The expected number of cancer cases in children aged between 0 and 14 years of age is approximately 7,000 in the period 2016- 2020, while the corresponding figure for adolescents between 15 and 19 years of age is 4,000, with no relevant variation in comparison with the previous five-year period. COMMENTS: The present findings update descriptive cancer epidemiology in children and adolescents in Italy based on data provided by an extensive network of general and specialized population-based cancer registries. Data obtained from cancer registries are supplemented by additional information collected by specialized clinical AIEOP centres and mortality reports collected by the National Institute of Statistics (ISTAT). Incidence rates reported in Italy were slightly higher in comparison to other developed Countries, but relatively consistent between different Italian areas. Our results also showed that the significant increase in cancer incidence observed until the end of Nineties has halted, with the exception solely of thyroid cancer in adolescents. Efficacy of therapeutic protocols has improved constantly since the Seventies, and recent findings confirm this trend in all age groups and, in particular, for rarer tumours and cancer types that have very poor prognosis. Findings derived from cross-analysis with AIEOP data suggest that it is possible to further improve the efficiency of our healthcare system, in particular for adolescents; migration can be reduced with a more rational use of hospitals throughout Italy.

Objectives: Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. Kaplan–Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables. Results: Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3–4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p

Introduction: Biliary tract cancers (BTCs) include four uncommon primary biliary malignancies characterized by poor prognosis: intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. To date, the available therapeutic options are limited; nevertheless, with the advent of targeted therapy and immunotherapy, the treatment scenario is constantly changing, opening toward future possibilities for the personalized treatment of BTC. Among these treatments, nivolumab is currently being investigated in BTC. Areas covered: This review provides a comprehensive overview of the recent progress and future perspectives of immunotherapy for the treatment of BTC, with a particular focus on nivolumab, which has demonstrated its effectiveness in many malignancies and is in its initial phase of evaluation in BTC. Expert opinion: BTCs are not among those tumors that demonstrated remarkable sensitivity to immunotherapy, such as melanoma or non-small-cell lung cancer. However, the results obtained with nivolumab are not disappointing if we analyze the population of the trials testing its efficacy, including pretreated patients, unselected for PD-L1 expression and with different BTCs. In our opinion, ICIs such as nivolumab could fill an empty spot in the treatment of selected BTC patients, especially in combination with other agents, and the results of ongoing clinical trials are awaited.

The administration of approved systemic treatments for advanced hepatocellular carcinoma (HCC) is limited to patients with preserved liver function (Child-Pugh A/B7) and performance status. Conversely, metronomic chemotherapy can be safely administered to patients with poor clinical conditions and severe liver impairment. The metronomic schedule demonstrated to exert different anticancer mechanisms compared to that of the same agent administered at its standard schedule, including immune stimulation and the inhibition of angiogenesis and vasculogenesis. Nevertheless, metronomic chemotherapy is a nearly neglected option for the treatment of advanced HCC patients, even among those who cannot afford standard treatments. Herein, we report the case of a 40-year-old patient affected by HBV-HDV-related cirrhosis who was diagnosed with advanced HCC. The severe liver impairment (Child-Pugh B9) did not allow to administer first-line treatment with tyrosine kinase inhibitors so that the patient received metronomic capecitabine as upfront therapy. Due to the suspect of progressive disease at the first radiologic assessment, metronomic cyclophosphamide was added to capecitabine aiming to enhance its efficacy. After 4 months of treatment, complete tumor response, alpha-fetoprotein (AFP) normalization and the recovery of a Child-Pugh A were achieved. The patient was then able to undergo liver transplantation, and, after 18 months from the diagnosis, he is still free of disease recurrence. This experience emphasizes the reliability of metronomic capecitabine as a well-tolerated and effective treatment when patient's conditions prevent the administration of standard first-line treatments. In fact, metronomic capecitabine demonstrated its effectiveness in advanced HCC in retrospective and prospective analyses, leading to median progression-free survival and overall survival of, respectively, 6.03 and 14.47 months in phase II single-arm trial. Moreover, in consideration of the raising interest in immune-checkpoint inhibition in HCC, we believe that the immunomodulating effects of metronomic chemotherapy, either capecitabine or cyclophosphamide, warrant future trials exploring its combination with immunotherapy.

The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.