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Intestinal epithelium renewal strictly depends on fine regulation between cell proliferation, differentiation, and apoptosis. While murine intestinal microbiota has been shown to modify some epithelial cell kinetics parameters, less is known about the role of the human intestinal microbiota. Here, we investigated the rate of intestinal cell proliferation in C3H/HeN germ-free mice associated with human flora (HFA, n = 8), and in germ-free (n = 15) and holoxenic mice (n = 16). One hour before sacrifice, all mice were intraperitoneally inoculated with 5-bromodeoxyuridine (BrdU), and the number of BrdU-positive cells/total cells (labelling index, LI), both in the jejunum and the colon, was evaluated by immunohistochemistry. Samples were also observed by scanning electron microscopy (SEM). Moreover, the microbiota composition in the large bowel of the HFA mice was compared to that of of human donor's fecal sample. No differences in LI were found in the small bowels of the HFA, holoxenic, and germ-free mice. Conversely, the LI in the large bowel of the HFA mice was significantly higher than that in the germ-free and holoxenic counterparts (p = 0.017 and p = 0.048, respectively). In the holoxenic and HFA mice, the SEM analysis disclosed different types of bacteria in close contact with the intestinal epithelium. Finally, the colonic microbiota composition of the HFA mice widely overlapped with that of the human donor in terms of dominant populations, although Bifidobacteria and Lactobacilli disappeared. Despite the small sample size analyzed in this study, these preliminary findings suggest that human intestinal microbiota may promote a high proliferation rate of colonic mucosa. In light of the well-known role of uncontrolled proliferation in colorectal carcinogenesis, these results may deserve further investigation in a larger population study. [ABSTRACT FROM AUTHOR]

FGFR inhibitors have been developed to inhibit FGFR activation and signal transduction; notwithstanding, currently the selection of intrahepatic cholangiocarcinoma (iCCA) patients for these drugs only relies on the detection of FGFR2 genetic alterations (GAs) in tumor tissues or circulating tumor DNAs, without concomitant assessment of FGFR2 signalling status. Accordingly, we performed multi-omic analyses of FGFR2 genes and FGFR2 signalling molecules in the tissue samples from 36 iCCA naïve patients. Gain-of-function FGFR2 GAs were detected in 7 patients, including missense mutations (n = 3; p.F276C, p.C382R and p.Y375C), translocations (n = 1) and copy number gain (n = 4; CNV ≥ 4). In contrast, among 29 patients with wild-type FGFR2, 4 cases showed activation of FGFR2 signalling, as they expressed the FGFR2 ligand FGF10 and phosphorylated FGFR2/FRS2α proteins; the remaining 25 cases resulted negative for activated FGFR2 signalling, as they lacked FGFR2 (n = 8) or phosphorylated FRS2α (n = 17) expression. Overall, we found that activation of FGFR2 signalling occurs not only in iCCA naïve patients with FGFR2 GAs, but also in a subgroup carrying wild-type FGFR2. This last finding entails that also this setting of patients could benefit from FGFR targeted therapies, widening indication of these drugs for iCCA patients beyond current approval. Future clinical studies are therefore encouraged to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Recent next-generation sequencing (NGS) studies on large cohorts of cholangiocarcinoma (CCA) patients have clearly revealed the extreme intra- and inter-tumoral molecular heterogeneity that characterizes this malignancy. The lack of a stereotyped molecular signature in CCA makes the identification of actionable therapeutic targets challenging, making it mandatory to have a better understanding of the origin of such heterogeneity in order to improve the clinical outcome of these patients. Compelling evidence has shown that the CCA genomic landscape significantly differs according to anatomical subtypes and the underlying etiology, highlighting the importance of conducting molecular studies in different populations of CCA patients. Currently, some risk factors have been recognized in CCA development, while others are emerging from recent epidemiological studies. Nevertheless, the role of each etiologic factor in driving CCA genetic heterogeneity still remains unclear, and available studies are limited. In an attempt to shed more light on this issue, here we review the current literature data on the mutational spectrum of this disease according to different etiologies. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of cholangiocarinoma (CCA), as well as the related mortality rate, has progressively increased over the last decades. Nevertheless improvement in patient management, diagnosis and therapies, recurrence rate remains high (50–70%) with a low 5-year survival (7–20%). Palliative chemotherapy and best supportive care are the treatment of choice in case of recurrence. In recent years, some reports have been published on repeated resection suggesting a survival benefit. The aim of this study was to evaluate the long-term outcome of all repeated resections for recurrent CCA in our institution. Materials and methods: We performed a retrospective analysis of all data recorded in our prospective maintained database of all patients who underwent repeated resection for recurrence of any type of CCA (intrahepatic, perihilar, distal, and gallbladder) with curative intent in our institution. Results: Between 1997 and 2017, twenty-six patients underwent repeated surgical resection for recurrent CCA. Median time to first recurrence was 20 months. Site of recurrence was liver in 18 patients (70%), lymph nodes in 6 (23%), and lungs in 2 (7%). Twenty-five patients (96%) underwent upfront surgical resection of the recurrence, while one received preoperative chemotherapy. Median overall and disease-free survival from repeated surgical resection was 21 and 18 months with a 1-, 3-, and 5-year survival of 87, 41, 29% and 75%, 27%, and 17% respectively. Five patients (21%) did not experience recurrence after repeated surgical resection after a median follow-up of 73 months. Conclusions: Repeated surgical resection of recurrent CCAs is feasible with good postoperative results and can lead to an increase in survival. [ABSTRACT FROM AUTHOR]

Systemic treatments have traditionally reported limited efficacy for biliary tract cancer (BTC), and although targeted therapies and immune checkpoint inhibitors have been found to play an increasingly important role in treatment, several questions remain unanswered, including the identification of biomarkers of response. The tumor microenvironment (TME) has recently attracted the attention of the BTC medical community, and is currently being studied due to its potential role in modulating response and resistance to systemic therapies, including immunotherapy. In this perspective article, we discuss available evidence regarding the interplay between TME, IDH inhibitors, and immunotherapy, providing rationale for the design of future clinical trials. [ABSTRACT FROM AUTHOR]

Clinical practice guidelines for the management of cholangiocarcinoma (CCA)/biliary tract cancer recommend genomic profiling to guide treatment decisions. Variable access to such profiling across Italy means many oncologists are unfamiliar with when and how to conduct genetic testing and prescribe targeted treatments. A Scientific Board of Italian oncologists who treat CCA (the authors) developed recommendations, based on recent clinical evidence, for using molecular testing in diagnosing, assessing, and treating CCA in Italy. The Delphi process was used to reach consensus on these recommendations among 38 Italian oncologists. Consensus was considered to be met if ≥ 66.7 % of the panel agreed or strongly agreed with each statement. Consensus was reached on 28 statements across four themes: (1) epidemiology and risk factors; (2) diagnosis, including molecular diagnosis; (3) treatment selection; and (4) treatment safety. These recommendations should aid Italian clinicians in selecting appropriate treatment options for their patients. [Display omitted] • Familiarity with genomic profiling for CCA varies in Italian oncologists. • Next-generation sequencing should be used for profiling at diagnosis in CCA. • Cisplatin+gemcitabine+durvalumab is considered a 1st-line therapy for advanced CCA. • Targetable gene alterations should guide 2nd-line therapy; if absent, use FOLFOX. • Ocular and cardiac toxicities should be monitored if using FGFR2 or IDH1 inhibitors. [ABSTRACT FROM AUTHOR]

Very few data are available in literature about the role of radiofrequency ablation (RFA) in intrahepatic cholangiocarcinoma (ICC) and previous studies are mainly case reports and case series on a very small number of patients and nodules. In this study, we aimed to evaluate effectiveness and safety of RFA for the treatment of unresectable ICC. This is a retrospective observational cohort study comprising all consecutive patients treated with RFA for unresectable ICC at Policlinico Sant’Orsola Malpighi Hospital, Bologna, Italy. Primary endpoint was Local Tumor Progression-Free Survival (LTPFS) while Overall Survival (OS) was also assessed as secondary endpoint. From January 2014 to June 2019, 29 patients with 117 nodules underwent RFA. Technique effectiveness 1 month after RFA was 92.3%; median LTPFS was 9.27 months. Univariate analysis and multivariate analysis showed that LTPFS was significantly related to tumor size ≥20 mm. At a median follow up of 39.9 months, median OS from the date of RFA was 27.5 months, with an OS of 89%, 45% and 11% at 1, 2 and 4 years, respectively. Number of overall lesions and the sum of their diameter at the moment of the first RFA significantly affected OS in multivariate analysis. Minor and major complication rates were 14% and 7%, respectively. Tumor size ≥20 mm was associated with lower LTPFS, representing a potential useful threshold value. A careful evaluation of tumor burden appears as a crucial element in choosing the best therapeutic strategy in unresectable ICC. [ABSTRACT FROM AUTHOR]

Purpose: Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC).Methods: 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed.Results: Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation.Conclusions: MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Clearly identifiable risk factors are lacking in up to 30% of HCC patients and most of these cases are attributed to non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Beyond the known risk factors for NAFLD, the intestinal microbiota, in particular dysbiosis (defined as any change in the composition of the microbiota commonly found in healthy conditions) is emerging as a new factor promoting the development of chronic liver diseases and HCC. Intestinal microbes produce a large array of bioactive molecules from mainly dietary compounds, establishing an intense microbiota-host transgenomic metabolism with a major impact on physiological and pathological conditions. A better knowledge of these 'new' pathways could help unravel the pathogenesis of HCC in NAFLD to devise new prevention strategies. Currently unsettled issues include the relative role of a 'negative microbiota' (in addition to the other known risk factors for NASH) and the putative prevention of NAFLD through modulation of the gut microbiota. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) has recently emerged as a disease entity with actionable molecular targets, broadening the therapeutic options and helping to improve clinical outcomes beyond the limited available standard-of-care treatment.[1] In I JCO Precision Oncology i , Gile et al[2] report the results of a cohort study of patients with CCA treated at the Mayo Clinic Enterprise with fibroblast growth factor receptor (FGFR) inhibitors. Third, the trial included a widely varying patient population from a single institution in the United States, something that limits the generalizability of the results reported by Gile et al. The authors included 61 patients with known FGFR alterations, highlighting a median progression-free survival on FGFR inhibitors of 5.8 months (95% CI, 4.9 to 9.0). [Extracted from the article]

Background: The human stomach, when healthy, is not a suitable host for microorganisms, but in pathological conditions such as gastritis, when gastric acid secretion is impaired, microbial overgrowth can be observed. Apart from Helicobacter pylori, the composition of microbiota, resident or exogenously introduced during neutral/high pH conditions, has not been investigated thoroughly. Thus, it is possible that Bifidobacteriaceae, important autochthonous and beneficial bacteria of human gastrointestinal microbiota, could over-colonize the stomach of hypochlorhydria patients suffering from autoimmune atrophic gastritis (AAG) or omeprazoletreated (OME) gastritis. This prompted us to characterize the Bifidobacteriaceae in such patients' gastric microbiota and to study its abnormal colonization. Methods: Samples of gastric juices, and antrum and corpus mucosa from 23 hypochlorhydria patients (13 AAG and 10 OME) and from 10 control volunteers with base-line normochlorhydria, were cultivated in Brain Heart Infusion (BHI) and selective Bifidobacterium-Tryptone-Phytone-Yeast extract (Bif-TPY) media. The isolates were characterized by the fructose-6-phosphate phosphoketolase (F6PPK) test, electrophoresis of cellular proteins, the fermentation test, guanine-cytosine% DNA content, and DNA-DNA hybridization. Negative F6PPK isolates were characterized by order-specific polymerase chain reaction (PCR). Results: A total of 125 isolates, assigned to the Bifidobacteriaceae family on the basis of their morphology, were obtained from AAG and OME patients, but not from normal subjects. Of these isolates, 55 were assigned to the Bifidobacteriaceae family on the basis of their fructose-6-phosphoketolase (PPK) activity, PPK being the key taxonomic enzyme of this family. The remaining 70 isolates, which were PPK-negative, were attributed to the Actinomycetales order following specific primer PCR analysis. We observed a significantly higher abundance of Bifidobacteriaceae (Bifidobacterium dentium, Scardovia inopinata, and Parascardovia denticolens) in OME group than the AAG group. Furthermore, the Actinomycetales distribution was homogeneous for both hypochlorhydria patient groups. Conclusions: This study suggests that the Bifidobacteriaceae species, typically found in the oral cavity, readily colonizes the hypochlorhydria stomach of OME patients. The clinical relevance and the mechanism underlying this Bifidobacteriaceae presence in OME gastritis requires further functional studies. [ABSTRACT FROM AUTHOR]

Research conducted during the past 30 years has increased our understanding of the mechanisms involved in colorectal cancer initiation and development. The findings have demonstrated the existence of at least three pathways: chromosomal instability, microsatellite instability and CpG island methylator phenotype. Importantly, new studies have shown that inflammation and microRNAs contribute to colorectal carcinogenesis. Recent data have demonstrated that several genetic and epigenetic changes are important in determining patient prognosis and survival. Furthermore, some of these mechanisms are related to patients' response to drugs, such as aspirin, which could be used for both chemoprevention and treatment in specific settings. Thus, in the near future, we could be able to predict disease behavior based on molecular markers found on tumors, and direct the best treatment options for patients. [ABSTRACT FROM AUTHOR]

Background Sorafenib is the standard treatment of advanced hepatocarcinoma ( HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase ( TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. Aims The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. Methods We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Results Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy ( HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Conclusions Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients. [ABSTRACT FROM AUTHOR]

Purpose: Limited data suggest that second resections for colorectal cancer metastases may improve survival, but no study has compared surgery with chemotherapy in this setting. Therefore, we retrospectively compared the clinical outcome of potentially resectable patients who received a second metastasectomy with those who did not in our single-centre experience. Methods: We retrospectively reviewed the clinical records of all patients treated for metastatic colorectal cancer in our centre over a period of 12 years. We selected patients who relapsed after radical resection of metastases from colorectal cancer and were deemed resectable again by our multidisciplinary team. We then compared the clinical outcome of those who received a second operation with those who refused surgery and also evaluated the role of prognostic factors. Results: We identified 60 patients fulfilling the inclusion criteria. Twenty-nine underwent a second resection and 31 refused surgery. Median overall survival rates were 58.7 and 24.0 months, median times to progression were 14.4 and 6.6 months. Patients who received surgery plus perioperatory chemotherapy (18/29) had a significantly better outcome; 4/29 achieved long-term disease-free survival. Conclusions: Our study suggests that in highly selected metastatic colorectal cancer patients, a multimodal treatment plan, including a second resection, can achieve longer survival with respect to medical therapy. [ABSTRACT FROM AUTHOR]

Recent years have seen the advent of novel treatment options for hepatocellular carcinoma (HCC). Given a strong biological rationale supporting this strategy, multiple studies have explored the role of combination treatments including locoregional plus systemic therapies to produce a synergistic effect and enhance antitumor activity. Among locoregional therapies, several clinical trials assessing trans-arterial chemoembolization (TACE) have been recently presented and published. In the current paper, we discuss available evidence and current and future research on combined TACE and systemic treatments, including antiangiogenic agents, immune checkpoint inhibitors, and immune-based combinations for HCC patients. [ABSTRACT FROM AUTHOR]

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted. [ABSTRACT FROM AUTHOR]

Abstract: Docetaxel is currently indicated for androgen-independent, metastatic prostate cancer; there is also evidence demonstrating the role of CYP1B1 in modulating the activity of the drug. We present the case of a man with residual disease after radical prostatectomy treated successfully with docetaxel chemotherapy. After only two cycles of therapy, a complete remission was obtained and then consolidated with additional cycles of docetaxel and radiotherapy. Prospective genetic analysis had shown that the patient had a favourable CYP1B1 genotype. He has been disease free since August 2006. Prospective trials investigating this strategy are warranted. [Copyright &y& Elsevier]

Recent pieces of evidence have emerged on the relevance of microorganisms in modulating responses to anticancer treatments and reshaping the tumor-immune microenvironment. On the one hand, many studies have addressed the role of the gut microbiota, providing interesting correlative findings with respect to etiopathogenesis and treatment responses. On the other hand, intra-tumoral bacteria are being recognized as intrinsic and essential components of the cancer microenvironment, able to promote a plethora of tumor-related aspects from cancer growth to resistance to chemotherapy. These elements will be probably more and more valuable in the coming years in early diagnosis and risk stratification. Furthermore, microbial-targeted intervention strategies may be used as adjuvants to current therapies to improve therapeutic responses and overall survival. This review focuses on new insights and therapeutic approaches that are dawning against pancreatic cancer: a neoplasm that arises in a central metabolic "hub" interfaced between the gut and the host. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIM: Many bacteria carry the urease enzyme in different human ecosystems, but Helicobacter pylori is the only known bacterium showing urease activity in gastric ecosystems. For this reason, the rapid urease test (RUT) on gastric biopsies and urea breath test (C-UBT) are used to detect H. pylori infection.The aim of this study was to evaluate the presence of urease-positive bacteria other than H. pylori in gastric juice and mucosa in hypochlorhydric subjects. METHODS: Twenty-five hypochlorhydric and 10 normochlorhydric patients were analyzed for the presence of H. pylori and bacterial overgrowth both in gastric juice and on the mucosa. During upper gastrointestinal endoscopy at 8.00 a.m. gastric juice samples and biopsy specimens were taken from the antrum and corpus. All samples were analyzed using standard microbiological procedures like aerobic/anaerobic growth, gram-staining, gas chromatography, API test, 96-clone method, and selective medium to search for specific bacteria. In addition, all strains isolated were screened for urease activity using the CP-test. Urease positive strains were tested for the capacity to survive in an acid environment with or without urea (10 mM/L), at pH 7, 4, 3, and 2, respectively, at different times (0, 20, 30, and 60 min). RESULTS: Six hypochlorhydric patients had 10 strains of urease-positive non- H. pylori bacteria among which Staphylococcus capitis urealiticum showed the strongest urease activity. CONCLUSIONS: Hypochlorhydric patients present many urease-positive bacteria other than H. pylori. The strong urease activity may be responsible for false positive results at RUT or UBT test in patients with suspected H. pylori infection. [ABSTRACT FROM AUTHOR]

Introduction: The progressive technologies in albumin in situ hybridization (ISH) changed the routine application and the differential diagnosis of hepatic malignancies in the last years. The aim of the present work was to assess the diagnostic utility of albumin ISH on different cholangiocarcinoma (CCA) subtypes, as well as to assess how albumin production changes along the biliary tree. Methods: Forty-five CCAs were retrospectively selected: 29 intrahepatic (15 small-duct and 14 large-duct subtypes), 7 perihilar, and 9 extrahepatic. Histology was revised in all cases, and albumin ISH was automatically performed by the RNAscope®. Results: ISH was always negative in extrahepatic CCAs, only 1 perihilar case was positive, and any positivity was observed in 25/29 (86.2%) intrahepatic CCAs (p < 0.001). Concerning CCA subtypes, mean cell positivity was 38.8 ± 29.8% in small-duct CCAs and 11.4 ± 21.9 in large-duct CCAs, respectively (p = 0.003); 12/15 (80.0%) small-duct and 3/14 (21.4%) large-duct CCAs showed >5% positive cells (p = 0.002; odds ratio 14.7). Conclusions: The introduction of more sensitive techniques changed the indications for ISH since most small-duct intrahepatic CCAs show diffuse positivity. Albumin positivity decreases from liver periphery to the large ducts, suggesting that ISH can be helpful in the differential diagnosis between small-duct and large-duct CCAs, as well as between intrahepatic large-duct CCAs and metastases. [ABSTRACT FROM AUTHOR]

Background: Polymorphisms in genes modulating xenobiotics metabolism, in particular the ABCC2 c.3972C > T single nucleotide polymorphism (SNP) at exon 28, have been suggested to increase primary liver cancer (PLC) risk. Conversely, the occurrence of PLCs in Wilson disease patients is a rare event, in contrast with the occurrence observed in other chronic liver diseases. Here we report the clinical case of five siblings carrying the ABCC2 c.3972C > T SNP; three of them were affected by Wilson disease and two brothers with Wilson disease also developed PLCs. Methods: The presence of the ABCC2 c.3972C > T SNP was assessed by Sanger sequencing and the exposure of PLC risk factors by standardized questionnaires. Results: Notably, PLCs occurred only in the two brothers with the ABCC2 c.3972C > T SNP and Wilson disease who resulted exposed to asbestos and cigarette smoking, but not in the other siblings with the ABCC2 c.3972C > T SNP, alone or in association with Wilson disease, not exposed to these carcinogens and/or to other known risk factors for PLCs. Conclusions: These findings suggest that ABCC2 c.3972C > T SNP and WD, also in association, may not represent a sufficient condition for PLC development, but that co-occurrence of further host/exogenous risk factors are needed to drive this process, reinforcing the notion that liver carcinogenesis is the result of a complex interplay between environmental and host genetic determinants. Due to the sporadic cases of this study and the paucity of data currently available in literature on this issue, future investigations in a larger population are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Introduzione. L'associazione tra esposizione occupazionale ad asbesto e colangiocarcinoma è stata ipotizzata, ma mai indagata analiticamente. Scopo di questo studio è esplorare, tramite un'a nalisi di tipo caso-controllo, la possibile associazione tra esposizione occupazionale ad asbesto e rischio di colangiocarcinoma. Metodi. Lo studio include i residenti che si sono presentati presso il centro per la diagnosi e cura del colangiocarcinoma del nostro policlinico tra il 2006 ed il 2010. Sono stati individuati 20 casi di colangiocarcinoma intraepatico (CCI) e 32 casi di colangiocarcinoma extraepatico (CCE). La popolazione di controllo è stata costruita utilizzando soggetti originariamente campionati ed intervistati (come controlli) per lo studio etiologico di altre patologie di possibile origine occupazionale. I casi sono stati appaiati individualmente a 4 controlli in base a: nascita (fasce di 5 anni) e sesso. L'esposizione occupazionale ad asbesto è stata valutata, in cieco, sulla base della storia lavorativa dei soggetti. CCI e CCE sono stati studiati separatamente con modelli di regressione logistica condizionati alle variabili di appaiamento. Risultati. Sono stati appaiati 20 casi di CCI (nascita: 1942± 10,0; uomini: 35%) a 80 controlli (nascita: 1942± 10; uomini: 35%) e 32 casi di ECC (nascita: 1944± 12; uomini: 47%) a 121 controlli (nascita: 1944± 12; uomini: 52%). Le analisi hanno evidenziato un aumento di rischio di CCI per i lavoratori esposti ad asbesto (OR 3,41, IC95% 1,01-11,54); al contrario, nessuna chiara evidenza di associazione tra CCE ed esposizione ad asbesto è emersa (OR 1,37, IC95% 0,40- 4,67). Discussione. I risultati della nostra analisi esplorativa supportano l'ipotesi che il rischio di CCI possa aumentare tra gli esposti ad asbesto; al contrario, nessuna evidenza è emersa per il CCE. [ABSTRACT FROM AUTHOR]

The link between asbestos exposure and the onset of thoracic malignancies is well established. However epidemiological studies have provided evidences that asbestos may be also involved in the development of gastrointestinal tumors, including intrahepatic cholangiocarcinoma (ICC). In line with this observation, asbestos fibers have been detected in the liver of patients with ICC. Although the exact mechanism still remains unknown, the presence of asbestos fibers in the liver could be explained in the light of their translocation pathway following ingestion/inhalation. In the liver, thin and long asbestos fibers could remain trapped in the smaller bile ducts, particularly in the stem cell niche of the canals of Hering, and exerting their carcinogenic effect for a long time, thus inducing hepatic stem/progenitor cells (HpSCs) malignant transformation. In this scenario, chronic liver damage induced by asbestos fibers over the years could be seen as a classic model of stem cell-derived carcinogenesis, where HpSC malignant transformation represents the first step of this process. This phenomenon could explain the recent epidemiological findings, where asbestos exposure seems mainly involved in ICC, rather than extrahepatic cholangiocarcinoma, development. [ABSTRACT FROM AUTHOR]

During the last few years, the gut microbiota has gained increasing attention as a consequence of its emerging role as a modulator of the immune system. With the advent of the era of checkpoint inhibitors immunotherapy and adoptive cell transfer (ACT) in oncology, these findings became of primary relevance in light of experimental data that suggested the microbiota involvement as a plausible predictor of a good or poor response. These remarks justify the efforts to pinpoint the specific actions of the microbiota and to identify new strategies to favorably edit its composition. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host‐specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co‐occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the potential of asbestos exposure to induce cholangiocarcinoma (bile ducts cancer). The study interviewed 66 of 258 patients treated with cholangiocarcinoma from 2002 to 2008 regarding their asbestos and other carcinogenic agents exposures. Results show that asbestos exposure is not associated with cholangiocarcinoma. It also mentions the ways on how asbestos fibers cause cancers including chronic inflammation, cytokines, and growth factors.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy associated with poor prognosis and a 5-year survival rate of 12%. Many drugs have been tested over the years with conflicting results. The aim of this review is to provide an overview of current therapies in MPM and how to best interpret the data available on these drugs. Furthermore, we focused on promising treatments under investigation, such as immunotherapy with targets different from anti-PD-1/PD-L1 inhibitors, vaccines, target therapies, and metabolism-based strategies. [ABSTRACT FROM AUTHOR]

(1) Background: Biliary tract cancers (BTCs) are a heterogeneous group of neoplasms with dismal prognosis and the role of adjuvant chemoradiotherapy in high-risk resected patients is unclear. (2) Methods: We retrospectively analyzed the outcomes of BTC patients who received curative intent surgery with microscopically positive resection margins (R1) and adjuvant chemoradioradiotherapy (CCRT) or chemotherapy (CHT) from January 2001 to December 201. (3) Results: Out of 65 patients who underwent R1 resection, 26 received adjuvant CHT and 39 adjuvant CCRT. The median recurrence-free survival (RFS) in the CHT and CHRT groups was 13.2 and 26.8 months, respectively (p = 0.41). Median overall survival (OS) was higher in the CHRT group (41.9 months) as compared to the CHT group (32.2 months), but the difference was not statistically significant (HR 0.88; p = 0.7). A promising trend in favor of CHRT was observed in N0 patients. Finally, no statistically significant differences were observed between patients undergoing adjuvant CHRT after R1 resection and patients treated with chemotherapy alone after R0 surgery. (4) Conclusions: Our study did not show a significant survival benefit with adjuvant CHRT over CHT alone in BTC patients with positive resection margins, while a promising trend was observed. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy, recently classified in small duct and large duct morphological subtypes. Growing evidence suggests asbestos as a putative risk factor for iCCA, albeit no correlation between asbestos and iCCA morphology has been investigated so far. The aim of the present study was to assess the relationship between asbestos exposure and iCCA morphological subtype. Forty patients with surgically removed iCCA were prospectively enrolled: asbestos exposure was assessed according to the Italian National Mesothelioma Register questionnaire. From the surgical iCCA specimens the main histopathological variables were collected, including the small duct (sd-iCCA, 32 patients) and large duct subtypes (ld-iCCA, 8 patients). Five sd-iCCA cases had a definite/probable occupational exposure to asbestos, while no cases of ld-iCCA were classified as being occupationally exposed (definite/probable). Other kind of asbestos exposure (i.e. possible occupational, familial, environmental) were recorded in 16 sd-iCCA and 3 ld-iCCA. Cases with unlikely exposure to asbestos were 11 sd-iCCA (35.5%) and 5 ld-iCCA (62.5%). In conclusion, these findings seem to indicate that sd-iCCA might be more frequently associated to asbestos exposure rather than ld-iCCA, suggesting that asbestos fibres might represent a parenchymal, rather than a ductal risk factor for iCCA. This pilot study must be confirmed by further case–control studies or large independent cohorts. [ABSTRACT FROM AUTHOR]

Recent years have observed the emergence of novel therapeutic opportunities for advanced hepatocellular carcinoma (HCC), such as combination therapies including immune checkpoint inhibitors. We performed a meta-analysis with the aim to compare median overall survival (OS), median progression-free survival (PFS), complete response (CR) rate, and partial response (PR) rate in advanced HCC patients receiving immune-based combinations versus sorafenib. A total of 2176 HCC patients were available for the meta-analysis (immune-based combinations = 1334; sorafenib = 842) and four trials were included. Immune-based combinations decreased the risk of death by 27% (HR, 0.73; 95% CI, 0.65–0.83; p < 0.001); similarly, a PFS benefit was observed (HR, 0.64; 95% CI, 0.5–0.84; p < 0.001). In addition, immune-based combinations showed better CR rate and PR rate, with ORs of 12.4 (95% CI, 3.02–50.85; p < 0.001) and 3.48 (95% CI, 2.52–4.8; p < 0.03), respectively. The current study further confirms that first-line immune-based combinations have a place in the management of HCC. The CR rate observed in HCC patients receiving immune-based combinations appears more than twelve times higher compared with sorafenib monotherapy, supporting the long-term benefit of these combinatorial strategies, with even the possibility to cure advanced disease. [ABSTRACT FROM AUTHOR]

Prostate cancer remains the most frequently diagnosed non-skin malignancy in male patients, still representing one of the main causes of cancer-related death worldwide. Evidence is mounting that suggests the putative role of microbiota in the carcinogenesis as well as in modulating the efficacy and activity of anticancer treatments (e.g., chemotherapy, immune checkpoint inhibitors, targeted therapies) in a large number of hematological and solid tumors. However, few data are available regarding the interactions between prostate cancer and microbiome so far, in particular in terms of the impact of microbiota on disease development, pathogenesis, and response to medical treatments in this genitourinary malignancy. Herein, we provide an overview of current knowledge, novel insights and emerging therapeutic approaches related to gastrointestinal and genitourinary microbiome in prostate cancer patients, especially focusing on available evidence and published trials on this topic. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a study titled "Effect of Simvastatin on Cetuximab Resistance in Human Colorectal Cancer with KRAS Mutations," by J. Lee, I. Lee , B. Han, et al. published online on March 11, 2011.

Background. Recent years have witnessed the advent of molecular profiling for intrahepatic cholangiocarcinoma (iCCA), and new techniques have led to the identification of several molecular alterations. Precision oncology approaches have been widely evaluated and are currently under assessment, as shown by the recent development of a wide range of agents targeting Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF. However, several knowledge gaps persist in the understanding of the genomic landscape of this hepatobiliary malignancy. Methods. In the current study, we aimed to comprehensively analyze clinicopathological features of BAP1-mutated iCCA patients in public datasets to increase the current knowledge on the molecular and biological profile of iCCA. Results. The current database study, including 772 iCCAs, identified BAP1 mutations in 120 cases (15.7%). According to our analysis, no differences in terms of overall survival and relapse-free survival were observed between BAP1-mutated and BAP1 wild-type patients receiving radical surgery. In addition, IDH1, PBRM1, and ARID1A mutations were the most commonly co-altered genes in BAP1-mutated iCCAs. Conclusions. The genomic characterization of iCCA is destined to become increasingly important, and more efforts aimed to implement iCCA genomics analysis are warranted. [ABSTRACT FROM AUTHOR]

Aim. The aim of this research was to assess the impact of an intensive follow-up program on BTC patients who had received surgery with curative intent at a tertiary referral hospital. Methods. BTC patients were followed-up every three months during the first two years after their first surgery and every six months from the third to the fifth post-operative year. Results. A total of 278 BTC patients who received R0/R1 surgery were included. A total of 17.7% of patients underwent a second surgery following disease relapse, and none of these patients experienced additional disease relapse. Conclusions. An intensive follow-up after surgical resection may help in the early identification of disease relapse, leading to early treatment and prolonged survival in selected cases. [ABSTRACT FROM AUTHOR]

Simple Summary: In pancreatic cancer, immunotherapy and targeted therapies have not brought about the therapeutic revolution that has been observed in other malignancies. Among the reasons to explain this difference is the possibly crucial role played by the pancreatic tumor microenvironment, which has unique features and is different from that of other neoplasms. The aim of this review is to provide a comprehensive overview of the distinctive tumor immune microenvironment of pancreatic cancer and to summarize existing data about the use of immunotherapy and immune biomarkers in this cancer. 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. [ABSTRACT FROM AUTHOR]

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarcinoma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy. [ABSTRACT FROM AUTHOR]

Commensal bacteria inhabiting the human intestine ( i.e., intestinal microflora) participate in the development and maintenance of gut sensory and motor functions, including the promotion of intestinal propulsive activity. On the other hand, intestinal motility represents one of the major control systems of gut microflora, through the sweeping of excessive bacteria from the lumen. There is emerging evidence indicating that changes in this bidirectional interplay contribute to the pathogenesis of gut diseases, such as small intestinal bacterial overgrowth and intestinal pseudo-obstruction. Recent interest has also been directed to the potential role of intestinal microflora in the pathogenesis of the irritable bowel syndrome. Although the status of intestinal microflora in the irritable bowel syndrome remains unsettled, small intestinal bacterial overgrowth (as detected with breath testing) and increased fermentation of foods with gas production, provide indirect evidence that microflora may contribute to symptom generation in irritable bowel syndrome. The potential benefit of antibiotic and probiotic therapy is currently under investigation and opens new perspectives in irritable bowel syndrome treatment. [ABSTRACT FROM AUTHOR]

Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p <0.01). The prognostic score could generate a highly significant stratification (all between-group p values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI95% 11.0–14.4), 7.1 (CI95% 5.8–8.4), and 3.2 months (CI95% 1.7–4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI95% 11.0–14.3), 7.5 (CI95% 6.1–8.9), and 1.4 months (CI95% 0.1–2.7), respectively (all between-group p values ≤0.05). A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the last decade, immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have dramatically changed the therapeutic algorithm of several hematological and solid tumors. Of note, these agents have been also investigated in biliary tract cancer (BTC), reporting controversial results so far; in this setting, the role of ICIs is still to be established, and available data on immunotherapy in BTC patients are mainly limited to sub-analyses of basket trials and small single-arm studies. A crucial challenge is represented by the lack of validated predictive biomarkers, that could help identify responders to immunotherapy, a high unmet need in these immunologically "cold" malignancies where ICIs are still looking for their niche. Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers. [ABSTRACT FROM AUTHOR]

Background: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001).Conclusions: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433). [ABSTRACT FROM AUTHOR]

The Clavien-Dindo classification (CDC) system and Comprehensive Complication Index (CCI®) are both widely used methods for reporting the burden of postoperative complications. This study aimed to compare the accuracy of the CDC and CCI® in predicting outcomes associated with pancreatic surgery. The CCI® and CDC were applied to 668 patients who underwent pancreatic resection. Length of postoperative stay (LOS) was chosen as the primary outcome variable. The comparison between CCI® and CDC was made with the Spearman test, reporting þs with standard error (SE) and logistic regression, reporting the Odds Ratio (OR) and Area Under the Curve with SE. The median value with the interquartile range (IQR) of CCI® was 20.9 (0–29.6). Both CCI® (þs = 0.609) and CDC (0.590) were significantly (P < 0.001) correlated to LOS. CCI (OR 1.056 and OR 1.052) and CDC (OR 1.978, and OR 1.994) predicted (P < 0.001) LOS over the median and 75th percentile. The accuracy of CCI® was superior to CDC for LOS over 50th (0.785 vs. 0.740; P = 0.004) and over 75th (0.835 vs. 0.761; P < 0.001) percentile. The accuracy of CCI® in measuring the complicated postoperative course was superior to CDC, correctly classifying eight patients every ten tested. [ABSTRACT FROM AUTHOR]

International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are a key element by which the choice of systemic treatment is decided. However, heterogeneity may exist among IMDC risk categories. The first site of metastatic disease occurrence is related to overall survival. The addition of this variable to the others within the recognized IMDC score improves prognosis prediction. Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria have been largely adopted in clinical practice. In a recent retrospective study, we assessed that the addition of the first site of metastatic disease to brain, bone, and liver improves prognostic stratification of patients with metastatic renal cell carcinoma (mRCC). Here, we performed an external validation in patients with mRCC. Our aim was to evaluate if the addition of a new independent variable could improve IMDC prognosis prediction and reduce heterogeneity within risk categories. Patients and Methods: We selected all 1073 patients treated at a single institution for mRCC and included in the Institute Gustave Roussy Renal Cell Carcinoma database. All patients included received at least 1 line of targeted therapy or immune checkpoint inhibitors. Univariate and multivariate analyses (Cox regression model) were performed. Bootstrap validation of the final model was also carried out for internal validation. The IMDC modified classification was defined by the addition of the seventh variable, and we defined the modified IMDC good-risk criteria as 0 risks, intermediate-risk as 1 to 2 risks, and poor-risk as 3 or more risks. Results: The presence of brain, bone, and/or liver as the first site of metastatic disease plus the other variables included in the IMDC score were statistically significant variables associated with overall survival (OS) after univariate and multivariate analysis and bootstrap validation. Finally, 122 (15%) patients had a modification of their initial risk category. The median OS in the poor-, intermediate-, and favorable-risk groups was 10, 26, and 52 months, respectively (P < .001). The bias-corrected concordance index in patients receiving immune checkpoint inhibitors (n =241) was 0.71. Conclusion: The addition of brain, bone, and/or liver metastases as an additional variable to the other IMDC variables improves the prognostic predictive power of the model. [ABSTRACT FROM AUTHOR]