Defining Long-Term Survivors Following Resection of Intrahepatic Cholangiocarcinoma

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary tumor of the liver. While surgery remains the cornerstone of therapy, long-term survival following curative-intent resection is generally poor. The aim of the current study was to define the incidence of actual long-term survivors, as well as identify clinicopathological factors associated with long-term survival. METHODS: Patients who underwent a curative-intent liver resection for ICC between 1990 and 2015 were identified using a multi-institutional database. Overall, 679 patients were alive with ≥ 5 years of follow-up or had died during follow-up. Prognostic factors among patients who were long-term survivors (LT) (overall survival (OS) ≥ 5) were compared with patients who were not non-long-term survivors (non-LT) (OS < 5). RESULTS: Among the 1154 patients who underwent liver resection for ICC, 5- and 10-year OS were 39.6 and 20.3% while the actual LT survival rate was 13.3%. After excluding 475 patients who survived  5 cm (OR 2.40, 95% CI, 1.54-3.74, p < 0.001), and direct invasion of an adjacent organ (OR 3.98, 95% CI, 1.18-13.4, p = 0.026). However, a subset of patients (< 10%) who had these pathological characteristics were LT. CONCLUSION: While ICC is generally associated with a poor prognosis, some patients will be LT. In fact, even a subset of patients with traditional adverse prognostic factors survived long term.info:eu-repo/semantics/publishedVersio

Impact of Microvascular Invasion on Clinical Outcomes After Curative-Intent Resection for Intrahepatic Cholangiocarcinoma

Background: Microvascular invasion (MiVI) is a histological feature of intrahepatic cholangiocarcinoma (ICC) that may be associated with biological behavior. We sought to investigate the impact of MiVI on long-term survival of patients undergoing curative-intent resection for ICC. Methods: A total of 1089 patients undergoing curative-intent resection for ICC were identified. Data on clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared among patients with no vascular invasion (NoVI), MiVI, and macrovascular invasion (MaVI). Results: A total of 249 (22.9%) patients had MiVI, while 149 (13.7%) patients had MaVI (±MiVI). MiVI was associated with higher incidence of perineural, biliary and adjacent organ invasion, and satellite lesions (all P 18 months) prognosis. Conclusions: Roughly 1 out of 5 patients with resected ICC had MiVI. MiVI was associated with advanced tumor characteristics and a higher risk of tumor recurrence.info:eu-repo/semantics/publishedVersio

Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma

Background: Recurrence of intrahepatic cholangiocarcinoma (ICC) after curative resection is common. Objective: The aim of this study was to investigate the patterns, timing and risk factors of disease recurrence after curative-intent resection for ICC. Methods: Patients undergoing curative resection for ICC were identified from a multi-institutional database. Data on clinicopathological and initial operation information, timing and first sites of recurrence, recurrence management, and long-term outcomes were analyzed. Results: A total of 920 patients were included. With a median follow-up of 38 months, 607 patients (66.0%) experienced ICC recurrence. In the cohort, 145 patients (23.9%) recurred at the surgical margin, 178 (29.3%) recurred within the liver away from the surgical margin, 90 (14.8%) recurred at extraheptatic sites, and 194 (32.0%) developed both intrahepatic and extrahepatic recurrence. Intrahepatic margin recurrence (median 6.0 m) and extrahepatic-only recurrence (median 8.0 m) tended to occur early, while intrahepatic recurrence at non-margin sites occurred later (median 14.0 m; p < 0.05). On multivariate analysis, surgical margin < 10 mm was associated with increased margin recurrence (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.11-2.60; p = 0.014), whereas female sex (HR 2.12, 95% CI 1.40-3.22; p < 0.001) and liver cirrhosis (HR 2.36, 95% CI 1.31-4.25; p = 0.004) were both associated with an increased risk of intrahepatic recurrence at other sites. Median survival after recurrence was better among patients who underwent repeat curative-intent surgery (48.7 months) versus other treatments (9.7 months) [p < 0.001]. Conclusions: Different recurrence patterns and timing of recurrence suggest biological heterogeneity of ICC tumor recurrence. Understanding timing and risk factors associated with different types of recurrence can hopefully inform discussions around adjuvant therapy, surveillance, and treatment of recurrent disease.info:eu-repo/semantics/publishedVersio

Survival after Resection of Multiple Tumor Foci of Intrahepatic Cholangiocarcinoma

Background: Multiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes after resection of ICC in patients with multiple foci. Methods: Patients who underwent resection for ICC between 1990 and 2017 were identified from 12 major HPB centers. Outcomes of patients with solitary lesions, multiple lesions (ML), and oligometastases (OM) were compared. OM were defined as extrahepatic metastases spread to a single organ. Results: One thousand thirteen patients underwent resection of ICC. On final pathology, 185 patients (18.4%) had ML and 27 (2.7%) had OM. Median survival of patients with a solitary tumor was 43.2 months, while the median survival of patients with 2 tumors was 21.2 months; the median survival of patients with 3 or more tumors was 15.3 months (p < 0.001). Five-year survival was 43.3%, 28.0%, and 8.6%, respectively. The median survival of patients without OM was 37.8 months versus 14.9 months among patients with OM (p < 0.001); estimated 5-year survival was 39.3% and 10.6%, respectively. In multivariable analysis, the presence of two lesions was not an independent poor prognostic factor for OS (HR 1.19; 95%CI 0.90-1.57; p = 0.229). However, the presence of three or more tumors was an independent poor prognostic factor for OS (HR 1.97; 95%CI 1.48-2.64; p < 0.001). Conclusion: Resection of multiple liver tumors for patients with ICC did not preclude 5-year survival: in particular, estimated 5-year OS for resection of two tumors was 28.0%.info:eu-repo/semantics/publishedVersio

Trends in Use of Lymphadenectomy in Surgery with Curative Intent for Intrahepatic Cholangiocarcinoma

Background: The role of routine lymph node dissection (LND) in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) remains controversial. The objective of this study was to investigate the trends of LND use in the surgical treatment of ICC. Methods: Patients undergoing curative intent resection for ICC in 2000-2015 were identified from an international multi-institutional database. Use of lymphadenectomy was evaluated over time and by geographical region (West versus East); LND use and final nodal status were analysed relative to AJCC T categories. Results: Among the 1084 patients identified, half (535, 49·4 per cent) underwent concomitant hepatic resection and LND. Between 2000 and 2015, the proportion of patients undergoing LND for ICC nearly doubled: 44·4 per cent in 2000 versus 81·5 per cent in 2015 (P < 0·001). Use of LND increased over time among both Eastern and Western centres. The odds of LND was associated with the time period of surgery and the extent of the tumour/T status (referent T1a: OR 2·43 for T2, P = 0·001; OR 2·13 for T3, P = 0·016). Among the 535 patients who had LND, lymph node metastasis (LNM) was noted in 209 (39·1 per cent). Specifically, the incidence of LNM was 24 per cent in T1a disease, 22 per cent in T1b, 42·9 per cent in T2, 48 per cent in T3 and 66 per cent in T4 (P < 0·001). AJCC T3 and T4 categories, harvesting of six or more lymph nodes, and presence of satellite lesions were independently associated with LNM. Conclusion: The rate of LNM was high across all T categories, with one in five patients with T1 disease having nodal metastasis. The trend in increased use of LND suggests a growing adoption of AJCC recommendations in the treatment of ICC.info:eu-repo/semantics/publishedVersio

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure\u2010freedom, seizure response ( 65&nbsp;50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results: A total of 1029 patients with a median age of 45&nbsp;years (33\u201356) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p&nbsp;&lt;&nbsp;0.001); the corresponding values for 65&nbsp;50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p&nbsp;&lt;&nbsp;0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p&nbsp;=&nbsp;0.341) and seizure response (39.7% vs. 26.9%; p&nbsp;=&nbsp;0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p&nbsp;=&nbsp;0.017). Conclusion: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations

Fighting autoinflammation in FIRES: The role of interleukins and early immunomodulation

Febrile infection-related epilepsy syndrome (FIRES) is a challenging condition with unfavorable outcome in most cases. Preliminary evidence suggests that some interleukins, in particular IL-1 Receptor Antagonist (IL-1RA), could be elevated due to a functional deficiency of anti-inflammatory pathways. Therefore, treatment strategies acting on innate immunity could represent a targeted treatment. We describe the case of an 11-year-old child with super-refractory status epilepticus (SE), lasting more than two months. After being treated aggressively with antiseizure medications, anesthetics and empiric treatment for autoimmune encephalitis without success, she responded to anakinra and ketogenic diet. Escalation of the therapy was supported by the finding of a very high serum level of IL-1RA. This immunomodulatory approach allowed to discharge the child from intensive care 48 days after the SE onset. After more than one year follow-up the patient has moderate intellectual disability but with good language skills; she is seizure free and without motor deficits. This case suggests that serum IL-1RA serum levels may help to support treatment escalation. Moreover, anakinra and ketogenic diet represent encouraging immunomodulatory strategies which deserve further studies and could potentially have a synergistic effect. Finally, structured neuropsychological testing is an important outcome measure that will help to define the effectiveness of different treatment strategies

Comparative Performances of the 7th and the 8th Editions of the American Joint Committee on Cancer Staging Systems for Intrahepatic Cholangiocarcinoma

BACKGROUND: We sought to evaluate and validate the 8th edition of the AJCC classification using a multi-institutional cohort of patients with intrahepatic cholangiocarcinoma (ICC). METHODS: Patients undergoing curative-intent hepatic resection for ICC between 1990 and 2015 at 14 major hepatobiliary centers were included and were staged according to 7th and 8th editions AJCC criteria. RESULTS: A total of 1154 patients underwent liver resection for ICC. When patients were staged using the AJCC 7th edition, T2a, T2b, and T4 patients had a higher hazard ratio (HR) of death compared with T1 (T2a, HR 1.43, P = 0.004; T2b, HR 1.99, P < 0.001; T4, HR 2.20, P < 0.001). T3 patients had a higher HR of death compared with T1 patients (HR 1.30, P = 0.029) but lower than T2a and T2b. According to AJCC 8th edition, T1b, T2, and T4 patients were at higher risk of death compared with T1a patients (T1b, HR 1.91, P < 0.001; T2, HR 2.29, P < 0.001; T4, HR 4.16, P < 0.001). As in the AJCC 7th edition, AJCC 8th edition T3 patients had a higher HR of death compared with T1 patients (HR 1.65, P  = 0.001) but lower than T1b and T2. AJCC 8th edition. T-category performed slightly better than AJCC 7th edition with a C-index of 0.609 versus 0.590. CONCLUSIONS: A staging system that perfectly discriminates between stages has not yet been developed, but the AJCC 8th edition was able to better stratify the risk of death of Stage III and T3 patients.info:eu-repo/semantics/publishedVersio

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32–56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12&nbsp;months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥&nbsp;50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results: A total of 1029 patients with a median age of 45&nbsp;years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p&nbsp;&lt;&nbsp;0.001); the corresponding values for ≥&nbsp;50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p&nbsp;&lt;&nbsp;0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p&nbsp;=&nbsp;0.341) and seizure response (39.7% vs. 26.9%; p&nbsp;=&nbsp;0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p&nbsp;=&nbsp;0.017). Conclusion: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations