Expanding the therapeutic armamentarium for advanced hepatocellular carcinoma: successful transarterial chemoembolization of peritoneal extrahepatic metastasis.

Hepatocellular carcinoma (HCC) is predominantly known for its intrahepatic manifestations, yet extrahepatic dissemination, particularly intraperitoneal, remains rare. Herein, we present the very first case of successful transarterial chemoembolization (TACE) for an extrahepatic peritoneal HCC nodule. This intervention underscores the potential efficacy of TACE as a viable alternative to surgery in cases where arterial vessels supplying the lesion do not nourish vital parenchymal organs.

Impact of Sarcopenia on the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND AND AIMS: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and hepatocellular carcinoma. We investigated the impact of sarcopenia on survival in patients with advanced hepatocellular carcinoma treated with Sorafenib. METHODS: A total of 328 patients were retrospectively analyzed. All patients had an abdominal CT scan within 8 weeks prior to the start of treatment. Two cohorts of patients were analyzed: the "Training Group" (215 patients) and the "Validation Group" (113 patients). Sarcopenia was defined by reduced skeletal muscle index, calculated from an L3 section CT image. RESULTS: Sarcopenia was present in 48% of the training group and 50% of the validation group. At multivariate analysis, sarcopenia (HR: 1.47, p = 0.026 in training; HR 1.99, p = 0.033 in validation) and MELD > 9 (HR: 1.37, p = 0.037 in training; HR 1.78, p = 0.035 in validation) emerged as independent prognostic factors in both groups. We assembled a prognostic indicator named "SARCO-MELD" based on the two independent prognostic factors, creating three groups: group 1 (0 prognostic factors), group 2 (1 factor) and group 3 (2 factors), the latter with significantly worse survival and shorter time receiving treatment.

Towards a Simplified and Cost-Effective Diagnostic Algorithm for the Surveillance of Intraductal Papillary Mucinous Neoplasms (IPMNs): Can We Save Contrast for Later?

The increased detection of pancreatic cysts in recent years has triggered extensive diagnostic investigations to clarify their potential risk of malignancy, resulting in a large number of patients undergoing numerous imaging follow-up studies for many years. Therefore, there is a growing need for optimization of the current surveillance protocol to reduce both healthcare costs and waiting lists, while still maintaining appropriate sensibility and specificity. Imaging is an essential tool for evaluating patients with intraductal papillary mucinous neoplasms (IPMNs) since it can assess several predictors for malignancy and thus guide further management recommendations. Although contrast-enhanced magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) has been widely recommended by most international guidelines, recent results support the use of unenhanced abbreviated-MRI (A-MRI) protocols as a surveillance tool in patients with IPMN. In fact, A-MRI has shown high diagnostic performance in malignant detection, with high sensitivity and specificity as well as excellent interobserver agreement. The aim of this paper is, therefore, to discuss the current available evidence on whether the implementation of an abbreviated-MRI (A-MRI) protocol for cystic pancreatic lesion surveillance could improve healthcare economics and reduce waiting lists in clinical practice without significantly reducing diagnostic accuracy.

Liver Lesions at Risk of Transformation into Hepatocellular Carcinoma in Cirrhotic Patients: Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement.

Recent technical advances in liver imaging and surveillance for patients at high risk for developing hepatocellular carcinoma (HCC) have led to an increase in the detection of borderline hepatic nodules in the gray area of multistep carcinogenesis, particularly in those that are hypointense at the hepatobiliary phase (HBP) and do not show arterial phase hyperenhancement. Given their potential to transform and advance into hypervascular HCC, these nodules have progressively attracted the interest of the scientific community. To date, however, no shared guidelines have been established for the decision management of these borderline hepatic nodules. It is therefore extremely important to identify features that indicate the malignant potential of these nodules and the likelihood of vascularization. In fact, a more complete knowledge of their history and evolution would allow outlining shared guidelines for their clinical-surgical management, to implement early treatment programs and decide between a preventive curative treatment or a watchful follow-up. This review aims to summarize the current knowledge on hepatic borderline nodules, particularly focusing on those imaging features which are hypothetically correlated with their malignant evolution, and to discuss current guidelines and ongoing management in clinical practice.

Bosniak Classification of Cystic Renal Masses: Looking Back, Looking Forward.

RATIONALE AND OBJECTIVES: According to the 2019 update of the Bosniak classification, the main imaging features that need to be evaluated to achieve a correct characterization of renal cystic masses include the thickness of walls and septa, the number of septa, the appearance of walls and septa, the attenuation/intensity on non-contrast CT/MRI and the presence of unequivocally perceived or measurable enhancement of walls and septa. Despite the improvement deriving from a quantitative evaluation of imaging features, certain limitations seem to persist and some possible scenarios that can be encountered in clinical practice are still missing. MATERIALS AND METHODS: A deep analysis of the 2019 update of the Bosniak classification was performed. RESULTS: The most notable potential flaws concern: (1) the quantitative measurement of the walls and septa; (2) the fact that walls and septa > 2 mm are always referred to as "enhancing", not considering the alternative scenario; (3) the description of some class II masses partially overlaps with each other and with the definition of class I masses and (4) the morphological variations of cystic masses over time is not considered. CONCLUSION: The present paper analyzes in detail the limitations of the 2019 Bosniak classification to improve this important tool and facilitate its use in daily radiological practice.

Prognostic Role of Early Cardiac Magnetic Resonance in Myocardial Infarction With Nonobstructive Coronary Arteries.

BACKGROUND: Cardiac magnetic resonance (CMR) plays a pivotal diagnostic role in myocardial infarction with nonobstructive coronary arteries (MINOCA). To date, a prognostic stratification of these patients is still lacking. OBJECTIVES: This study aims to assess the prognostic role of CMR in MINOCA. METHODS: The authors assessed 437 MINOCA from January 2017 to October 2021. They excluded acute myocarditis, takotsubo syndromes, cardiomyopathies, and other nonischemic etiologies. Patients were classified into 3 subgroups according to the CMR phenotype: 1) presence of late gadolinium enhancement (LGE) and abnormal mapping (M) values (LGE+/M+); 2) regional ischemic injury with abnormal mapping and no LGE (LGE-/M+); and 3) nonpathological CMRs (LGE-/M-). The primary outcome was the presence of major adverse cardiovascular events (MACE). The mean follow-up was 33.7 ± 12.0 months and CMR was performed on average at 4.8 ± 1.5 days from the acute presentation. RESULTS: The final cohort included 198 MINOCA; 116 (58.6%) comprised the LGE+/M+ group. During follow-up, MACE occurred significantly more frequently in MINOCA LGE+/M+ than in the LGE+/M- and normal-CMR (LGE-/M-) subgroups (20.7% vs 6.7% and 2.7%; P = 0.006). The extension of myocardial damage at CMR was significantly greater in patients who developed MACE. In multivariable Cox regression, %LGE was an independent predictor of MACE (HR: 1.123 [95% CI: 1.064-1.185]; P < 0.001) together with T2 mapping values (HR: 1.190 [95% CI: 1.145-1.237]; P = 0.001). CONCLUSIONS: In MINOCA with early CMR execution, the %LGE and abnormal T2 mapping values were identified as independent predictors of adverse cardiac events at ∼3.0 years of follow-up. These parameters can be considered as high-risk markers in MINOCA.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia: Study of a Cohort of Patients from a Single Italian Center.

Testicular adrenal rest tumors (TARTs) are a common complication in male patients with congenital adrenal hyperplasia (CAH). The aim of our cross-sectional cohort study is to estimate the frequency of TARTs with the correlation of genotype and disease control on tumor development. Thirty-five male patients, aged 14-26 years, were included in the study, all followed by the same center of pediatric endocrinology in Bologna. We studied genotypes, hormonal profiles at different time intervals and testicular ultrasound. A logistic regression model with multivariant analysis was developed for the statistical analysis. TARTs were detected in 31.4% of the cases, 90.9% of them had a classic form with salt wasting, while 9.1% had a non-classic form. Additionally, a significant correlation between the incidence of TARTs and severity of genotype was detected. Patients with TARTs had markedly worse metabolic control on average (p = 0.027), reflected by high ACTH, 17OH progesterone, and overall delta4-androstenedione. In conclusion, a screening tool is mandatory, especially (but not exclusively) in patients with the most severe forms of CAH and poor endocrine control of the disease.

Reverse Mirizzi Syndrome.

A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the neonatal period because of initial misdiagnosis of biliary atresia. Laboratory investigations showed hyperbilirubinemia (total bilirubin 1.76 mg/dL [<1.2 mg/dL]; conjugated 1.06 mg/dL [<0.3 mg/dL]) and cholestasis (GGT 78 U/L [<50 U/L]; ALP 200 U/L [<50 U/L]). Transabdominal ultrasound was limited by aerobilia due to the cholecystojejuno-anastomosis. Subsequent basal CT scan revealed an impacted stone within the patient's native common bile duct (CBD). Aerobilia in intrahepatic bile ducts and gallbladder was reported. Magnetic Resonance cholangiopancreatography confirmed the gallstone in the CBD compressing cystic duct and common hepatic duct, with dilation of the upstream bile ducts. Furthermore, the native CBD was obstructed by other gallstones. In Mirizzi syndrome, gallstones impacted in gallbladder's Hartmann's pouch or cystic duct extrinsically compress CBD. We suggest naming the present condition "Reverse Mirizzi Syndrome" (Renzulli Matteo Syndrome, RMS) because it is the exact opposite of Mirizzi syndrome.

5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial.

BACKGROUND & AIMS: ß-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction in intrahepatic vascular resistance. 5-Methyltetrahydrofolate (5-MTHF) can prevent oxidative loss of tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase coupling. It also converts homocysteine (tHcy) into methionine and enables the degradation of asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase. The aim of this study was to evaluate the effects of 5-MTHF in combination with propranolol on HVPG and nitric oxide bioavailability markers in patients with cirrhosis and portal hypertension. METHOD: Sixty patients with cirrhosis and HVPG ≥12 mmHg were randomized 1:1 to receive treatment with 5-MTHF+propranolol or placebo+propranolol for 90 days under double-blind conditions. HVPG and markers of nitric oxide bioavailability (BH4, ADMA and tHcy) were measured again at the end of treatment. RESULTS: Groups were similar in terms of baseline clinical and hemodynamic data and nitric oxide bioavailability markers. HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percentage decrease, 20 [29-9] vs. 12.5 [22-0], p = 0.028), without differences in hepatic blood flow. At the end of treatment, 5-MTHF+propranolol (vs. placebo+propranolol) was associated with higher BH4 (1,101.4 ± 1,413.3 vs. 517.1 ± 242.8 pg/ml, p <0.001), lower ADMA (109.3 ± 52.7 vs. 139.9 ± 46.7 µmol/L, p = 0.027) and lower tHcy (µmol/L, 11.0 ± 4.6 vs. 15.4 ± 7.2 µmol/L, p = 0.010) plasma levels. CONCLUSION: In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation. CLINICAL TRIAL EUDRACT NUMBER: 2014-002018-21. IMPACT AND IMPLICATIONS: Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, such as esophageal varices rupture, is based on the use of ß-blockers, but some patients still present with acute variceal bleeding, mainly due to an insufficient reduction of portal pressure. In this study, we sought to demonstrate that the addition of folic acid to ß-blockers is more effective in reducing portal pressure than ß-blockers alone. This finding could represent the basis for validation studies in larger cohorts, which could impact the future prophylactic management of variceal bleeding in cirrhosis. Enhancing the benefit of ß-blockers with a safe, accessible, cost-effective drug could improve clinical outcomes in cirrhosis, which in turn could translate into a reduction in the rates and costs of hospitalization, and ultimately into improved survival.

Personalised management of patients with hepatocellular carcinoma: a multiparametric therapeutic hierarchy concept.

Advances in the surgical and systemic therapeutic landscape of hepatocellular carcinoma have increased the complexity of patient management. A dynamic adaptation of the available staging-based algorithms is required to allow flexible therapeutic allocation. In particular, real-world hepatocellular carcinoma management increasingly relies on factors independent of oncological staging, including patients' frailty, comorbid burden, critical tumour location, multiple liver functional parameters, and specific technical contraindications impacting the delivery of treatment and resource availability. In this Policy Review we critically appraise how treatment allocation strictly based on pretreatment staging features has shifted towards a more personalised treatment approach, in which expert tumour boards assume a central role. We propose an evidence-based framework for hepatocellular carcinoma treatment based on the novel concept of multiparametric therapeutic hierarchy, in which different therapeutic options are ordered according to their survival benefit (ie, from surgery to systemic therapy). Moreover, we introduce the concept of converse therapeutic hierarchy, in which therapies are ordered according to their conversion abilities or adjuvant abilities (ie, from systemic therapy to surgery).

Uterine Artery Embolization for the Treatment of Symptomatic Uterine Fibroids of Different Sizes: A Single Center Experience.

The present study aimed to evaluate the clinical and radiological 1-year outcomes of uterine artery embolization (UAE) performed in a selected population of women with symptomatic myomas and who do not wish to conceive. Between January 2004 and January 2018, a total of 62 patients with pre-menopausal status and with no wish to conceive in the future underwent UAE for the treatment of symptomatic fibroids. All the patients underwent magnetic resonance imaging (MRI) and/or transvaginal ultrasonography (TV-US) before and after the procedure at 1-year follow-up. Clinical and radiological parameters were recorded, stratifying the population into 3 groups according to the size of the dominant myoma (group 1: <50 mm; group 2: ≥50 and ≤80 mm; group 3: >80 mm). Mean fibroid diameter was significantly reduced (42.6% ± 21.6%) at 1-year follow-up, with excellent improvements in terms of both symptoms and quality of life. No significant difference was observed regarding baseline dimension and the number of myomas. No major complications were reported (2.5%). The present study confirms the safety and efficacy of UAE in the treatment of symptomatic fibroids in pre-menopausal women with no desire to conceive.

The Synergistic Effect of Interventional Locoregional Treatments and Immunotherapy for the Treatment of Hepatocellular Carcinoma.

Immunotherapy has remarkably revolutionized the management of advanced HCC and prompted clinical trials, with therapeutic agents being used to selectively target immune cells rather than cancer cells. Currently, there is great interest in the possibility of combining locoregional treatments with immunotherapy for HCC, as this combination is emerging as an effective and synergistic tool for enhancing immunity. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of locoregional treatments, improving patients' outcomes and reducing recurrence rates. On the other hand, locoregional therapies have been shown to positively alter the tumor immune microenvironment and could therefore enhance the efficacy of immunotherapy. Despite the encouraging results, many unanswered questions still remain, including which immunotherapy and locoregional treatment can guarantee the best survival and clinical outcomes; the most effective timing and sequence to obtain the most effective therapeutic response; and which biological and/or genetic biomarkers can be used to identify patients likely to benefit from this combined approach. Based on the current reported evidence and ongoing trials, the present review summarizes the current application of immunotherapy in combination with locoregional therapies for the treatment of HCC, and provides a critical evaluation of the current status and future directions.

Effectiveness and Safety of Different Vascular Closure Devices: Multicentre Prospective Observational study.

AIM: The aim of this prospective, multicentre, observational study was to compare the efficacy and safety of balloon-based and non-balloon-based vascular closure devices (VCDs). MATERIALS AND METHODS: From March 2021 to May 2022, 2373 participants from 10 different centres were enrolled. Among them, 1672 patients with 5-7 Fr accesses were selected. Successful haemostasis, failure and safety were evaluated. Successful haemostasis was defined as the possibility to obtain complete haemostasis with the use of VCDs, without any complication. Failure management was defined as the need of manual compression. Safety was defined as the rate of complications. Cases of haematomas/pseudoaneurysms (PSA) and artero-venous fistula (AVF) were collected. RESULTS: VCDs mechanism of action is statistically significant associated with the outcome. Non-balloon-based VCDs demonstrated a statistically significant better outcome: successful haemostasis was obtained in 96.5% vs. 85.9%, of cases when compared to balloon occluders (p < 0.001). The incidence of AVF was statistically more frequent using non-balloon occluders devices (1.57% vs 0%, p: 0.007). No significant statistical difference was found in comparing haematoma and PSA occurrence. Thrombocytopenia, coagulation deficit, BMI, diabetes mellitus and anti-coagulation were demonstrated to be independent predictors of failure management. CONCLUSION: Our study suggests a better outcome with the same complication rate, except that for AVF incidence for non-balloon collagen plug device if compared to balloon occluders vascular closure devices.

Update of the Bologna Experience in Radioembolization of Intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primitive liver cancer and is rising in incidence worldwide. Given its low survival and resectability rates, locoregional therapies such as Yttrium-90 transarterial radioembolization (Y-TARE) are increasingly being employed. This retrospective study aim was to confirm and update our previous results about overall survival (OR), safety, and efficacy of Y-TARE in patients with unresectable/recurrent ICC. MATERIALS AND METHODS: OS was evaluated as primary endpoint while radiological tumor response at 3 months, based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, was considered as secondary endpoint. RESULTS: Over a total of 49 patients, the overall median survival was 16 months (27-41 months, 95% confidence interval [CI]) from Y-TARE procedure. A significantly longer survival was recorded in naive patients compared to patients previously submitted to any type of liver-directed treatment and radical surgery (18 vs 14 months, P=.015 and 28 vs 14 months, P=.001, respectively). Target lesion and overall objective response for RECIST 1.1 criteria were 64.6% and 52.1%, respectively. Low rates of postprocedural and late complications were recorded. CONCLUSIONS: In unresectable and recurrent ICC, Y-TARE confirms its safety and its potential in increasing OS, especially in naive patients.

A case of peri­stomal ectopic variceal bleeding in a patient with decompensated cirrhosis treated with TIPS placement.

Peri-stomal variceal bleeding is an underestimated complication in patients with colostomy and portal hypertension. Due to the small number of reported cases, there is currently no unified consensus on the best treatment and several options may be available. We report a case in which TIPS placement was effective.

Association between anatomic variations of extrahepatic and intrahepatic bile ducts: Do look up!

Biliary anatomic variations are usually asymptomatic, but they may cause problems in diagnostic investigations and interventional and surgical procedures, increasing both their technical difficulty and their postoperative complication rates. The aim of the present study was to evaluate the prevalence of anatomic variations in the intrahepatic biliary ducts (IHBD) in relation to demographical and clinical characteristics in a large study population requiring magnetic resonance cholangiopancreatography (MRCP) for various clinical conditions. The possible association between IHBD and extrahepatic biliary ducts (EHBD) variants was then explored. From January 2017 to May 2019, 1004 patients underwent MRCP. Demographical and clinical data were collected. IHBD and EHBD anatomy were recorded and the EHBD anatomy was classified using both qualitative and quantitative classifications. The presence of a type 3 EHBD variant (an abnormal proximal cystic duct [CD] insertion) in both qualitative and quantitative classifications and an intrapancreatic CD were associated with the presence of IHBD variants at univariate analysis (p = 0.008, p = 0.019, and p = 0.001, respectively). The presence of a posterior or medial insertion of the CD into the EHBD was a strong predictive factor of the presence of IHBD variants both at uni- and multivariate analysis (p = 0.002 and p = 0.003 for posterior insertion and p = 0.002 and p = 0.002 for medial insertion, respectively). The presence of gallstones on MRCP resulted in a strong predictor of the presence of an anatomical variant of the IHBD both at uni- and multivariate analysis (p = 0.027 and p = 0.046, respectively). In conclusion, the presence of a type 3 variant of the EHBD, an intrapancreatic CD and, especially, a posterior/medial CD insertion into the EHBD represent predictive factors of the concomitant presence of IHBD variants, thus radiologists must be vigilant when encountering these EHBD configurations and always remember to "look up" at the IHBD. Finally, the presence of an IHBD variant is a strong predictive factor of gallstones.