Reply to Lissing et al. Comment on "Ramai et al. Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review. Cancers 2022, 14, 2947".

We thank Dr. Lissing and colleagues for providing us with these helpful comments [...].

Utilization of Hepatocellular Carcinoma Surveillance Programs in Patients With Cirrhosis: A Systematic Review and Meta-Analysis.

Patients with cirrhosis are advised to undergo hepatocellular carcinoma (HCC) surveillance every 6 months. Routine surveillance is associated with early tumor detection and improved survival. However, surveillance is underutilized. We aimed to characterize the uptake of HCC surveillance in cirrhotic patients following the implementation of interventional programs. We performed a comprehensive literature search of major databases (from inception to October 2020). Surveillance was defined as having an abdominal sonogram every 6 months. Nine studies were included for meta-analysis which involved 4550 patients. The etiology of liver cirrhosis was largely due to hepatitis C or B (n=2023), followed by alcohol (n=857), and nonalcoholic steatohepatitis (n=432). Patients enrolled in surveillance programs were 6 times more likely to undergo abdominal sonography when compared with standard of care (odds ratio=6.00; 95% confidence interval: 3.35-10.77). On subgroup analysis, clinical reminders were associated with a 4 times higher rate of HCC surveillance compared with standard of care (odds ratio=3.80; 95% confidence interval: 2.25-6.39). Interventional programs significantly improve the rate of HCC surveillance. This is clinically impactful and should be considered as a means for improving surveillance rates.

Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review.

Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy. Porphyrias are inborn defects in the heme biosynthesis pathway resulting in neurovisceral manifestations and cutaneous photosensitivity attacks with multi-systemic involvement. Its estimated prevalence nears 5 per 100,000 patients worldwide. Subclinical liver disease is common, which can progress into transaminitis, fibrosis, cirrhosis, and malignancy. However, data on the incidence of primary liver cancer are lacking. We aim to determine the risk of hepatocellular carcinoma (HCC) in patients with porphyria. A systematic review and pooled analysis were conducted through 2021 on studies assessing blood tests, imaging, cancer development, liver transplant, surgical resection, and outcomes in porphyria. In total, 19 studies, which included 7381 patients with porphyria (3476 females), were considered for the final review. In eight studies, alpha-fetoprotein levels were elevated between 200 and 1000 IU/mL. Of the total cohort of patients with porphyria, primary liver cancer was diagnosed in 351 patients (4.8%), of whom 243 (3.3% of the total) were found to have HCC. A subset of patients was found to have cholangiocarcinoma (n = 18; 0.3% of the total). Interestingly, advanced liver disease or cirrhosis was not a prerequisite for the formation of HCC in a small group of patients. Of the total cohort, 30 patients underwent liver resection, 48 patients underwent liver transplantation, and 327 patients died. Patients with porphyria are at risk of developing primary liver malignancy. Further studies should aim to develop diagnostic and prognostic models aimed at the early detection of HCC in porphyria.

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies: A systematic review with meta-analysis.

BACKGROUND: It is unclear whether patients with intraductal papillary mucinous neoplasia harbor a higher risk of developing extrapancreatic malignancies. AIMS: We performed a pooled estimate of the incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasia, with a particular focus on the comparison to the general population. METHODS: Computerized bibliographic search of main databases was performed through February 2021. The primary endpoint was the pooled incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms. Additional outcome was the comparison between intraductal papillary mucinous neoplasia patients and the general population, expressed in terms of standardized incidence ratio along with 95% confidence intervals. RESULTS: Eighteen studies with 8709 patients were included. The pooled rate of metachronous extrapancreatic malignancies was 10 (6-13)/1000 persons-year. No difference was observed according to intraductal papillary mucinous neoplasia histology and sex, whereas a significantly superior incidence of extrapancreatic malignancies was observed in patients with main-duct (36.7%, 25.4%-48%) as compared to branch-duct intraductal papillary mucinous neoplasia (26.2%, 17.6%-34.8%; p = 0.03). Pooled standardized incidence ratio comparing expected rates in the general population was 1.01 (0.79-1.29); no difference was observed concerning rates of metachronous gastric cancer (standardized incidence ratio 1.60, 0.72-3.54) and colorectal cancer (1.29, 0.92-1.18), whereas biliary cancer was observed more frequently in intraductal papillary mucinous neoplasia patients (2.29, 1.07-4.93). CONCLUSION: Patients with intraductal papillary mucinous neoplasia harbor an overall rate of extrapancreatic malignancies as high as 27.3%. The rate of metachronous extrapancreatic malignancies is not superior to the general population.

Endoscopic Management of Ampullary Adenomas in Familial Adenomatous Polyposis Syndrome: A Systematic Review with Pooled Analysis.

BACKGROUND: Endoscopic papillectomy is a viable therapy in ampullary lesions. Prior studies have reported on outcomes of sporadic ampullary lesions, and only small cohort studies have reported outcomes associated with familial adenomatous polyposis (FAP) syndrome. AIMS: We performed a systematic review with pooled analysis to assess the safety and efficacy of EP for treating ampullary adenomas in FAP. METHODS: We performed a comprehensive literature search of major databases from inception to May 2020. Studies that included patients with endoscopically resected ampullary lesions and FAP were eligible. The rate of technical success, en bloc resection, piecemeal resection, recurrence, and adverse events was pooled by means of a random-effects model to obtain a proportion with a 95% confidence interval (CI). RESULTS: Six studies, including a total of 99 patients, were included in our final analysis. Patient age ranged from 28 to 91 years. Pooled technical success was 90.3% (CI 76.9-96.3%, I2 = 31%). Rate of en bloc resection was 60.6% (CI 47.9-72.0%, I2 = 0%). Recurrence rate was 25.4% (5.7-65.9%, I2 = 82%). The post-procedural pancreatitis rate was 14.7% of which 68% (51 of 75) utilized prophylactic pancreatic stenting. Other adverse events included bleeding (9.2%) and perforation (4%). CONCLUSION: Endoscopic papillectomy offers high technical success but remains challenging in patients with FAP, particularly due to high recurrence rates.

Predictors of Lymph Node Metastasis in T1 Colorectal Cancer in Young Patients: Results from a National Cancer Registry.

The objective of this study is to fill the knowledge gap by examining predictors of lymph node metastasis (LNM) in young patients, less than 45 years, using a national cancer registry. Methods: Patients diagnosed with T1 colorectal cancer were identified in the Surveillance, Epidemiology, and End Results registry. In total, 692 patients with T1 colorectal cancer were identified. Most tumors occurred in white race (77.7%), between 40 and 44 years of age (49.4%), with grade III tumor differentiation (59.8%) and 1 to 1.9 cm size (32.2%), and were left-sided tumors (61.1%). The overall rate of LNM was 22.5% (n = 149). LNM was associated with tumor grade IV (undifferentiated) (odds ratio (OR) 2.94, CI: 1.06-8.12; p = 0.038), and increasing tumor size (1 cm-1.9 cm: OR 2.92, CI: 1.71-4.97, p < 0.001; 2.0 cm-2.9 cm: OR 2.00, CI: 1.05-3.77, p = 0.034; and ≥3.0 cm: OR 2.68, CI: 1.43-5.01, p = 0.002). Five-year cancer-specific survival for patients with LNM was 91% and for patients without LNM this was 98%. Adjusted cox proportion models showed that LNM was associated with a four times higher rate of mortality (hazard ratio (HR) 4.43, CI: 1.27-15.52, p = 0.020). In this population-based analysis of patients with T1 colorectal cancer, tumor size and grade were significant predictors of LNM.

Comparison of left versus right lateral starting position on colonoscopy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Modifying patient position during colonoscopy has been proposed as a simple and inexpensive technique to increase luminal distention and improve navigation through the large bowel. The left lateral (LL) decubitus starting position is commonly used during colonoscopy. However, reports indicate that other starting positions may offer additional benefit. We aimed to determine if the right lateral (RL) starting position compared to the standard LL starting position could improve outcomes in colonoscopy. METHODS: We searched PubMed, Medline, and EMBASE through June 2020 to identify studies comparing RL and LL starting positions during colonoscopy. The primary outcomes included mean cecal insertion time and cecal intubation rate, and adverse events were assessed by pooling data using a random-effects model expressed in terms of odds ratio (OR), mean difference, and 95% confidence interval (CI). RESULTS: We identified 5 randomized controlled trials, including 809 participants, that compared LL vs. RL colonoscopy. The pooled OR for cecal intubation rate was 1.3 (95%CI 0.8-2.3; P=0.3). The mean difference in mean cecal insertion time was 0.08 (95%CI -0.09 to 0.26; P=0.4). Heterogeneity between studies was low (I 2=0%). No complications were reported in either arm of the study. Pain scores assessed using a visual analog scale were comparable among both arms of the study. CONCLUSION: The RL starting position for colonoscopy was comparable to the LL and offered no additional benefit in terms of cecal intubation time, intubation rate, or patient discomfort.

Metabolic disorders and the risk of cholangiocarcinoma.

Introduction: Cholangiocarcinoma (CCA) is a malignancy which arises from the biliary epithelium. Carcinogenesis of CCA is mainly linked to aberrant glucose metabolism and creation of an immunosuppressive environment around normal biliary epithelium. The incidence of CCA is higher in the East due to Opisthorchis viverrini, an endemic liver fluke. CCA has also be attributed to genetic, metabolic, and lifestyle risk factors.Areas covered: Differences in epidemiological risk factors are associated with varying phenotypes of CCA. Metabolic risk factors include diabetes, obesity, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome. Inherited metabolic risk factors include Wilson's disease and hemochromatosis. Metabolic disease is associated with a higher risk of CCA, with higher risk for the intrahepatic form. In this review, the authors provide an overview of available evidence regarding metabolic conditions associated with the development of CCA.Expert opinion: Metabolic disease is associated with a higher risk of intrahepatic CCA compared to its extrahepatic or hilar counterpart. As rates of obesity and metabolic syndrome increase, particularly in the West, it is conceivable that the incidence of CCA will also rise in the next years.

Locoregional Treatments in Cholangiocarcinoma and Combined Hepatocellular Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a primary and aggressive cancer of the biliary tree. Combined hepatocellular cholangiocarcinoma (CHC) is a distinctive primary liver malignancy which has properties of both hepatocytic and cholangiocytic differentiation. CHC appears to have a worse prognosis compared to hepatocellular carcinoma, and similar to that of intrahepatic CCA. While significant advances have been made in understanding the pathophysiology and treatment of these two tumor types, their prognosis remains poor. Currently, liver resection is the primary treatment modality; however, only a minority of patients are eligible for surgery. However, the use of locoregional therapies proves an alternative approach to treating locally advanced disease with the aim of converting to resectability or even transplantation. Locoregional therapies such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), radiofrequency ablation (RFA), and photodynamic therapy (PDT) can provide patients with tumor control and increase the chances of survival. In this review, we appraise the evidence surrounding the use of locoregional therapies in treating patients with CCA and CHC.

Wet- versus dry-suction techniques for EUS-FNA of solid lesions: A systematic review and meta-analysis.

The optimal sampling techniques for EUS-FNA remain unclear and have not been standardized. To improve diagnostic accuracy, suction techniques for EUS-FNA have been developed and are widely used among endoscopists. The aim of this study was to compare wet-suction and dry-suction EUS-FNA techniques for sampling solid lesions. We performed a comprehensive literature search of major databases (from inception to June 2020) to identify prospective studies comparing wet-suction EUS-FNA and dry-suction EUS-FNA. Specimen adequacy, sample contamination, and histologic accuracy were assessed by pooling data using a random-effects model expressed in terms of odds ratio (OR) and 95% confidence interval (CI). Six studies including a total of 418 patients (365 wet suction vs. 377 dry suction) were included in our final analysis. The study included a total of 535 lesions (332 pancreatic lesions and 203 nonpancreatic lesions). The pooled odds of sample adequacy was 3.18 (CI: 1.82-5.54, P = 0.001) comparing wet- and dry-suction cohorts. The pooled odds of blood contamination was 1.18 (CI: 0.75-1.86, P = 0.1). The pooled rate for blood contamination was 58.33% (CI: 53.65%-62.90%) in the wet-suction cohort and 54.60% (CI 49.90%- 59.24%) in the dry-suction cohort (P = 0.256). The pooled odds of histological diagnosis was 3.68 (CI 0.82-16.42, P = 0.1). Very few adverse events were observed and did not have an impact on patient outcomes using either method. EUS-FNA using the wet-suction technique offers higher specimen quality through comparable rates of blood contamination and histological accuracy compared to dry-suction EUS-FNA.

Systematic review with meta-analysis: bariatric surgery reduces the incidence of hepatocellular carcinoma.

BACKGROUND: Obesity is a risk factor for non-alcoholic steatohepatitis (NASH) and increases the risk of several cancer types including cancers of the liver. Bariatric surgery can provide durable weight loss, but little is known about the later development of hepatocellular carcinoma (HCC) after surgery. AIM: To determine whether bariatric surgery reduces the risk of HCC. METHODS: We performed a comprehensive literature search of major databases (from inception to November 2020) to identify studies which assess the incidence and risk of HCC following bariatric surgery. Pooled data were assessed using a random-effects model expressed in terms of odds ratio (OR), incidence rate ratio and 95% confidence interval (CI). RESULTS: Nine studies (two abstracts and seven full texts) were included for meta-analysis which involved 19 514 750 patients (18 423 546 controls and 1 091 204 bariatric patients). Pooled unadjusted odds ratio (OR) was 0.40 (95% CI: 0.28-0.57) which favoured bariatric surgery, though with high heterogeneity (I2 : 79%). Using an adjusted model derived from matched cohorts (five studies) yielded an OR of 0.63 (95% CI: 0.53-0.75) with moderate heterogeneity (I2 : 38%). The pooled rate/1000 person-years was 0.05 (95% CI: 0.02-0.07) in bariatric surgery patients and 0.34 (95% CI: 0.20-0.49) in the control group with an incidence rate ratio of 0.28 (95% CI: 0.18-0.42). CONCLUSION: Bariatric surgery is associated with a decreased risk of HCC.

Influence of the Elipse Intragastric Balloon on Obesity and Metabolic Profile: A Systematic Review and Meta-Analysis.

BACKGROUND: Intragastric balloons (IGBs) have been used to bridge the obesity treatment gap with the benefits of being minimally invasive but still required endoscopy. The Elipse IGB is a swallowable balloon that is spontaneously excreted at ∼16 weeks. However, studies are limited by small sample sizes. The authors aim to assess clinically relevant endpoints, namely weight loss outcomes, metabolic profile, balloon tolerability, and adverse events. METHODS: A literature search was performed from several databases from inception to July 2020. The pooled means and proportions of our data were analyzed using a random effects model. RESULTS: Seven studies involving 2152 patients met our eligibility criteria and were included. The mean baseline body mass index ranged from 32.1 to 38.6. The pooled mean difference (MD) in body mass index was 0.88 [confidence interval (CI): 0.58-1.18, I2=98%]. Total body weight loss was 12% (CI: 10.1-14.3, I2=94%) and excess body weight loss was 49.1% (CI: 30.6-67.5, I2=97%). The MD in waist circumference was 0.89 (CI: 0.72-1.05, I2=53%). MD in triglyceride level was 0.66 (CI: 0.21-1.1, I2=96%). Pooled early deflation rate was 1.8% (CI: 0.6-5.1, I2=74%). Our study also showed that the Elipse balloon was associated with less adverse events when compared with other IGBs. CONCLUSIONS: This meta-analysis demonstrates that the Elipse intragastric balloon is a safe, effective, and tolerable device for weight loss and obesity with a minimal side effect profile.

Demographics, tumor characteristics, treatment, and clinical outcomes of patients with ampullary cancer: a Surveillance, Epidemiology, and End Results (SEER) cohort study.

BACKGROUND: Ampullary cancer accounts for only 0.2% of gastrointestinal cancers. The objective of this study was to investigate the incidence, demographics, tumor characteristics, treatment, and survival of patients with ampullary tumors. METHODS: Data on ampullary cancer between 2004 and 2013 was extracted from the Surveillance, Epidemiology and End Results (SEER) Registry. The clinical epidemiology of these tumors was analyzed using SEER*Stat. RESULTS: A total of 6803 patients with ampullary cancer were identified. Median age at diagnosis was 71±13 years. The overall age-adjusted incidence of ampullary cancer was 0.59 per 100,000 per year. A higher incidence of ampullary cancer was observed in males compared to females (0.74 vs. 0.48 per 100,000 per year). Most tumors were moderately differentiated (39.5%). The most common stage at presentation was Stage I (21%), followed by Stage II (20%). The majority (63%) of these tumors were surgically resected while 20% of patients received radiotherapy. One and 5-year cause-specific survival for ampullary cancer was 71.7% and 38.8% respectively, with a median survival of 31 months. On Cox regression analysis, black race, increasing cancer stage and grade, N1 stage, and non-surgical treatment were associated with poorer prognosis. Those who were not treated with surgical intervention were at 4.5 times increased risk for death (hazard ratio 4.5, 95% CI: 3.93-5.09, P=0.000). CONCLUSIONS: The annual incidence of ampullary cancer has been fairly constant, though males are more likely to be affected. While its incidence increases with age, patients who are treated by surgical intervention have significantly better outcomes. Additionally, through the use of endoscopic techniques, ampullary cancer can be detected and treated much earlier.

Role of complement component C1q in the onset of preeclampsia in mice.

Preeclampsia (PE) is a life-threatening, pregnancy-induced disease and a leading cause of maternal and fetal morbidity and mortality. Despite considerable research, the causes of PE remain unclear, and there is no effective treatment. Studies in animal models that resemble this complex pregnancy-related disorder may help to identify possible therapies for PE. Complement component C1q has an important role in trophoblast migration, spiral arteries remodeling, and normal placentation. Here we show that pregnant C1q-deficient (C1q(-/-)) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, decreased placental vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1 (sFlt-1) that correlate with increased fetal death. In addition, decreased blood flow and increased oxidative stress are observed in placentas from C1q(-/-) mice. Treatment of C1q(-/-) mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of PE. Serum-soluble receptors for VEGF-1 levels were reduced and placental VEGF levels were significantly increased in C1q(-/-) mice treated with pravastatin compared with untreated C1q(-/-) mice (VEGF: 1067±171 versus 419±194 pg/mL; P<0.01). Pravastatin treatment reduced hypertension (change in mean arterial pressure: 1±1 versus 18±3 mm Hg in C1q(-/-) untreated mice), and albuminuria (of creatinine) was reduced from 820±175 to 117±45 µg/mg (both P<0.01). Renal damage and endothelial dysfunction were significantly attenuated with pravastatin. This model that highlights the causative role of impaired trophoblast invasion in the pathogenesis of PE allowed us to identify pravastatin as a good therapeutic option to prevent PE.

A new mouse model to explore therapies for preeclampsia.

BACKGROUND: Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels) that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF) signaling by soluble VEGF receptor 1 (sFlt-1) is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies. CONCLUSIONS/SIGNIFICANCE: We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.