The Role of Colonoscopy in the Management of Individuals with Lynch Syndrome: A Narrative Review.

The history of Lynch syndrome changed definitively in 2000, when a study published in Gastroenterology demonstrated a significant reduction in mortality among individuals with Lynch syndrome who undergo regular endoscopic surveillance. As a consequence of this clinical evidence, all scientific societies developed guidelines, which highlighted the role of colonoscopy in the management of Lynch syndrome, especially for individuals at high risk of colorectal cancer. Over the years, these guidelines were modified and updated. Specialized networks were developed in order to standardize endoscopic surveillance programs and evaluate all the clinical data retrieved by the results of colonoscopies performed for both the screening and the surveillance of individuals with Lynch syndrome. Recent data show that the impact of colonoscopy (with polypectomy) on the prevention of colorectal cancer in individuals with Lynch syndrome is less significant than previously thought. This narrative review summarizes the current discussion, the hypotheses elaborated and the algorithms depicted for the management of individuals with Lynch Syndrome on the basis of the recent data published in the literature.

Impact of endobiliary radiofrequency ablation on survival of patients with unresectable cholangiocarcinoma: a narrative review.

Cholangiocarcinoma (CCA) is a rare cancer originating from the biliary epithelium and accounts for about 3% of all gastrointestinal malignancies. Unfortunately, the majority of patients are not eligible for surgical resection at the time of diagnosis, because of the locally advanced stage or metastatic disease. The overall survival time of unresectable CCA is generally less than 1 year, despite current chemotherapy regimens. Biliary drainage is often required as a palliative treatment for patients with unresectable CCA. Recurrent jaundice and cholangitis tend to occur because of reobstruction of the biliary stents. This not only jeopardizes the efficacy of chemotherapy, but also causes significant morbidity and mortality. Effective control of tumor growth is crucial for prolonging stent patency and consequently patient survival. Recently, endobiliary radiofrequency ablation (ERFA) has been experimented as a treatment modality to reduce tumor mass, and delay tumor growth, extending stent patency. Ablation is accomplished by means of high-frequency alternating current which is released from the active electrode of an endobiliary probe placed in a biliary stricture. It has been shown that tumor necrosis releases intracellular particles which are highly immunogenic and activate antigen-presenting cells, enhancing local immunity directed against the tumor. This immunogenic response could potentially enhance tumor suppression and be responsible for improved survival of patients with unresectable CCA who undergo ERFA. Several studies have demonstrated that ERFA is associated with an increased median survival of approximately 6 months in patients with unresectable CCA. Furthermore, recent data support the hypothesis that ERFA could ameliorate the efficacy of chemotherapy administered to patients with unresectable CCA, without increasing the risk of complications. This narrative review discusses the results of the studies published in recent years and focuses on the impact that ERFA could have on overall survival of patients with unresectable cholangiocarcinoma.

Risk Assessment and Pancreatic Cancer: Diagnostic Management and Artificial Intelligence.

Pancreatic cancer (PC) is one of the deadliest cancers, and it is responsible for a number of deaths almost equal to its incidence. The high mortality rate is correlated with several explanations; the main one is the late disease stage at which the majority of patients are diagnosed. Since surgical resection has been recognised as the only curative treatment, a PC diagnosis at the initial stage is believed the main tool to improve survival. Therefore, patient stratification according to familial and genetic risk and the creation of screening protocol by using minimally invasive diagnostic tools would be appropriate. Pancreatic cystic neoplasms (PCNs) are subsets of lesions which deserve special management to avoid overtreatment. The current PC screening programs are based on the annual employment of magnetic resonance imaging with cholangiopancreatography sequences (MR/MRCP) and/or endoscopic ultrasonography (EUS). For patients unfit for MRI, computed tomography (CT) could be proposed, although CT results in lower detection rates, compared to MRI, for small lesions. The actual major limit is the incapacity to detect and characterize the pancreatic intraepithelial neoplasia (PanIN) by EUS and MR/MRCP. The possibility of utilizing artificial intelligence models to evaluate higher-risk patients could favour the diagnosis of these entities, although more data are needed to support the real utility of these applications in the field of screening. For these motives, it would be appropriate to realize screening programs in research settings.

A multicenter randomized phase 4 trial comparing sodium picosulphate plus magnesium citrate vs. polyethylene glycol plus ascorbic acid for bowel preparation before colonoscopy. The PRECOL trial.

Background: Adequate bowel preparation before colonoscopy is crucial. Unfortunately, 25% of colonoscopies have inadequate bowel cleansing. From a patient perspective, bowel preparation is the main obstacle to colonoscopy. Several low-volume bowel preparations have been formulated to provide more tolerable purgative solutions without loss of efficacy. Objectives: Investigate efficacy, safety, and tolerability of Sodium Picosulphate plus Magnesium Citrate (SPMC) vs. Polyethylene Glycol plus Ascorbic Acid (PEG-ASC) solutions in patients undergoing diagnostic colonoscopy. Materials and methods: In this phase 4, randomized, multicenter, two-arm trial, adult outpatients received either SPMC or PEG-ASC for bowel preparation before colonoscopy. The primary aims were quality of bowel cleansing (primary endpoint scored according to Boston Bowel Preparation Scale) and patient acceptance (measured with six visual analogue scales). The study was open for treatment assignment and blinded for primary endpoint assessment. This was done independently with videotaped colonoscopies reviewed by two endoscopists unaware of study arms. A sample size of 525 patients was calculated to recognize a difference of 10% in the proportion of successes between the arms with a two-sided alpha error of 0.05 and 90% statistical power. Results: Overall 550 subjects (279 assigned to PEG-ASC and 271 assigned to SPMC) represented the analysis population. There was no statistically significant difference in success rate according to BBPS: 94.4% with PEG-ASC and 95.7% with SPMC (P = 0.49). Acceptance and willing to repeat colonoscopy were significantly better for SPMC with all the scales. Compliance was less than full in 6.6 and 9.9% of cases with PEG-ASC and SPMC, respectively (P = 0.17). Nausea and meteorism were significantly more bothersome with PEG-ASC than SPMC. There were no serious adverse events in either group. Conclusion: SPMC and PEG-ASC are not different in terms of efficacy, but SPMC is better tolerated than PEG-ASC. SPMC could be an alternative to low-volume PEG based purgative solutions for bowel preparation. Clinical trial registration: [ClinicalTrials.gov], Identifier [NCT01649674 and EudraCT 2011-000587-10].

Nab-Paclitaxel and Gemcitabine in Advanced Pancreatic Cancer: The One-year Experience of the National Cancer Institute of Naples.

BACKGROUND: Pancreas adenocarcinoma is the sixth cause of cancer-related death worldwide with an increasing mortality in the Western countries. Recently, the association between nab-paclitaxel (nab-P) and gemcitabine (GEM) has significantly improved progression-free and overall survival. PATIENTS AND METHODS: Patients affected by metastatic pancreas adenocarcinoma were treated at the Department of Abdominal Oncology of the National Cancer Institute of Naples from July 2015 to July 2016 with nab-P at 125 mg per square meter of body-surface area followed by GEM at 1,000 mg per square meter on days 1, 8 and 15 every 4 weeks. Computed tomography (CT) was performed every three months of therapy. Toxicity was graded with National Cancer Institute-Common Toxicity Criteria (NCI-CTC) v4.0. Objective responses were evaluated with Response Evaluation Criteria in Solid Tumors (RECIST). Analysis of time-to-progression is only descriptive. Pain was evaluated with a visual analogue scale (VAS). RESULTS: Twenty-three patients were treated. Median age was 67 years (range=45-81); 8 patients were ≥70 years old. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 2 in 8 patients, 1 in 10 and 0 in 5. Twelve patients presented with diffuse hepatic metastases, 4 with carcinosis, 7 with more than one organ involvement. Nab-P was reduced at 100 mg per square meter in all patients. The most common G3/G4 adverse events were neutropenia (13.0% G4, 8.6% G3; none was febrile), neuropathy (30.4% G3) and asthenia (G3 17.3%). The disease control rate was 43.4% (partial response+stable disease (PR+SD) 10/23). The median time-to-progression was 7.9 months (95% confidence interval (CI)=5.8-11.2). After three months of therapy the PS improved in 14 patients, as well as pain in 18 patients. CONCLUSION: We present an experience with nab-P and GEM association in a series with poor PS and highly metastatic disease relatively to a previous randomized study. The schedule is feasible, with nab-P at 100 mg per square meter achieving a good disease control rate, as well as a clinical benefit.

Role of endoscopic ultrasonography in the loco-regional staging of patients with rectal cancer.

The prognosis of rectal cancer (RC) is strictly related to both T and N stage of the disease at the time of diagnosis. RC staging is crucial for choosing the best multimodal therapy: patients with high risk locally advanced RC (LARC) undergo surgery after neoadjuvant chemotherapy and radiotherapy (NAT); those with low risk LARC are operated on after a preoperative short-course radiation therapy; finally, surgery alone is recommended only for early RC. Several imaging methods are used for staging patients with RC: computerized tomography, magnetic resonance imaging, positron emission tomography, and endoscopic ultrasound (EUS). EUS is highly accurate for the loco-regional staging of RC, since it is capable to evaluate precisely the mural infiltration of the tumor (T), especially in early RC. On the other hand, EUS is less accurate in restaging RC after NAT and before surgery. Finally, EUS is indicated for follow-up of patients operated on for RC, where there is a need for the surveillance of the anastomosis. The aim of this review is to highlight the impact of EUS on the management of patients with RC, evaluating its role in both preoperative staging and follow-up of patients after surgery.

Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it.

Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors (PNETs) can be functional, hormone secreting tumors, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNETs, usually present later either incidentally or due to tumor bulk symptoms. Currently Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is the most promising drug for patients with unresectable, metastatic disease, in progressive well-differentiated PNETs and many studies are ongoing to demonstrate its effects on the other neuroendocrine histotipes. Food and Drug Administration (FDA) and European Medicines Agency (EMA) registered Everolimus in advanced/metastatic breast cancer, in advanced/metastatic renal cell carcinoma and in well/moderately differentiated pancreatic neuroendocrine tumors. Nevertheless only a subset of patients respond to the therapy due to the development of drug resistance. Thus the powerful Everolimus antitumor activity have prompted extensive efforts to overcome drug resistance and to maximize clinical benefit. In this review we aim to summarize current knowledge on mechanisms of Everolimus and other mTOR inhibitors molecules resistance with the intent to overcome it.

A clinical and radiological objective tumor response with somatostatin analogs (SSA) in well-differentiated neuroendocrine metastatic tumor of the ileum: a case report.

Somatostatin analogs (SSAs) are typically used to treat the symptoms caused by neuroendocrine tumors (NETs), but they are not used as the primary treatment to induce tumor shrinkage. We report a case of a 63-year-old woman with a symptomatic metastatic NET of the ileum. Complete symptomatic response was achieved after 1 month of treatment with SSAs. In addition, there was an objective response in the liver, with the disappearance of secondary lesions noted on computed tomography scan after 3 months of octreotide treatment. Our experience suggests that SSAs could be useful for downstaging and/or downsizing well-differentiated NETs, and they could allow surgery to be performed. Such presurgery therapy could be a promising tool in the management of patients with initially inoperable NETs.

Is preoperative endoscopic biliary drainage indicated for jaundiced patients with resectable pancreatic cancer?

The role of preoperative biliary drainage (PBD) in the management of jaundiced patients with resectable pancreatic cancer (RPC) is controversial. Obstructive jaundice determines hepatic dysfunction which can increase the operative risks. Experimental studies demonstrated that PBD could be associated with improved surgical outcomes. However, clinical studies did not confirm these findings. Initial clinical studies conducted with percutaneous approach failed to demonstrate a real advantage for patients undergoing PBD before pancreaticoduodenectomy. Overall morbidity was higher in patients undergoing PBD, because of procedure-related complications. Similar results were obtained with endoscopic PBD. Six meta-analyses have not clarified the role of PBD in the management of patients with malignant jaundice undergoing pancreaticoduodenectomy, because of lack of uniformity among all the studies published. Recently, the results of a large randomized controlled trial indicated that direct surgery should be the best therapeutic strategy for jaundiced patients with RPC. The debate whether jaundiced patients with RPC should undergo PBD continues and the advent of neoadjuvant chemoradiotherapy added some arguments in favor of PBD. The latter is still considered the first step for jaundiced patients when they present with cholangitis, intense pruritus or severe jaundice; surgery cannot be scheduled within 7-10 days from the diagnosis; neoadjuvant chemoradiation is planned, as part of the treatment. While endoscopic PBD is considered the preferred approach, there is still controversy about the type of biliary stent which should be used. Emerging data support the insertion of short (4-6 cm) biliary self-expandable metallic stent, especially if surgery is not immediately planned.

Accuracy of endoscopic ultrasound in staging and restaging patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation.

BACKGROUND: To date, the role of endoscopic ultrasound (EUS) in restaging locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (NAT) have not been thoroughly investigated. AIM: To evaluate accuracy and clinical usefulness of EUS for both staging and restaging LARC. METHODS: According to EUS staging, patients with LARC were enrolled in the study. Those who underwent surgery directly represented a control group useful for evaluating the accuracy of EUS in staging LARC. In the study group, EUS was repeated seven weeks after NAT, before surgery. The results of EUS were compared with the corresponding pTN stages. RESULTS: From 2000 to 2006, 212 consecutive patients with RC underwent EUS staging. Among them EUS diagnosed 162 LARC (M/F = 93/69; mean age: 60 years [range 40-80]). The final study group included 85 patients with LARC. EUS restaging had an overall accuracy of 61% and 59% for T and N-stage, respectively. In the control group, the accuracy of EUS in staging LARC was 86% and 58% for T and N-stage, respectively. CONCLUSION: EUS accurately stages LARC and enables appropriate decision-making, with selection of those patients who need NAT. On the other hand, EUS restaging of LARC after NAT has low accuracy and should not be used in clinical practice.

Lower prevalence of diverticulosis in patients with ulcerative colitis.

PURPOSE: Colonic diverticulosis is characterized by abnormal thickening of the bowel wall, associated with luminal overpressure and increase of sigmoid contractility. However, patients with ulcerative colitis show chronic inflammatory alterations determining a reduction of both bowel wall muscle tone and contractility. Thus, we could presume ulcerative colitis and colonic diverticulosis as two pathophysiologically and mutually excluding diseases. This study was designed to evaluate the prevalence of colonic diverticulosis in patients with ulcerative colitis compared with a control endoscopic population. METHODS: We prospectively analyzed the prevalence of colonic diverticulosis in 85 patients, older than aged 45 years, with known ulcerative colitis compared with that in 85 age/gender-matched patients without colitis. All patients underwent pancolonoscopy with ulcerative colitis and colonic diverticulosis diagnosis made by endoscopy and histopathology. The patients with ulcerative colitis also were divided in three subgroups according to the age at diagnosis (<30 years, 30-45 years, >45 years) and extension of disease (sigmoiditis, left colitis, extensive colitis). RESULTS: Colonic diverticulosis was present in 7 of 85 patients with and in 24 patients without ulcerative colitis (8.2 vs. 28.2 percent; P < 0.001; relative risk, 3.4; 95 percent confidence interval, 1.56-7.52). All seven patients with both diseases were diagnosed with ulcerative colitis when older than age 45 years. No differences were found between the two groups in terms of extension of diverticula. CONCLUSIONS: Patients with ulcerative colitis show a significantly lower prevalence of colonic diverticulosis, with this finding probably reflecting the motor alterations caused by chronic bowel wall inflammation. In the patients affected by ulcerative colitis with late onset of the disease, the reduced prevalence of colonic diverticulosis is not evident.

Bowel wall thickness at abdominal ultrasound and the one-year-risk of surgery in patients with Crohn's disease.

OBJECTIVES: Abdominal ultrasound can assess the extent and localization of Crohn's disease, and an increased bowel wall thickness is the most common finding. Our aim was to correlate bowel wall thickness at ultrasound, with the risk of short-term surgical outcome in patients with Crohn's disease. MATERIALS AND METHODS: From 1997 to 2000 we performed ultrasound in 174 consecutive patients with Crohn's disease. Surgical operations were recorded over a 1-yr follow-up. Logistic regression analysis was performed to identify clinical and ultrasound risk factors for surgery. RESULTS: Fifty-two patients underwent surgery within 1 yr. Indication for surgery was strictures in most of the cases. Median bowel wall thickness was higher in patients with surgery (8 mm) than those without surgery (6 mm) (p < 0.0001). A receiver operating characteristic (ROC) curve was constructed taking into account bowel wall thickness for selecting patients with a high risk of surgery. The optimized cut-off for equally important sensitivity and specificity was calculated at 7.008 mm. The binary regression analysis showed that CDAI > 150, absence of previous surgery, stricturing-penetrating pattern, the presence of intestinal complications, and intestinal wall thickness >7 mm were associated with an increased risk of surgery. Patients with intestinal wall thickness >7 mm at ultrasound had the highest risk (OR: 19.521, 95% CI: 5.362-71.065). CONCLUSIONS: Data suggest that bowel wall thickness >7 mm at ultrasound is a risk factor for intestinal resection over a short period of time. Routine use of abdominal ultrasound during evaluation of patients with Crohn's disease may identify a subgroup that is at high risk for surgery. (Am J Gastroenterol 2004;99:1-7)