Elisa Piromalli

Gallbladder cancers: associated conditions, histological types, prognosis, and prevention.

Introduction Gallbladder cancer has a poor prognosis, with a reported 5-year survival of 5%. The prognosis improves when an R0 resection is feasible, but an early diagnosis is rare. The aim of the present study is to analyze the different conditions associated with gallbladder carcinomas and to report the main prognostic factors for these tumors to enable prevention. Materials and methods From 1986 to 2012, 75 patients were found to have gallbladder cancer during the study of 2942 patients affected by biliary tract diseases; 34 of these patients had gallbladder and gallstones, and had been subjected to bile analysis. Pancreatobiliary reflux was studied by biliary trypsin and C-Ki-ras genes were analyzed in 11 cases. Results Gallstones were found in 72 of 75 gallbladder cancer patients; in particular, large gallstones were associated with 88.88% of squamous-cell carcinoma, 68.2% of adenocarcinoma, and never with papillary adenocarcinoma. Pancreatobiliary reflux was associated with papillary adenocarcinoma in 100% of cases, but seldom with squamous cell carcinoma. C-Ki-ras mutations were found in 100% of patients with papillary carcinoma. Discussion and conclusion R0 resection in in-situ cancer has the best prognosis. Preventive cholecystectomy should be performed in high-risk patients (gallstones larger 3 cm; adenomatous polyps>1 cm; pancreatobiliary reflux, porcelain gallbladder, segmental adenomyomatosis, xanthogranulomatous cholecystitis). The histological stratification of gallbladder cancer should be carried out before starting further studies because squamous-cell carcinoma, adenocarcinoma, and papillary carcinoma are associated with different risk factors and genetic mutations and have different responsiveness to chemotherapies.

Role of parietal (gallbladder mucosa) factors in the formation of black pigment gallstones

In a recent number of Clinics and Research in Hepatology nd Gastroenterology a very interesting article of Vitek and arey about the pathogenesis of black pigment gallstones as been published [1]. In the conclusion, authors stated that endogenous biliary -glucuronidase hydrolysis of bilirubin conjugates provides ydrogen bilirubinate that precipitates with ionized calcium nd that inflamed gallbladder mucosa secretes reactive oxyen species that transform the initial precipitates into hard lack pigment gallstones with the participation of a mixed ucin glycoprotein matrix acting as the gallstones scaffoldng.

Ultrastructural basis of the failure of oral dissolution therapy with bile salts and/or statin for cholesterol gallstones

.The efficacy of oral bile salts and statins in the dissolution of calcium bilirubinateor calcium phosphate, as well as in the elimination of the parietal (gallbladdermucosa) factors of gallstone formation have never been described or proved.In conclusion, the persistence of the parietal (gallbladder mucosa) factors ofcholesterol gallstones heterogeneous nucleation and the persistence of the pig-mented center of cholesterol gallstones

Chemotherapy and histological stratification of biliary tract cancers.

combination therapy with gemcitabine in the treatment of pancreatic cancer and has shown promising results in phase 2 trials in patients with advanced biliary tract cancers [4] , but there was no significant difference in median progression-free survival among the chemotherapy group and chemotherapy plus erlotinib group; moreover, the progression-free survival was only 5.8 months [4] (vs. 11.7 months in the ABC-02 trial) [5] . Also, other phase 2 clinical trials with gemcitabine and capecitabine [2] or with gemcitabine plus oxaliplatin, panitumumab and capecitabine [3] reported lower progression-free survival rates of 6.33 and 8.3 months, respectively [2, 3] . The results reported by these studies are probably related to the great histological and biological variation in biliary tract cancers. A histological stratification of biliary tract cancer patients has been suggested to be important for a better interpretation of phase 2 and 3 chemotherapy trials [6, 7] . In fact, chemotherapeutics have different mechanisms of action and different targets: platinum-based agents exert their cytotoxic effects on tumor cells by inducing a strong binding to DNA during the G1 phase; 5-fluorouracil (FU) and pemetrexed are folate antimetabolites that inhibit three enzymes required for purine and pyrimidin synthesis; gemcitabine acts at three levels: (a) it is a nucleotide analog Dear Editor, Recently, several studies about chemotherapy in biliary tract cancers have been published [1–4] . Emerging therapeutic options of chemotherapy were reported and the authors concluded that further studies are necessary in order to improve the prognosis of these diseases [1–4] . In fact, since gallbladder cancers and cholangiocarcinomas are usually diagnosed in advanced stage, prognosis is poor. Recently, the use of the following treatment regimens has been proposed: gemcitabine plus capecitabine [2] , gemcitabine plus oxaliplatin and panitumumab [3] , or gemcitabine and oxaliplatin plus erlotinib in biliary tract cancers [4] , and these authors continue to conduct multicenter trials on ‘biliary tract’ cancer rather than on gallbladder cancer and cholangiocarcinoma separately [1–4] . This methodological bias negatively affected the final results. Some considerations are necessary in order to improve future trial results by comparing homogeneous data. Combination therapy with gemcitabine and a platinum-based agent is actually the best treatment for inoperable biliary tract cancers with a reported median overall survival of 11.7 months in a phase 3 trial [5] . Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor that targets the adenosine triphosphate binding site and inhibits EGFR tyrosine kinase activity. Erlotinib has been approved for Received: March 12, 2012 Accepted after revision: April 5, 2012 Published online: June 6, 2012

Prevention of biliary stent occlusion.

Dear Editor, An interesting article has been recently published in Digestive Diseases and Sciences on the comparative evaluation of early biliary stent occlusion among traditional plastic and wing stents [1]. The authors treated 364 patients affected by malignant and benign biliary tract diseases with conventional and wing plastic stents. Plastic biliary stents were preferred to metal stents also in patients with malignant biliary tract diseases because of their lower costs [1]. In fact, plastic traditional and wing stents have an average costs of 146 and 68 US dollars, respectively [1], and metal stents have an additional cost of nearly 1,820 US dollars [2, 3]. The 3-month stent occlusion rates were 27 and 21% for the wing and the conventional plastic stents, respectively [1]. The 3-month stent occlusion is nearly 9% in a novel double stent metal system [4]. Treatment with ursodeoxycholic acid and/or antibiotics cannot be recommended routinely for the prevention of biliary stent occlusion [5], in particular because it is ineffective in the dissolution of calcium bilirubinate, which is the principal constituent of the clogging material that is very similar to brown pigment gallstones. Ultrastructural analysis of brown pigment gallstones reveals large amounts of calcium bilirubinate, calcium palmitate, bacteria, and little cholesterol [6]. Infrared spectroscopy reported the percentage of calcium bilirubinate in brown pigment stones to range from 34 to 68% [7]. In vitro dissolution of brown and black pigment gallstones (calcium bilirubinate gallstones) has been achieved using a buffered alkaline 1% ethylene-diamine-tetra-acetate solution (BA-EDTA) [8]. Intravenous chelation therapy with disodium ethylenediamine-tetra-acetic acid (Na2EDTA) has been used for the treatment of coronary disease but has since been abandoned [9]. Intravenous ethylene-diamine-tetra-acetate compounds (EDTA-compounds) have never been used in vivo for gallstone dissolution. A model of hydrophobincoated plastic biliary stents seems to reduce the amount of deposition of adherent material on the stents [10]. In conclusion, further in vivo studies on the biliary stent patency of coated plastic stents with hydrophobin or with hydrophobin in combination with heparin will be necessary to state if these stents will be a good compromise for a lower stent cost and the necessity for delay of the calcium bilirubinate clogging processes that actually cause the stent obstruction in 21–27% of patients after 3 months [1].

Could omega-3 fatty acid prolonged intake reduce the incidence of symptomatic cholesterol gallstones disease?

Dear Editor, I read with great interest a recent debate on the influence of omega-3 fatty acid intake, during total parenteral nutrition, on cholesterol gallstones.1 In fact, cholesterol gallstones formation can be distinguished into two steps2: a) cholesterol suprasaturation and cholesterol crystals precipitation, that is quite well known and b) cholesterol crystals aggregation and fusionwith the participation of mucin, unconjugated bilirubin and calcium salts, to form macroscopic gallstones, that is still unclear. Some drugs as ursodeoxycholic acid (UDCA) or Statins or Ezetimibe can reduce cholesterol saturation in bile but they do not radically act on gallstones formation or dissolution.3 The main limit of these drugs is that they do not affect the so called mucosal or parietal factors of gallstones formation (as mucin) nor the deconjugation of bilirubin3 (Table 1). The interesting finding of Diamante et al. is related to the disappearance of a radiolucent cholesterol gallstone after long-term use of 3-omega fatty acid.1 This effect could be related to a possible influence of omega-3 fatty acid on both cholesterol (saturation) and mucosal factors of gallstones formation (Table 1). In fact, in an experimental model with mice, N-3 polyunsaturated fatty acid reduces cholesterol gallstones formation by suppressing the mucin production and the MUC2, MUC5AC, MUC5B and MUC 6 mRNA expression levels.4 The protective

Anal stretch for chronic anal fissure: an old operation that stood the test of time

Dear Editor, In a recent issue, an interesting article on botulinum toxin injection versus lateral internal sphincterotomy for the treatment of chronic anal fissure has been published [1]. In the results, the authors reported that lateral internal sphincterotomy has a higher risk of anal incontinence (4 %) [1] and that botulinum has higher recurrence rate [1]; in the conclusion, it appears that these two approaches do not completely satisfy patients. We would like to make a comment on the role of anal stretch plus fissurectomy in chronic anal fissure. From 2008 to 2011, we managed 428 medical therapyresistant patients by two-digital (one finger per hand) stretch operation plus fissurectomy (performed with lowpower electric coagulator). Patients were sent to us by family doctors after failure of medical therapy. At the same time, 27 left lateral internal sphincterotomy have been done. Digital stretch has been done for 2–3 min, with patients in spinal (epidural) anesthesia, in gynecological position, acting only at 3 and 9 o’clock anal points, over the internal sphincter and never on the external one. Follow-up has been done during ambulatory controls every 2 weeks for 1–6 months. Minor transient incontinence rates were 3 % after anal stretch and 14.8 % after sphincterotomy (p<0.05). Major incontinence rates were nihil after manual stretch and 3 % after sphincterotomy (p nearly 0.05). Anal stretch had good results in more than 95 % of patients. Old studies reported a 12.5 % rate of minor incontinence after anal dilatation for chronic anal fissure [2]. Recent studies comparing controlled intermittent anal dilatation versus lateral sphincterotomy reported an 85– 90 % rate of healing without incontinence [3]. Moreover, a randomized study on pneumatic balloon dilatation versus lateral internal sphincterotomy reported, after a 24months follow-up, a nihil incontinence rate after anal dilatation and a 16 % incontinence rate after sphincterotomy (p<0.001) [4]. Recently, Gupta reported the good results of the closed manipulation of the internal sphincter on 301 patients with a 96 % rate of complete healing and a 97 % rate of complete restoration of anal continence after 1 month [5] (Table 1). Anal stretch, when correctly performed (as all the surgical techniques) is an excellent and safe procedure for the treatment of medical therapyresistant chronic anal fissure patients. It has more than 95 % of good results without a risk of major and persistent anal incontinence. A recent review article [6] indicated, among anal stretching treated patients, high recurrence rate (up to 80 %) and high anal incontinence rate (up to 51 %) [6]. Probably, these data could be related to the old Lord technique (performed using four fingers/each hands!) that have been obviously abandoned. The risk of such reports is to underestimate the value of an old operation that in expert hands (and fingers) has very good results. Our technique act as a low energy anal dilatation (that do not damage sphincters) plus fissurectomy that enhance wound healing. In this way, we obtain high A. Cariati (*) : I. Torelli General Surgery, San Martino, IST Hospital, Via Fratelli Coda 67/5 a, 16166 Genoa, Italy e-mail: andrea.cariati@libero.it

Postpneumonectomy bronchial stump recurrence and bronchopleural fistula

Objective: To reduce the incidence of postpneumonectomy local recurrence, and to prevent the onset of bronchopleural fistula. Background: A long bronchial stump with a short tumor-free bronchial margin has been found to be associated with a higher incidence of local recurrence, and with the development of bronchopleural fistula in some cases. Methods: 134 patients underwent pneumonectomy for non-small-cell lung cancer in 2 institutions. Bronchial stump length was measured intra- and postoperatively. Results: 30-day postoperative mortality was 2.9%. There were 3 postoperative bronchopleural fistulas after right pneumonectomy (3/61) and one after left pneumonectomy (1/73; p = 0.2; fistula was more frequent in the long-stump group), which were successfully treated with carina sutures in 75% of cases. The overall incidence of local recurrence was strongly related to the presence of tumoral microinvasion in the resection margin (100%). Conclusion: To prevent postpneumonectomy bronchial stump complications, it might be useful to use carina closure instead of bronchial closure. Carina closure can reduce local recurrence, significantly reduce the fistulization rate, and eliminate the stump diverticulum. Reduction of the length of the bronchial stump can be achieved using a TA Roticulator linear stapler.

Conservative or operative management (open or laparoscopic) of acute appendicitis

We read with interest the recent article on antibiotics versus appendectomy in the management of acute appendicitis.1 A randomized controlled trial by Hansson and colleagues2 with a median follow-up of 1 year reported that of 202 patients who received antibiotics, 96 (nearly 50%) were subsequently admitted for surgery. A trial by Styrud and colleagues3 reported that of 128 patients receiving antibiotics, 18 were subsequently operated (15%). All these data confirmed that it is not possible to manage all the cases of acute appendicitis with antibiotics alone.1

Effects of compression therapy and antibiotics on lymphatic flow and chronic venous leg ulceration

Dear Editor, In a recent number of Archives of Dermatological Research, an interesting article on the treatment of venous ulcer has been published [6]. Authors stated that oral doxycycline as an adjunction to compression therapy improves treatment results of lower limb chronic venous ulceration, but that the mechanism of action remain unclear [6]. During the last 20 years, we published some studies about the role of lymphatic in leg acute venous thrombosis and in post-thrombotic syndrome [2]. In fact, after the relief of the venous obstruction that is always associated with a compensatory acceleration of the lymph flow in the affected limb [2], it is possible to find two conditions: in patients without several venous and lymphatic damages, the lymph flow return to normality; on the contrary, in patients with a retarded limb lymph flow (patients with lymphangitis, lymphatic hypoplasia, dermatitis), the risk of skin ulceration is high because an inadequate lymph flow is always associated with the formation and the persistence of the venous ulcers [2]. The elastic compression therapy and the local disinfection are of fundamental importance to prevent and to cure skin ulceration [5] also in the presence of arterial insufficiency [4]. Penicillin and other antibiotics contribute to a significant reduction in adenolymphangitis when combined with foot-care [1]. In conclusion, after the diagnosis with echo-doppler, a lymphoscintigraphy should be performed in order to follow the progression of the disease, because in patients with a normal lymphoscintigraphy the risk of skin ulceration is lower; on the contrary, in patients with an abnormal lymphoscintigraphy the risk of the formation of venous ulcer is higher. In these last cases, a particular effort should be done to cure venous hypertension (ligation of incompetent perforating veins, use of elastic compression therapy) and to prevent the lymphatic damages due to the dermatolymphangitis, which are the main factors associated with venous skin ulceration. The prevention and the treatment of dermatolymphangitis with antibiotics as penicillin or oral doxycycline allow maintaining the patency of lymphatics. In fact, in patients with uncured venous ulcers, bacteria and bacteria fragments (as cellular membrane proteins) are present in lymphatic capillaries, collectors and lymph nodes. Bacteria recall white blood cells [7, 8] that stimulate lymphocytes growth. Lymphatic collectors and nodes are blocked or clogged by lymphocytes, white cells and macromolecules [3]. Antibiotics kill and depress bacterial activity in lymphatic collectors and nodes. The reduction of the infection and of the inflammation of the lymphatics and of the lymph nodes allows an improvement of the lymphatic drainage of the interstitial fluids and catabolins. The local reduction of white cells, lysosomal enzymes and catabolins facilitate the healing of the ulcer.