Dear Editors, We recently read the interesting article by Wang et al. on the spatio-temporal characteristics of the COVID-19 epidemic in the United States; they reported that COVID-19 cases diagnosed in the United States displayed statistically significant differences related to geographic and socio-demographic factors, including rural/urban context, the percentage of ethnic minorities, the percentage of the population aged 65 years or more etc [1]. However, they failed to report another important factor: the role of working activity. In Italy, COVID-19 mortality among medical doctors has been significantly higher than nurses or pharmacists. Indeed, at 1 March 2021 332 deaths have occurred among 403,454 medical doctors [2, 3], 81 among 426,707 nurses [4], and 23 among 127,513 pharmacists [5]. Two-tailed Chi-square test reveals statistically significant differences in COVID19-related mortality, with a p value < 0.00001, between physicians and nurses (Chi-square test value with Yates correction: 165.8748) (relative risk > 1 = 4.33) and between medical doctors and pharmacists (Chisquare test value with Yates correction: 58.9093) (relative risk > 1 = 4.56). In addition, in the 25-70-year age-range, on comparing COVID-19 mortality among medical doctors (240/358161) [3] and in the general population (12500/35665609) [6], the Chi square test and relative risk yielded values of 102.3566 and 1.91 respectively, confirming the higher COVID-19 mortality risk among medical doctors than in the general population in this age range. Moreover, a study on serum conversion to COVID-19 in Italy showed conversion in 2.5% of the general population and in 5.6% of healthcare personnel [7] indicating increased circulation of the virus in healthcare workers than the general population in the first pandemic period. In conclusion, the Chi square test, and relative risk have demonstrated that medical doctors have a higher risk of dying from COVID-19 than nurses, pharmacists and, in the 25-70-year age range, also versus the general population. Interestingly, the same results have been obtained in the USA and other countries. This is a major problem and one that could be tackled through extensive vaccination of the general population and healthcare personnel. In this regard, a particular effort should be made to convince skeptics that COVID-19 vaccination is of crucial importance not only to the individual but also to the community.

Introduction: Hernia surgery in cirrhotic patients can represent a life threatening condition.The aim of the study is to analyze the outcome of these patients in order to propose a modification of the MELD criteria for the liver transplantation waiting list. Material and Methods:Seventeen patients with cirrhosis (13 Child A and B, 4 Child C) and abdominal wall hernia (9 umbilical, 5 incisional, 3 inguinal hernias) that underwent elective (10 cases) or emergency (7 cases) surgery in our Institution, have been retrospectively studied.Hepatocellular carcinoma has been present in 7 cases. Results: Mortality have been null among Child A and B patients and it has been of the 100% among Child C patients with umbilical or incisional hernia (p ≤ 0.0004). All the patients with hepatocellular carcinoma and Child C died (mortality 100%). (p value result of comparison with Child A and B stages patients has been: 0,0286). Conclusion:These data suggest us to propose a modification of the MELD exceptions criteria P1 to organ allocation model for Child C patients that underwent emergency umbilical or incisional hernia.Also patients with hepatocellular carcinoma, Child C cirrhosis that underwent elective surgery for umbilical and incisional hernia could obtain extra-points in the waiting list prioritization.

Introduction: Biliary tract cancer (BTC) represents a rare and heterogenic tumour with aggressive behaviour. Mismatch repair deficiency (dMMR) seems to be associated with favourable prognostic characteristics in different gastrointestinal cancer types but its prevalence and correlation with clinical and pathological features in biliary tract cancer remain unclear. The aim of this study is to determine the incidence and characteristics of dMMR in a large multicentric cohort of cholangiocarcinoma and to explore its putative prognostic role both in resectable and in advanced settings. Methods: We retrospectively evaluated mismatch repair (MMR) status in a cohort of 149 patients with BTC including intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinoma and gallbladder cancer (GBC). Tumour sections were assessed by immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. A dMMR tumour was defined by the loss of expression of any of the four MMR proteins. The primary objective of the study was to evaluate the incidence of dMMR. Correlation between the presence of dMMR and different clinicopathological characteristics was evaluated by the Mann-Whitney test and Chi-square test. Association with chemotherapy activity in advanced disease setting was assessed by Chi-square test whereas log-rank test was used for correlation between MMR status and disease-free survival (DFS), progression free survival (PFS) and overall survival (OS). Results: Out of 149 enrolled patients, 67 had iCCA, 36 dCCA, 20 pCCA and 26 GBC; stage was 1 in 32, 2 in 40, 3 in 23 and 4 in 53 patients. At diagnosis 110 patients had resectable disease and were submitted to surgery (R0 90%, R1 8%, R2 2%). Among the patients with initially metastatic or recurrent disease, 60% received gemcitabine + platinum. Nine patients (7 diagnosed with resectable and 2 with metastatic disease) presented dMMR tumour (1 with loss of MLH1, 5 with loss of MLH-1 and PMS-2, 2 with loss of MSH-6 and 1 with loss of MLH-1, PMS-2 and MSH-6). Among the investigated characteristics, dMMR status was significantly correlated with tumour site (iCCA 11% vs others 2.4 %, p = 0.041) and mucinous histology (yes 50% vs no 4%, p0.005). Conclusion: A not negligible percentage of patients with BTC shows dMMR status. This seems to be more prevalent among patients with iCCA and tumours with mucinous histology. Putative poor prognostic role after potentially curative resection needs to be confirmed at longer follow up and in independent larger cohorts.

Although Prof. Erminio Cariati is no longer physically with us, his invaluable heritage remains with us forever, above all, for having conceived the new translational and interdisciplinary role of Lymphology and of Lymphatic Surgery in General and Specialistic Surgical Fields. Ingenious, innovative, and an enormously technically skilled surgeon, Prof. Cariati represented throughout his long scientific-clinical career, a constant landmark for his pupils, both direct and indirect, within the great School of his Mentor, Prof. Egidio Tosatti, including the undersigned, who had the high honor and privilege of working with him for so many years. The acme of his meritorious national, European and international success can be summed up in two main peaks, represented by the completion of his "Magna Opera" Treatise with the title "La Linfostasi e la Patologia del Dotto Toracico / Lymphostasis and Thoracic Duct Pathology" (Ed. Piccin, Padova, Italy 1978), and by his enlightened Presidency, in September 1979 in Florence, of the 7th International Congress of the International Society of Lymphology, that marked a turning-point in the history of the Congresses of our beloved ISL Society. Prof. Cariati was also a Member of the ISL Executive Committee and of the Editorial Board of Lymphology, Founder and Chairman of the European Academy of Lymphology. He was also a passionate Art lover and, above all, of painting: in his rare moments of free time from work, he himself loved to paint with an absolutely original and naturalistic chromatic style. Prof. Cariati was particularly distinguished by his great human qualities, such as loyalty to friends, self-denial, and absolute respect for familial traditions, as well as the ability to maintain always his patients in the center of his affections! "We will always remember you, dear Professor Cariati, above all in the most elated moments shared in scientific and research activity, and especially in the operating theatre!" Unfortunately Professor Erminio Cariati left us on the July 20, 2019, in Genoa san Martino Hospital where he worked for 45 years until, 15 years ago, a major left sided haemorragic stroke left him with a severe hemiplegia. Erminio was born in a small town, Torano Castello (on February 28, 1934), near Cosenza in the South of Italy as the last of 13 sons. At that time infant mortality was high and only 5 (Clementina, Abramo, Maria, Francesco, and the last, Erminio) of 13 sons, survived to croup, other infections and malnutrition. The father Giuseppe decided to give a better future for them and send the three brothers to study school at the catholic San Demetrio Corone College near Cosenza and then to Medicine university; Francesco and Erminio went to Siena University. Erminio, in Siena met professor Egidio Tosatti, who belonged to the school of Raffaele Paolucci from Valmaggiore, heroes of the First World War as a sinker of the Viribus Unitis battleship in Pola. Under Professor Tosatti, Erminio began studies on the lymphatic system and started publishing several articles. In 1967, the Master Tosatti started to move from Siena to Genoa University and three pupils - Prior, Casaccia and Cariati - followed him. In Genoa, Erminio continued studies on the lymphatic system publishing several articles and the masterpiece Book "La Linfostasi" edited by Piccin Padua; moreover, he opened the School of Thoracic Surgery of Genoa, and in 1979, he organized as President, the 7th International Congress of Lymphology in Florence; in the same years, he won the roles of Associate Professor in General Surgery and then of Ordinary Professor in General Surgery at Genoa University. During the years, he followed the transition of lymphatic surgery from excision surgery to lymph-venous anastomosis stressing the antigravitational role of lymph nodes in lymphatics and chylous reflux (chyledema, chylous ascites and chylothorax), and the different functions and roles of the lymphatic system also in neoplastic diseases (1-25); finally, he passed the baton of lymphatic surgery to Professors Campisi and Boccardo. During the last years of life, despite disease, he continued to follow patients that had been successfully operated on in the past for chylous and lymphatic disease and qho developed with him a true friendship.

Genomic analyses are identifying novel genes involved in the pathogenesis of non-small cell lung cancer (NSCLC). TMPRSS4, a membrane-anchored serine protease, was previously found as highly overexpressed in NSCLC. Since proteases have been functionally related to cancer growth and metastasis, we sought to study the prognostic value and role of TMPRSS4 in NSCLC. TMPRSS4 expression was evaluated by immunohistochemistry and H-score calculation in TMAs containing a total number of 455 cases. Kaplan-Meier, log-rank and Cox analyses were used to study the prognostic value. In addition, functional assays using NSCLC cell lines and in vivo models were used to assess the possible role of this protease in NSCLC. High expression of TMPRSS4 was associated with reduced relapse-free survival (RFS, p=0.003) and overall survival (OS, p=0.007) in NSCLC patients. The prognostic value was also found in patients with stages I-II. Multivariant Cox regression analysis identified TMPRSS4 as an independent prognostic factor in NSCLC for both RFS (HR 1.61 [1.16-2.23], p<0.004) and OS (HR 1.52 [1.14-2.03], p<0.005). In functional studies we developed genetic systems to overexpress or reduce TMPRSS4 levels in lung cancer cells lines. Overexpression in LKR13 cells led to increased clonogenicity, migration and multiorganic metastasis in liver, bone and suprarenal gland. Abrogation of TMPRSS4 in H358 and H2170 cell lines caused a very strong reduction in proliferation (>70%, 96h after plating), clonocenicity (>90%, after 15 days in culture) and subcutaneous tumor growth. Reduction in S and G2/M phases of the cell cycle, increased apoptosis, and changes in gene expression of cell replication- and migration-promoting genes (i.e. MCM6, TYMS and CDKN1A(p21)) were also found. Cells lacking TMPRSS4 were highly sensitized to chemotherapy, including cisplatin, paclitaxel and gemcitabine, which significantly enhanced the antiproliferative, antitumor and proapoptotic effect of these drugs. Our results show that TMPRSS4 is a biomarker of poor prognosis in NSCLC and plays an important role in tumor growth and metastasis, and suggest that its blockade may enhance sensitivity to chemotherapy.

BACKGROUND:The aim of this study was to report 2 cases of liver transplantation (LT) for iatrogenic bile-vascular injury (BVI) sustained during cholecystectomy and to review the literature for LT after cholecystectomy.METHODS:Between March 2001 and July 2013, within our institution, 12 patients were treated after cholecystectomy, 3 of 12 received LT, 1 for acute de-compensation in a cirrhotic patient and 2 after iatrogenic lesions.RESULTS:The majority of iatrogenic injury occurred during video-laparocholecystectomy (63,6%; 7/11). Three patients of 12 (25%) received LT: the first patient developed acute de-compensation in chronic and after liver failure. The second patient developed recurrent cholangitis and secondary biliary cirrhosis. The third patient had undergone emergency hepatectomy because of bleeding and subsequent total hepatectomy with porto-caval shunt. Five of 12 (42%) patients were treated with bilio-digestive anastomosis: 1 patient with direct repair on T-tube; 2 patients (17%) with arterial vascular lesion requiring surgical treatment; and 1 patient treated with medical therapy. No deaths occurred. The post-operative morbidity included 1 re-intervention, 3 recurrent cholangitis, 1 anastomotic biliary stricture, 1 anastomotic bile leak, and cholestasis in 3 patients. The overall hospital stays were higher after LT. Median follow-up was 8.25 years (range, 2-14).CONCLUSIONS:The management of iatrogenic injury during cholecystectomy depends on the time of recognition, extent of injury, experience of the surgeon, and the patient's general condition. If safe repair is possible, BVI should be treated promptly, otherwise all patients should be treated in an experienced center.

Biliary tract cysts are a group of rare congenital diseases that have been classified by Todani in 8 types. Hepaticojejunostomy has been the preferred intervention for Type I and IV biliary cysts. It has been postulated that, due to the low incidence of cancerization of Types II and III biliary cysts, a less invasive approach could be suggested, namely cyst resection in Type II, and endoscopic sphincterotomy with opening of choledochocele in small (<3 cm) Type III cysts from old patients. Moreover, Caroli disease has been proposed to be treated by percutaneous biliary drainages. The aim of the present study is to propose the therapeutics strategies to follow for the management of biliary tract cysts, in case of failure of percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP). From 2008 to May 2014, three patients with congenital biliary tract cysts were followed. Two patients were found to be affected by bilateral liver Caroli disease and another young patient was found to be affected by a Type III biliary cyst (choledochocele). Patients affected by Caroli disease presented cholangitis, jaundice and fever and have been submitted to PTC. PTC, after an initial brief relief of the symptoms, failed in both cases. One of these patients with recurrent post PTC cholangitis was then successfully treated by orthotopic liver transplant. The other patient affected by Caroli disease died after multiple PTC. The young patient affected by choledochocele suffered from pancreatitis and jaundice and was submitted to ERCP. Endoscopic resection of choledochocele was followed by hemorrhagia and a fatal fungal sepsis. Minimally invasive approaches have been widely used in the management of biliary tract cysts. Diffuse bilateral Caroli disease of the liver can be initially managed by percutaneous drainage but if cholangitis recurs, in our opinion, it is useful to consider an open surgery procedure such as orthotopic liver transplant. Type III biliary cyst (choledococele) can be managed by ERCP if patient is old and the cyst is small (<3 cm) but when the cyst is larger than 3 cm, symptomatic, and the patient is young, one approach to take into consideration is open duodenostomy with choledochocele resection and reimplantation of the common bile and of Wirsung ducts into the duodenal mucosa. [Arch Clin Exp Surg 2016; 5(2.000): 128-133]

The aim of the present study is to report our data on the treatment of third-and fourth-degree hemorrhoids with stapled technique and Milligan–Morgan operation in terms of postoperative results, costs, and recurrence.

In order to compare gallstone disease data from India and Asian countries with Western countries, it is fundamental to follow a common gallstone classification. Gallstone disease has afflicted humans since the time of Egyptian kings, and gallstones have been found during autopsies on mummies. Gallstone prevalence in adult population ranges from 10 to 15 %. Gallstones in Western countries are distinguished into the following classes: cholesterol gallstones that contain more than 50 % of cholesterol (nearly 75 % of gallstones) and pigment gallstones that contain less than 30 % of cholesterol by weight, which can be subdivided into black pigment gallstones and brown pigment gallstones. It has been shown that ultrastructural analysis with scanning electron microscopy is useful in the classification and study of pigment gallstones. Moreover, x-ray diffractometry analysis and infrared spectroscopy of gallstones are of fundamental importance for an accurate stone analysis. An accurate study of gallstones is useful to understand gallstone pathogenesis. In fact, bacteria are not important in cholesterol gallstone nucleation and growth, but they are important in brown pigment gallstone formation. On the contrary, calcium bilirubinate is fundamental in black pigment gallstone formation and probably also plays an important role in cholesterol gallstone nucleation and growth.

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.

Background. Echinococcosis is a zoonosis caused by the Echinococcus adult or larvae tapeworms. Surgery has been the mainstay for large cysts, those that are likely to rupture, or infected, or exerting an important mass effect, but it has been said to be impractical in patients with multiple cysts in several organs. The aim of this study is to report our strategy for the surgical resection or for the drainage of large (> 5 cm) and/or complicated liver and multi-organ hydatid cysts. Methods. From 1992 to 2012, 13 patients have been evaluated for open surgery or a minimally invasive approach for cystic echinococcosis. After Albendazole administration, liver cysts have been treated by pericystectomy in nine cases, partial pericystectomy in three cases, and in one case we preferred to consider the percutaneous drainage. In case of multiple extra-abdominal organ localization, we first treated the liver localizations. Results. There has not been operative or post-operative mortality. Follow-up has been done for 1 and ndash;10 years and has revealed no recurrence. Conclusion. Surgery could have satisfactory results among patients with single and multiple large (> 5 cm) cysts in multiple organs. In case of recurrence, adhesion to the inferior cava vein or when general conditions are poor, the percutaneous intracystic injection of 90% ethanol followed by the cyst drainage (PAIR) is strongly recommended. [Arch Clin Exp Surg 2014; 3(2.000): 102-106]

Unconjugated bilirubin plays an important role in cholesterol gallstone formation. Patients with symptomatic gallstone disease who have high bilirubin plasma levels and/or are homozygous for the rs6742078 TT variant of the bilirubin glucuronidating gene UGT1A1 should not undergo oral dissolution therapy with ursodeoxycholic acid. A large Danish study has shown that high bilirubin plasma levels and the genetic variant rs6742078 TT of the enzyme bilirubin glucuronidase UGT1A1 are associated with an increased risk of developing symptomatic gallstone disease. Recent reports regarding the significant association between bilirubin levels and symptomatic gallstone disease open a new chapter about the indication and exclusion criteria for oral dissolution therapy of symptomatic gallstone disease. A highly select subgroup of patients with small, single, radiolucent cholesterol gallstones who received oral dissolution therapy with ursodeoxycholic acid (UDCA) had a reported recurrence of symptomatic gallstone disease of 50% over five years. This is probably related to the persistence of other causal risk factors for gallstones in addition to that of cholesterol suprasaturation. A subgroup of patients with high plasma bilirubin levels and the UGT1A1 genetic variant rs6742078 have a greater risk of recurrence. In conclusion, oral dissolution therapy with UDCA might still be appropriate for patients that refuse laparoscopic cholecystectomy provided they have small (< 0.5 cm), radiolucent cholesterol gallstones and a functioning gallbladder, and have mean plasma bilirubin levels below 1.33 mg/dL and are not homozygous for the UGT1A1 rs6742078 TT genotype. [Arch Clin Exp Surg 2014; 3(3.000): 161-165]

Fistula in ano is a common proctological disease. Several authors stated that internal and external anal sphincters preservation is in the interest of continence maintenance. The aim of the present study is to report our experience using a decisional algorithm on sphincter saving procedures that achieved us to obtain good results with low rate of complications. From 2008 to 2011, 206 patients underwent surgical treatment for anal fistula; 28 patients underwent perianal abscess drainage plus seton placement of trans-sphincteric or supra-sphincteric fistula (13.6 %), 41 patients underwent fistulotomy for submucosal or low inter-sphincteric or low trans-sphincteric anal fistula (19.9 %) and 137 patients underwent partial fistulectomy or partial fistulotomy (from cutaneous plan to external sphincter muscle plan) and cutting seton placement without internal sphincterotomy for trans-sphincteric anal fistula (66.50 %). Healing rates have been of 100 % and healing times ranged from 1 to 6 months in 97 % of patients treated by setons. Transient fecal soiling was reported by 19 patients affected by trans-sphincteric fistula (11.5 %) for 4-6 months and then disappeared or evolved in a milder form of flatus occasional incontinence. No major incontinence has been reported also after fistulotomy. Fistula recurred in five cases of trans-sphincteric fistula treated by seton placement (one with abscess) (1/28) (3.5 %) and four with trans-sphincteric fistula (4/137) (3 %). Our algorithm permitted us to reduce to 20 % sphincter cutting procedures without reporting postoperative major anal incontinence; it seems to open an interesting way in the treatment of anal fistula.

Black pigment gallstones represent nearly the 15% of all gallstones and are usually related with the typical “hyperbilirubinbilia” factors as hemolysis, ineffective erythropoiesis, pathologic enterohepatic cycling of unconjugated bilirubin, cirrhosis and with gallbladder mucosa (parietal) factors as adenomyomatosis. During a prospective study on 179 patients who underwent cholecystectomy for gallstone disease a 69-year-old female with predialysis chronic kidney disease was operated for symptomatic gallstone. The removed gallstones were black pigment gallstones, with an irregular (as small blackberry) surface. Analysis of the stones revealed a great amount of whitlockite (Ca Mg)3 (PO4)2. Recent studies on chronic renal failure patients found that chronic uremia is associated with an increased risk of gallstones formation (22%) as it seems in women affected by primary hyperparathyroidism (30%). The presence of calcium phosphate gallstones in these patients have been never described. In conclusion, further studies could be necessary to establish the role of chronic renal failure and of primary and secondary hyperparathyroidism in gallstones formation and, in particular, if dialysis and predialysis patients have an higher risk to develop cholesterol and black pigment gallstones in particular of the “blackberry” (whitlockite) subtype.