\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Choledochal cysts (CCs) are congenital dilatations of extrahepatic and/or intrahepatic bile ducts defined by Vater and Ezler in 1723. It is a rare biliary entity with an estimated incidence of 1:100–150,000 live births in Western countries. In the Asian population, the incidence can be as high as 1:1000 live births. CC is primarily a childhood disease—up to 80% of patients are diagnosed before 10 years of age. The original classification, first described by Alanso-Lej and colleagues in 1959, was changed in 1977 by Todani and colleagues that classified the CCs as five types. In addition, isolated cystic dilatation of the cystic canal was identified subsequently and proposed as type VI, apart from the revised Todani classification. Although the etiology is controversial, the main elements in the natural historical emergence of the type I and type IV, which make up the majority of all types, have become clearer. A common symptom is nonspecific abdominal pain in older children. When the cyst is complicated, the diagnosis is delayed, the treatment becomes complex, and the results are affected. External drainage (ED), internal drainage (ID), total cyst excision (CE) + hepaticoduodenostomy (HD), and total CE + hepaticojejunostomy (HJ) were defined according to historical development of treatment. Resection is considered that is necessary to prevent further complications and long-term sequel.
The anatomist Abraham Vater first described the normal anatomy of the bile ducts and the fusiform dilatation of the common bile duct (CBD) in 1723 [1]. Then, Doctor Halliday Douglas first described clinically CBD dilatation in 1852. Douglas had detected a large tenderness cystic mass on the right upper quadrant by physical examination of a 17-year-old girl who had an intermittent right-sided pain, obstructive jaundice, and fever complaints in her history. Despite performing external drainage promptly, she died within 1 month. Subsequently, Douglas detected a CC with her autopsy [2]. In 1894, British surgeon William Swain performed the first successful operation in a 17-year-old girl presented with CC, by anastomosing the jejunum to a giant CC. This patient had been reported 2 months later with no jaundice. In 1922, Golder McWhorter underwent hepaticoduodenostomy after excising the CC in a 49-year-old patient who had complaints since infancy. In 1959, Alanso-Lej and colleagues first published the series of CCs. In this publication, they reviewed 94 cases, published previously, together with their own 2 cases and classified the congenital cystic dilatations of the bile ducts anatomically for the first time [3]. In 1977, Todani and colleagues modified the classification of CCs according to cholangiographic images [4, 5, 6, 7, 8].
CCs are more common in Asian populations with an incidence of 1 in 13,000, even 1:1000 in Japan [9], versus 1 in 100,000–150,000 in Western populations [10]. The reason for this Asian preponderance is still unknown [11]. Although predominately diagnosed in children, CCs are found with increasing frequency in adults such that adults comprise the majority of patients in recent series [12, 13], which in part may be due to the increased use of diagnostic imaging [14]. In both adult and children [15], females are higher risk for the disease with a nearly 4:1 female preponderance [10, 16]. Nearly, 80% of CCs are diagnosed in early infancy [10, 17].
Grossly, CCs appear as a diffuse dilatation of the bile ducts [18]. In the congenital dilatations of the bile ducts, the cyst wall thickness is between 2 and 7 mm in diameter and usually involves an inflammatory reaction (80%) [18] that becomes severe after 10 years of age. Cysts, especially infected, are usually being adherent to the surrounding tissues. Bile ducts and columnar epithelium can be seen in the microscopic examination of the cyst wall. Choledochocele that is covered with duodenal mucosa appears different from other types of CCs according to epithelial histology. Liver biopsy findings usually vary with the age in patients with CC. Although, newborn liver is mostly normal, mild periportal fibrosis may be seen in older children. Varying degrees of histological hepatic changes severity may be seen in most patients with CC when it is diagnosed [19]. Higher degree of liver damage associates with the presence of an anomalous pancreaticobiliary ductal union (APBDU), more severe symptoms, type IVa CC, and younger age [19, 20, 21]. It has been observed by investigating liver biopsies that most of these changes resolve after surgical excision; however, preoperative portal fibrosis and central venous distension may remain stable or increase in severity [19]. It is considered that carcinoma of the cyst wall may develop due to recurrent chronic inflammation attacks. However, it can also be seen in non-APBDU-associated CC patients. Additionally, the cancer can develop from anywhere such as the cyst wall, the gall bladder, or the common channel junction nearly pancreas, as a consequence of chronic inflammation due to cholangitis [22, 23].
Despite the existence of numerous theories and laboratory works to explain the etiology of the disease, the exact etiology remains incompletely understood. Initial theories, put forward in this regard, were congenital weakness of the choledochal wall, distal obstruction, oligoganglionosis, and disturbances in the process of recanalization. However, more accepted theories have been produced parallel to the progress in radiological imaging methods [24, 25]. Today, there are two main theories that are widely accepted; (1) reflux of trypsin and other pancreatic enzymes to the bile ducts due to an APBDU; (2) obstruction of distal CBD [26, 27, 28]. The idea that the choledochal and pancreatic ducts’ abnormality about joint and angle was first reviewed by Babbitt in 1969, and subsequently many number of studies, supporting this view, were made [22, 23, 29, 30, 31, 32]. A normal pancreaticobiliary junction usually has an acute angle between the CBD and the pancreatic duct [33] and is located within the duodenal wall [34]. The common channel (distance from between the junction of the CBD and the pancreatic duct to ampulla Vater) length is 4 mm or less, normally. In patients with CCs, this distance (common channel length) increases 5–20 mm [22, 23, 35, 36] that makes the common channel longer [37]. Okada defined it as “common channel syndrome” [36, 38]. It is considered that an abnormal long common channel (especially >15 mm proximal to ampullary sphincter) [39, 40] causes the pancreatic duct communicating with the choledochal duct without the support of ampulla Vater’s circular muscular layer (sphincter of Oddi) [41], which protects the biliary tree from reflux of pancreatic enzymes and bile [34]. Another observation is that the junction angle of the two ducts that should be acute normally, however, is close to 90° in these patients. It also causes the pancreatic fluids to flow into the CBD due to the higher pressure of pancreatic duct (Figure 1) [41]. Eventually, it is considered that APBDU has a tendency to cause reflux of the pancreatic enzyme into biliary tree with consequent biliary duct inflammation and increased duct pressure, leading to duct wall damage and cystic changes [42, 43]. In animal models of murine APBDU, this mechanism has also been demonstrated [44, 45]. APBDU is seen in up to 90% of patients with CC [25, 46], compared with 2% in the general population [10] and this seems to have important clinical implications. In a comparison of APBDU-associated CC versus non-APBDU-associated CC, APBDU-associated CC patients were significantly more likely to have evidence of pathologically confirmed inflammation including hepatitis, cholangitis, and pancreatitis [47, 48]. However, APBDU is not enough to explain the etiology of all CCs, such as diverticular cyst (type II), where the bile ducts were normal except cyst and the cyst is considered to be a sequel of an intrauterine CC rupture, such as meconium pseudocyst [28]. Additionally, type V CCs are possibly due to dysfunctional remodeling of the ductal plate during embryogenesis [40, 49].
Anomalous pancreaticobiliary union.
In addition, it is considered that primary strictures of the CBD may also play a role in the development of CCs. The types of the CCs are determined according to the location, severity, and length of the stricture. Detection of these strictures preoperatively is important because treating the CC without addressing the stricture may lead to recurrent episodes of cholangitis. This mechanism has been under estimated and is now believed to be more significant in the pathophysiology of CCs [50].
The association of CC with congenital anomalies remains ambiguous. Previous reports have demonstrated an association of pediatric CC and congenital anomalies. Murphy et al. reported in 2012 that screening for cardiac anomalies may be prudent in CC patients [51]. Other reports have postulated an association of CC with duodenal atresia, colonic atresia, gastroschisis, annular pancreas, and pancreatic cysts [10, 52, 53, 54, 55, 56, 57].
CCs are first classified in 1959 by Alanso-Lej and colleagues [58]. The original classification identified four types of biliary cysts (types I–IV). In 1977, Todani and colleagues [8] modified this classification and added a fifth category of CC, type V biliary cysts or Carol disease (Figure 2) [10]. Apart from types I–V included in the revised Todani classification, isolated cystic dilatation of the cystic duct has been described and suggested as type VI [59].
Types of choledochal cysts, classified by Todani et al.
Type I CC, most commonly seen, 80–90% of all CC, is a dilatation of the extrahepatic biliary tree. Importantly, the intrahepatic biliary tree is sometimes dilated secondarily due to biliary stasis. Type I cyst can be further subdivided into type Ia, Ib, and Ic cysts [10, 60]. Type Ia CCs are composed of the gallbladder arising directly from the CC, dilated extrahepatic biliary tree, and a nondilated intrahepatic tree. Type Ib CCs are focal segmental dilatation of the CBD and contain no evidence of APBDU [50, 60]. Finally, type Ic CCs are represented by a fusiform dilatation of the common hepatic duct and CBD in the presence of APBDU [10, 50, 60], and often also a low-grade stricture at the distal CBD [50]. In type I CC, usually, gallbladder is involved in cyst structure, and cyst extends from hepatic bifurcation to duodenum [61]. Most commonly, the ducts above (right, left, and intrahepatic ducts) and below of the CC are not dilated [14], except type Ic. In type Ic, cyst extends continuously to the common hepatic duct or intrahepatic ducts [62]. Type I CCs, along with type IV cysts, have the highest risk of malignancy [10]. This is not surprising because both of them have extrahepatic involvement associated with APBDU [63].
Type II CCs (2% of all CCs) consist of a diverticular dilatation of the extrahepatic bile duct system and is considered true diverticulum. During the diagnostic cholangiography study, the diverticulum is filled with radiopaque substance and can be confused with the gall bladder duplication seen rarely [10].
Type III CCs (choledochoceles), 4% of all CCs, are characterized by distal (located at the pancreaticobiliary junction) CBD dilatation, confined to the wall of the duodenum and often bulging into the duodenal lumen [25]. Type III choledochal cysts are dissimilar to other types of CCs, with features such as appearing in both sexes equally and low malignancy incidence [10, 64]. Cysts are mostly not associated with APBDU. Because of all these characteristics, it has been suggested that type III CCs should not be classified as a type of CCs revised by Todani [25, 64, 65]. In addition, Ziegler et al. reported that choledochoceles occur more frequently in older male patients presenting with acute pancreatitis [64].
Type IV CCs, the second most common (15–20% of all), are multiple cysts which can involve both the intrahepatic and extrahepatic biliary trees. Type IV CC can be further subdivided into type IVa and IVb cysts depending on intrahepatic involvement. Type IVa CC refers to multiple segmental communicating biliary dilatations located in the intra- and extrahepatic biliary tracts, and relative stricture at the junction that is used to distinguish the true type IVa CC from type I [11]. Type IVa CCs are usually associated with APBDU [50]. Type IVb CC refers to multiple extrahepatic biliary cysts without intrahepatic involvement [25]. Some recent studies have shown that intrahepatic ductal dilatations seen on preoperative imaging are thought to have been caused by distal obstruction and not true intrahepatic biliary duct disease [11]. Additionally, the question of “Is the distinguishing type I from type IVa really necessary preoperatively?” has not answered yet. Because distinguishing between types I and IVa CCs is controversial for some authors due to complete excision of the extrahepatic bile ducts, and intensive long-term follow-up still remains standard of care for both types [11].
Type V CC or Carol disease, added by Todani, is characterized by multifocal segmental intrahepatic biliary ductal dilatation [14] without the evidence of extrahepatic dilatation [66]. Caroli disease is uncommon, accounting for less than 10% of cases. Patients often present in adolescence or early adulthood with recurrent cholangitis, abdominal pain, or jaundice. However, they may present later with the sequel of portal hypertension and cirrhosis [67]. Renal abnormalities, such as medullary sponge kidney, autosomal dominant polycystic kidney disease, and medullary cystic disease can be seen in Caroli disease [49]. Some authors call Caroli disease as Caroli syndrome when congenital hepatic fibrosis is also seen, as in half of the patients [68, 69].
Type VI CC, isolated cystic dilatation of the cystic duct, is rare with only several case reports describing it. Although it is not officially part of the revised Todani classification, it has been proposed to be called type VI CC [70]. If the cyst emerges from the cystic duct near a level close to the CBD, it can be confused with type II CCs. In such cases, the relation of the cyst with the cystic duct should be thoroughly evaluated to differentiate them [59].
Type IC cysts are the earliest cysts that can be detected by 15-gestational week fetal ultrasonography [71, 72]. There are two clinical forms of disease: adult and infant. In infant form, symptoms such as obstructive jaundice, clay colored stools, and hepatomegaly make it difficult to distinguish from biliary atresia. Adult form of CCs is also congenital, although they usually remain silent until the age of 2 years. There are three main symptoms in the classical clinical triad: recurrent jaundice 69–75%, right upper quadrant pain 47–60%, and right upper quadrant mass 47–80%. But the classic triad only presents in 10% of cases (6–25%) [46, 73, 74].
Abdominal pain is the most common symptom (93.8%) [75], especially in older patients and presents with colic pattern which has a variable interval time (between attacks) up to several years. When investigating the cause of CBD dilatation and differential diagnosis of unclear upper abdominal pain, jaundice, and pancreatitis in children, CCs must be considered [76]. Unfortunately, 29–62% of pediatric patients with CC have been reported that they have choledocholithiasis [77, 78], that is, distinguishing this two situation (CC-associated choledocholithiasis and -nonassociated choledocholithiasis) may be difficult. Choledocholithiasis can also lead to CBD dilatation which can be misdiagnosed as a CC [79].
In 1–2% of cases, especially in infants, CCs may present with rupture and biliary peritonitis prompting emergency biliary drainage [80, 81]. It is not a surprise in diagnosing pancreatitis in patients with CC, because of association of the presence of APBDU [10, 46, 82].
The risk for development of biliary carcinoma in the general population starts after the fourth decade and the incidence increase with age to 0.15% after the eighth decade. However, the risk for the development of carcinoma in patients with a CC starts in childhood and shows a significant increase with age. Interestingly, the age of biliary carcinoma development in patients who have undergone internal drainage without cyst excision has been reported to be 15 years earlier on average than patients who have never had surgery. This is thought to be associated with intestinal bacterial contamination and pancreatic enzymes added to biliary stasis [83]. The malignancy incidence in resected bile duct material has been reported as 7.5% for all age groups, and 0.4 and 11.4% for those under and over the age of 18, respectively. The incidence has been reported to gradually increase every decade to 38.2% over the age of 60, possibly related to chronic inflammation [5]. The incidence of a biliary malignancy development following CC excision is reported as 0.7–5.4%. The malignancy can arise from anywhere such as the porta hepatis, pancreas, or the intrahepatic bile ducts. The time to onset after primary surgical intervention is reported to be 1–34 years. The total excision of the cyst significantly decreases the probability of a malignancy although it does not eliminate it completely [84, 85].
Ultimately, multimodality imaging techniques are often utilized including computed tomography (CT), magnetic resonance imaging (MRI), and/or endoscopic retrograde cholangiopancreatography (ERCP) to confirm the extent of ductal involvement or the presence of extrahepatic disease [25]. Frequently, further imaging techniques are used to differentiate type I CC from type IVa, in the presence of intrahepatic biliary dilatation [11]. A cyst, presenting in the porta hepatitis, separated from the gallbladder and continuing with enlarged biliary ducts can be shown by ultrasound (US). Additionally, fusiform dilatation of choledoch, intrahepatic biliary dilatation (60–80%), biliary stones, and state of liver parenchyma can be shown by US [86].
Other intraabdominal cysts, such as pancreatic pseudocysts, echinococcal cysts, or biliary cystadenomas should also be differentiated from CCs, whether the cyst has continuity with the biliary tree or not [40]. CT is not only useful for demonstrating continuity of the cyst with the biliary tree, but also demonstrates relation of the cyst with the surrounding structures and the presence of associated malignancy [87]. In order to correctly plan surgery, CT cholangiography can be used to identify the full anatomy of the biliary tree but unfortunately it has been reported to be less sensitive for imaging the pancreatic duct which is responsible for the reflux of contrast into the biliary ducts [87]. As it is well known today, the nephro-hepatotoxicity of the contrast and the ionized radiation exposed are the restrictions of CT utilization in pediatric population (Figure 3) [62].
Type III CC. (a) MRCP; (b) CT image.
MRCP is noninvasive and highly sensitive (70–100%) and specific (90–100%) in the diagnosis of CCs [88, 89], so, is considered the current gold standard imaging even for initial evaluation [62]. Additionally, there is no irradiation, and modern scanners have alleviated the need for protracted breath-hold making it more amenable to the pediatric population [10, 90]. Although both ultrasound and CT are highly sensitive and specific in the diagnosis of CCs, MRCP can better identify the CCs subtypes and coexisting abnormalities [89]. For example, MRI can easily identify the pancreaticobiliary ductal anatomy, while ultrasound cannot accurately demonstrate the APBDU [89, 91]. Additionally, MRCP is preferred modality in the pediatric population due to invasive nature and inherent risks of endoscopic ultrasound and ERCP, despite their ability of detecting the abnormality of the common channel [89]. MRCP has also been shown to be as effective as intraoperative cholangiography in planning surgery [18]. In addition, lower cost and morbidity compared to other imaging/diagnostic modalities, and reliability for detecting abnormalities associated with CCs such as cholangiocarcinoma and choledocholithiasis, are some of the favorable features of MRCP [89, 92]. Unfortunately, as seen often in patients with CCs, intraductal air, debris, stones, or protein plugs can interfere with the signal and alter visualization (Figure 4) [93].
PTC reveals the detailed anatomy of the biliary tracts and associated CC.
Although it is highly sensitive, invasiveness and associated risks including cholangitis, bleeding, pancreatitis, and perforation makes percutaneous transhepatic cholangiography (PTC) or ERCP utilization less frequently [94]. Moreover, PTC and ERCP can be technically challenging and require general anesthesia in the pediatric population. A lot of surgeons are finding the use of diagnostic ERCP and PTC in CCs unnecessary due to advantages of both MRCP and perioperative cholangiography (performed in nearly almost patients and give highly detailed information about biliary anatomy) [10, 95, 96]. Contemporary, ERCP should only be performed in cases where the appropriate diagnosis cannot be made by other less-invasive examinations, or when therapeutic performance (complications such as cholangitis or biliary stone obstruction [97, 98] and stabilization of the patients with preparing them to the next definitive surgery) is required (Figure 4) [39, 99, 100].
Another method that is not preferred now for diagnostic purposes is hepatobiliary scintigraphy. Although it is possible to do it with all IDA variants, DISIDA is the best. The radio isotopic substance is collected in the liver and is normally thrown into the biliary tract, but accumulates in the cyst space in patients with CC [101, 102].
There are many diseases including biliary atresia, infectious hepatitis, embryonal hepatic rhabdomyosarcoma, biliary lithiasis, pancreatitis, biliary hamartoma in the differential diagnosis of CCs, especially biliary atresia that is one of the two causes of neonatal obstructive jaundice in neonatal period [10]. Differentiating cystic biliary atresia (CBA), a subtype of biliary atresia and has an entirely different treatment approach, from CCs is particularly difficult. Therefore, prompt accurate diagnosis is critical [103]. While earlier presentation (<months of age), smaller cysts with less dilatation of the intrahepatic biliary system, and an atretic gallbladder with irregular and hypoplastic biliary radicles that is seen on ultrasound and cholangiography are characteristics of CBA patients [10, 20, 104, 105]; a dilated gallbladder communicated with the cyst in addition with a dilated intrahepatic biliary tree is mostly a determiner to infantile CC [104].
It is still important to differentiate biliary rhabdomyosarcoma, a rare soft tissue tumor that affects only 1% of children, from CC [106, 107]. In the presence of a mass or intraductal growth that causes obstructive jaundice, the possible diagnosis should return in favor of rhabdomyosarcoma in children and prompt evaluation is necessary [107].
“Children with CBD dilatation did not differ significantly in clinical characteristics compared with children who had obstructive CBD dilatation” said Oh and colleagues [78] by evaluating the cholangiographic characteristics of 85 children with CBD dilatation to differentiate obstructive and congenital CBD dilatation. Indeed, it can be difficult to distinguish them. Therefore, in the pediatric population with dilated biliary trees, ruling out a distal biliary obstruction that causes secondary biliary dilatation is prudent and essential [18].
As noted above, type I CC may present with intrahepatic biliary dilatation secondary to biliary stasis, thus resembling a type IVa CC. Some authors consider that this distinction is critical given the therapeutic implications and the need to include hepatic resection (in the case of type IVa CC) in addition to extrahepatic biliary tree excision [18], whereas the others consider that the need preoperatively distinguishing between type I and IVa CCs is controversial because for both, complete excision of the extrahepatic bile duct and intensive long-term follow-up remains standard of care [11].
The treatment time of antenatal diagnosed of CCs has been still a matter of debate. Some reports say that they can be operated within 2–6 weeks, even if they are asymptomatic, due to a potential complication risk of cysts, whereas, the others suggest that they can be followed-up for a time of period with US and regular monitoring of liver functions [108, 109].
Surgical treatment of CCs should be performed electively except complicated ones such as cyst perforation. Children, who have acute problems related to liver and pancreas, should be initially received appropriate medical treatment to remove inflammation and associated obstruction at the pancreaticobiliary system before surgery [110].
In the first half of this century, treatment methods such as cyst aspiration, marsupialization, and external drainage (cholecystostomy, tube drainage) had been used more extensively in the surgical treatment of CCs. And as expected, high mortality and morbidity rates had been detected in patient’s follow-up period. Surgical methods such as partial cyst excision and cystoduodenostomy were defined between 1920 and 1930 [111, 112]. Especially, cystoduodenostomy has been the preferred method by many surgeons until the early 1970s [113, 114] when the long-term morbidity was detected as higher (30–50%) [7]. Therefore, in those years, Roux-en-Y cystojejunostomy had identified with the idea of preventing the reflux of the duodenal contents into the bile ducts [7, 30, 115]. Indeed, the cholangitis had been significantly reduced with this method, but not completely eliminated [28]. After soon, it had been demonstrated that anastomosis with a large stoma, as possible as (at least 4 cm) is more important for protecting reflux-related cholangitis attacks than which intestinal segment it is performed (duodenum or jejunum) [116]. The recognition of the cancer development from the left cystic wall and Babbitt’s APBDU theory made the idea of cyst excision popular soon after. It had been reported that carcinoma develops after the internal drainage procedures at a frequency of 2.5–17.5% several years later as a consequence of chronic inflammation of the cyst wall. Therefore, cyst excision had gain popularity in a very short time [116].
Contemporarily, the definitive treatment for CCs are total excision that has become preferred management strategy over the internal drainage procedures (choledochocystoduodenostomy or choledochocystojejunostomy), which have an only historical value today despite they had been used as a treatment method in the past although caused high morbidity (probably because of not relieving biliary stasis sufficiently) [117, 118]. Furthermore, only complete resection can fully decrease the risk of malignant degeneration: a critical point in the pediatric population with a large number of expectant life years. The general aim is to remove the cyst completely and restore biliary enteric drainage either into the duodenum by hepaticoduodenostomy (HD) or jejunum by Roux-en-Y hepaticojejunostomy (RYHJ), although specific approaches for types vary minimally. Surgical intervention should be elective and patients should be medically optimized prior to operative intervention. İf patient has a cholangitis or pancreatitis attack preoperatively, the infection should be adequately treated with broad-spectrum intravenous antibiotics or biliary decompression if needed [118].
Surgery for CC disease can be performed open or laparoscopically based on patient characteristics and surgeon preference.
HD and RYHJ are the two most commonly utilized techniques of reconstruction [119], although other replacement conduits such as jejunal interposition HD, valved jejunal interposition HD, nonrefluxing biliary appendicoduodenostomy, hepaticoenterostomy, and wide hilar hepaticojejunostomy have been reported [120, 121, 122, 123, 124, 125]. HD has been favored by some groups [126, 127] but most series suggests significantly more bile reflux compared with RYHJ [121], which is currently the most commonly utilized reconstruction.
In all cases, cholangiography should be performed initially to obtain detailed anatomical information about the intra- and extrahepatic bile ducts, irrespective of preoperative examinations. Dissection of extrahepatic bile ducts starts from the gallbladder. The terminal end of the cyst opening to the duodenum should be isolated, clamped, cut, and transfixed, firstly. Some surgeons suggest that dissection should be continued until the appearance of pancreatic ducts, while the others not suggest. Additionally, some surgeons taking into account that dissection toward the lower end of the cyst may cause inevitable unplanned pancreatic duct injury that pancreaticoduodenectomy requirement should be in your mind, although very rarely [75]. After the distal portion of the cyst is ligated and cut, the posterior wall is dissected from the surface of the portal vein. In cases of marked inflammation, the cyst may be excised by leaving the posterior wall on the portal vein. The dissection should go on till the hepatic hilus. The best strategy to obtain a wide anastomosis stoma is to make a hepatic dissection more proximally until the left hepatic duct is seen. Although all parts of CCs need to be removed, sometimes residual proximal cyst walls can be left to facilitate biliary anastomosis [75]. Dilated bile ducts should be irrigated with heparinized saline to clear the gallstones before anastomosis. After the cyst is excised, one of the hepaticoenterostomy methods, such as hepaticojejunostomy, HD, jejunal interposition HD, valved jejunal interposition HD, nonrefluxing biliary appendicoduodenostomy, hepaticoenterostomy, and wide hilar hepaticojejunostomy [120, 121, 122, 123, 124, 125] is performed for biliary reconstruction. In RYHJ, 40-cm jejunal loop replaces to the hepatic hilus. In RYHJ surgery, to avoid the elongation of a blind pouch as the child grows, an end-to-end anastomosis of the jejunum to the CBD is recommended if technically possible [128]. If an end-to-side anastomosis is required (in some cases, the bile duct is too small), it should be as close as possible to the closed end of the jejunal limb. Additionally, although it is not possible to predetermine the length of the Roux limb, it should be appropriate to the child’s overall bowel length considering future growth. In HD, anastomosis is performed between the duodenum second part and the bile duct. The duodenum was mobilized to a limit. The duodenum is anchored to the liver at porta to avoid tension on the anastomosis (Figure 5).
Intraoperative pictures and drawn cartoon showing of the procedure.
The intraabdominal drain, kept in Morison’s pouch, may be removed on the seventh postoperative day [124].
Laparoscopic treatment of choledochal cysts was first described in 1995 [129] and demonstrated that it could be performed in children as young as 3 months [130] and as small as 6 kg [131]. As with most surgical diseases, longer operating time and shorter hospital stay [132] were comparable with open surgical approaches, and in the absence of cholangitis or pancreatitis, it becomes more suitable treatment [132]. While four or five ports are typically used in the traditional laparoscopic approach [130, 133], the use of single-port laparoscopy [134] and robotic surgical system [135] has also been reported. In a prospective randomized study of 121 children undergoing laparoscopic cyst excision with RYHJ, routine postoperative drainage has been shown to be unnecessary [136].
The most commonly performed operations for biliary reconstruction after complete surgical resection of CCs are RYHJ or HD [124]. There is a debate regarding the optimal technique for biliary reconstruction [124]. RYHJ is considered as an ideal technique for the repair of CC, but HD has gained wide acceptance and favored by many surgeons open as well as laparoscopically because of its advantages over hepaticojejunostomy. HD is more physiologic, but theoretically, the closeness of hepaticoenterostomy to stomach makes HD to have greater chance of cholangitis and bile gastritis, but in a meta-analyzed study [137], it has been shown that while the incidence of bile gastritis after HD is even higher when examined endoscopically, interestingly, there is no difference of cholangitis between HD and RYHJ. Additionally, HD is simpler to perform and associated with fewer complications such as adhesive bowel obstruction, anastomotic leakage, and peptic ulcer as compared to RYHJ [138]. HD requires less operative time, allows faster recovery of bowel function, and produces fewer complications requiring reoperation [139]. If there is an anastomotic stricture following HD, it can be easily managed by endoscopy as against hepaticojejunostomy [124]. But, when the diameter of the common hepatic duct more than 10 mm that lets duodenal contents more likely to reflux easily into the intrahepatic bile ducts through the HD anastomosis or when the intrahepatic biliary dilatation is present that lets refluxed duodenal contents remain longer in the intrahepatic bile ducts, HD is not recommended because of higher risk of cholangitis or anastomotic stricture formation [124]. Some studies have demonstrated high incidence of secondary bile reflux proven by endoscopy after HD [121]. Recently, a patient with hilary bile duct carcinoma, who was performed HD for the biliary reconstruction at the age of 13 months, has been reported in the 19 years follow-up after the primary cyst excision. Reflux of duodenal contents (including activated pancreatic enzymes) into the intrahepatic bile ducts through the HD anastomosis is thought to be hazardous to the bile duct mucosa in this patient [124]. Adhesive bowel obstruction is seen with a higher incidence in RYHJ that comprises a Roux-en-Y jejuna limb and two anastomoses, compared with HD. Cholangitis, peptic ulcer, fat malabsorption, diarrhea, and malnutrition are the other complications [126]. A significant incidence of long-term complications requiring reoperation such as anastomosis stenosis has been observed with the follow-up studies of patients who underwent hepaticojejunostomy after cyst excision [138, 140], and a wide hilar hepaticojejunostomy extending into the left hepatic duct is advocated for the way to prevent it [125].
Treatment of type I CC includes excision of the extrahepatic biliary tract, cholecystectomy, and reconstruction of the biliary system. If the duct is dilated at the distal margin, the mucosa may be left behind to prevent damage to the pancreaticobiliary system and can be striped. Infrequently, because of recurrent episodes of the cholangitis, the cyst wall may densely adherent to the portal vein, precluding safe resection [141]. In such cases, resection of the anterior wall with careful fulguration of the mucosa of the posterior wall can be performed [141]. Hepatic bifurcation is carefully evaluated for stricture and inflammation before performing anastomosis during proximal transection. If one of them is seen, more proximal transection should be considered [18].
For type II CCs, mostly, diverticulectomy or simple cyst excision is enough for the treatment. Primary or over a T-tube closure can be performed, and reconstruction is occasionally required if there is significant luminal narrowing [18].
One of the methods such as endoscopic sphincterotomy, sphincteroplasty, sphincteroplasty with cyst excision, or pancreaticoduodenectomy may be used to manage pediatric patients with type III CCs (choledochoceles) [10, 25]. Various reports denote adequate symptom control with this approach [142, 143]; however, long-term follow-up is lacking. Cysts not amenable to endoscopic intervention may benefit from lateral duodenotomy with sphincteroplasty and unroofing or marsupialization of the cavity [18].
Type IV CC is approached differently based on the presence or absence and location of intrahepatic disease [15]. Type IVb cysts are treated in the same fashion as type I. Management for IVa disease differs due to the presence of intra- as well as extrahepatic involvement, as well as the presence of functional liver disease. Of foremost importance is the characterization of actual type IVa as opposed to type I with upstream ductal dilatation due to stasis and functional obstruction [50]. If the dilatation is anatomic and isolated (limited; i.e., left hemiliver), partial hepatectomy with reconstruction to the remaining hepatic ducts may be warranted due to the ongoing risk of malignant transformation in the intrahepatic biliary system [85]. However, not all patients are appropriate candidates for partial hepatectomy [144]. Those patients with obvious dilatations and stenosis of intrahepatic ducts, intrahepatic duct stones, or parenchymal atrophy may benefit from hepatectomy [144]. If hepatectomy is planned concomitantly with extrahepatic duct excision, the distribution should allow removal of all disease (of the vast majority of the severe disease) with adequate future liver remnant [15]. If the pattern is more diffuse or imaging is inconclusive, treatment in a type I paradigm with close postoperative surveillance to follow intrahepatic ducts has been utilized [145]. This approach is justified by studies demonstrating that patients who progress to malignancy most commonly develop extrahepatic cholangiocarcinoma or gallbladder cancer (approximately 85% of malignancy), whereas intrahepatic cholangiocarcinoma rarely occurs [144]. It is reported that the intrahepatic component has actually resolved in 3–6 months with adequate drainage [146]. To differentiate type IVa from type I, while in adults, preoperative percutaneous biliary drainage to decompress the intrahepatic biliary ductal system has been advocated [147], in children, this practice has not been reported probability due to the difficulty in maintaining the external tube. Although long-term results are not known, intrahepatic cystojejunostomy, in addition to hepaticojejunostomy, has been described as a way of preventing liver resection in type IVa cysts [148]. Complete extrahepatic excision with hepaticoenterostomy and drainage of the remaining cyst externally or internally should adequately ameliorate biliary stasis in the presence of bilobar unresectable intrahepatic cyst [18].
Management of patients with Caroli’s disease can be particularly difficult given the location of the cysts and frequent necessity for surgery (considerable potential for cholangitis, liver complications, and biliary cirrhosis; moderate potential for neoplasia (7%)) [15]. In Caroli disease, intrahepatic cysts can be seen as limited disease restricted to a single segment/lobe or diffuse disease involving the entire intrahepatic biliary tree. If the patient has not developed cirrhosis and portal hypertension, the unilobar cystic disease should be treated with anatomic hepatectomy and biliary enteric bypass. However, bilobar disease should be treated with symptom-directed nonoperative treatment methods as including litholytic agents such as ursodiol, antibiotics, and percutaneous drainage if possible. Close follow-up is required for malignant transformation. Although there is no identification for prophylactically orthotopic liver transplantation in the treatment of the disease, it should be kept in mind for the choice of the treatment in patients who have diffuse symptomatic disease with cirrhosis or portal hypertension [149].
Patients should be monitored every 6 months during the postoperative 3 years and then annually. On initial follow-up, while all patients should be evaluated with complete blood count, liver function tests and abdominal US, on subsequent follow-up, investigations are done only in symptomatic ones. Long-term follow-up can be made by visits, telephonic conversations, and postal inquiry [124].
Resection of pediatric CC is generally well tolerated [18]. Despite recent advances in surgical techniques and perioperative management, short- and long-term complications are not rare in children, while they are more common in adults [6]. Complications such as recurrent cholangitis attacks, malignant transformation, intracystic or intrahepatic gallstone formation, cirrhosis development, and pancreatitis are common in patients who are not operated on. Complications such as anastomotic leakage, gastrointestinal or intraabdominal bleeding, acute pancreatitis, pancreatic leakage, wound infection, wound dehiscence, intraabdominal infection/abscess, intussusception can be seen in early postoperative period defined as short-term complications [150]. Most early complications can be treated conservatively [151].
However, most series are without early mortality and report rates of acute complications including wound infections from 0 to 17%, without significant difference between infants and children [46, 132].
Surgical inexperience and severe inflammation are often implicated in the development of anastomotic bile leakage [151]. The diagnosis of bile leakage is difficult and delayed in some cases due to nonspecific symptoms [151]. It may not always be possible to differentiate with the imaging findings of US and CT because not all of the intraabdominal fluid collection after surgery is associated with bile leakage, and so, this late diagnosis may result in mortality due to septicemia and septic shock [151]. However, it is reported that MRCP can be used to diagnose and accurately localize the site of bile leakage noninvasively [7, 151]. Bile leaks in the hepaticooenterostomy line can self-limited within a few weeks if they can be drained externally. If the bowel movement is sufficient during this period, the child can be fed by enterally. If the extracted bile is given back to the stomach with NG catheter, electrolyte losses can also be prevented. The bilirubin level of the child may remain high due to edema in the anastomosis line within the first 2 weeks, even if the operation has been successfully performed. If this takes longer, biliary tree, even anastomosis, can be evaluated with PTC [110]. Reoperation is considered only after the failure of conservative treatment [151]. The leakage can be repaired by a circumferential buried suture around the anastomotic site, peritoneal lavage, and effective drainage [151].
Gastrointestinal bleeding may be due to hepaticojejunostomy or stress ulcer.
Acute pancreatitis occurs in patients with CC, both preoperatively and due to injury of the pancreatic tissue during distal dissection of the cyst or to edema in the distal part of the pancreatic duct related postoperatively (4.2%) [151]. Therefore, it has been recovered with a conservative treatment for a short time period. Some reports say that CC excision without ligation of the distal stenotic stump decreases the incidence of pancreatic duct injury [75]. A probe inserted into the pancreatic duct through a duodenotomy may help to prevent pancreatic duct injury in difficult cases [75]. Additionally, Urushihara et al. [152] consider that using bipolar electro cautery to scrape pancreatic tissue away from the bile duct wall during the dissection of the intrapancreatic part of the bile duct causes minimal bleeding and enables clear identification of the narrow part of the CBD [151]. Eventually, complete resection of the distal portion of the cyst, removal of debris and protein plugs in the long common channel and pancreatic duct, and correction of anomalous arrangement of the pancreaticobiliary duct junction are essential to minimize pancreatic complications after the operations [151]. The pancreatic fistula occurs because of not closing the distal choledoch well after the cyst excision or injured pancreatic duct during the dissection. An external drainage of 3–4 weeks allows the fistulas closing.
Late/long-term complications (5–15%) [151] include anastomotic stricture, cholangitis, hepatolithiasis, ileus, cirrhosis, and malignancy. Benign anastomotic stricture with recurrent cholangitis is less common than in adults but is still seen in many as 10–25% of patients and can be associated with both intrahepatic and bile duct stone formation [117].
After intraabdominal surgery, small bowel obstructions, mostly due to adhesions, are common [154]. Patients should be closely monitored for any possible clinical deterioration [154]. If there is no improvement after 48 h of follow-up, there is a high risk of bowel resection due to bowel necrosis despite it has not been clearly defined [156]. Furthermore, it has been defined that during biliary reconstruction, the length and placement of the Roux loop is very important in adhesive bowel obstruction developing postoperatively [156].
In terms of anastomotic stricture, improvement of surgical skills, preservation of blood supply, no or mild inflammation cyst wall, and construction of wide (larger than 1 cm) and tension-free stoma are key factors to reduce anastomosis-related complication [138]. There should be no delay in surgical or endoscopic intervention once biliary obstruction develops postoperatively, but a great deal of planning and a thoughtful workup are required [151]. Kim et al. [155] reported that PTC with stone removal and balloon dilatation was useful in patients with anastomotic stricture. However, some investigators consider that recurrent anastomotic strictures may occur due to fibrosis even after balloon dilatation with PTCS, and repeated cholangitis may cause multiple intrahepatic biliary strictures, recurrent hepatic stones, and development of biliary carcinoma [152, 153]. Hence, especially in young patients, it is recommended that revision of the hepaticojejunostomy followed by ductoplasty, to create a wide stoma for sufficient bile drainage [152, 153].
Rigorous long-term follow-up after pediatric CC resection is limited, but the risk of biliary carcinoma (cholangiocarcinoma, squamous cell carcinoma, sarcoma, gallbladder cancer [12, 157], most often cholangiocarcinoma) clearly remains elevated even after CC excision compared to the general population [18]. The malignancy risk is considered to increase with age at surgery, and the cumulative biliary malignancy risk 25 years after primary surgery has been reported to be as high as 11% [75]. Malignant disease has been noted in up to 14% 0f patients after CC resection as a child [46]. In fact, cancer is the most frequent cause of late mortality in pediatric CC series [18]. Even after complete excision, patients are at higher risk for malignancy than general population [158]. Continued surveillance is, therefore, strongly recommended, though it is not known whether there are risk factors such as retained portion of cyst or not [18]. In those with known malignancy, oncologic principles should apply; patients who can undergo safe resection with negative margins are appropriate for operation [15]. Resection may include hepatectomy with regional lymphadenectomy, extirpation of extrahepatic bile ducts with regional lymphadenectomy (and cholecystectomy), or pancreaticoduodenectomy [15]. However, the 5-year survival rate for patients with CCs complicated by malignancy is high, up to 55% in patients with cholangiocarcinoma [159].
Chalcones (trans-1,3-diaryl-2-propen-1-ones) (1) are α,β-unsaturated ketones consisting of two aromatic rings (ring A and B) having diverse array of substituents (Figure 1). Chalcone skeleton contains two aromatic rings linked by an aliphatic three-carbon chain. The two rings of chalcone are interconnected by a highly electrophilic three-carbon α,β-unsaturated carbonyl system that assumes linear or nearly planar structure. They possess conjugated double bonds and a completely delocalized π-electron system on both the aromatic rings.
\nStructure of chalcone.
Chalcones, named so by Kostanecki and Tambor, are commonly known by different names such as benzylideneacetophenone, phenyl styryl ketone, β-phenylacrylophenone α-phenyl-β-benzoylethylene, etc. and constitute the central core of biologically active heterocyclic compounds. Chalcones constitute good synthons for a variety of novel heterocycles of high therapeutic potential and good pharmaceutical profile [1, 2]. Chalcones themselves are identified as interesting entities associated with several biological activities [3].
\nThe structural modifications of the chalcone rings have led to a high degree of diversity that has proven useful for the development of new medicinal agents, and thus chalcones have become an object of continued interest in both academia and industry. The chalcones are well documented for a broad spectrum of biological activities including antimicrobial, anticancer, cytotoxic, antioxidative, anti-inflammatory, antiviral, and others [4]. Currently, chalcone derivatives have been widely used for the treatment of viral disorders, cardiovascular diseases, stomach cancer, food additives, and cosmetic formulation ingredients [5]. However, much of the pharmacological potential of chalcones and their recent updates need to be understood. The purpose of this chapter is to cover and describe the recent developments, preferably after 2015 to date, the utility of chalcones as medicinally significant scaffolds, and their biological activities. It covers and highlights the recent advances in the use of chalcones as antimicrobial, anticancer, antitubercular, antioxidant, anti-inflammatory, and miscellaneous applications in biological and medicinal fields.
\nAntimicrobial agents are the drugs used to treat infectious diseases caused by different types of bacteria and fungi. The use of these drugs is now common, and continuous efforts are put by the scientific community to search for newer antimicrobial agents due to antimicrobial resistance (AMR) shown by the microbes. Mutation, gene transfer, phenotypic change, and selective pressure are some of the causes behind AMR [6]. Antimicrobial or drug resistance is commonly developed by bacteria, fungi, parasites, and viruses when the microbe no longer responds to a drug that previously treated them effectively. This AMR can lead to several issues including difficulty in controlling the disease, a longer stay of the microbes in the host, higher risks of spreading, and increase in mortality rates. Infectious diseases are one of the common problems encountered globally. Although several commercially marketed drugs are available, the search for new drug molecules becomes essential for the treatment of infectious diseases [7]. Consequently, the search for new antimicrobial agents becomes essential. Herein we discuss the recent updates in the search of chalcones as an attempt to develop antimicrobial agents:
\nMethoxy-4’-amino chalcones (2) showed good in vitro antimicrobial activities against Escherichia coli, Staphylococcus aureus, and Candida albicans. A molecular docking study also supported the observed results showing good interactions with the active sites of dihydropteroate synthase enzyme of E. coli and S. aureus [8].
\nThe quinoxalinyl chalcones (3) synthesized by the Claisen-Schmidt condensation were found to be good antimicrobial agents. The antimicrobial studies were carried out against Staphylococcus aureus, Escherichia coli, and Candida albicans using the disk diffusion method. The selected chalcones were evaluated for anticancer and cytotoxicity activity against MCF-7 cancer cell lines using the MTT assay method showing good anticancer activity [9].
\nSome fluorinated chalcone-triazole hybrids (4) were studied for antimicrobial activities against S. epidermidis, B. subtilis, E. coli, and P. aeruginosa bacterial and two fungal strains, namely, A. niger and C. albicans, by standard serial dilution method [10]. The results of the in vitro antimicrobial activity were compared with ciprofloxacin and fluconazole standard drugs.
\nDehydroacetic acid chalcone-1,2,3-triazole hybrids (5) were shown to possess good in vitro antimicrobial activities against Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa bacteria and two fungal strains, viz., Aspergillus niger and Candida albicans [11].
\nThiazole-based chalcones including thiazolo[2,3-b]quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogs (6 and 7) screened against both gram-positive and gram-negative bacteria revealed that the tilted compounds had minimum inhibitory concentration (MIC) values in the ranges of 1–4.0 μg/ml against S. aureus, B. subtilis, M. luteus, E. coli, and P. aeruginosa [12]. The results were found to be comparable with the ampicillin and ciprofloxacin standards.
\nBurmaoglu et al. reported antimicrobial activity of fluoro-substituted chalcones (8) and (9) against S. aureus, S. pyogenes, E. faecalis, E. coli, and P. aeruginosa bacteria and C. albicans, C. glabrata, and C. parapsilosis fungal strains. Some of the tested compounds also exhibited antitubercular activity against Mycobacterium tuberculosis [13].
\nChalcones incorporated with a piperazine ring (10) exhibited promising antimicrobial activity against Escherichia coli, Aspergillus niger, Salmonella typhi, Penicillium chrysogenum, and Staphylococcus aureus bacterial strains as well as Aspergillus flavus, Bacillus subtilis, and Candida albicans fungi [14].
\nTalniya and Sood documented the synthesis and antibacterial activity of chalcones (11) against Bacillus subtilis bacteria and Aspergillus niger fungi by disk diffusion method [15]. The chalcones possessing o-chloro, p-chloro, and p-hydroxyl substituents showed remarkable antimicrobial activity against the screened microbes.
\nOxazolidinones incorporated with chalcone hybrids (12) were evaluated for in vitro antibacterial and antifungal activities by using the serial dilution method [16]. Results showed moderate antimicrobial activities as compared with the standard drugs ciprofloxacin and linezolid.
\nNovel diarylsulfonylurea-chalcone hybrids (13) were evaluated by agar well diffusion method against various strains of bacteria and fungi including Bacillus subtilis, Escherichia coli, Bacillus pumilus, Staphylococcus aureus, Micrococcus luteus, Candida albicans, and Penicillium chrysogenum. Most of the compounds showed promising antibacterial and antifungal activity suggesting that the diarylsulfonylurea-chalcone hybrids can be used for the treatment of diseases caused by these microbial organisms [17].
\nVanillin moiety containing chalcones (14), (15), and (16) were synthesized by the Claisen-Schmidt condensation of vanillin with different acetophenone derivatives and were studied for antimicrobial activities by using agar disk diffusion and microdilution methods [18]. The researchers found S. aureus and C. albicans to be the most sensitive strains and E. faecalis to be the least sensitive against these chalcones. The presence of halogens in chalcones increased their microbial susceptibility. The structures of some antimicrobial chalcones are shown in Figure 2.
\nStructures of antimicrobial chalcones.
Cancer is a widely spreading disease all over the world, necessitating the need to develop new anticancer agents [19]. Anticancer or antineoplastic drugs are those that are effective in the treatment of malignant or cancerous disease. Increasing recurrence of mammalian tumors and severe side effects of chemotherapeutic agents reduce the clinical efficiency of a large variety of commonly used anticancer agents, and thus, there is always a constant need to develop alternative or synergistic anticancer drugs with minimal side effects [20].
\nThe treatment of cancer is a complicated process as the drugs used target human cells and albeit cells that have undergone genetic changes and are dividing at a fast and uncontrolled rate. However, only a few anticancer drugs can differentiate between normal tissue cells and cancer cells to a large extent. Thus, there is always a constant need to develop alternative or synergistic anticancer drugs with minimal side effects. This part of the present chapter highlights significant and recent developments in chalcones used as anticancer agents:
\nSulfonylpiperazines linked with [1,3]dioxolo[4,5-g]chromenones (17) were synthesized by the aldol condensation and evaluated as antioxidants against DPPH, ABTS, as well as antiproliferative agents against non-cancer MDCK cell lines [21].
\nThe design, synthesis, and antitumor potential of chalcones (18) were studied against human breast adenocarcinoma MCF-7 cells in a concentration-dependent manner [22]. They triggered significant changes in cell morphology and biochemical/molecular parameters and revealed the apoptosis inductor nature of the titled compounds and their application as promising alternatives for the treatment of neoplasia, especially in terms of drug resistance development.
\nNovel anthraquinone-chalcone hybrids (19) possessing amide functionality were synthesized, then characterized, and reported for good cytotoxic potential against K562, Jurkat, and HL-60 leukemia cell lines [23].
\nAn apoptosis is an important phenomenon, which affects many diseases, such as cancer and Alzheimer’s disease. Chalcones (20) induced apoptosis of human hepatic and lung cancer cells and inhibited cancer cell migration and invasion [24].
\nThe bis-chalcone derivatives (21) were studied for their ability to inhibit xanthine oxidase and growth inhibitory activity against MCF-7 and caco-2 human cancer cell lines in vitro. The bis-chalcone with fluoro group at the 2nd or 2, 5th position of B-ring was found to be a potent inhibitor of the enzyme possessing IC50 values in the low micromolar range. The activities of the compounds were found to be around seven times higher than the standard allopurinol [25].
\nChalcones (22) were synthesized and evaluated for anticancer activities on human colorectal carcinoma cell line HCT116 by Dias et al. [26]. Halogens at the third position of the chalcones were found to enhance the anticancer activity of the titled compounds.
\nLeao et al. reported the chalcone derivatives (23) and (24) for cytotoxicity against human tumor cells [27]. Some novel xanthine-chalcone hybrids (25) and (26) were reported as promising anticancer agents [28].
\nA series of novel dithiocarbamate-chalcone derivatives (27) and (28) was designed, synthesized, and evaluated for antiproliferative activity against three selected cancer cell lines (EC-109, SK-N-SH, and MGC-803). Almost all the synthesized compounds exhibited moderate to potent activity against all the tested cancer cell lines [29].
\nPd(II) and Pt(II) complexes of chalcones (29) were studied for in vitro antimicrobial and antitumor activities against different microorganisms and the human hepatocellular carcinoma cells indicating their use as promising antimicrobial agents and anticancer drug candidates [30].
\nSome novel Pt(IV) complexes of chalcone analogs (30) were synthesized and evaluated for antiproliferative activity by using MTT assay. The in vitro evaluation revealed that all Pt(IV) complexes showed good activity against the three human cancer cells [31].
\nThe overexpression of the CYP1 class of enzymes is associated with the development of human carcinomas. The pyridine-4-yl series of chalcones (31) were synthesized and screened for the inhibition of CYP1 isoforms in Sacchrosomes TM and live human HEK293 cells. The chalcones bearing tri-alkoxy groups on non-heterocyclic ring displayed selective inhibition of the CYP1A1 enzyme with IC50 values less than 70 nM [32].
\nThe pyrazolic chalcone analogous compounds (32) were synthesized and evaluated as potential chemotherapeutic agents for the treatment of hepatocellular carcinoma [33]. Some of the screened compounds exhibited potent cytotoxic activity against all the cancer cell lines tested and had good cytotoxic activities.
\nDNA ligases play a crucial role in causing cancer. Gupta et al. reported the inhibition DNA ligases resulting in DNA nick-sealing activity followed by the antiproliferative activity of the indole-chalcone based benzopyran chalcones (33) on cancer cells [34].
\nIndolizine-chalcone hybrids (34) were synthesized and studied for apoptosis and anticancer effect on human lymphoma cells by S. Park and coworkers [35].
\nPrenyl and geranyl group-bearing chalcones (35) were synthesized by using regioselective iodination followed by the Suzuki coupling reaction and studied for in vitro anticancer activity against human tumor cell line K562 by MTT assay. Morphology changes revealed that the chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis [36].
\nLeukemia is a hematologic malignancy with poor prognosis in humans. Diprenylated chalcone (36) was studied as a new potential antileukemia agent [37].
\nChalcones (37) were studied for antiproliferative activities against the human TRAIL-resistant breast (MCF-7, MDA-MB-231), cervical (HeLa), ovarian (Caov-3), lung (A549), liver (HepG2), colorectal (HT-29), nasopharyngeal (CNE-1), erythromyeloblastoid (K-562), and T-lymphoblastoid (CEM-SS) cancer cells by Mai [38].
\nTriazole incorporated with chalcones (38) and (39) was synthesized and evaluated for 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay against a series of four human cancer cell lines (MCF-7, MIA-Pa-Ca-2, A549, HepG2) [39]. The structures of anticancer chalcones are depicted in Figures 3 and 4.
\nStructures of anti-cancer chalcones (17-28).
Structures of anticancer chalcones (29-39).
Tuberculosis (TB), caused by the acid-fast gram-positive bacillus, Mycobacterium tuberculosis, remains the leading source of bacterial infectious disease [40]. M. tuberculosis establishes an infection through an invasion of alveolar macrophages. The Mycobacterium tuberculosis encodes for more than 60 adenylating enzymes, mainly tRNA synthetases, acyl-AMP ligases, etc. [41]. Currently, the treatment of TB employs four first-line drugs, isoniazid, rifampin, pyrazinamide, and ethambutol, which must be administered in the body daily for a 2-month intensive phase. However, for susceptible TB strains, this therapy is 95% effective. The emergence of multidrug-resistant (MDR) strains, defined as resistant to isoniazid and rifampin, requires the use of less effective and more toxic second-line TB drugs. Herein we discuss some recent updates in the application of chalcones against tuberculosis:
\nNew sulfonamide-bearing chalcones (40) were synthesized by the Claisen-Schmidt condensation and were reported as excellent antituberculosis hits showing low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells [42].
\nGomes et al. studied antitubercular activities of chalcones (41) and (42). The chalcones showed good selectivity towards M. tuberculosis with low cytotoxicity against Vero cells and thus possess promising antitubercular potential [43].
\nSpirochromone annulated chalcone conjugates (43) were documented for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Molecular docking studies performed against the receptors revealed MTB phosphotyrosine phosphatase B protein as the most probable target based on the high binding-affinity scores [44].
\nBabu et al. studied chalcones containing nitrophenyl moieties (44) for antitubercular activity using MABA assay and antibacterial and antifungal activities by cup plate method. Molecular docking study predicted the inhibition of thymidine kinase of the Mycobacterium tuberculosis [45]. Anti-tubercular chalcones are depicted in Figure 5.
\nStructures of anti-tubercular chalcones.
Antioxidants are the compounds that inhibit the oxidation process. These substances can prevent or slow damage to cells caused by free radicals. Oxidation is a chemical reaction that generates free radicals, thereby leading to chain reactions which may damage the cells of organisms and hence responsible for oxidative stress resulting in chronic diseases such as heart diseases, stroke, cancer, arthritis, respiratory diseases, Parkinson’s disease, and other inflammatory conditions [46].
\nCao et al. documented a series of 4′-OH-flurbiprofen-chalcone hybrids (45) and evaluated them as potential multifunctional agents for the treatment of Alzheimer’s disease. Besides, the compounds were reported for good antioxidant activities, MAO inhibitions, biometal chelating abilities, and in vitro anti-neuroinflammatory activities [47].
\nSelenoenzymes and nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated phase II enzymes constitute the main components of cellular redox and antioxidant systems giving information about multiple interrelations involved in the oxidation processes. Chalcones (46) were proved to interfere with the biosynthesis of Nrf2-regulated selenoenzymes [48].
\nEl-Sayed et al. documented the antioxidant activity of chalcones (47) [49].
\nThe chalcone derivatives (48) were synthesized by the Claisen-Schmidt condensation with KOH in ethanol at room temperature under sonication conditions and screened for antioxidant potential by Polo et al. [50].
\nThe chalcones (49) were studied as potent antioxidants by Tajammal and coworkers. These compounds have lower IC50 values than the Trolox and ascorbic acid standards [51].
\nA series of chalcone (50) analogs were designed, synthesized, and screened for antioxidant activities. The chalcone was found as a promising anti-ischemic stroke drug candidate, providing novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related disease treatment [52]. The prenylated chalcones (51) were reported for good antioxidant activity [53]. Figure 6 represents the structures of antioxidant chalcones.
\nStructures of antioxidant chalcones.
Anti-inflammatory drugs are the drugs which are used to reduce pain and inflammation. In other words, these are pain-relieving drugs. These drugs work mainly by inhibiting the cyclooxygenase enzymes, COX-1 and COX-2, that produce prostaglandins [54]. Herein we discuss some of the efforts for the development of chalcone-based heterocycles as effective anti-inflammatory compounds:
\nIndole-based chalcones (52) were synthesized and evaluated for in vitro COX-1 and COX-2 inhibitory activity [55].
\nα-Substituted 2′,3,4,4′-tetramethoxychalcones (53) and (54) were evaluated for their ability to modulate inflammatory responses to influence on heme oxygenase-1, nitric oxide synthase, and cytokine expression levels. Anti-inflammatory activity was correlated with thiol-alkylating activity, i.e., stronger electrophiles substituted with CF3, Br, and Cl were found to be more potent than the remaining derivatives [56].
\nZhang et al. identified methoxy chalcones (55) as a potential candidate for treating acute inflammatory diseases [57].
\nPyrazole- and morpholine-containing chalcones (56) were reported for anti-inflammatory activity by Gadhave and Uphade. The anti-inflammatory activity performed by carrageenan-induced rat paw edema method showed good potency of some of the tested compounds as compared with the standard diclofenac drug [58].
\nNurkenov et al. studied the in vitro anti-inflammatory effect of chalcones (57) to inhibit the lipopolysaccharide-induced production of anti-inflammatory cytokine interleukin-6 and tumor necrosis factor [59].
\nThe imidazole containing chalcone molecule (58) demonstrated noteworthy anti-inflammatory activity as compared with the standard drug, indomethacin [60].
\n1-[3-Methoxy-4-(5-nitro-furan-2-ylmethoxy)-phenyl]-3-(substituted phenyl)-propenones (59) synthesized by the condensation of furfural and apocynin were evaluated for anti-inflammatory activity [61]. The structures of anti-inflammatory chalcones are shown in Figure 7.
\nStructures of anti-inflammatory chalcones.
Besides the above-discussed applications, chalcones are useful for miscellaneous applications. Some of them are mentioned as follows:
\n\nLeishmania is a genus of trypanosomes responsible for the disease leishmaniasis. Leishmaniasis is spread through sand flies of the genus Phlebotomus, primary hosts being the vertebrates. The chalcone (60) was evaluated against 29 promastigotes of Leishmania donovani exhibiting low toxicity against mammalian cells [62].
\nA series of new chalcone-rivastigmine hybrids (61) was designed, synthesized, and evaluated in vitro for the ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Results showed that these compounds exhibited selective activity in micro- and submicromolar ranges as compared with the standard rivastigmine and thus the compounds can serve as the lead ones for the treatment of Alzheimer’s disease [63].
\nSang et al. reported AChE/BChE inhibitory, MAO-A/MAO-B inhibitory, and antioxidant activities of chalcone-O-carbamate derivatives (62). Results revealed that the compounds show highly selective BChE inhibitory activity with IC50 values of 1–3 mM range [64].
\nSome 1,3,4-oxadiazole/thiadiazole-chalcone conjugates (63) were synthesized and evaluated for in vitro and in vivo antiviral activities against TMV. These conjugates have low binding constant values which were comparable to the standard ningnanmycin [65].
\nAmide tethered 7-chloroquinoline-chalcone bifunctional hybrids (64) were synthesized and employed as antimalarial agents against the resistant strain of Plasmodium falciparum. Methoxy substituent at the para position of ring B on chalcones and longer alkyl chain lengths significantly improved the antiplasmodial profiles of the chalcone derivatives [66].
\nThe halogenated 1-tetralone or 6-amino-1-tetralone chalcone derivatives (65) were synthesized and evaluated for inhibitory effects against ROS production in LPS-stimulated RAW 264.7 macrophages. The structure-activity relationship revealed that amino moiety at the sixth position of 1-tetralone chalcones plays an important role for greater ROS inhibitory potency [67].
\nChalcone derivatives (66) were studied for hepatoprotective ability, and the results were compared with the standard hepatoprotective drug silymarin. The experimental results were supported by a molecular docking study [68].
\nTriazole-linked 4-aminoquinoline-chalcone/-N-acetylpyrazoline conjugates (67) were synthesized and evaluated for antiplasmodial activities against cultured chloroquine-resistant strain. The activities were found to be dependent on the length of the alkyl chain as well as on the presence of methoxy substituents on the chalcone rings [69].
\nChalcone analogs (68) were synthesized and evaluated for cytotoxic effects in human hepatoma HepG2 cells. The percentage of apoptotic cells was significantly higher in the compounds than that in the control cells [70].
\nThe oxygenated chalcones (69) were found to inhibit monoamine oxidases, and the lead compounds were found to be nontoxic at 200 μg/mL in normal rat spleen cells [71].
\nHameed et al. studied the quinoline-based chalcone compounds (70) as reverse transcriptase inhibitors. Bromo- and chloro-substituted chalcones exhibited a high degree of inhibition against the reverse transcriptase [72].
\nHistoplasmosis is a fungal infection caused by the dimorphic fungus Histoplasma 27 capsulatum. Hydroxyl group-bearing chalcones (71) and (72) were studied for histoplasmosis by Wanessa et al. [73].
\nSashidhara et al. documented the antiulcer activity of some novel quinoline-chalcone hybrids (73) in various ulcer models in Sprague Dawley rats. Additional studies including in vitro metabolic stability and in vivo pharmacokinetics showed their potential to act as an orally active and safe candidate for the development of an antiulcer agent [74].
\nPyrene ring-bearing chalcone (74) was studied as a sensitive and highly selective sensor for the detection of aluminum (Al3+) ions by fluorimetric studies by Suresh et al. The chalcone was found to be useful for the electrosorptive removal of Al3+ ion and several other biological applications including the bio-imaging of bacterial cells [75].
\nChalcones (75) were reported for potent antimalarial activities against Plasmodium falciparum using Rieckmann’s method. Allyloxy, hydroxy, and alkoxy functional groups increased the antimalarial activity of the chalcone derivatives [76].
\nHuman African trypanosomiasis is an infectious disease that affects the lives of people living in rural areas of Africa. Beteck et al. studied the antitrypanosomal activities of indanone-based chalcone analogs (76) by screening against T.b. brucei [77]. The structures of chalcones having miscellaneous activities are depicted in Figure 8.
\nStructures of chalcones having miscellaneous activities.
Chalcones and their analogs possess significant biological activities including antimicrobial, anticancer, antitubercular, antioxidant, anti-inflammatory, antileishmanial, enzyme inhibitory, and miscellaneous applications and hence acquire a unique place in medicinal chemistry. The growing interest of synthetic organic, pharmacological, and medicinal chemists towards chalcones and their derivatives will be continued in the future also. This chapter is expected to provide a stimulus for researchers to design, synthesize, and carry out further investigation on the pharmacological effects of new chalcone derivatives for different biological activities.
\nThe authors declare no conflict of interest.
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