Novel Target therapy in the gastrointestinal cancers

Gastrointestinal cancers are of different types mainly focusing on the biliary tract cancers (BTC) are a heterogeneous group of cancers that are clinically and genetically divergent. BTC can be divided anatomically into gallbladder cancers (GBC), intrahepatic cholangiocarcinomas (IHCC), hilar cholangiocarcinomas (HCC), and extrahepatic cholangiocarcinomas (EHCC).

Personalized cancer medicines have occurred in current years and a number of targeted drugs have emerged. Various targeted therapies like erlotinib, trastuzumab and cetuximab have been approved in lung, breast, and colon cancers respectively.Combination chemotherapy involving cisplatin and gemcitabine is the current standard of care in the metastatic setting.

BTC are rare malignancies with poor prognosis with GBC being the most common among all BTC. Risk factors for BTC include parasitic infections by liver flukes, gallstones, diabetes mellitus, obesity, alcohol, inflammatory bowel disease, bile duct cysts, smoking, and hepatitis B and C. The presence of gallstones is by far the most important risk factor. The exact mechanism by which gallstones cause carcinogenesis is unknown but is probably due to persistent inflammation leading to dysplasia and accumulation of loss of heterozygosity at various tumour suppressor genes.

GBC have the worst prognosis among all BTC. Treatment of early BTC is surgery which offers potential cure. For advanced inoperable BTC systemic therapy is the only option. Poor prognostic factors after resection include the presence of lymph node metastases, positive margins, and poor differentiation. The use of chemotherapy over best supportive care was first supported in a clinical trial comparing combination of 5-fluorouracil and etoposide vs. best supportive care.

Recent studies revealed multiple clinically targetable mutations in BTC. Different molecular pathways are incriminating in carcinogenesis, and agents targeting these pathways have shown some efficacy in BTC cell lines.

GBC, the most aggressive cancer among all, is categorized as an orphan disease. Despite recent advances in our knowledge on the pathogenesis of BTC at the molecular level prognosis remains poor.

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Gastrointestinal Cancer in humans

Gastrointestinal cancers are the most occurring malignancies and quiet the most prevalence cause of cancer‐related mortality worldwide. Cancer stem cells (CSCs) are thought to be liable for tumour initiation, drug and radiation resistance, invasive growth, metastasis, and tumour relapse which are the main causes of cancer‐related deaths. Gastrointestinal CSCs are also thought to be contrary to conventional therapies an effective and novel cancer treatment is imperative.

CSCs were found in other gastrointestinal cancers, such as oesophagus, stomach, liver, and pancreas. Specific phenotypes could be used to differentiate CSCs from non‐CSCs.

Gastrointestinal cancers cover a variety of diseases; many of them have poor prognoses worldwide. Only Colorectal cancer (CRC) is listed in the top 10 for incidence rate of tumour. Three gastrointestinal cancers including pancreatic, hepatic and biliary tract, and oesophageal cancers are in the top 10 for death rates from tumours.

Combining several therapeutic approaches like surgery, endoscopic therapy, chemotherapy, and radiation may improve survival in patients with gastrointestinal cancer. Nevertheless, the effectiveness of this mediational care builds upon the cancer's status specifically, on metastasis, resistance to radiation/chemotherapy, and recurrence which are all thought to be caused by CSCs. Therefore, new therapeutic options for these diseases must be developed.

Many chemotherapeutic and biological agents have been developed against gastrointestinal cancers but, they target the cells found in the bulk tumour and cannot efficiently remove CSCs, which leads to treatment failure, chemo resistance, and recurrence. Consequently, gastrointestinal cancer therapies targeting CSCs have been investigated.

Anticancer therapies are usually evaluated on their ability to shrink tumours. If these therapies do not eliminate CSCs, a relapse could occur, and CSCs could enable tumours to develop further resistance. The best way to eliminate gastrointestinal CSCs is to identify the specific markers for gastrointestinal CSCs, but not for normal cells. Targeted therapy in opposition to these specific molecules could offer new start to eradicate the malignant phenotypes of cancer without influencing normal stem cells.

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Endoscopy in different diseases related to gastroenterology

Endoscopy plays an important role in the diagnosis and management of disease related to gastroenterology. It is useful to exclude other causes to differentiate between ulcerative colitis (UC) and Crohn’s disease (CD) and to define the extent and activity of inflammation. Ileocolonoscopy is used for monitoring of the disease, which in turn helps to optimize the management. It plays a key role in the surveillance of UC for dysplasia or neoplasia and assessment of post-operative CD. Capsule endoscopy and double balloon enteroscopy are increasingly used in patients with CD. Therapeutic applications relate to stricture dilatation and dysplasia resection. The endoscopist’s role is vital in the overall management of diseases.

Of the different endoscopic tools, colonoscopy remains the primary diagnostic tool. Gastroscopy, enteroscopy and endoanal ultrasound scan may be useful in the assessment of specific organ involvement in CD and to differentiate between UC and CD. Novel tools such as capsule endoscopy and double balloon enteroscopy have been playing an increasing role for small bowel Crohn’s disease assessments. Both CD and UC can be complicated by primary sclerosing cholangitis (PSC). This will focus on the role of colonoscopy in Inflammatory Bowel Disease IBD as this is by far the most important tool.

Colonoscopy technology have led to more comfortable procedures with better quality image definition like narrow band imaging, chromo endoscopy, endomicroscopy and high definition screens. Training in colonoscopy has optimised the use of this instrument for various diagnostic purposes. Colonoscopy remains the first line endoscopic investigation for suspected CD.

The use of colonoscopy as a diagnostic tool is non-contentious. Its value in disease monitoring is an evolving indication for the procedure. The thrust in this direction comes from the more recent focus on mucosal healing or reducing inflammatory activity in inflammatory bowel disease (IBD).

One of the limitations of colonoscopy is the need for oral bowel preparation to enhance adequate mucosal views. In some situations, a limited examination of the left colon with flexible sigmoidoscopy may suffice. The procedure may be undertaken following an enema or sometimes-unprepared procedure. Sigmoidoscopy provides useful information in many situations particularly, when colonoscopy is considered high risk or contraindicated e.g., acute severe colitis or fulminant colitis.

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Laparoscopic Surgery for Different Diseases related to Gastroenterology

Gastroenterology diseases like Crohn disease remains a challenging clinical entity, both medically and surgically. It frequently presents in early adulthood and imposes a lifetime exposure to chronic inflammation that can affect the entire gastrointestinal tract. 

Approximately 70 to 90% of the patients with Crohn disease will ultimately require surgery. There is no definitive cure for Crohn disease and surgery is reserved for failed medical therapy or the complications of the disease, namely, obstruction, septic complications and fistulas.

In fact, laparoscopic surgery offers many advantages, which are particularly beneficial to this subset of patients, such as fewer wound complications, a shortened hospital course, less tissue trauma and subsequent adhesion formation, and earlier resumption of oral intake and bowel function.  

Ileocolic inflammation is the most common pattern of disease in Crohn disease. Laparoscopic surgery for small bowel Crohn disease is safe and feasible but did not impart a definitive advantage over open surgery. Specifically, there are no statistical significant differences in rates of wound infection, pneumonia, urinary tract infection, anastomotic leak, intra-abdominal abscess, duration of hospital stays, or reoperation for disease recurrence.

Hand-assisted laparoscopic surgery (HALS) has gained considerable acceptance as a practical alternative to traditional laparoscopic surgery, HALS results in similar clinical outcomes as compared with standard laparoscopy. HALS provides tactile feedback and the ability for adequate retraction that may be beneficial in this subset of patients due to the inflammation, thickened mesentery, the potential for abscesses and fistulas, and bulky specimens that may not be appropriate for standard laparoscopy.

Single-Incision Laparoscopic Surgery has become increasingly used in a variety of colorectal procedures, including inflammatory bowel disease. Hence, Laparoscopy offers excellent short- and long-term outcomes like conventional open surgery. Although operative times are generally longer in a laparoscopic approach, there are well-established benefits in improved cosmesis, quicker return of bowel function, and shorter hospital stay. Laparoscopy is also possible in recurrent disease and confers similar benefits to primary resections.

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Improvement in Pancreatic and Colorectal Cancer Therapies

Improvement in medicine has led to advances in the detection, prevention, and analysis of cancer for patients with inherited risks of GI cancer, particularly genetic colorectal cancer and genetic pancreatic cancer.

The current practices for identifying, evaluating, and managing patients with suspected genetic colorectal cancer and pancreatic cancer risk is improving. The impact of next-generation sequencing technologies in the clinical diagnosis of hereditary gastrointestinal cancer and in discovery efforts of novel genes linked to familial cancer risk is increasing. Emerging targeted therapies that may play a particularly important role in the treatment of patients with hereditary forms of colorectal cancer and pancreatic cancer are giving good results.

Recent innovations in genetic medicine and next-generation sequencing technologies have led to tremendous advances in the understanding of the role that genetics plays in carcinogenesis.

The availability of novel diagnostic, risk-reducing, and therapeutic strategies that exist for patients with hereditary risk for colorectal or pancreatic cancer. It is imperative that clinicians be vigilant about evaluating patients for hereditary cancer syndromes. Continuing to advance genetics research in hereditary gastrointestinal cancers will allow for more progress to be made in personalized medicine and prevention.

Colorectal cancer remains the fourth most incident cancer and the second most common cause of cancer-related mortality. Over the past decade, scientific knowledge about the genetics of colorectal cancer has grown exponentially, and the coming years promise continued advances in the identification, management, and understanding of patients with hereditary predisposition to colorectal cancer.

There is no single gene that is responsible for hereditary or familial pancreatic cancer risk. Rather, there are multiple hereditary cancer syndromes and associated genes which confer an increased lifetime risk of pancreatic cancer.

Advances have also been made in the realm of aspirin chemoprevention for patients with hereditary colorectal cancer.

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Effect of Hepatitis C Virus on patients

Liver cirrhosis has a significant impact on patient’s quality of life and socioeconomic status and is associated with increased susceptibility to vehicle accidents and falls.

Hepatic encephalopathy (HE) represents a major cause of morbidity and mortality in patients suffering from chronic liver diseases. It is characterized by serious neuropsychiatric and neurocognitive complications, including confusion, disorientation, ataxia and coma.

It is characterized by poor health-related quality of life, impaired daily functioning, poor socio-economic status, susceptibility to vehicle accidents and, increased occurrence rate of overt HE, leading to increased mortality in patients with liver cirrhosis. Hence early diagnosis of psychosocial impairment is crucial in cirrhotic patients to prevent further progression and potential life-threatening risk.

Now a day, liver biopsy is the standard method for the detection of liver fibrosis. However, invasiveness is an important drawback in implementing this method particularly in patients with early stages of liver fibrosis as well as sampling error and variability in results interpretation.

Transient Elastography (TE) known by the name FibroScan is a non-invasive test to determine the amount of liver fibrosis present. It also identifies and evaluates steatosis concurrently using the Controlled Attenuation Parameter (CAP). It is a type of elastography.

There is no consensus regarding a standard test for early diagnosis of the neuropsychiatric changes, associated with minimal liver encephalopathy. Indeed, there are several confounding factors which strongly affect patient’s performance in neuropsychiatric tests, including age, gender, level of education and socioeconomic status

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The Analysis of Continuous and Malignant Liver Diseases

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequently occurring types of primary liver cancer worldwide and account for 80% and 15% of primary liver cancer respectively. Current studies have reported that the worldwide incidence of these liver and biliary tract diseases is increasing.

Environmental and cultural factors are important determinants of the incidence of HCC. Non-alcoholic liver disease is a potential key player in the increasing incidence of HCC in the population.

Unfortunately, the early diagnosis of these diseases remains difficult and, in most cases, the disease is diagnosed late because of the absence of symptoms in the early stages.

At present, the most accurate diagnostic methods for these disorders, such as endoscopic retrograde cholangio-pancreatography guided by bile duct biopsy, percutaneous Tran’s hepatic cholangiography and endoscopic ultrasonography guided by fine needle aspiration is invasive.

Recently, there has been remarkable progress in applying proteomics to the identification of potential biomarkers for HCC, CCA, and PSC. However, these biomarkers are useful for discriminating between benign and malignant biliary conditions only in patients who have undergone bile drainage.

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