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Review Interpretation and Management of Pancreatic Cancer

Ganesh N. Sharma*1, Deenanath Jhade2, Bhushan Hatwar3 and Dr. D. C. Goupale4

1School of Pharmaceutical Sciences, Jaipur National University, Jaipur- 302017, India 2School of Pharmacy, Chouksey Engineering College, Bilaspur, India, 495001 3Bansal College of Pharmacy, Bhopal, India 462021 4Principal, Bajirao Karanjekar College of Pharmacy, Sakoli, District Bhandara (M.S.)

A R T I C L E I N F O A B S T R A C T

Received 28 Sep. 2014 Received in revised form 20 Oct. 2014 Accepted 28 Oct. 2014 The uncontrolled division and growth of pancreatic cell results in abnormal physiological and anatomical modifications of the pancreas, subsequently pancreatic carcinoma, which is a major Keywords: Pancreatic cancer, cause of death in humans among other cancers worldwide, which Adenocarcinoma, often has a poor prognosis, even when diagnosed early, and also Chemotherapy, referred as “silent” disease, because symptoms are rarely present Oncogenes. in its early stages. Although; most pancreatic cancer is exocrine, but may be endocrine also. The present review aims to compile data on all the aspects of pancreatic cancer, including its

pathogenesis, diagnosis, symptoms and treatment. The attention has also been made towards the recent approaches used in all these Corresponding author: School of procedures. Pharmaceutical Sciences, Jaipur National University, Jaipur-302017, India. E-mail address: [email protected] © 2014 British Biomedical Bulletin. All rights reserved

Sharma et al______ISSN-2347-5447 Introduction Cancer begins when cells in a part of Usually, cancer is named after the the body start to grow out of control. There body part in which it originated; thus are many kinds of cancer, but they all start pancreatic cancer refers to the erratic growth because of out-of-control growth of and proliferation of cells that originate in the abnormal cells. Cancer cell growth is pancreatic tissue4. Pancreatic cancer is the different from normal cell growth. Instead of fourth most common cause of cancer-related dying, cancer cells continue to grow and deaths in the United States and the eighth form new, abnormal cells. Cancer cells can worldwide. Pancreatic cancer has an also invade (grow into) other tissues, extremely poor prognosis for all stages5. something that normal cells cannot do. Pancreatic cancer is a malignant neoplasm Growing out of control and invading other originating from transformed cells arising in tissues are what makes a cell a cancer cell1. tissues forming the pancreas. The most Cancer can be induced by other common type of pancreatic cancer, factors such as; nuclear radiation, accounting for 95% of these tumors, electromagnetic radiation (microwaves, X- is adenocarcinoma6. rays, Gamma-rays, Ultraviolet-rays, etc.), The pancreas is prismoid in shape viruses, bacteria and fungi, parasites (due to and appears triangular in cut section with tissue inflammation / irritation, heat, superior, inferior, and anterior borders as chemicals in the air, water and food, well as anterosuperior, anteroinferior, and mechanical cell-level injury, free radicals, posterior surfaces (Figure1). The head of the and ageing of DNA and RNA, etc. All these pancreas lies in the duodenal C loop in front can produce mutations that may start of the inferior vena cava (IVC) and the left cancer2. renal vein (see the following images). The In most cases the cancer cells form a uncinate process is an extension of the lower tumor. Some cancers, like leukemia, rarely (inferior) half of the head toward the left; it form tumors. Cancer cells often travel to is of varying size and is wedged between the other parts of the body, where they begin to superior mesenteric vessels (vein on the grow and form new tumors that replace right, and artery on left) in front and aorta normal tissue. This process is called behind it. The body and tail of the pancreas metastasis. It happens when the cancer cells run obliquely upward to the left in front of get into the bloodstream or lymph vessels of the aorta and left kidney7. our body. Different types of cancer can The body and tail of the pancreas lie behave very differently. For example, lung in the lesser sac (omental bursa) behind the cancer and breast cancer are very different stomach. The main pancreatic duct (of diseases. They grow at different rates and Wirsung) runs from the tail through the respond to different treatments. That is why body to the head of the pancreas where it people with cancer need treatment that is descends into the lower (inferior) part of the aimed at their particular kind of cancer. Not head. There, it joins the duct of the uncinate all tumors are cancerous. Tumors that aren't process coming from the left and then the cancer are called benign. Benign tumors can lower part of the common bile duct to form cause problems – they can grow very large a common channel (called the and press on healthy organs and tissues. But hepatopancreatic ampulla, when dilated), they cannot grow into (invade) other tissues. which runs through the medial duodenal Because they can't invade, they also can't wall and opens on the dome of the major spread to other parts of the body duodenal papilla (a nipple like projection on (metastasize)3.

BBB[2][4][2014]602-612 Sharma et al______ISSN-2347-5447 the medial wall of the middle segment of the  Intraductal papillary - mucinous second part [C loop] of the duodenum) 8. neoplasm (IPMN): An IPMN grows from the main pancreatic duct or from Epidemiology of pancreatic cancer side branches of the duct. The tumor Pancreatic cancer is currently the may appear as a finger-like, or papillary, fourth leading cause of cancer death in the a projection into the duct. However, it western countries, claiming 32,000 lives has a high risk of progressing to annually. The rate of incidence seems to be malignancy. An IPMN may therefore be increasing; not only is the disease becoming a precursor for adenocarcinoma. more common, but it is also extremely  Mucinous cystadenocarcinoma: It is difficult to treat: signs and symptoms of the rare, malignant, spongy, cystic tumor. disease seldom show until more advanced The cyst is filled with a thick fluid called stages of cancer. By the time symptoms do mucin. It is similar to an IPMN, but show up, cancer cells are likely to have occurs in just one area of the pancreas. metastasized to other parts of the body, often  Pancreatoblastoma: The rare form of rendering surgical removal of tumors pancreatic cancer found primarily in impossible. While there is currently no children under the age of 10, and also treatment for pancreatic cancer, medical called as pancreatic cancer of infancy. 9 research is advancing rapidly .

2. Endocrine pancreatic cancer11: Types of pancreatic cancer  Gastrinoma (Zollinger - Ellison It may be further categorized as; syndrome): Associated with over exocrine pancreatic cancer and endocrine production of gastrin, and is malignant pancreatic cancer. or have the ability to become malignant. The genetic basis of the same is Multiple 10 1. Exocrine pancreatic cancer : This Endocrine Neoplasia Type 1 (MEN1). type of cancer is further sub categorized  Glucagonoma: it has over production of as; glucagon, and are large, often  Acinar cell carcinoma: It is a very rare metastasize and about 70% are form of pancreatic cancer, which leads malignant. Commonly found in the body excessive production of pancreatic and tail of the pancreas. lipase, a fat digesting enzyme, and is an  Insulinoma: It induces over production indication of acinar cell carcinoma. of insulin, and are most common &  Adenocarcinoma: it accounts about benign. 90% of all pancreatic cancer, which  Nonfunctional islet cell tumor: This is begins in the cell lining of the pancreatic usually malignant and hard to detect. duct. It may form glands, or a collection  Somatostatinoma: It includes over of cells surrounding an empty space. production of somatostatin. They vary in  Adenosquamous carcinoma: Similar to their potential to become malignant. adenocarcinoma, but the glands becomes  Vasoactive intestinal peptide-releasing flattened as it grows. tumor (VIPoma or Verner-Morrison  Giant cell tumor: They are extremely syndrome): These tumors are usually rare and may not be as aggressive as located in the body and tail of the adenocarcinoma. They contain larger pancreas. Two-thirds of VIPomas are cells. found in women. The syndrome is also known as Watery Diarrhea and

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Hypokalemia Achlorhydria (WDHA) present in a similar fashion to pancreatic Syndrome. head cancer, but have a slightly better prognosis, probably because early Pathophysiology obstruction of the bile duct and jaundice A number of risk factors and basis leads to the diagnosis. In addition to ductal for pancreatic cancer have been reported viz. adenocarcinoma, which makes up about age, gender12, cigarette smoking13, obesity 75% of nonendocrine cancers of the and physical activity14, diabetes15, chronic pancreas, there are a variety of less common pancreatitis16, cirrhosis of the liver17, types of pancreatic cancer. The figure 2 genetic causes18, stomach problems, diet, shows the growth of pancreatic intra alcohol19 etc. neoepithelial cells along with activation of Pancreatic cancer probably arises tumor inducing genes such as K-ras, DPC4 through a stepwise progression of cellular and others. changes, just as colon cancer progresses by stages from hyperplastic polyp to invasive Interpretation of pancreatic cancer cancer. Systematic histologic evaluation of There are several stages involved in areas surrounding pancreatic cancers has pancreatic cancer, and two models for revealed the presence of precursor lesions accurately describing them. that have been named pancreatic intraepithelial neoplasia Three stages of 1. Tumor node metastasis (TNM) model: pancreatic intraepithelial neoplasia have In this system, tumor size, lymph node been defined. These lesions demonstrate the health and metastasis activity are same oncogene mutations and loss of tumor- measured separately, each with its own suppressor genes found in invasive cancers, number scale. For tumors, T1 means the frequency of these abnormalities that a tumor is less than 2cm across in increasing with progressive cellular atypical any direction; T2 means that the tumor is and architectural disarray. Any change in larger than 2cm across; T3 means that sequence leads to pancreatic cancer20,21. the tumor has started to grow into the The ability to detect these precursor tissues, duodenum and bile ducts that lesions in humans at a stage where the surround the pancreas; finally, T4 means cancer can still be prevented or cured is an that the tumor has grown into the spleen, important goal of current pancreatic cancer large intestines and major blood vessels. research. About two thirds of pancreatic For lymph nodes, N0 means that there adenocarcinoma arise within the head or are no lymph nodes containing cancer; uncinate process of the pancreas; 15% are in N1 means that there are lymph nodes the body, and 10% in the tail, with the containing cancer, and so the tumor has remaining tumors demonstrating diffuse likely metastasized beyond the involvement of the gland. Tumors in the pancreas. Finally, for metastasis (tumor pancreatic body and tail were generally migration), M0 means the tumor has not larger at the time of diagnosis, and therefore, spread, and M1 means that it has. less commonly respectable. Tumors in the head of the pancreas are typically diagnosed 2. Stage Model: The second model for earlier because they cause obstructive pancreatic cancer involves 4 numbered jaundice. Ampullary carcinomas, stages, as follows: carcinomas of the distal bile duct, and  Stage 1: The tumor has not progressed periampullary duodenal adenocarcinoma outside of the pancreas. The TNM

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equivalent would be T1 or 2; N0; M0, Common diagnostic approaches meaning that there has been no spread  Ultrasound of the abdomen: An and that the tumor is relatively small. ultrasound can identify a tumor or mass  Stage 2: The tumor has grown into in the pancreas or the bile duct system nearby tissues and perhaps the that may be causing a blockage and duodenum. Lymph nodes are not jaundice24. affected. The TNM equivalent would be  Endoscopic ultrasonography (EUS): T3; N0; M0. The EUS test is done with a lighted tube  Stage 3: The tumor may be quite large that is inserted through the mouth and and has spread to the lymph node placed into the stomach. Ultrasound system, and thus is capable of spread to images of the pancreas are obtained other organs. The TNM equivalent through the stomach wall. It is highly would be T1, 2 or 3; N1; M0. sensitive for diagnosing pancreatic  Stage 4: This stage is often divided into cancer. EUS is particularly useful for two sub-stages. 4A describe a situation detecting small (<2 cm) pancreatic in which cancer has grown into nearby tumors, which may not be well organs, including the spleen and/or visualized by CT. It can also identify stomach, as well as large blood vessels. tumors that may involve important blood The TNM equivalent of this stage would vessels. The procedure can provide be T4; N1 or 2; M0. Stage 4B describes details about the arteries and veins next a situation in which cancer has spread to to the pancreas. A biopsy with a small or other organs such as the liver or lungs, fine needle aspiration (FNA) of the and has a TNM equivalent of T1, 2, 3, or tumor may also be performed during 4; N0 or 1; M122. EUS for diagnosis pancreatic cancer. Intravenous sedation is used for this Signs and symptoms procedure25. Upper abdominal pain that may  Endoscopic retrograde cholangio- extend to middle or upper back, weight loss pancreatography (ERCP): An ERCP is due to malignant cancer cells tendency to done with a lighted tube called an deprive healthy cells of nutrients. Jaundice endoscope to look at the bile ducts. It leads to yellowing of the skin and whites of can also be used to place a stent or tube the eyes. This condition is fairly common to open a blocked bile duct for drainage. among pancreatic cancer patients, and Intravenous sedation is most commonly develops when blood cells become worn out used for this procedure26. and break down into bilirubin. Normally,  Computed tomography (CT): The CT bilirubin is eliminated in the bile, which is a scan can show small tumors as well as fluid produced by the liver. However, if a important blood vessels that the tumor pancreatic tumor blocks the flow of bile, might be growing in or around. A CT jaundice may occur. Nausea and vomiting scan can also look at surrounding organs can occur during later stages, if a pancreatic for spread (metastasis) of the cancer into tumor has grown sufficiently large to block lymph nodes, liver and other areas27. a portion of the digestive tract (usually the duodenum) Digestive problems may occur, Recent advancement in diagnosis of as the pancreas is an integral part of the pancreatic cancer digestive system. Due to Zollinger Ellison Andraka’s diagnostic tool which is syndrome, stomach ulcers can also happen23. dipped in a solution of carbon nanotubes

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(Figure 3), having hollow cylinders with tumor is found to be at the head of the walls the thickness of a single atom, coated pancreas and is operable, the surgical with a specific antibody designed to bind procedure performed is a with the virus or protein one is looking for. pancreaticoduodenectomy, also called a Andraka’s key insight is that there are Whipple procedure (Figure 4). This surgery noticeable changes in the electrical involves removing the head of the pancreas, conductivity of the nanotubes when the the gallbladder, part of the bile duct, and distances between them changes. When the part of the stomach. Surgery includes re- antibodies on the surface of the nanotubes connecting the remainder of the bile duct, come in contact with a target protein, the pancreas and stomach to bowel so that these proteins bind to the tubes and spread them structures can drain properly30. apart a tiny bit. That shift in the spaces  Radiation therapy: Radiation therapy between tubes can be detected by an (also called radiotherapy, x-ray therapy, electrical meter28. or irradiation) is the use of a beam of A nanotube sensor with a targeted energy to kill cancer cells and shrink antibody is extremely sensitive. In a single- tumors. Radiation therapy injures or blinded test of 100 patient samples, destroys cells in the area being treated Andraka’s sensor spotted the presence of by damaging their genetic material, mesothelin, a protein commonly used as a making it impossible for these cells to biomarker for pancreatic cancer, at a limit of continue to grow and divide. Although 0.156 nano grams per milliliter, well below radiation damages both cancer cells and the 10 ng/mL considered an over expression normal cells, most normal cells can of mesothelin consistent with pancreatic recover from the effects of radiation and cancer. It’s also 100 times more selective function properly31. than existing diagnostic tests, which means  Chemotherapy: Chemotherapy may be 29 no false positives or false negatives . used at any stage of pancreatic cancer

and is commonly used when the cancer Management of pancreatic cancer is advanced and can’t be removed The following approaches are to be completely with surgery. It may also be made for the management of breast cancer. used as adjuvant treatment after the They are as follows; cancer has been removed with surgery to  Surgery: Approximately 20% of the try to kill any cancer cells that have been tumors are found to be operable or left behind. It can also be used as resectable. The location of the pancreas neoadjuvant to surgery to try to shrink adds to the technical difficulties of a the tumor. Gemcitabine, 5-fluorouracil surgical operation. Ideally, surgery (5-FU), Cisplatin, Irinotecan, Paclitaxel, would remove the tumor with a wide Docetaxel, Capecitae, or Oxaliplatin are band of surrounding normal tissue. prescribed as single or in combination However, important veins and arteries with each other. The adverse reactions are located near the pancreas and it may are there, which depend on the type of not be possible to do surgery. drugs, the amount taken, and the length Diagnostic tests give information of treatment. Many of the chemo drugs about the size, location and involvement of used for pancreatic cancer can cause other surrounding tissues and vessels. These diarrhoea. For example; cisplatin can tests help the surgeon determine whether a cause nephropathy, and in combination cancer is operable or resectable. If the with oxaliplatin may produce

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neuropathy. Now days, targeted therapy Recent approaches in management of (for certain gene) have also been being pancreatic cancer employed to achieve better therapeutic Although a number of approaches effects and to minimize adverse drug have been made for the rectification of the reactions. The drug Sunitinib (approved problem, still work is going on. Recently, by FDA) attacks both blood vessel attention has been made on other targets. growth and other targets that stimulate  Gene therapy: Pancreatic cancer cell growth. Everolimus works by adenocarcinoma, is an area where gene blocking cell protein (mTOR), which transfer and immunotherapy have a normally promotes cell growth and maximal opportunity to demonstrate division. Somatostatin analogs: efficacy. These therapies, which do not Octreotide, lanreotide and Pasireotide require efficient gene transfer, generally are very helpful as they can stop the lead to systemic biological effects and tumor from releasing its hormone into therefore the effects of limited gene the bloodstream. This reduces symptoms transfer are biologically "amplified." and helps patients feel better. The second category of gene transfer Diazoxide block insulin release, which strategies requires the delivery of can be used to prevent hypoglycemia in therapeutic genetic material to all or patients with Insulinomas. Beside these; most tumor cells34. proton pump is being used to inhibit  Oncogenes inactivation: The KRAS 32 gastrinomas . oncogene is frequently mutated in Gemcitabine (2', 2'-difluorudeoxy- human malignancies such as colon, lung, cytidine, dFdC) is a nucleoside cytidine and ovarian cancer. In pancreatic cancer, analogue that exhibits antitumor mutations in KRAS are found in more activity. This drug exhibits cell phase than 90% of patient samples. The most specificity by primarily inhibiting cell frequent mutation is the constitutively proliferation in DNA synthesis (S-phase) active KRASG12D allele Interestingly, and on the G1/S-phase boundary. KRAS mutations are frequently detected Gemcitabine is intracellularly metabolized in the most common precursor lesion to to the active diphosphate and triphosphate pancreatic cancer, pancreatic nucleosides by nucleoside kinases. The intraepithelial neoplasia (PanIN), mechanisms of action of gemcitabine indicating a potential role early in the involve competition for incorporation into disease35. DNA, thereby inhibiting the synthesis of  Immune enhancement: Autologous DNA; preventing DNA repair by masked natural killer (NK) cell and activated T- termination; and undergoes self-potentiation. lymphocyte based immunotherapy Gemcitabine undergoes phosphorylation by termed as autologous immune deoxycytidine kinase to gemicitabine di- and enhancement therapy (AIET) can be then triphosphate. Gemcitabine diphosphate used to enhance immunity36. inhibits ribonucleotide reductase, which is  Enzyme therapy: Pancreatic enzyme the primary enzyme involved in the administration serves to reverse the formation of deoxycytidine triphosphate effects of pancreatic exocrine (dCTP) that is a natural substrate in DNA insufficiency and may reduce or replication, thus allowing the incorporation alleviate the pain experienced by of gemcitabine triphosphate nucleotides patients. Conventional enzyme 33 into the DNA chain during replication . preparations are partially degraded by

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gastric acid, but are available within the 10. http://www.pancan.org/section-facing- duodenal and jejunal regions to bind to pancreatic-cancer/learn-about-pan-cancer/ CCK-releasing peptide, and down types-of-pancreatic-cancer/exocrine/. regulate the release of CCK37. 11. http://www.pancan.org/section-facing- pancreatic-cancer/learn-about-pan-cancer/ types-of-pancreatic-cancer/endocrine- Conclusion pancreatic-neuroendocrine-tumors/ Pancreatic cancer is the major cause 12. Brunton LL, Lazo SJ, Keith P. Goodman & of death around the world. Due to its poor Gilman’s: The pharmacological basis of therapeutics. 11th edi, New Delhi: McGraw prognosis, the mortality rate with pancreatic Hill Medical Publishing Division, 2005: 401- cancer is high, so that newly developed 420. cheaper and sensitive diagnostic tools are 13. Fuchs CS, Colditz GA, Stampfer required to create a breakthrough to MJ, Giovannucci EL, Hunter DJ, Rimm determine it. Although a number of EB, Willett WC, Speizer FE. A prospective approaches have been made to identify the study of cigarette smoking and the risk of disease, and its management, still a lot of pancreatic cancer. Arch Intern Med. 1996; work is required to minimize mortality rate 156(19): 2255-2260. and to minimize adverse reactions of the 14. Gukovesky I, Li N, Gukovskaya A, Todoric synthetic drugs. J, Karin M. Inflammation autophagy and obesity: Common features in pathogenesis of pancreatitis and pancreatic cancer. References Gastroenterology. 2013; 144 (6): 1199–209. 15. Rang HP, Dale MM, Ritter JM, Flower RJ. 1. Heiken J. Pancreatic cancer. 1st edi, USA: Rang and Dales Pharmacology. 6th edi, Cambridge University Press; 2008: 60-150. Elsevier publication, 2007: 525-530. 2. Bennet PN, Brown MJ. Clinical 16. Casper ES, Green MR, Kelsen DP, Heelan pharmacology. 9th edi., New Delhi: Elseiver RT, Brown TD, Flombaum CD, India Pvt. Ltd, 2006: 659-665. Trochanowski B, Tarassoff PG. Phase II trial 3. Roger W, Cate W. Clinical pharmacy and of gemcitabine (2,2'-difluorodeoxycytidine) therapeutics. 4th edi, Churchill Livingstone in patients with adenocarcinoma of the Elseiver, 2008: 480-85. pancreas. Invest New Drugs, 1994; 12 4. Goyton AC, Hall JE. Textbook of medical (1):29-34. physiology. 10th edi, New Delhi: Reed 17. Loscalzo, Hauser. Harrison’s Priciples of Elsevier India Pvt Ltd, 2011: 747-766. internal medicine. 17th edi., New Delhi: Mc 5. Bertran K, Masters S, Anthony T. Basic and Graw Hill Medical Publishers, 1:580-620. clinical pharmacology. 10th edi., New Delhi: 18. Lynch HT, Lynch JF, Lanspa JS. Familial Tata McGraw Hill Education Pvt Ltd, pancreatic cancer. Cancers (Basel). 2010; 2009:721-751. 2(4): 1861–1883. 6. John N. Pancreatic cancer. USA: Springer 19. Valiang WG, Anna G, Stephan JP. Alcohol Science, 2010: 4-60. and pancreatic cancer. Alcohol Journal, 7. Steven G, Gennaro, Alfonso R. Remington: 2005; 35:205-211. The science and practice of pharmacy, 21st 20. Hidalgo M. Pancreatic cancer. The New South Asian edi, 2005:1110-1115. Eng. J.of Med. 2010, 362: 1605-1617. 8. Satou A, Nakamura. Pancreas: Anatomy, 21. Heiser PW, Hebrok M. Development and diseases and health implications. Nova cancer: Lessons learned in pancreatic cancer. Sciences Publishers, 2012: 45; 50-110. Cell cycle, 2004; 3 (3): 270-272. 9. Bhattacharya SK. Pharmacology. New 22. Tamm PE, Silver Man MP, Charnsagavej C, Delhi: Elesevier India Pvt. Ltd., 2004: 335- Evans DB. Diagnosis staging and survillence 340. of pancreatic cancer. American J. of Roentgenology, 2003; 180 (5): 1311-1323.

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Figure 1. Human pancreas

Figure 2. Progression of pancreatic cancer

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Figure 3. Carbon nanotubes

Figure 4. Whipple procedure for pancreatic cancer surgery

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