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The Product of a Pancreas Cancer Think Tank

❶These subgroups would aid efforts to screen for the disease by a better targeting of clinical resources and the provision of new markers for screening efforts 34 , For example, in colon cancer, it is well recognized that there is improved survival when the disease is found at an early stage.


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Is magnetic resonance imaging-guided biopsy more accurate? A note on plagiarism please read before submission: Latest Impact Factor 3. Anahid Jewett, et al. Cited by 45 Chikezie O. Novel diagnostic biomarkers for prostate cancer. Cited by 76 Ohtani H, et al. A meta-analysis of the short-and long-term results of randomized controlled trials that compared laparoscopy-assisted and conventional open surgery for colorectal cancer.

Cited by 70 Dario Sangiolo. Cited by 61 Sara A. Cited by 45 Inhaled therapy for lung cancer is a local form of treatment. Currently inhaled non-specific cytotoxic agents have been evaluated as a future treatment for local disease control and distant metastasis control.

There are few information regarding the influence of local transporters and gene expression of the respiratory epithelium to the absorption of administered drugs.

Drugs blocking PD-L1 or its receptor are in clinical development and early data suggests that tumor PD-L1 expression may predict response. The group unanimously agreed to adopt the designation Pan creatic I ntraepithelial N eoplasia, or PanIN, as originally proposed by Klimstra and Longnecker 21 , for these lesions. This terminology was adopted because the group felt that it reflected the growing body of evidence supporting the neoplastic nature of many of these duct lesions 22 , 23 , 24 , 25 , 26 , 27 , 28 , PanIN-1A designates flat nonpapillary epithelial lesions composed of tall columnar mucin-containing cells that show slight or no atypia.

It was recognized that the neoplastic nature and the precursor potential of many of PanINs-1A has not been established, and some investigators may therefore choose to add the modifier [L] for lesion to PanINs-1A i.

PanIN-1B designates epithelial lesions that have a papillary, micropapillary, or basally pseudostratified architecture but are otherwise identical to PanIN-1A.

PanIN-2 are epithelial lesions that may be nonpapillary or papillary with no more than moderate cytological atypia, including loss of polarity, nuclear crowding, nuclear enlargement, pseudo-stratification, and nuclear hyperchromatism.

PanIN-3 epithelial lesions are usually papillary or micropapillary, but they are rarely flat. Cribriform growth and the budding-off of small clusters of epithelial cells into the lumen support the diagnosis of PanIN Severe atypia is manifested cytologically as the loss of polarity, the loss of differentiated cytoplasmic features, cellular and nuclear pleomorphism, and the presence of mitoses—especially if atypical suprabasal or luminal in location.

Details of this new nomenclature as well as representative examples of each lesion can be found on the World Wide Web. Although the establishment of a new standard nomenclature for incipient pancreatic cancer is an important first step, the participants in the histology working group agreed that additional studies are needed to validate the reproducibility of this classification system and, very importantly, to define the genetic alterations associated with each grade of PanIN as well as the risk of each lesion progressing to cancer.

It is hoped that such studies will form a foundation for the development of new screening tests for the early detection, and possibly the prevention, of pancreatic cancer. A second pathway for the development of invasive carcinomas in the pancreas was the subject of limited discussion.

IPMNs 3 of the pancreas may progress from adenomas to borderline tumors to intraductal carcinomas and then to invasive carcinomas. The infiltrating carcinomas associated with IPMNs may show solid desmoplastic, mucinous noncystic, or adenosquamous growth patterns. The histology working group noted that IPMNs may serve as a useful model system for the study of genetic progression in the pancreas. The genetics, risk, and prevention working group represented a broad range of interests, including those of somatic genetics, inherited susceptibility, and environmental influences and epidemiology.

Among the members there was also considerable interest in the subjects represented by the other working groups, especially in the application of screening techniques, early disease progression, and the histological classification of tumors. The members felt that their work was highly translational, having a practical importance for the ultimate benefit of pancreatic cancer patients.

Their goals included the better recognition of disease variants and an improved classification of patients into distinct and relevant subgroups. These subgroups would aid efforts to screen for the disease by a better targeting of clinical resources and the provision of new markers for screening efforts 34 , Genetic markers are currently aiding the development of a tumor-progression model and a nomenclature system for the precursor lesions.

There exists considerable hope that therapeutic advances also will benefit from these classifications, and that rational new therapies might be suggested by the genetic and other etiological insights that clarify the biological foundations of this disease. The long-term goals proposed by the group included: No borders were seen for these goals, in that there remains hope that general models will emerge to aid the understanding of multiple tumor types as well as that considerable cross-pollination between various tumor types and scientific disciplines would continue to enrich the overall problem of controlling cancer.

This is evidenced by the remarkable ties between dissimilar cancers, such as the susceptibility to melanoma and pancreatic cancer seen in families that harbor a p16 gene mutation 36 and the increased rates of breast, pancreatic, and other cancers in those with a BRCA2 gene mutation 37 , An enhanced outreach to the nonneoplastic diseases was envisioned as well, especially a need to better understand the relationships between exocrine and endocrine diseases especially diabetes of the pancreas.

A number of problems were seen as hindering research in this area. The attainment of adequate family histories is complicated by the late onset of pancreatic cancer, the high variety of other cancer types to be seen in susceptible families, and the low penetrance for the disease among persons with inherited susceptibility. Financial, legal, and ethical considerations provide barriers to the collection of the tissues, blood, and other archival resources necessary to better understand this disease.

There is a need for increased input from outside fields and diseases. Facilitation of interactions between basic scientists and clinicians to the point of significant and productive collaborative efforts will be essential, but this remains inadequate in many of the current research settings.

The current size of the scientific community in pancreatic cancer remains far inadequate to attain the necessary pace of discovery—a work force 20— times larger was thought to be more comparable with the tasks at hand and also more comparable with the efforts now devoted to other major cancer types.

These considerations produced recognition of the need for additional funding, added visibility of the field itself, and the welcoming of the emerging advocacy movements in pancreatic cancer. These emerging and fluid issues can be seen as vital to research progress as is the performance of current research efforts. There is a need for seed money to establish banks of resources modeled after the successful sharing of CEPH family DNA samples and pedigree information.

There is a need to attract young investigators and the money to provide stability in their early career development. The greatest excitement among this working group concerned the opportunities to improve the study of inherited risks. A definition of FEPC was undertaken.

There was recognition of the need for an open definition to emphasize that classification and reclassification is an ongoing process as we gain new knowledge of the patterns of inherited disease.

Two major divisions of FEPC were obvious: Clinicians are most often responsible for the recognition of affected families, and need to be familiar with inheritance patterns that predispose to pancreatic cancer. In contrast, idiopathic FEPC is a category of exclusion, comprising families that cannot be classified as syndromic. This category has a moving, operational definition that is flexibly redefined as needed for particular clinical or research needs, and it is broadly recognized as any clustering of pancreatic cancer within a family, with or without associations with other cancer types.

A number of caveats were seen as important when referring to FEPC. An individual with FEPC may come to clinical attention because of multiple neoplasms rather than because of a classic family pedigree.

Depending on the particular aims of a research study, the designation as FEPC may be based on two first-degree relatives with pancreatic cancer or on two second-degree relatives connected by a blood relative having any form of cancer. The designation as FEPC may require a systematic review of all cases of cancer in the family, including a full histological reevaluation of archival specimens and a review of clinical records. Major goals related to the study of FEPC include the establishment of a large collaborative research effort and database made possible by new resources but preceded by the coordination of current databases based in a core center.

One immediate suggestion was to analyze by linkage, sibpair analysis, or mutational study of candidate genes the families that have three affected first-degree relatives. There is a need to define and disentangle the etiological [ i. Consideration should be given to eventually developing a resource of families for screening and for intervention.

The aim of this working group was to explore many of the vital issues involved in the early detection of adenocarcinoma of the pancreas. Some of the challenges presented by pancreatic adenocarcinoma include the retroperitoneal location of the pancreas, difficulties in differentiating between focal pancreatitis and carcinoma, and the identification of high-risk groups.

One approach to improve the dismal prognosis for an individual affected with pancreatic adenocarcinoma consists of diagnosing the disease at an earlier, and hopefully more curable, stage. Members of this working group came from diverse backgrounds, including gastroenterology, oncology, epidemiology, surgery, radiology, and molecular biology.

It is essential to resolve this issue, because the assumption of any surveillance or screening program is that it will be of benefit to the patient. For example, in colon cancer, it is well recognized that there is improved survival when the disease is found at an early stage. Only limited data are available to address this issue in pancreatic cancer.

A recent paper from Ariyama et al. One member of the working group, A. Lowenfels 41 , performed a general analysis of surveillance for patients at high risk for pancreatic cancer. The following assumptions were used in the analysis: An additional analysis by Lowenfels to determine the years of life gained in screening high-risk patients at 50 years of age for adenocarcinoma of the pancreas is shown below and emphasizes the importance of the sensitivity and specificity of the screening method.

There was general consensus among the working group that the ideal histological stage that warrants aggressive intervention, such as a total pancreatectomy, and offers the best chance of cure would be an advanced precursor lesion PanIN-3 or carcinoma- in situ. However, the working group felt that the current imaging studies were inadequate for the identification of lesions at the severe dysplastic stage PanIN There was a great deal of discussion about the recently published University of Washington experience that evaluated various imaging studies including EUS, computed tomography, and ERCP in pancreatic cancer-prone families They felt that pancreatic ductal abnormalities detected on ERCP represented dysplasia.

More importantly, every patient with an abnormal ERCP had an abnormal EUS that demonstrated echogenic foci, hypoechoic nodules, or an echogenic main duct. The majority of the working group would not recommend a pancreatectomy based on these findings alone, but preferred confirmation by another method such as a biological marker. Some participants felt that using biological markers to decide upon pancreatectomy would have to await long-term studies addressing the predictive value of such markers.

Most of the group felt that EUS was an appropriate first choice for an imaging technique in screening high-risk individuals, and all members of the working group believed it should only be done in a research setting. It was also recognized that imaging studies might have limited, if any, value in certain high-risk groups with underlying pancreatic changes, e.

Magnetic resonance imaging and positron emission tomography were two promising imaging modalities that were discussed, and which group members particularly believed warranted additional investigation. There was a general consensus regarding the importance of biological markers for the early detection of pancreatic cancer. Potential specimen sources include serum or plasma; pancreatic juice obtained via ERCP or secretin stimulation; or pancreatic cells obtained by fine-needle aspiration, cytological brushings, or large-bore-needle biopsy.

It was recognized that there were no tumor-specific markers available for pancreatic cancer. Members of the group felt that the best means of improving specificity and sensitivity was to use a panel of markers. It was concluded that K-ras will not suffice as a marker alone, because of poor specificity, and it probably will not be that useful, even as part of a panel, for the same reason. Limitations of some of these markers, such as p53, are the need for neoplastic cells, which are few in numbers with current collection techniques such as secretin stimulation.

No consensus could be reached on when surveillance should begin for pancreatic cancer-prone families. Suggestions included the initiation of surveillance at either 5 or 10 years before the earliest age of onset of pancreatic cancer in the family. Treatment options for high-risk individuals were discussed briefly. No participant supported the approach of prophylactic pancreatectomy. Some participants stated that they would follow the natural course of these patients while collecting specimens prospectively and banking them.

Other participants favored the approach from the University of Washington, with the performance of a pancreatectomy in patients believed to have dysplasia by ERCP. However, there were concerns expressed with the latter approach related to the fact that these findings may not be applicable to all pancreatic cancer-prone families because of the heterogeneous make-up of these families.

In summary, several important points should be emphasized from this working group. First, all participants felt that surveillance of high-risk individuals should only be performed in a research setting. Second, the goal of surveillance should be the detection of an advanced precursor stage, such as carcinoma- in situ PanIN It was perceived that this could best be achieved by the use of a panel of biological markers in association with imaging studies, again stressing that this should be done in the context of a research protocol.

Third, the importance of studying these high-risk patients cannot be overstated. It was believed that focusing our limited resources on high-risk individuals was a more effective and efficient means to evaluate different detection techniques; and furthermore, that any new advances could eventually be applied to sporadic pancreatic carcinoma cases. Lastly, members of the working group identified several areas of research that merit immediate attention.

The cachexia and metabolic disturbance working group represented rather diverse, but overlapping, interests in the mechanisms of weight loss and wasting in pancreatic cancer. There was some contention about which factors are of greatest importance in mediating cachexia, and much of the discussion centered around cataloguing possible factors of importance.

However, the group was in total agreement that cachexia represents a major clinical problem in these patients and is an area where therapeutic improvements are likely to have a great impact. Cancer cachexia is a complex syndrome that is directly responsible for the death of a large number of cancer patients and contributes to morbidity and mortality in many other cases.

In addition to anorexia, cachexia is characterized by muscle wasting, weakness, and weight loss that progress until the time of death. The metabolic abnormalities associated with cachexia include negative nitrogen balance attributable to an increased muscle proteolysis, alterations in carbohydrate metabolism, and accelerated adipose tissue dissolution. In pancreatic cancer patients, the onset of cachexia usually takes place long before the tumor is diagnosed.

Erosion of skeletal muscle is a major contributory factor in the poor survival of these patients, leading to death by respiratory failure and hypostatic pneumonia. The major metabolic event activated during muscle wasting is the ATP- and ubiquitin-dependent proteolytic system. Activation of this pathway promotes amino acid release from skeletal muscle in to the circulation.

The amino acids released are taken by the tumor mass and the liver to sustain growth and acute phase protein synthesis as well as to provide substrate for the increased gluconeogenesis associated with cachexia. Of particular interest is recent progress with the polyunsaturated fatty acid EPA, a fish-derived n-3 fatty acid. A clinical trial in the United Kingdom suggested EPA was effective in attenuating the development of weight loss in pancreatic cancer patients and when combined with nutritional supplementation resulted in significant weight gain This weight gain is attributable to the accumulation of lean body mass with no change in adipose tissue or body water.

Energy expenditure is decreased and food intake increased. A double-blind, placebo-controlled randomized clinical trial currently underway in Europe was designed to determine whether this leads to improved survival. The effect appears to be attributable to the inhibition of downstream signaling events. EPA also inhibits proteolysis, including factor production by the tumor, which may be evidence of a direct effect on tumor cell proliferation.

A full knowledge of the mechanism of the beneficial effect of EPA on cancer cachexia will provide vital information for the development of new agents. The profound cachexia associated with pancreatic cancer also includes characteristic abnormalities in carbohydrate metabolism and marked peripheral insulin resistance. Most likely, this results from the release of islet-associated pancreatic polypeptide. The abnormal metabolism of proteins, carbohydrates, and lipids in pancreatic cancer patients apparently arises from a complex interplay between cancer-derived factors and probably also involves inflammatory cytokines and circulating metabolic hormones.

Understanding these relationships will advance our understanding of pancreas cancer biology. In addition, PIF, lipid-mobilizing factor, selected inflammatory cytokines, and other cachexia- or wasting-inducing polypeptides could serve as novel new targets for cancer therapy.

Progress in the development of more effective treatments for pancreatic adenocarcinoma has been slow, a problem that is reflected in the fact that there has not been much change in mortality rates over many decades. Therefore, the overall goals of the working group on therapy were: Participants in this group brought a wide range of expertise to the table, including surgery, medical oncology, radiation therapy, immunotherapy, and cancer biology.

The participants were asked to identify areas of pancreatic cancer therapy that required immediate focus. As a result, four main areas were identified that require significant progress. These included the immediate need for: Regarding therapeutic agents, a number of participants felt that priority should be given to the immediate testing of currently available agents or modalities that are active in other diseases and not yet tested in patients with pancreatic adenocarcinoma or of existing agents that target biological pathways and which have already been identified as critical to pancreatic cancer tumorigenesis but have not yet been optimized or tested in combinations.

Another approach would entail primary focus on new discoveries in pancreas cancer biology leading to new targets, which might include proteins involved in tumor growth and signaling pathways 58 , 59 , 60 , 61 or new or altered proteins that are the products of the genetic alterations occurring during the process of tumorigenesis 62 , Another category of potential targets are the proteins recognized by activated immune cells Controversy ensued when the question was asked, How do we proceed with the clinical development of existing agents and new agents directed at potential new targets?

It was agreed that some empiricism in testing combinations of existing agents is warranted because pancreatic cancer patients are in immediate need of new therapies 67 , 68 , but that decisions concerning these agents and combinations should be based on our current knowledge of the mechanism of the drug action.

However, at the same time, preclinical studies must proceed in parallel to test and optimize various combinations and to identify new targets for intervention. This two-step approach toward the development of new therapies takes into consideration the needs of patients who are currently in need of new therapeutic options and who cannot wait for the results of preclinical studies.

New targets for pancreatic cancer therapy are likely to arise from a better understanding of pancreas cancer biology. Two requirements to facilitate this process were identified. First, there needs to be a focused effort at developing relevant preclinical models for pancreatic cancer Examples of animal models were suggested based on the panel of known tumor suppressor genes and oncogenes involved in the tumorigenesis of pancreatic adenocarcinomas that have already been identified.

Specifically, it should now be possible to develop transgenic animal models that incorporate serial gene expression of these tumor suppressor genes and oncogenes to simulate the gene alterations that occur in pancreatic adenocarcinomas. The development of gene knockout mice deficient in these tumor suppressor genes and oncogenes found to be implicated in both pancreatic adenocarcinoma development and progression are also needed Both the transgenic and knockout mice should rapidly clarify which genes and gene products are critical to tumorigenic pathways in pancreatic adenocarcinoma.

This knowledge should then lead to the rapid identification of important therapeutic targets. Second, there needs to be a focused effort to collect and store pancreatic adenocarcinoma tissue. Pancreatic cancer is less common than other malignancies and is difficult to treat.

Many patients are not referred to experienced centers, limiting access of patients to clinical trials. Even within centers with access to a larger number of patients, it is difficult to obtain tumor tissue because a minority of patients are candidates for resection. Also, the development of new therapies may require repeated tumor sampling pre- and posttreatment to assess intermediate end points. Therefore, the development of less invasive methods for tissue sampling will be important.

It is also critical that a plan be formulated to educate professionals in cancer care and regulatory agencies about the importance of tissue procurement, especially at the time of autopsy. The recent emergence of pancreatic cancer advocacy groups can help with this process. The participants all agreed that there is an urgent need to test new treatment approaches more rapidly. However, many questions were raised about how to effectively accomplish this task.

One set of questions concerned implementing trials. How can we do it faster? How can we learn more with less testing? Who should sponsor these studies? The answers to the first two questions were clear: In addition, multicenter studies will permit wider access to patients.

It is also important to identify improved methods for recruiting patients into the trials. A minority of pancreatic cancer patients currently enroll in studies.

Patient education programs can heighten awareness about opportunities in clinical investigation. The answer to the third question is more difficult. All of the participants agreed that industry should play a significant role in the development of new therapies.

One issue that often arises is that pancreatic is not a common cancer although it is a deadly one , and it is often viewed by industry as a low priority. However, experience with gemcitabine has shown that a drug active in pancreatic cancer is likely to translate into a treatment with wide application for more common cancers. Therefore, industry, the National Cancer Institute, and extramural investigators need to partner closely and invest more in the development of new agents for pancreatic cancer.

A second set of questions was raised that focused on improving clinical trial design so that more can be learned about a new treatment in less time. The questions raised included: Who should be treated? All participants agreed that we need to target both minimal residual disease and advanced disease.

In the case of minimal residual disease, we need to introduce new agents in sequence with existing treatments in the adjuvant setting. The recent trend toward preoperative adjuvant therapy offers an excellent opportunity to test developing new single agents later in the postoperative setting. In the case of advanced disease, we need to develop predictors of response and surrogate markers of efficacy to select and sequence agents more efficiently Currently, overall survival, time-to-tumor progression, and objective response are still the most common end points used in clinical trial design.

However, measurements of time-to-tumor progression can be difficult because this parameter requires frequent evaluations, involves some subjectivity, and is difficult to use in comparative or Phase II settings.

Objective response is difficult to measure in this disease; technical factors can lead to inaccurate measurements of the primary site; and both primary and secondary tumors can be composed largely of reactive tissue desmoplasia , which overestimates disease bulk. Quality of life and symptom relief are also considered end points; however, these studies are more labor intensive.

A wish list for the development of new methods for measuring pancreatic adenocarcinoma response to therapy was created. In summary, a plan of attack for improving therapy for pancreas cancer was formulated by the working group.

We need to accelerate testing treatments against known targets in new ways. In parallel, we need to aggressively support and encourage the development of new, rationally derived therapies that target molecules that are identified as a result of studies aimed at dissecting pancreatic cancer genetics and biology. The development of clinically relevant animal models and improved access to patient tumor tissue will greatly facilitate progress in the identification of new biologically relevant targets for therapeutic manipulation.

Better predictors of outcome will also facilitate these efforts. The development of non- or minimally invasive methods for assessing mechanisms of action or predicting response to new agents are essential.

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Aug 18,  · You can contact our custom research paper writing service which provides college and university students with high-quality custom written essays, term papers, research papers, thesis papers and dissertations on Cancer topics. Research Paper on Breast Cancer - According to the American Cancer Society, Each year, more than , women are diagnosed with breast cancer; furthermore Twelve percent of all women will contract the disease, and % of them will die from breast cancer (American Cancer Society, ).

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Cancer Research Papers begin by over viewing the characteristics of cancer, which are abnormality, uncontrollably, and invasiveness. Research papers show normal functions of the body are carried out by healthy cells, but cancer cells stop behaving normally. Contrasting with improved survival for most other gastrointestinal cancers, the 5-year survival of patients with ductal adenocarcinoma of the pancreas remains low at a dismal 4%. In , an estimated 28, patients were diagnosed with pancreatic cancer in the United States These patients can.