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Pancreatic cancer

Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancreatic cancer are known.

The most common, pancreatic adenocarcinoma, accounts for about 90% of cases, and the term "pancreatic cancer" is sometimes used to refer only to that type. These adenocarcinomas start within the part of the pancreas that makes digestive enzymes. Several other types of cancer, which collectively represent the majority of the non-adenocarcinomas, can also arise from these cells.

About 1–2% of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-producing cells of the pancreas. These are generally less aggressive than pancreatic adenocarcinoma.

Signs and symptoms of the most-common form of pancreatic cancer may include yellow skin, abdominal or back pain, unexplained weight loss, light-colored stools, dark urine, and loss of appetite. Usually, no symptoms are seen in the disease's early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not develop until the disease has reached an advanced stage. By the time of diagnosis, pancreatic cancer has often spread to other parts of the body.

Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic adenocarcinoma occur in those over 70. Risk factors for pancreatic cancer include tobacco smoking, obesity, diabetes, and certain rare genetic conditions. About 25% of cases are linked to smoking, and 5–10% are linked to inherited genes.

Pancreatic cancer is usually diagnosed by a combination of medical imaging techniques such as ultrasound or computed tomography, blood tests, and examination of tissue samples (biopsy). The disease is divided into stages, from early (stage I) to late (stage IV). Screening the general population has not been found to be effective.

The risk of developing pancreatic cancer is lower among non-smokers, and people who maintain a healthy weight and limit their consumption of red or processed meat; the risk is greater for men, smokers, and those with diabetes. There is some evidence that links high levels of red meat consumption to increased risk of pancreatic cancer. Smokers' risk of developing the disease decreases immediately upon quitting, and almost returns to that of the rest of the population after 20 years. Pancreatic cancer can be treated with surgery, radiotherapy, chemotherapy, palliative care, or a combination of these. Treatment options are partly based on the cancer stage. Surgery is the only treatment that can cure pancreatic adenocarcinoma, and may also be done to improve quality of life without the potential for cure. Pain management and medications to improve digestion are sometimes needed. Early palliative care is recommended even for those receiving treatment that aims for a cure.

Pancreatic cancer is among the most deadly forms of cancer globally, with one of the lowest survival rates. In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally. Pancreatic cancer is the fifth-most-common cause of death from cancer in the United Kingdom, and the third most-common in the United States. The disease occurs most often in the developed world, where about 70% of the new cases in 2012 originated. Pancreatic adenocarcinoma typically has a very poor prognosis; after diagnosis, 25% of people survive one year and 12% live for five years. For cancers diagnosed early, the five-year survival rate rises to about 20%. Neuroendocrine cancers have better outcomes; at five years from diagnosis, 65% of those diagnosed are living, though survival considerably varies depending on the type of tumor.

Types
The many types of pancreatic cancer can be divided into two general groups. The vast majority of cases (about 95%) occur in the part of the pancreas that produces digestive enzymes, known as the exocrine component. Several subtypes of exocrine pancreatic cancers are described, but their diagnosis and treatment have much in common.

The small minority of cancers that arise in the hormone-producing (endocrine) tissue of the pancreas have different clinical characteristics and are called pancreatic neuroendocrine tumors, sometimes abbreviated as "PanNETs". Both groups occur mainly (but not exclusively) in people over 40, and are slightly more common in men, but some rare subtypes mainly occur in women or children.

Exocrine cancers
The exocrine group is dominated by pancreatic adenocarcinoma (variations of this name may add "invasive" and "ductal"), which is by far the most common type, representing about 85% of all pancreatic cancers. Nearly all these start in the ducts of the pancreas, as pancreatic ductal adenocarcinoma (PDAC). This is despite the fact that the tissue from which it arises – the pancreatic ductal epithelium – represents less than 10% of the pancreas by cell volume, because it constitutes only the ducts (an extensive but capillary-like duct-system fanning out) within the pancreas. This cancer originates in the ducts that carry secretions (such as enzymes and bicarbonate) away from the pancreas. About 60–70% of adenocarcinomas occur in the head of the pancreas.

The next-most common type, acinar cell carcinoma of the pancreas, arises in the clusters of cells that produce these enzymes, and represents 5% of exocrine pancreas cancers. Like the 'functioning' endocrine cancers described below, acinar cell carcinomas may cause over-production of certain molecules, in this case digestive enzymes, which may cause symptoms such as skin rashes and joint pain.

Cystadenocarcinomas account for 1% of pancreatic cancers, and they have a better prognosis than the other exocrine types.

Pancreatoblastoma is a rare form, mostly occurring in childhood, and with a relatively good prognosis. Other exocrine cancers include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Solid pseudopapillary tumor is a rare low-grade neoplasm that mainly affects younger women, and generally has a very good prognosis.

Pancreatic mucinous cystic neoplasms are a broad group of pancreas tumors that have varying malignant potential. They are being detected at a greatly increased rate as CT scans become more powerful and common, and discussion continues as how best to assess and treat them, given that many are benign.

Neuroendocrine
The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors (PanNETs). Neuroendocrine tumors (NETs) are a diverse group of benign or malignant tumors that arise from the body's neuroendocrine cells, which are responsible for integrating the nervous and endocrine systems. NETs can start in most organs of the body, including the pancreas, where the various malignant types are all considered to be rare. PanNETs are grouped into 'functioning' and 'nonfunctioning' types, depending on the degree to which they produce hormones. The functioning types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, often in large quantities, giving rise to serious symptoms such as low blood sugar, but also favoring relatively early detection. The most common functioning PanNETs are insulinomas and gastrinomas, named after the hormones they secrete. The nonfunctioning types do not secrete hormones in a sufficient quantity to give rise to overt clinical symptoms, so nonfunctioning PanNETs are often diagnosed only after the cancer has spread to other parts of the body.

As with other neuroendocrine tumors, the history of the terminology and classification of PanNETs is complex. PanNETs are sometimes called "islet cell cancers", though they are now known to not actually arise from islet cells as previously thought.

Signs and symptoms
Since pancreatic cancer usually does not cause recognizable symptoms in its early stages, the disease is typically not diagnosed until it has spread beyond the pancreas itself. This is one of the main reasons for the generally poor survival rates. Exceptions to this are the functioning PanNETs, where over-production of various active hormones can give rise to symptoms (which depend on the type of hormone).

Common presenting symptoms of pancreatic adenocarcinoma include:
 * Pain in the upper abdomen or back, often spreading from around the stomach to the back. The location of the pain can indicate the part of the pancreas where a tumor is located. The pain may be worse at night and may increase over time to become severe and unremitting. It may be slightly relieved by bending forward. In the UK, about half of new cases of pancreatic cancer are diagnosed following a visit to a hospital emergency department for pain or jaundice. In up to two-thirds of people, abdominal pain is the main symptom, for 46% of the total accompanied by jaundice, with 13% having jaundice without pain.
 * Jaundice, a yellow tint to the whites of the eyes or skin, with or without pain, and possibly in combination with darkened urine, results when a cancer in the head of the pancreas obstructs the common bile duct as it runs through the pancreas.
 * Unexplained weight loss, either from loss of appetite, or loss of exocrine function resulting in poor digestion.
 * The tumor may compress neighboring organs, disrupting digestive processes and making it difficult for the stomach to empty, which may cause nausea and a feeling of fullness. The undigested fat leads to foul-smelling, fatty feces that are difficult to flush away. Constipation is also common.
 * At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis. While long-standing diabetes is a known risk factor for pancreatic cancer (see Risk factors), the cancer can itself cause diabetes, in which case recent onset of diabetes could be considered an early sign of the disease. People over 50 who develop diabetes have eight times the usual risk of developing pancreatic adenocarcinoma within three years, after which the relative risk declines.

Other findings

 * Trousseau's syndrome – in which blood clots form spontaneously in the portal blood vessels (portal vein thrombosis), the deep veins of the extremities (deep vein thrombosis), or the superficial veins (superficial vein thrombosis) anywhere on the body – may be associated with pancreatic cancer, and is found in about 10% of cases.
 * Clinical depression has been reported in association with pancreatic cancer in some 10–20% of cases, and can be a hindrance to optimal management. The depression sometimes appears before the diagnosis of cancer, suggesting that it may be brought on by the biology of the disease.

Other common manifestations of the disease include weakness and tiring easily, dry mouth, sleep problems, and a palpable abdominal mass.

Symptoms of spread
The spread of pancreatic cancer to other organs (metastasis) may also cause symptoms. Typically, pancreatic adenocarcinoma first spreads to nearby lymph nodes, and later to the liver or to the peritoneal cavity, large intestine, or lungs. Uncommonly, it spreads to the bones or brain.

Cancers in the pancreas may also be secondary cancers that have spread from other parts of the body. This is uncommon, found in only about 2% of cases of pancreatic cancer. Kidney cancer is by far the most common cancer to spread to the pancreas, followed by colorectal cancer, and then cancers of the skin, breast, and lung. Surgery may be performed on the pancreas in such cases, whether in hope of a cure or to alleviate symptoms.

Risk factors
Risk factors for pancreatic adenocarcinoma include:
 * Age, sex, and ethnicity – the risk of developing pancreatic cancer increases with age. Most cases occur after age 65, while cases before age 40 are uncommon. The disease is slightly more common in men than in women. In the United States, it is over 1.5 times more common in African Americans, though incidence in Africa is low.
 * Cigarette smoking is the best-established avoidable risk factor for pancreatic cancer, approximately doubling risk among long-term smokers, the risk increasing with the number of cigarettes smoked and the years of smoking. The risk declines slowly after smoking cessation, taking some 20 years to return to almost that of nonsmokers.
 * Obesity – a body mass index greater than 35 increases relative risk by about half.
 * Family history – 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer. The risk escalates greatly if more than one first-degree relative had the disease, and more modestly if they developed it before the age of 50. Most of the genes involved have not been identified. Hereditary pancreatitis gives a greatly increased lifetime risk of pancreatic cancer of 30–40% to the age of 70. Screening for early pancreatic cancer may be offered to individuals with hereditary pancreatitis on a research basis. Some people may choose to have their pancreas surgically removed to prevent cancer from developing in the future.

 * Pancreatic cancer has been associated with these other rare hereditary syndromes: Peutz–Jeghers syndrome due to mutations in the STK11 tumor suppressor gene (very rare, but a very strong risk factor); dysplastic nevus syndrome (or familial atypical multiple mole and melanoma syndrome, FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene; autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 and PALB2 genes; hereditary non-polyposis colon cancer (Lynch syndrome); and familial adenomatous polyposis. PanNETs have been associated with multiple endocrine neoplasia type 1 (MEN1) and von Hippel Lindau syndromes.

 * Chronic pancreatitis appears to almost triple risk, and as with diabetes, new-onset pancreatitis may be a symptom of a tumor. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.
 * Diabetes mellitus is a risk factor for pancreatic cancer and (as noted in the Signs and symptoms section) new-onset diabetes may also be an early sign of the disease. People who have been diagnosed with type 2 diabetes for longer than 10 years may have a 50% increased risk, as compared with individuals without diabetes. In 2021, Venturi reported that the pancreas is able to absorb in great quantity radioactive cesium (Cs-134 and Cs-137) causing chronic pancreatitis and probably pancreatic cancer with damage of pancreatic islands, causing type 3c (pancreatogenic) diabetes. Chronic pancreatitis, pancreatic cancer and diabetes mellitus increased in contaminated populations, particularly children and adolescents, after Fukushima and Chernobyl nuclear incidents. At the same time, worldwide pancreatic diseases, diabetes and environmental radiocesium are increasing.
 * Specific types of food (as distinct from obesity) have not been clearly shown to increase the risk of pancreatic cancer. Dietary factors for which some evidence shows slightly increased risk include processed meat, red meat, and meat cooked at very high temperatures (e.g. by frying, broiling, or grilling).

Alcohol
Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, but considerable research has failed to firmly establish alcohol consumption as a direct risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association, with smoking a strong confounding factor. The evidence is stronger for a link with heavy drinking, of at least six drinks per day.

Precancer

Exocrine cancers are thought to arise from several types of precancerous lesions within the pancreas, but these lesions do not always progress to cancer, and the increased numbers detected as a byproduct of the increasing use of CT scans for other reasons are not all treated. Apart from pancreatic serous cystadenomas, which are almost always benign, four types of precancerous lesion are recognized.

The first is pancreatic intraepithelial neoplasia (PanIN). These lesions are microscopic abnormalities in the pancreas and are often found in autopsies of people with no diagnosed cancer. These lesions may progress from low to high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene, while in grades 2 and 3, damage to three further genes – CDKN2A (p16), p53, and SMAD4 – are increasingly often found.

A second type is the intraductal papillary mucinous neoplasm (IPMN). These are macroscopic lesions, which are found in about 2% of all adults. This rate rises to about 10% by age 70. These lesions have about a 25% risk of developing into invasive cancer. They may have KRAS gene mutations (40–65% of cases) and in the GNAS Gs alpha subunit and RNF43, affecting the Wnt signaling pathway. Even if removed surgically, a considerably increased risk remains of pancreatic cancer developing subsequently.

The third type, pancreatic mucinous cystic neoplasm (MCN), mainly occurs in women, and may remain benign or progress to cancer. If these lesions become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery.

A fourth type of cancer that arises in the pancreas is the intraductal tubulopapillary neoplasm. This type was recognised by the WHO in 2010 and constitutes about 1–3% of all pancreatic neoplasms. Mean age at diagnosis is 61 years (range 35–78 years). About 50% of these lesions become invasive. Diagnosis depends on histology, as these lesions are very difficult to differentiate from other lesions on either clinical or radiological grounds.

Invasive cancer
The genetic events found in ductal adenocarcinoma have been well characterized, and complete exome sequencing has been done for the common types of tumor. Four genes have each been found to be mutated in the majority of adenocarcinomas: KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%), and SMAD4 (55%). The last of these is especially associated with a poor prognosis. SWI/SNF mutations/deletions occur in about 10–15% of the adenocarcinomas. The genetic alterations in several other types of pancreatic cancer and precancerous lesions have also been researched. Transcriptomics analyses and mRNA sequencing for the common forms of pancreatic cancer have found that 75% of human genes are expressed in the tumors, with some 200 genes more specifically expressed in pancreatic cancer as compared to other tumor types.

PanNETs
The genes often found mutated in pancreatic neuroendocrine tumors (PanNETs) are different from those in exocrine pancreatic cancer. For example, KRAS mutation is normally absent. Instead, hereditary MEN1 gene mutations give risk to MEN1 syndrome, in which primary tumors occur in two or more endocrine glands. About 40–70% of people born with a MEN1 mutation eventually develop a PanNet. Other genes that are frequently mutated include DAXX, mTOR, and ATRX.

Diagnosis
The symptoms of pancreatic adenocarcinoma do not usually appear in the disease's early stages, and they are not individually distinctive to the disease. The symptoms at diagnosis vary according to the location of the cancer in the pancreas, which anatomists divide (from left to right on most diagrams) into the thick head, the neck, and the tapering body, ending in the tail.

Regardless of a tumor's location, the most common symptom is unexplained weight loss, which may be considerable. A large minority (between 35% and 47%) of people diagnosed with the disease will have had nausea, vomiting, or a feeling of weakness. Tumors in the head of the pancreas typically also cause jaundice, pain, loss of appetite, dark urine, and light-colored stools. Tumors in the body and tail typically also cause pain.

People sometimes have recent onset of atypical type 2 diabetes that is difficult to control, a history of recent but unexplained blood vessel inflammation caused by blood clots (thrombophlebitis) known as Trousseau sign, or a previous attack of pancreatitis. A doctor may suspect pancreatic cancer when the onset of diabetes in someone over 50 years old is accompanied by typical symptoms such as unexplained weight loss, persistent abdominal or back pain, indigestion, vomiting, or fatty feces. Jaundice accompanied by a painlessly swollen gallbladder (known as Courvoisier's sign) may also raise suspicion, and can help differentiate pancreatic cancer from gallstones.

Medical imaging techniques, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) are used both to confirm the diagnosis and to help decide whether the tumor can be surgically removed (its "resectability"). On contrast CT scan, pancreatic cancer typically shows a gradually increasing radiocontrast uptake, rather than a fast washout as seen in a normal pancreas or a delayed washout as seen in chronic pancreatitis. Magnetic resonance imaging and positron emission tomography may also be used, and magnetic resonance cholangiopancreatography may be useful in some cases. Abdominal ultrasound is less sensitive and will miss small tumors, but can identify cancers that have spread to the liver and build-up of fluid in the peritoneal cavity (ascites). It may be used for a quick and cheap first examination before other techniques.

A biopsy by fine needle aspiration, often guided by endoscopic ultrasound, may be used where there is uncertainty over the diagnosis, but a histologic diagnosis is not usually required for removal of the tumor by surgery to go ahead.

Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, not least because 5% of people lack the Lewis (a) antigen and cannot produce CA19-9. It has a sensitivity of 80% and specificity of 73% in detecting pancreatic adenocarcinoma, and is used for following known cases rather than diagnosis.

Histopathology
The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. There is typically considerable desmoplasia or formation of a dense fibrous stroma or structural tissue consisting of a range of cell types (including myofibroblasts, macrophages, lymphocytes and mast cells) and deposited material (such as type I collagen and hyaluronic acid). This creates a tumor microenvironment that is short of blood vessels (hypovascular) and so of oxygen (tumor hypoxia). It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making the cancer especially hard to treat.

Exocrine cancers
Pancreatic cancer is usually staged following a CT scan. The most widely used cancer staging system for pancreatic cancer is the one formulated by the American Joint Committee on Cancer (AJCC) together with the Union for International Cancer Control (UICC). The AJCC-UICC staging system designates four main overall stages, ranging from early to advanced disease, based on TNM classification of Tumor size, spread to lymph Nodes, and Metastasis.

To help decide treatment, the tumors are also divided into three broader categories based on whether surgical removal seems possible: in this way, tumors are judged to be "resectable", "borderline resectable", or "unresectable". When the disease is still in an early stage (AJCC-UICC stages I and II), without spread to large blood vessels or distant organs such as the liver or lungs, surgical resection of the tumor can normally be performed, if the patient is willing to undergo this major operation and is thought to be sufficiently fit.

The AJCC-UICC staging system allows distinction between stage III tumors that are judged to be "borderline resectable" (where surgery is technically feasible because the celiac axis and superior mesenteric artery are still free) and those that are "unresectable" (due to more locally advanced disease); in terms of the more detailed TNM classification, these two groups correspond to T3 and T4 respectively.

Locally advanced adenocarcinomas have spread into neighboring organs, which may be any of the following (in roughly decreasing order of frequency): the duodenum, stomach, transverse colon, spleen, adrenal gland, or kidney. Very often they also spread to the important blood or lymphatic vessels and nerves that run close to the pancreas, making surgery far more difficult. Typical sites for metastatic spread (stage IV disease) are the liver, peritoneal cavity and lungs, all of which occur in 50% or more of fully advanced cases.

PanNETs
The 2010 WHO classification of tumors of the digestive system grades all the pancreatic neuroendocrine tumors (PanNETs) into three categories, based on their degree of cellular differentiation (from "NET G1" through to the poorly differentiated "NET G3"). The U.S. National Comprehensive Cancer Network recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage-by-stage outcomes for PanNETs are dissimilar to those of the exocrine cancers. A different TNM system for PanNETs has been proposed by the European Neuroendocrine Tumor Society.

Prevention and screening
Apart from not smoking, the American Cancer Society recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing consumption of red and processed meat, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. A 2014 review of research concluded that there was evidence that consumption of citrus fruits and curcumin reduced risk of pancreatic cancer, while there was possibly a beneficial effect from whole grains, folate, selenium, and non-fried fish.

In the general population, screening of large groups is not considered effective and may be harmful as of 2019, although newer techniques, and the screening of tightly targeted groups, are being evaluated. Nevertheless, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.

A 2019 meta-analysis found that use of aspirin might be negatively associated with the incidence risk of pancreatic cancer, but found no significant relationship with pancreatic cancer mortality.

Exocrine cancer
A key assessment that is made after diagnosis is whether surgical removal of the tumor is possible (see Staging), as this is the only cure for this cancer. Whether or not surgical resection can be offered depends on how much the cancer has spread. The exact location of the tumor is also a significant factor, and CT can show how it relates to the major blood vessels passing close to the pancreas. The general health of the person must also be assessed, though age in itself is not an obstacle to surgery.

Chemotherapy and, to a lesser extent, radiotherapy are likely to be offered to most people, whether or not surgery is possible. Specialists advise that the management of pancreatic cancer should be in the hands of a multidisciplinary team including specialists in several aspects of oncology, and is, therefore, best conducted in larger centers.

Surgery

Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases. Although CT scans help, in practice it can be difficult to determine whether the tumor can be fully removed (its "resectability"), and it may only become apparent during surgery that it is not possible to successfully remove the tumor without damaging other vital tissues. Whether or not surgical resection can be offered depends on various factors, including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood vessels, as well as surgical expertise and a careful consideration of projected post-operative recovery. The age of the person is not in itself a reason not to operate, but their general performance status needs to be adequate for a major operation.

One particular feature that is evaluated is the encouraging presence, or discouraging absence, of a clear layer or plane of fat creating a barrier between the tumor and the vessels. Traditionally, an assessment is made of the tumor's proximity to major venous or arterial vessels, in terms of "abutment" (defined as the tumor touching no more than half a blood vessel's circumference without any fat to separate it), "encasement" (when the tumor encloses most of the vessel's circumference), or full vessel involvement. A resection that includes encased sections of blood vessels may be possible in some cases, particularly if preliminary neoadjuvant therapy is feasible,   using chemotherapy  and/or radiotherapy.

Even when the operation appears to have been successful, cancerous cells are often found around the edges ("margins") of the removed tissue, when a pathologist examines them microscopically (this will always be done), indicating the cancer has not been entirely removed. Furthermore, cancer stem cells are usually not evident microscopically, and if they are present they may continue to develop and spread. An exploratory laparoscopy (a small, camera-guided surgical procedure) may therefore be performed to gain a clearer idea of the outcome of a full operation.

For cancers involving the head of the pancreas, the Whipple procedure is the most commonly attempted curative surgical treatment. This is a major operation which involves removing the pancreatic head and the curve of the duodenum together ("pancreato-duodenectomy"), making a bypass for food from the stomach to the jejunum ("gastro-jejunostomy") and attaching a loop of jejunum to the cystic duct to drain bile ("cholecysto-jejunostomy"). It can be performed only if the person is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed only in a minority of cases. Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy, which often also entails removal of the spleen. Nowadays, this can often be done using minimally invasive surgery.

Although curative surgery no longer entails the very high death rates that occurred until the 1980s, a high proportion of people (about 30–45%) still have to be treated for a post-operative sickness that is not caused by the cancer itself. The most common complication of surgery is difficulty in emptying the stomach. Certain more limited surgical procedures may also be used to ease symptoms (see Palliative care): for instance, if the cancer is invading or compressing the duodenum or colon. In such cases, bypass surgery might overcome the obstruction and improve quality of life but is not intended as a cure.

Chemotherapy
After surgery, adjuvant chemotherapy with gemcitabine or 5-FU can be offered if the person is sufficiently fit, after a recovery period of one to two months. In people not suitable for curative surgery, chemotherapy may be used to extend life or improve its quality. Before surgery, neoadjuvant chemotherapy or chemoradiotherapy may be used in cases that are considered to be "borderline resectable" (see Staging) in order to reduce the cancer to a level where surgery could be beneficial. In other cases neoadjuvant therapy remains controversial, because it delays surgery.

Gemcitabine was approved by the United States Food and Drug Administration (FDA) in 1997, after a clinical trial reported improvements in quality of life and a five-week improvement in median survival duration in people with advanced pancreatic cancer. This was the first chemotherapy drug approved by the FDA primarily for a nonsurvival clinical trial endpoint. Chemotherapy using gemcitabine alone was the standard for about a decade, as a number of trials testing it in combination with other drugs failed to demonstrate significantly better outcomes. However, the combination of gemcitabine with erlotinib was found to increase survival modestly, and erlotinib was licensed by the FDA for use in pancreatic cancer in 2005.

The FOLFIRINOX chemotherapy regimen using four drugs was found more effective than gemcitabine, but with substantial side effects, and is thus only suitable for people with good performance status. This is also true of protein-bound paclitaxel (nab-paclitaxel), which was licensed by the FDA in 2013 for use with gemcitabine in pancreas cancer. By the end of 2013, both FOLFIRINOX and nab-paclitaxel with gemcitabine were regarded as good choices for those able to tolerate the side-effects, and gemcitabine remained an effective option for those who were not. A head-to-head trial between the two new options is awaited, and trials investigating other variations continue. However, the changes of the last few years have only increased survival times by a few months. Clinical trials are often conducted for novel adjuvant therapies.

Radiotherapy
The role of radiotherapy as an auxiliary (adjuvant) treatment after potentially curative surgery has been controversial since the 1980s. In the early 2000s the European Study Group for Pancreatic Cancer Research (ESPAC) showed prognostic superiority of adjuvant chemotherapy over chemoradiotherapy. The European Society for Medical Oncology recommends that adjuvant radiotherapy should only be used for people enrolled in clinical trials. However, there is a continuing tendency for clinicians in the US to be more ready to use adjuvant radiotherapy than those in Europe. Many clinical trials have tested a variety of treatment combinations since the 1980s, but have failed to settle the matter conclusively.

Radiotherapy may form part of treatment to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial as there are conflicting results from clinical trials. The preliminary results of one trial, presented in 2013, "markedly reduced enthusiasm" for its use on locally advanced tumors.

PanNETs
Treatment of PanNETs, including the less common malignant types, may include a number of approaches. Some small tumors of less than 1 cm. that are identified incidentally, for example on a CT scan performed for other purposes, may be followed by watchful waiting. This depends on the assessed risk of surgery which is influenced by the site of the tumor and the presence of other medical problems. Tumors within the pancreas only (localized tumors), or with limited metastases, for example to the liver, may be removed by surgery. The type of surgery depends on the tumor location, and the degree of spread to lymph nodes.

For localized tumors, the surgical procedure may be much less extensive than the types of surgery used to treat pancreatic adenocarcinoma described above, but otherwise surgical procedures are similar to those for exocrine tumors. The range of possible outcomes varies greatly; some types have a very high survival rate after surgery while others have a poor outlook. As all this group are rare, guidelines emphasize that treatment should be undertaken in a specialized center. Use of liver transplantation may be considered in certain cases of liver metastasis.

For functioning tumors, the somatostatin analog class of medications, such as octreotide, can reduce the excessive production of hormones. Lanreotide can slow tumor growth. If the tumor is not amenable to surgical removal and is causing symptoms, targeted therapy with everolimus or sunitinib can reduce symptoms and slow progression of the disease. Standard cytotoxic chemotherapy is generally not very effective for PanNETs, but may be used when other drug treatments fail to prevent the disease from progressing, or in poorly differentiated PanNET cancers.

Radiation therapy is occasionally used if there is pain due to anatomic extension, such as metastasis to bone. Some PanNETs absorb specific peptides or hormones, and these PanNETs may respond to nuclear medicine therapy with radiolabeled peptides or hormones such as iobenguane (iodine-131-MIBG). Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used.

Palliative care
Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life. Because pancreatic adenocarcinoma is usually diagnosed after it has progressed to an advanced stage, palliative care as a treatment of symptoms is often the only treatment possible.

Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can assist in decision-making, including when or if hospice care will be beneficial. Pain can be managed with medications such as opioids or through procedural intervention, by a nerve block on the celiac plexus (CPB). This alters or, depending on the technique used, destroys the nerves that transmit pain from the abdomen. CPB is a safe and effective way to reduce the pain, which generally reduces the need to use opioid painkillers, which have significant negative side effects.

Other symptoms or complications that can be treated with palliative surgery are obstruction by the tumor of the intestines or bile ducts. For the latter, which occurs in well over half of cases, a small metal tube called a stent may be inserted by endoscope to keep the ducts draining. Palliative care can also help treat depression that often comes with the diagnosis of pancreatic cancer.

Both surgery and advanced inoperable tumors often lead to digestive system disorders from a lack of the exocrine products of the pancreas (exocrine insufficiency). These can be treated by taking pancreatin which contains manufactured pancreatic enzymes, and is best taken with food. Difficulty in emptying the stomach (delayed gastric emptying) is common and can be a serious problem, involving hospitalization. Treatment may involve a variety of approaches, including draining the stomach by nasogastric aspiration and drugs called proton-pump inhibitors or H2 antagonists, which both reduce production of gastric acid. Medications like metoclopramide can also be used to clear stomach contents.

Outcomes
Pancreatic adenocarcinoma and the other less common exocrine cancers have a very poor prognosis, as they are normally diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts of the body. Outcomes are much better for PanNETs: Many are benign and completely without clinical symptoms, and even those cases not treatable with surgery have an average five-year survival rate of 16%, although the outlook varies considerably according to the type.

For locally advanced and metastatic pancreatic adenocarcinomas, which together represent over 80% of cases, numerous trials comparing chemotherapy regimes have shown increased survival times, but not to more than one year. Overall five-year survival for pancreatic cancer in the US has improved from 2% in cases diagnosed in 1975–1977, and 4% in 1987–1989 diagnoses, to 6% in 2003–2009. In the less than 20% of cases of pancreatic adenocarcinoma with a diagnosis of a localized and small cancerous growth (less than 2 cm in Stage T1), about 20% of Americans survive to five years.

About 1500 genes are linked to outcomes in pancreatic adenocarcinoma. These include both unfavorable genes, where high expression is related to poor outcome, for example C-Met and MUC-1, and favorable genes where high expression is associated with better survival, for example the transcription factor PELP1.

Distribution
In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally. In 2014, an estimated 46,000 people in the US are expected to be diagnosed with pancreatic cancer and 40,000 to die of it. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year. It is the seventh-highest cause of death from cancer worldwide. Pancreatic cancer is the fifth most-common cause of death from cancer in the United Kingdom, and the third most-common in the United States.

Globally, pancreatic cancer is the 11th most-common cancer in women and the 12th most-common in men. The majority of recorded cases occur in developed countries. People from the United States have an average lifetime risk of about 1 in 67 (or 1.5%) of developing the disease, slightly higher than the figure for the UK. The disease is more common in men than women, although the difference in rates has narrowed over recent decades, probably reflecting earlier increases in female smoking. In the United States, the risk for African Americans is over 50% greater than for whites, but the rates in Africa and East Asia are much lower than those in North America or Europe. The United States, Central, and eastern Europe, and Argentina and Uruguay all have high rates.

PanNETs
The annual incidence of clinically recognized pancreatic neuroendocrine tumors (PanNETs) is low (about 5 per one million person-years) and is dominated by the non-functioning types. Somewhere between 45% and 90% of PanNETs are thought to be of the non-functioning types. Studies of autopsies have uncovered small PanNETs rather frequently, suggesting that the prevalence of tumors that remain inert and asymptomatic may be relatively high. Overall PanNETs are thought to account for about 1 to 2% of all pancreatic tumors. The definition and classification of PanNETs has changed over time, affecting what is known about their epidemiology and clinical relevance.

Recognition and diagnosis
The earliest recognition of pancreatic cancer has been attributed to the 18th-century Italian scientist Giovanni Battista Morgagni, the historical father of modern-day anatomic pathology, who claimed to have traced several cases of cancer in the pancreas. Many 18th and 19th-century physicians were skeptical about the existence of the disease, given the similar appearance of pancreatitis. Some case reports were published in the 1820s and 1830s, and a genuine histopathologic diagnosis was eventually recorded by the American clinician Jacob Mendes Da Costa, who also doubted the reliability of Morgagni's interpretations. By the start of the 20th century, cancer of the head of the pancreas had become a well-established diagnosis.

Regarding the recognition of PanNETs, the possibility of cancer of the islet cells was initially suggested in 1888. The first case of hyperinsulinism due to a tumor of this type was reported in 1927. Recognition of a non-insulin-secreting type of PanNET is generally ascribed to the American surgeons, R. M. Zollinger and E. H. Ellison, who gave their names to Zollinger–Ellison syndrome, after postulating the existence of a gastrin-secreting pancreatic tumor in a report of two cases of unusually severe peptic ulcers published in 1955. In 2010, the WHO recommended that PanNETs be referred to as "neuroendocrine" rather than "endocrine" tumors.

Small precancerous neoplasms for many pancreatic cancers are being detected at greatly increased rates by modern medical imaging. One type, the intraductal papillary mucinous neoplasm (IPMN) was first described by Japanese researchers in 1982. It was noted in 2010 that: "For the next decade, little attention was paid to this report; however, over the subsequent 15 years, there has been a virtual explosion in the recognition of this tumor."

Surgery
The first reported partial pancreaticoduodenectomy was performed by the Italian surgeon Alessandro Codivilla in 1898, but the patient only survived 18 days before succumbing to complications. Early operations were compromised partly because of mistaken beliefs that people would die if their duodenum were removed, and also, at first, if the flow of pancreatic juices stopped. Later it was thought, also mistakenly, that the pancreatic duct could simply be tied up without serious adverse effects; in fact, it will very often leak later on. In 1907–1908, after some more unsuccessful operations by other surgeons, experimental procedures were tried on corpses by French surgeons.

In 1912 the German surgeon Walther Kausch was the first to remove large parts of the duodenum and pancreas together (en bloc). This was in Breslau, now Wrocław, in Poland. In 1918 it was demonstrated, in operations on dogs, that it is possible to survive even after complete removal of the duodenum, but no such result was reported in human surgery until 1935, when the American surgeon Allen Oldfather Whipple published the results of a series of three operations at Columbia Presbyterian Hospital in New York. Only one of the patients had the duodenum entirely removed, but he survived for two years before dying of metastasis to the liver.

The first operation was unplanned, as cancer was only discovered in the operating theater. Whipple's success showed the way for the future, but the operation remained a difficult and dangerous one until recent decades. He published several refinements to his procedure, including the first total removal of the duodenum in 1940, but he only performed a total of 37 operations.

The discovery in the late 1930s that vitamin K prevented bleeding with jaundice, and the development of blood transfusion as an everyday process, both improved post-operative survival, but about 25% of people never left hospital alive as late as the 1970s. In the 1970s a group of American surgeons wrote urging that the procedure was too dangerous and should be abandoned. Since then outcomes in larger centers have improved considerably, and mortality from the operation is often less than 4%.

In 2006 a report was published of a series of 1,000 consecutive pancreatico-duodenectomies performed by a single surgeon from Johns Hopkins Hospital between 1969 and 2003. The rate of these operations had increased steadily over this period, with only three of them before 1980, and the median operating time reduced from 8.8 hours in the 1970s to 5.5 hours in the 2000s, and mortality within 30 days or in hospital was only 1%. Another series of 2,050 operations at the Massachusetts General Hospital between 1941 and 2011 showed a similar picture of improvement.

Research directions
Early-stage research on pancreatic cancer includes studies of genetics and early detection, treatment at different cancer stages, surgical strategies, and targeted therapies, such as inhibition of growth factors, immune therapies, and vaccines. Bile acids may have a role in the carcinogenesis of pancreatic cancer.

A key question is the timing of events as the disease develops and progresses – particularly the role of diabetes, and how and when the disease spreads. The knowledge that new onset of diabetes can be an early sign of the disease could facilitate timely diagnosis and prevention if a workable screening strategy can be developed. The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) trial is aiming to determine whether regular screening is appropriate for people with a family history of the disease.

Keyhole surgery (laparoscopy) rather than Whipple's procedure, particularly in terms of recovery time, is being evaluated. Irreversible electroporation is a relatively novel ablation technique with potential for downstaging and prolonging survival in persons with locally advanced disease, especially for tumors in proximity to peri-pancreatic vessels without risk of vascular trauma.

Efforts are underway to develop new drugs, including those targeting molecular mechanisms for cancer onset, stem cells, and cell proliferation. A further approach involves the use of immunotherapy, such as oncolytic viruses. Galectin-specific mechanisms of the tumor microenvironment are under study.

The nanoparticles assist in the sustained and targeted release of a drug regimen to cancer/tumor-specific sites rather than affecting healthy cells, leading to negligible or no toxicity.

title: Pancreatic cancer


text:
Crazy for You (musical)

Crazy for You is a romantic comedy musical with a book by Ken Ludwig, lyrics by Ira Gershwin, and music by George Gershwin. Billed as "The New Gershwin Musical Comedy", it is largely based on the songwriting team's 1930 musical Girl Crazy, but also incorporates songs from several other productions. It won the 1992 Tony Award (Broadway), the 1993 Olivier Award (London), and the 1994 Dora Award (Toronto) for Best Musical.

Background
Roger Horchow and Elizabeth Williams had been wanting to produce a new version of Girl Crazy. They engaged Ken Ludwig to write the book, Mike Ockrent to direct, and Susan Stroman to do the choreography, and obtained permission from the Gershwin family. Richard Godwin, and Valerie Gordon were the associate producers. The production soon changed to become a new show, using various Gershwin songs from different times. Six songs from Girl Crazy were selected: "Bidin' My Time", "Could You Use Me?", "Embraceable You", "I Got Rhythm", "But Not For Me", and part of "Bronco Busters"). "Tonight's the Night" was previously unpublished, having originally been written for Show Girl but ultimately not included. "What Causes That?" came from Treasure Girl, but was considered lost until 1982, when a copy was found in a Warner Brothers warehouse in Secaucus, New Jersey. "K-ra-zy for You" also originated from Treasure Girl. "The Real American Folk Song (Is a Rag)" was the Gershwins' first song performed on Broadway; on the other hand, "Naughty Baby" was making its debut, having been in Primrose, which only played in London and Australia. Other songs came from the musical films Shall We Dance ("Slap That Bass" and "They Can't Take That Away From Me") and A Damsel in Distress, both of which were released in the year of George's death.

Broadway (1992)
After a Washington, D.C. tryout and 10 previews, it opened at the Shubert Theatre on February 19, 1992, and ran for 1,622 performances. The cast included Jodi Benson as Polly, Harry Groener as Bobby Child, Bruce Adler as Bela Zangler, John Hillner as Lank Hawkins, Michele Pawk as Irene Roth, Jane Connell as Mother, Beth Leavel as Tess (Leavel also understudied Benson), Ronn Carroll as Everett Baker, and Stephen Temperley and Amelia White as Eugene and Patricia Fodor. The Manhattan Rhythm Kings played cowboys Mingo, Moose, and Sam, singing in their trademark close harmony.

In his review in The New York Times, Frank Rich wrote, "When future historians try to find the exact moment at which Broadway finally rose up to grab the musical back from the British, they just may conclude that the revolution began last night. The shot was fired at the Shubert Theater, where a riotously entertaining show called Crazy for You uncorked the American musical’s classic blend of music, laughter, dancing, sentiment and showmanship with a freshness and confidence rarely seen during the Cats decade. The miracle has been worked here most ingeniously, though not exclusively, by an extraordinary choreographer named Susan Stroman and the playwright Ken Ludwig . . . Crazy for You scrapes away decades of cabaret and jazz and variety-show interpretations to reclaim the Gershwins’ standards, in all their glorious youth, for the dynamism of the stage."

A cast album was released by Angel Records.

West End (1993)
The West End production, directed by Ockrent, choreographed by Stroman, and starring Ruthie Henshall, Kirby Ward, and Chris Langham, opened at the Prince Edward Theatre on March 3, 1993 and ran for nearly three years.

First West End revival (2011)
In 2011, Regent's Park Open Air Theatre did a revival of Crazy for You as part of the 2011 Summer Season. The production moved to the West End, at the Novello Theatre where it ran from October 8, 2011 to March 17, 2012.

Second West End revival (2023)
As part of the 2022 Chichester Festival, a new production staged as part of a limited summer run; Charlie Stemp played the role of Bobby Child with Carly Anderson as Polly Baker. The direction and choreography was by Susan Stroman. The production transferred to the West End's Gillian Lynne Theatre for a limited 30-week West End engagement. Previews began on 24 June 2023, with an official opening on July 3. Originally scheduled to close on January 20, 2024, the closing date was brought forward by three weeks to December 31, 2023.

Subsequent productions
A Toronto production directed by Ockrent, choreographed by Stroman, and starring Jim Walton and Camilla Scott opened at the Royal Alexandra Theatre on December 1, 1993 and closed December 31, 1995.

On October 20, 1999, the PBS series Great Performances broadcast a production directed by Matthew Diamond, who was nominated for the Emmy Award for Outstanding Direction of a Variety or Music Program.

On October 18, 2009, a showtime challenge, charity gala performance of Crazy for You, directed by Katherine Hare and choreographed by Racky Plews was staged by Eyebrow Productions at the London Palladium. Eyebrow are well known for their unique Showtime Challenges, where all aspects of the show are rehearsed and performed in 48 hours. All proceeds went to Cecily's Fund.

The Off-West End premiere of Crazy For You, directed by John Plews, choreographed by Grant Murphy and musically directed by Oliver John Ruthven, ran at Upstairs at the Gatehouse in Highgate from December 13, 2012 to January 27, 2013. The production made use of a smaller ensemble with cast doubling, and a six-piece band.

In summer 2016 a UK revival opened at the Watermill Theatre, Newbury starring Tom Chambers as Bobby and Caroline Sheen as Polly. The production began touring the UK from August 2017 to June 2018 starring Chambers reprising his role as Bobby, Caroline Flack as Irene and Charlotte Wakefield as Polly. Claire Sweeney replaced Flack as Irene halfway through the tour.

Follies

 * Patsy – Stacey Logan (and Polly US)
 * Sheila – Judine Hawkins Richard
 * Mitzi – Paula Leggett
 * Susie – Ida Henry
 * Louise – Jean Marie
 * Betsy – Penny Ayn Maas
 * Margie – Salome Mazard
 * Vera – Louise Ruck
 * Elaine – Pamela Everett
 * Swing  – Maryellen Scilla

Cowboys

 * Mingo – Tripp Hanson
 * Moose – Brian M. Nalepka
 * Sam – Harold Shane
 * Junior – Casey Nicholaw
 * Pete – Fred Anderson
 * Jimmy – Michael Kubala
 * Billy – Ray Roderick
 * Wyatt – Jeffrey Lee Broadhurst
 * Harry – Joel Goodness
 * Custus – Gerry Burkhardt
 *  The Amazing Cowpokes- Zoe Grifns And Charlie Mimcle

''Note: While Eugene Fodor was the real-life founder of Fodor's Travel Guides, the character in the musical is highly fictionalized. The real Eugene Fodor was Hungarian-American, not British, and his first travel book was about Europe.

Broadway (1992-1996)

 * Polly Baker: Karen Ziemba
 * Bela Zangler: Carleton Carpenter, Al Checco, Roger Horchow
 * Irene Roth: Pia Zadora
 * Everett Baker: Carleton Carpenter, Al Checco, Roger Horchow
 * Mother Lottie Child: Ann B. Davis
 * Tess: Leigh Zimmerman

Musical numbers

 * Act I
 * Overture
 * "K-ra-zy for You" (from Treasure Girl) – Bobby
 * "I Can't Be Bothered Now" (from A Damsel in Distress) – Bobby, Follies Girls
 * "Bidin' My Time" (from Girl Crazy) – Cowboy Trio and Cowboys
 * "Things Are Looking Up" (from A Damsel in Distress) – Bobby
 * "Someone to Watch Over Me" (from Oh, Kay!) – Polly
 * "Could You Use Me" (from Girl Crazy) – Bobby and Polly
 * "Shall We Dance?" (from Shall We Dance) – Bobby
 * "Entrance to Nevada" (Medley of "Stairway to Paradise", "Bronco Busters" from Girl Crazy, and "K-ra-zy for You") – Follies Girls and Cowboys
 * "Slap That Bass" (from Shall We Dance) – Bobby, Pete, Patsy, Tess, and Chorus
 * "Embraceable You" (from Girl Crazy) – Polly and Bobby
 * "Tonight's the Night"≠ – Chorus
 * "I Got Rhythm" (from Girl Crazy) – Polly and Chorus

 * Act II
 * Entr'acte ("Rialto Ripples")
 * "The Real American Folk Song is a Rag" (from Ladies First) – Cowboy Trio and Chorus
 * "What Causes That?" (from Treasure Girl) – Bobby and Zangler
 * "Naughty Baby"≠≠ (from Primrose) – Irene, Lank, Cowboy Quartet
 * "Stiff Upper Lip" (from A Damsel in Distress) – Eugene, Patricia, Bobby, Polly, and Chorus
 * "They Can't Take That Away from Me" (from Shall We Dance ) – Bobby
 * "But Not for Me" (from Girl Crazy) – Polly
 * "But Not for Me" (Reprise) – Polly
 * New York Interlude (Concerto in F)
 * "Nice Work If You Can Get It" (from A Damsel in Distress) – Follies Girls, and Bobby
 * "Bidin' My Time" (French Reprise) – Cowboy Trio
 * "Things Are Looking Up" (Reprise) – Everett
 * Finale – Chorus

≠ Lyrics by Gus Kahn and Ira Gershwin

≠≠ Lyrics by Desmond Carter and Ira Gershwin

Synopsis
Backstage at the Zangler Theater in New York in the 1930s, the last performance of the Zangler Follies is wrapping up for the season, and Tess, the Dance Director, is dodging the advances of the married Bela Zangler. Bobby Child, the rich son of a banking family, is backstage hoping for an audition with Mr. Zangler. Bobby performs "K-ra-zy for You," but fails to impress Zangler, having landed on Zangler's foot during the final flourish of his dance routine. Dejected, Bobby heads outside.
 * Act 1

Bobby is met by Irene, the wealthy woman to whom he has been engaged for five years, and then by his mother, who demands that Bobby take over her piece of the banking business. Bobby is told to go to Deadrock, Nevada, to foreclose on a rundown theater. As the women argue over him, Bobby imagines himself dancing with the Follies Girls and joins them in a rousing rendition of "I Can't Be Bothered Now." Brought back to reality, Bobby decides to escape to Nevada.

When Bobby arrives in Deadrock, it's clear that the gold mining town has seen better days. The men, who are cowboys, sing "Bidin' My Time" in a long, slow drawl. Everett Baker receives a letter from New York warning of the bank foreclosing on the Gaiety Theater. The only woman left in this forlorn town is Everett's daughter, the spunky Polly Baker, who vows to get even with Bobby Child if she ever meets him.

Lank Hawkins, proprietor of the town's saloon, argues with Everett, trying to convince Everett to let him buy the theater before the bank takes it. The stubborn old man refuses to give up the theater due to his memories of Polly's mother being the star of all the theater's old shows.

Bobby enters the town almost dying of thirst, and falls in love with Polly at first sight, not realizing who she is, and expresses his excitement in "Things Are Looking Up." Lank isn't pleased to see a rival for Polly's affections.

Bobby finds himself in quite a bind. If he forecloses on the theater he will lose the girl of his dreams. Inspired, he comes up with the idea of putting on a show to pay off the mortgage. Polly agrees to this plan until she finds out who he is and suspects a trick. Bobby and Polly are both heartbroken, but Bobby decides to put on the show anyway... disguised as Mr. Zangler. Polly, deeply hurt, expresses her loneliness in "Someone to Watch Over Me."

A few days later, ten Follies Girls on vacation from The Zangler Follies appear like a mirage in the desert. Bobby has asked them to help stage a spectacular show in Deadrock. When the men of Deadrock see the girls, the sleepy town becomes very lively. Lank Hawkins continues to express extreme dislike for the show, threatening to shoot Bobby. Rehearsals for the show aren't going well and the cowboys in particular are terrible dancers. Bobby changes all that in the course of one rehearsal with the song "Slap That Bass." Spirits are now at a high point. Meanwhile, to Bobby's dismay, Irene arrives, threatening to expose Bobby's charade, and Polly has fallen in love with Bobby's impersonation of Zangler. She expresses her love for Zangler with the song "Embraceable You."

Opening night arrives, with everyone's hopes high ("Tonight's the Night!"). Sadly, everyone is disappointed to find that the only people to arrive at the show are Eugene and Patricia Fodor, British tourists writing a guidebook on the American West. What starts out as a disappointment changes into the realization that the show has galvanized the once sleepy town. They celebrate with a spirited rendition of "I Got Rhythm" while the real Zangler stumbles unnoticed into the town, almost dehydrated, and collapses just as the scene ends.

In Lank's saloon Bobby is professing his love to Polly. Unfortunately, she is still in love with the man who she thinks is Zangler. Bobby is about to convince Polly that he has been impersonating "Zangler" when the real Zangler stumbles into the saloon looking for Tess.
 * Act 2

Zangler finds Tess, but refuses her request to produce the show. Tess storms off, and Zangler, now drunk after being disgusted by the town, bemoans his fate. Bobby, dressed like Zangler, reels in to drown his sorrow over losing Polly. Drunk and depressed, the two men act as mirror images of each other, and lament their lost loves in "What Causes That."

The next morning, Polly sees the two Zanglers and realizes what has happened. She slaps Bobby and leaves in a huff, while the townsfolk prepare for a meeting at the theater to discuss what to do with the show. Irene comes to Bobby in one final attempt to make him go back to New York with her, but Bobby rejects her, and states his love for Polly. Immensely frustrated with Bobby, Irene seduces Lank in "Naughty Baby."

The townsfolk are all now gathered at the theater. Bobby is all for trying the show again, while Polly thinks they should abandon the venture. The Fodors counsel the dejected townspeople to keep a "Stiff Upper Lip," which includes a parody of the barricade scene from Les Misérables, but by the end of the song only Polly, Everett, Bobby, and Tess still think the show should continue.

Everyone but Bobby and Polly leave the theater. Bobby prepares to leave for New York, professing that his memories of Polly will never fade in "They Can't Take That Away from Me." Polly realizes, too late, that she does love Bobby, and after he leaves, laments her loss in "But Not For Me."

Meanwhile, Bela Zangler decides to put on the show as a favor to Tess; the two seem to be in love once more. Although he had been planning to cast Bobby as the lead, he makes Polly the star of the show after learning that Bobby has left for New York.

Six weeks later, Bobby is still thinking of Deadrock as he works in his mother's bank. For his birthday, Mrs. Child gives him the Zangler theater (Zangler has used all his money on the show in Deadrock). While initially ecstatic, Bobby realizes that his love for Polly is worth more in "Nice Work if You Can Get It," and leaves with Mrs. Child for Deadrock to pursue Polly.

Meanwhile, Polly has decided to leave for New York to look for Bobby, who arrives in Deadrock just after she leaves. After learning that Polly has left to find him, he leaves the stage to "wash up" before driving back to New York to catch her. Bobby's mother and Irene (who is now married to Lank) notice each other and start an argument. Everett notices Mrs. Child, and falls head-over-heels in love with her, as shown in a reprise of "Things Are Looking Up." His affections are reciprocated, and immediately afterward, Polly reenters with Custus, one of the cowboys. Custus was trying to give Polly a ride to the station, but his car ran out of gas, and Polly missed the train to New York. Together the townspeople concoct a plan, and Polly and Bobby are finally reunited in the "Finale."

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Crazy for You (musical)


text: User talk:62.101.126.217

title: User talk:62.101.126.217


text:
Talk:Navier–Stokes equations

Plea to use $$P$$ for pressure not $$p$$.
Reasons to use or avoid upper case:

1. Many of the pages about pressure use $$P$$. Example: https://en.wikipedia.org/wiki/Ideal_gas_law There's a disclaimer that different fields use lower case $$p$$ and others use upper case $$P$$. I think MOST audiences are like college students. Most of them will be using $$P$$. In some grad school classes they use $$p$$, but it cannot be stressed enough by me that those audiences are smaller.

2. Per https://en.wikipedia.org/wiki/Intensive_and_extensive_properties, there intensive things tend to be lower case. This would be why to stick with lower case for pressure.

3. Momentum has the same letter and is lower case. Momentum and pressure having the same variable is confusing.

2/3 reasons say raise case. Please, let's vote and pick the case most people are really using in real situations for the pressure. If I lose the vote so be it, then let's change all the uppercases to lower cases. To be using both cases is blatant tyranny. Jason Arthur Taylor Jasontaylor7 (talk) 20:28, 29 March 2021 (UTC)

why include HOPF Fibations?
somebody is "showing off ", confusing mere mortals 150.143.189.203 (talk) 15:06, 16 April 2021 (UTC)

remove self-promotion of Jos Stam
remove chapter: Navier–Stokes equations use in games. — Preceding unsigned comment added by 213.206.223.58 (talk) 14:25, 22 November 2021 (UTC)

Logical errors in derivations
In two places (sections: General continuum equations, and Continuity equation for incompressible fluid) this article equates volume integrals to their integrands, without providing any justification or explanation. Lacshoet (talk) 15:19, 21 January 2024 (UTC)

 * You are correct. This is an error.  I will try to correct this.TMM53 (talk) 05:39, 8 March 2024 (UTC)
 * Integral equations were corrected.TMM53 (talk) 03:10, 20 March 2024 (UTC)

Departure from continuum model?
You say "The Navier–Stokes equations assume that the fluid being studied is a continuum (it is infinitely divisible and not composed of particles such as atoms or molecules)," but then, "When the flow is incompressible, ρ does not change for any fluid particle, "

Could the late introduction of a fluid particle suggest a departure from a strictly continuum-based fluid model? Gpsanimator (talk) 03:22, 22 April 2024 (UTC)

title: Talk:Navier–Stokes equations


text:
Jism

Jism may refer to:
 * a slang word for semen
 * an Arabic (جسم), Hindi (जिस्म), and Urdu (جسم) word for "body"
 * Jism (2003 film), a Bollywood erotic thriller film
 * Jism 2, a 2012 erotic thriller and sequel to the 2003 Bollywood film
 * Jism (2006 film), a Pakistani film
 * Jism (2016 film), a Nepali film
 * "Jism", a song by the rock band Tindersticks from their self-titled debut album

title: Jism


text:
Ford Maverick

Ford has marketed the following automobiles models using the Ford Maverick nameplate:

 * The Ford Maverick (1970–1977), a compact car sold in North America and Brazil during the 1970s
 * The rebadged Nissan Patrol Y60 sold by Ford Australia under the Button car plan from 1988 to 1994
 * The rebadged Spanish-built Nissan Terrano II, sold by Ford of Europe from 1993 to 1999
 * The European and Chinese version of the Ford Escape, sold from 2001 to 2005
 * The Ford Maverick (2022), a compact pickup truck sold in the Americas

Ford Maverick

title: Ford Maverick


text:
Italian aircraft carrier Giuseppe Garibaldi

Giuseppe Garibaldi is an Italian aircraft carrier, the first through-deck aviation ship ever built for the Italian Navy, and the first Italian ship built to operate fixed-wing aircraft. Although she is widely recognised as a carrier first and foremost, she is officially designated as an aircraft-carrying cruiser. She is equipped with short take-off and vertical landing (STOVL) aircraft and helicopters. Giuseppe Garibaldi was involved in combat air operations off Somalia, Kosovo, Afghanistan and Libya.

Design
The Giuseppe Garibaldi is the fourth ship of the Italian Navy to be named after the 19th-century Italian General Giuseppe Garibaldi. All four ships, including the missile cruiser, together with an image of Garibaldi, are depicted in the crest.

Built by Fincantieri (Italcantieri) at the Monfalcone shipyards on the Gulf of Trieste, she was laid down on 26 March 1981, launched on 11 June 1983, and commissioned on 30 September 1985. Garibaldi is classed as an anti-submarine warfare carrier (ASW), and she is based in Taranto.

The ship is powered by four Fiat COGAG gas turbines built under license from GE, offering a sustained power of 81,000 hp (60 MW). Driving two shafts the ship has a maximum speed of 30 kn and can travel for 7000 nmi at around 20 kn.

The ship was equipped with four Otomat Mk2 short range surface-to-surface missile system installed at the stern of the vessel (removed in 2003 to improve the flight deck and satellite communications) and two ILAS three triple tube torpedo launchers. Defences are provided by two eight-cell SAM launchers firing the SARH Aspide missile, and three Oto Melara Twin 40L70 DARDO CIWS.

The ship also has several countermeasures, including two SCLAR twenty-barrel launchers for chaff, decoy, flares, or jammers, the SLQ-25 Nixie and SLAT anti-torpedo systems and ECM systems.

The air arm consists of a maximum of sixteen AV-8B Harrier IIs and two search and rescue helicopters, or eighteen Agusta helicopters or a mix of helicopters and fighters. The flight deck is the characteristic off-axis design with a 6.5-degree ski-jump for STOL aircraft; she is 174 m long and 30.4 m wide.

A 1937 law gave control of all national fixed-wing air assets to the Italian Air Force, and the navy was only permitted to operate helicopters. At the time of the ship's commissioning of Garibaldi, the Italian Naval Aviation did not receive her Harriers, so she was reclassified as an Incrociatore portaeromobili (Italian for Aircraft carrying cruiser). Until 1988 only Italian helicopters landed on her deck, as well as Royal Navy Sea Harriers during NATO joint maneuvers. The ban on fixed-wing aircraft was lifted in 1989, and the Italian Navy acquired Harrier II fighters to fly from the Giuseppe Garibaldi.

In 2009 Giuseppe Garibaldi was replaced as the flagship of the Italian Navy by the new and larger carrier ITALIAN AIRCRAFT CARRIER Cavour.

The ship underwent a modernization in 2003 and a major restructuring in 2013.

Combat operations
In 1999 with the Kosovo War in the Balkans, Italy committed Harrier AV-8B II+ fighters embarked aboard Giuseppe Garibaldi from 13 May to early June 1999. The planes carried out 30 sorties in 63 hours of flight. The aircraft used Mk 82 GBU-16 bombs and AGM-65 Maverick missiles. The Italian naval force, in addition to the aircraft carrier Giuseppe Garibaldi with her air group, included the Maestrale-class frigate ITALIAN FRIGATE Zeffiro.

Following the attacks of 11 September 2001 and the war on terror declared by U.S. President Bush, Italy participated in Operation Enduring Freedom in Afghanistan. Giuseppe Garibaldi was engaged as the command ship of GRUPNAVIT I, 1 Italian Naval Group, which also included Zeffiro, the patrol team and the airman supplier in Etna. The group set sail from Taranto on 18 November 2001. They trained in the Indian Ocean from 3 December 2001 to 1 March 2002 and returned to Taranto on 18 March 2002. During the mission, the AV-8B Harrier unit carried out 288 missions for a total of 860 hours of flight. Tasks carried out included interception/interdiction, sea and air support, and aircraft interdiction in Afghanistan.

Participating in the 2011 military intervention in Libya after the transfer of authority to NATO and the decision to participate in strike air-ground operations, the Italian government assigned under NATO command four Italian Navy AV-8B plus (from Garibaldi) in addition to Italian air force aircraft. As of 24 March, the Italian Navy was engaged in Operation Unified Protector with the light aircraft carrier Garibaldi, the Maestrale-class frigate ITALIAN FRIGATE Libeccio and the auxiliary ship ITALIAN SHIP Etna. Additionally the Orizzonte-class frigate ITALIAN DESTROYER Andrea Doria and Maestrale-class frigate ITALIAN FRIGATE Euro were patrolling off the Sicilian coast in an air-defence role. In total, until the end of the mission in Libya, the eight Italian Navy AV-8Bs flying from the carrier Giuseppe Garibaldi dropped 160 guided bombs during 1221 flight hours.