Myles George Glasgow

Friday, February 02, 2007

Gallbladder Cancer Can Be Beat

Gallbladder cancer can be beat.

The best article I have read and which I encourage you to read is "Gallbladder Cancer: Lessons From a Rare Tumour, posted 10/21/2004 by Ignacio I. Wistuba; Adi F. Gazdar. It is at
At the end it suggests that symptomatic gallbladder disease (gallstones, eg, particularly 3 millimeters in diameter) calls for removal of the gallbladder. Read the final paragraphs of the paper in the section called "Future Perspectives." It says that "lack of scientific knolwedge is the main factor for failing to prevent or treat gallbladder cancer. Important areas of research are the crucial role of inflammation, cytokine and chemokine network, the range of antagoinists targeted at inflammatory and allergic diseases, antagonists of tumour-necrosis factor and COX2 and inhibition of specific cytokines including interleukins, non steroidal anti-inflammatory drugs, possibly antimicrobial therapies, biochemical prevention therapies, molecular research. "Creative approaches for funding and research will be required to overcome ..."obstacles such as insufficient number of cases available to research centers, lack of a multidisciplinary team required to "translate" the findings from the bench to the bedside.."

correspondence should go to Adi F. Gazdar at

On July 10, 2006 an article reported that in India in 2005 a 48 year old woman in India with metastasized gall bladder cancer was successfully treated with dendritic cell vaccine therapy which is described in the article: “: Successful immunological treatment of gallbladder cancer in India―Case report* by Jamal A. Khan† and Sharmin Yaqin Microbiology Research Lab, C-38/Sector 20, Noida Zip 201301, India † Received April 27, 2006; Accepted July 10, 2006 . Find this on On the web at:

Later in 2006 in Biochem Biophys Res Commun. 2006 Sep 29;348(3):1075-81. Epub 2006 . There appeared the article “Arsenic trioxide induces gallbladder carcinoma cell apoptosis via downregulation of Bcl-2.” which concluded that ” Taken together, these results suggest that arsenic trioxide induces gallbladder carcinoma cell apoptosis via downregulation of Bcl-2, which may have important therapeutic implications in gallbladder carcinoma patients. See PMID: 16904648 [PubMed - indexed for MEDLINE]

See this and other articles at

But what individuals or groups are collecting samples of all gallbladder tumors and genetic information of those who have gallbladder cancer and using that overview to see what therapies are most likely going to beat gallbladder cancer for the Chileans, American Indians, Japanese, Alaskan Eskimos, those from the Punjab area of India and elsewhere? Read on.

Gallbladder cancer is world wide, affects mostly women, and is found in high concentrations in Chile, American Indians and elsewhere. A good overview is at

Much is known about Gallbladder cancer:

A Google search lists numerous articles about the overexpression of p53 in older gallbladder, but the high concentration of c-erbB-2 in younger and early stage gallbladder. See , and

Also see the following:

1: Pathologica. 2000 Aug;92(4):249-56.

[Expression of p53 in gallbladder carcinoma and in dysplastic and metaplastic lesions of the surrounding mucosa]
[Article in Italian]
· Billo P,
· Marchegiani C,
· Capella C,
· Sessa F.
Dipartimento di Scienze Cliniche e Biologiche, Universita dell'Insubria, Varese.
We studied the expression of p53 in 80 gallbladder carcinomas, 43 peritumoral mucosae, 5 adenomas and 20 mucosae of non tumoral gallbladders. Gallbladder cancers were classified according to WHO criteria. We found p53 overexpression in 51 out of the 80 gallbladder cancers (64%). p53 expression was variable in different histologic subtypes: 100% of intestinal type, 66% of papillary type, 83% of adenosquamous carcinomas and 66% of giant cells cancers showed immunoreactive cells. In well and moderately differentiated conventional gallbladder adenocarcinomas we found 60% of positive cases, while, among poorly differentiated conventional cancers, 83% were immunoreactive. All mucinous adenocarcinomas were p53-negative. In peritumoral dysplastic mucosae, p53 was expressed in 23 out 38 cases (60%), 22 (96%) of which were associated to a p53-positive adenocarcinoma. On the contrary, only 5 of the 15 p53-negative dysplastic lesions (33%) were associated to an p53-immunoreactive adenocarcinoma. Metaplastic lesions, of gastric and intestinal type, and adenomas were completely p53-negative. In conclusion, our data suggest that p53 expression is an early event, frequently involved in gallbladder carcinogenesis, and related to different histologic subtypes of gallbladder adenocarcinomas.
PMID: 11029885 [PubMed - indexed for MEDLINE]

The value of p53 protein expression in gallbladder carcinoma: analysis of 60 cases.
· da Rocha AO,
· Coutinho LM,
· Scholl JG,
· Leboutte LD.
Pathology Department, Fundacao Faculdade Federal de Ciencias Medicas de Porto Alegre, Porto Alegre, Brazil.
BACKGROUND/AIMS: Few studies, with small samples and diverging results, have been performed to evaluate the p53 protein expression in gallbladder carcinoma and its relationship to different clinicopathological parameters. Based on these facts, we performed a study for the purpose of assessing p53 expression in this disease and its association to prognostic factors. METHODOLOGY: Samples of 141 gallbladders, with 60 cases of carcinoma, 62 cholelithiasis and 19 without gallstones were assessed using an immunohistochemical technique for the expression of p53 protein, and analyzed for prognosis, survival and other clinicopathological parameters. RESULTS: p53 expression was positive in 58.3% of carcinomas of the gallbladder, 9.7% of the chronic cholecystitis and 10.5% of the gallbladders not associated to stones. In cases of carcinoma of the gallbladder there was no statistically significant association between the expression of this protein, the prognostic factors, histological type or grade, presence of gallstones and survival. CONCLUSIONS: The mutation of gene p53 is involved in the pathogenesis of carcinoma of the gallbladder, and the intense chronic inflammatory process associated or not with cholelithiasis, appears to be one of the factors involved in the genesis of this process. Our data do not show an association between p53 protein expression and patient's survival prognosis.
PMID: 15362740 [PubMed - indexed for MEDLINE]
Clinical Cancer Research Vol. 9, 693-702, February 2003© 2003 American Association for Cancer Research

Gene mutation is observed in a high incidence of gallbladder cancers . see “p53 gene mutation in gallbladder cancer” Rev Med. Chil. 2000 Mar; 128(3):251-8, by Roa I, Melo A, Roa J, Araya 3, Villaseca M, de Aretxabaia X of the Unidad de Anatomia Patologica y Citopatologia Hospital Temuco, Chile at

The types of gallbladder cancers are listed at the National Cancer Institute web site. They are
1 Carcinoma in situ,
2 Adenocarcinoma, not otherwise specified (NOS),
3 Papillary carcinoma,
4. adenocarcinoma,
5. intestinal type,
6. mucinous carcinoma,
7. clear cell adenocarcinoma,
8. signet-ring cell carcinoma,
9. adenosquamous carcinoma,
10. squamous cell carcinoma,
11. small cell (oat cell) carcinoma,
12. undifferentiated carcinoma,
13. carcinoma, NOS, and
14. carcinosarcoma.

Are these cells unique to gallbladder? I don’t think so! Why then is gallbladder cancer so lethal? I have no idea.

What different therapies need to be used for 13 different types of gallbladder tissue cells if cancerous? When these types of cells appear elsewhere in the body and are there hormonal or genetic treatments for them which could work if used against gallbladder cancer?

What is it that is making certain gallbladder cancer cell more aggressive and lethal than other cancer? I am sure someone knows, but I don't. What can we do now to help those with gallbladder cancer buy enough time until the industry adopts this "orphan site" and gives persons with gallbladder cancer world wide as good a chance as those with breast cancer to live their lives longer and healthier?

Will you help a national or international or even a local foundation or organization advocate to cure cancer in this “orphan site”? Where is it and why is there so little progress?

A. Where do people live who experience a high incidence of various types of Gallbladder cancer and who gets it?

CA Cancer J Clin 2001; 51:349-364
© 2001 American Cancer Society
Epidemiology and Molecular Pathology of Gallbladder Cancer
Eduardo C. Lazcano-Ponce, MD, PhD, J. F. Miquel, MD, Nubia Muñoz, MD, Rolando Herrero, MD, PhD, Catterina Ferrecio, MD, Ignacio I. Wistuba, MD, Patricia Alonso de Ruiz, MD, Gerardo Aristi Urista, MD and Flavio Nervi, MD
Dr. Lazcano-Ponce is Director, Epidemiology Department, Population Health Research Center, National Institute of Public Health, Cuernavaca, Morelos, Mexico.
Dr. Miquel is Associate Professor, Gastroenterology Department, Catholic University of Chile, Santiago, Chile.
Dr. Muñoz is Consultant, International Agency for Research on Cancer, Lyon, France.
Dr. Herrero is Consultant, International Agency for Research on Cancer, Lyon, France, and Costa Rica Cancer Institute, San José, Costa Rica.
Dr. Ferrecio is Assistant Professor, Public Health Department, Catholic University of Chile, Santiago, Chile.
Dr. Wistuba is Associate Professor, Pathology Department, Catholic University of Chile, Santiago, Chile.
Dr. Alonso de Ruiz is Head of Cytopathology Laboratory, Autonomous National University of Mexico, Mexico General Hospital, Mexico City, DF.
Dr. Aristi Urista is Assistant Professor, Cytopathology Laboratory, Autonomous National University of Mexico, Mexico General Hospital, Mexico City, DF.
Dr. Nervi is Professor Titular, Gastroenterology, Public Health and Pathology Departments, Catholic University of Chile, Santiago, Chile.
Gallbladder cancer is usually associated with gallstone disease, late diagnosis, unsatisfactory treatment, and poor prognosis. We report here the worldwide geographical distribution of gallbladder cancer, review the main etiologic hypotheses, and provide some comments on perspectives for prevention. The highest incidence rate of gallbladder cancer is found among populations of the Andean area, North American Indians, and Mexican Americans. Gallbladder cancer is up to three times higher among women than men in all populations. The highest incidence rates in Europe are found in Poland, the Czech Republic, and Slovakia. Incidence rates in other regions of the world are relatively low. The highest mortality rates are also reported from South America, 3.5–15.5 per 100,000 among Chilean Mapuche Indians, Bolivians, and Chilean Hispanics. Intermediate rates, 3.7 to 9.1 per 100,000, are reported from Peru, Ecuador, Colombia, and Brazil. Mortality rates are low in North America, with the exception of high rates among American Indians in New Mexico (11.3 per 100,000) and among Mexican Americans.
The main associated risk factors identified so far include cholelithiasis (especially untreated chronic symptomatic gallstones), obesity, reproductive factors, chronic infections of the gallbladder, and environmental exposure to specific chemicals. These suspected factors likely represent promoters of carcinogenesis. The main limitations of epidemiologic studies on gallbladder cancer are the small sample sizes and specific problems in quantifying exposure to putative risk factors. The natural history of gallbladder disease should be characterized to support the allocation of more resources for early treatment of symptomatic gallbladder disease in high–risk populations. Secondary prevention of gallbladder cancer could be effective if supported by cost–effective studies of prophylactic cholecystectomy among asymptomatic gallstone patients in high–risk areas.

This article has been cited by other articles: (Search Google Scholar for Other Citing Articles)

D. Schottenfeld and J. Beebe-Dimmer
Chronic inflammation: a common and important factor in the pathogenesis of neoplasia.
CA Cancer J Clin, March 1, 2006; 56(2): 69 - 83.
[Abstract] [Full Text] [PDF]

P Kornprat, P Rehak, J Ruschoff, and C Langner
Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours
J. Clin. Pathol., February 1, 2006; 59(2): 202 - 206.
[Abstract] [Full Text] [PDF]

S. W. Oh, Y. S. Yoon, and S.-A. Shin
Effects of Excess Weight on Cancer Incidences Depending on Cancer Sites and Histologic Findings Among Men: Korea National Health Insurance Corporation Study
J. Clin. Oncol., July 20, 2005; 23(21): 4742 - 4754.
[Abstract] [Full Text] [PDF]

T. Takahashi, N. Shivapurkar, E. Riquelme, H. Shigematsu, J. Reddy, M. Suzuki, K. Miyajima, X. Zhou, B. N. Bekele, A. F. Gazdar, and I. I. Wistuba
Aberrant Promoter Hypermethylation of Multiple Genes in Gallbladder Carcinoma and Chronic Cholecystitis
Clin. Cancer Res., September 15, 2004; 10(18): 6126 - 6133.
[Abstract] [Full Text] [PDF]

M. Tang, S. Baez, M. Pruyas, A. Diaz, A. Calvo, E. Riquelme, and I. I. Wistuba
Mitochondrial DNA Mutation at the D310 (Displacement Loop) Mononucleotide Sequence in the Pathogenesis of Gallbladder Carcinoma
Clin. Cancer Res., February 1, 2004; 10(3): 1041 - 1046.
[Abstract] [Full Text] [PDF]

M. G. House, I. I. Wistuba, P. Argani, M. Guo, R. D. Schulick, R. H. Hruban, J. G. Herman, and A. Maitra
Progression of Gene Hypermethylation in Gallstone Disease Leading to Gallbladder Cancer
Ann. Surg. Oncol., October 1, 2003; 10(8): 882 - 889.
[Abstract] [Full Text] [PDF]

K. O'Brien, V. Cokkinides, A. Jemal, C. J. Cardinez, T. Murray, A. Samuels, E. Ward, and M. J. Thun
Cancer Statistics for Hispanics, 2003
CA Cancer J Clin, July 1, 2003; 53(4): 208 - 226.
[Abstract] [Full Text]

D. E. Hansel, A. Rahman, M. Hidalgo, P. J. Thuluvath, K. D. Lillemoe, R. Shulick, J.-L. Ku, J.-G. Park, K. Miyazaki, R. Ashfaq, I. I. Wistuba, R. Varma, L. Hawthorne, J. Geradts, P. Argani, and A. Maitra
Identification of Novel Cellular Targets in Biliary Tract Cancers Using Global Gene Expression Technology
Am. J. Pathol., July 1, 2003; 163(1): 217 - 229.
[Abstract] [Full Text] [PDF]

. I. Wistuba, R. Ashfaq, A. Maitra, H. Alvarez, E. Riquelme, and A. F. Gazdar
Fragile Histidine Triad Gene Abnormalities in the Pathogenesis of Gallbladder Carcinoma
Am. J. Pathol., June 1, 2002; 160(6): 2073 - 2079.
[Abstract] [Full Text] [PDF]

Read all eLetters
Cost Analysis of Secondary Prevention of Gallbladder Cancer
Andrea Cariati
CA Online, 7 Jun 2005 [Full text]

Electronic Letters to:
Eduardo C. Lazcano-Ponce, J. F. Miquel, Nubia Muñoz, Rolando Herrero, Catterina Ferrecio, Ignacio I. Wistuba, Patricia Alonso de Ruiz, Gerardo Aristi Urista, and Flavio Nervi
Epidemiology and Molecular Pathology of Gallbladder Cancer
CA Cancer J Clin 2001; 51: 349-364 [Abstract] [Full text] [PDF]
eLetters: Submit a response to this article

Electronic letters published:
Cost Analysis of Secondary Prevention of Gallbladder Cancer
Andrea Cariati (7 June 2005)

Cost Analysis of Secondary Prevention of Gallbladder Cancer 7 June 2005

Andrea Cariati,
Medical Director, General Surgery
Villa Scassi Hospital
Send letter to journal:
Re: Cost Analysis of Secondary Prevention of Gallbladder Cancer
Email Andrea Cariati

Gallbladder cancer is usually a fatal complication of cholelithiasis. It is the most common malignant lesion of the biliary tract (1). In the different countries it has large variations of incidence. It has an annual incidence of 0.4 (men)-1 (women)/100,000 in USA and of 3.8-10.3 /100,000 among American Indians of New Mexico (1). The highest incidences (up to 7.5 per 100,000 for men and 15 per 100,000 for women) are seen in Bolivians (1). The incidence rises with age with a peak among females over the age of 65 (1). Surgical treatment in advanced cases is ineffective. The prognosis is poor: only 0-10% five-year survival rate for all stages (2, 3). The etiology of this tumour is multifactorial. In fact, gallbladder carcinomas can be divided in: a) carcinoma related to gallstones (squamous cell carcinoma, adeno-squamous cell carcinoma, the majority of adenocarcinomas); b) carcinoma non associated at all with gallstones but with other factors or conditions as pancreato-biliary reflux, pancreaticobiliary maljunction and gallbladder adenoma (gallbladder polyps of 1 cm. or more) (4).
However the 80% of gallbladder cancer is associated with large cholesterol or combination gallstones (1, 5) and in particular with long- standing gallstones (4). The progression from epithelium dysplasia to invasive carcinoma of the gallbladder is nearly 15 years. Several studies have shown that the overall incidence of carcinoma of the gallbladder in patients with cholelithiasis is 0.1-1 % (8, 9).

The prevalence of gallstones in the adult general population range from 10 % (men) to 20 % (women) in Europe and it increase with age (10). It means that among adult population the prevalence of gallstones is 10000(men)-20000(women) / 100000.
It is possible to estimate that in low incidence areas for gallbladder cancer as USA and Italy (0.5-1 / 100000) (1) a group of 20000 woman with gallstones will develop a gallbladder carcinoma during a 20- year period in 20 cases. The prevalence of gallstones in Chile is nearly 20% in men and 40% in women (11). The annual incidence of gallbladder carcinoma in these populations is 5-15/100,000. It means that, in these areas, in a group of 40000 women with gallstones, 300 will develop a gallbladder carcinoma over a 20-year period.
In theory, the prophylactic cholecystectomy among people with asymptomatic gallstones could prevent almost the 80% of all gallbladder cancer. The main limit of this procedure is the excessive cost. In fact, actually elective laparoscopic cholecystectomy has a cost of nearly 2000,00 euro (12, 13). It means that in high risk areas the secondary prevention of 300 gallbladder cancers would cost 80.000.000,00 euro (40000 x 2000,00 euro).
Actually nearly the 20% of the women with gallstones underwent operation for symptomatic disease (14). It means that in a group of 40,000 women with gallstones 8,000 would be operated at the time of diagnosis for biliary diseases and among the other 32,000 patients another 20% (6,400) would be operated during the successive 20 years (total 14.400). Three hundreds women would be cured or operated for gallbladder cancer (each DRG for biliary or pancreatic malignant diseases in Italy is 10.000,00 euro) with a cost of 300.000,00 euro. The comprehensive costs are of 28.800.000,00 euro (14.400 x 2000,00 euro) for cholelithiasis and 300.000,00 euro for gallbladder cancer (total: 29.100.000,00 euro) with a spare of nearly 50.000.000,00 euro.

In conclusion, the secondary prevention of gallbladder cancer among people with asymptomatic gallstones would triplicate the costs of public health for the treatment of benignant and malignant biliary tract diseases.

At the moment the secondary prevention of gallbladder cancer in low- and high-risk countries can be achieved by prophylactic cholecystectomy in selected high risk groups as: patients with porcelain gallbladder (15), patients with cholesterol or combination stones larger than 3 cm. (5), patients with gallbladder polyps larger than 1 cm. (16).
1) Lazcano-Ponce EC, Miquel JF, Muñoz N, Herrero R, Ferrecio C, Wistuba II, Alonzo de Ruiz P, Aristi Urista G, Nervi F. CA Cancer J Clin 2001;51:349-364.
2) Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg Gynecol Obstet 1978;147:929-942.
3) Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer 2004;4:695-706.
4) Cariati A, Cetta F. Squamous-cell and non-squamous cell carcinomas of the gallbladder have different risk factors. Lancet Oncol 2003;4:393- 394.
5) Lowenfels AB, Walker AM, Althaus DP, Townsend G, Domellŏf L. Gallstone Growth, size, and risk of gallbladder cancer: an interracial study. International J Epidemiology 1989;18:50-54.
6) Albores-Saavedra J, Alcantra-Vazguez A, Cruz-Ortiz H, Herra- Goepfer R. The precursor lesions of invasive gallbladder carcinoma: hyperplasia, atypical hyperplasia and carcinoma in situ. Cancer 1980;45:919-927.
7) Roa I, Araya JC, Villaseca M, De Aretxabala X, Riedman P, Endoh K, Roa J. Preneoplasic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology 1996;111:232-236.
8) Wenckert A, Robertson B. The natural course of gallbladder disease: eleven year review of 781 non-operated cases. Gastroenterology 1966;50:376-381.
9) Chianale J, del Pino G, Nervi F. Increasing gallbladder cancer mortality rate during the last decade in Chile, a high risk area. Int J Cancer 1990;46:1131-1133.
10) Heaton KW, Braddon FE, Mountford RA, Huges AO, Emmett PM. Symptomatic and silent gallstones in the community. Gut 1991;32:316-318.
11) Nervi F, Duarte I, Gomez G, Rodriguez G, del Pino G, et al. Frequency of gallbladder cancer in Chile, a high-risk area. Int J Cancer 1988;41:657-660.
12) Bosh F, Wehman U, Saeger HD, Kirch W. Laparoscopic or open conventional cholecystectomy: clinical and economic considerations. Eur J Surg 2002;168:270-277.
13) Soria V, Pellicer E, Flores B, Carrasco M, Candel Maria F, Aguayo JL. Evaluation of the clinical pathway for laparoscopic cholecystectomy. Am Surg 2005;71:40-45.
14) Ransohoff DF, Gracie WA. Treatment of gallstones. Ann Intern Med 1983;119:606-619.
15) Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 2001;129: 699-703.
16) Aldridge MC, Bismuth H. Gallbladder cancer: the polyp cancer sequence. Br J Surg 1990;77:363-364.

B. Is Gallbladder Cancer different from similar cancers in the biliary duct? Should they be studied in the same trials or separately studied. The debate exists as the following discussion shows:

"Gallbladder cancer is the leading cause of cancer-related deaths for Chilean women (18 per 100,000)" in the Journal of Clinical Oncology, the Official Journal of the American Society of Clinical Oncology, October 20, 2005 Volume 23, No. 30, pages 7753-7754 by Jorge Gallardo, Betzabe Rubio, Luis Villanueva, Olga Barajas of the Oncologica Hospital Clinico Universidad de Chile; facultad de Clencias Quimicas y Farmaceuticas Universidad de Chile; Instituto Terapias Oncologicas Providencia, Santiago, Chile. This article by Jorge Gallardo et al focuses on the fact that "gallbladder carcinoma is a "rappidly progressive disease" and "more aggressive disease than cholangiocarcinoma" and the "metastasis pattern, tumor localization, and other clinical parameters differ sufficiently to warrant further investigation into the molecular biology of these two different diseases, and to warrant different clinical trials."

In response to the above referenced article, Jennifer J. Knox of the Princess Margaret Hospital, University health Network Toronto, ON, Cnada sent correspondence which appears in the same issue, immediately after that article, on pages 7754-7755 in which she described the gallbladder as an "orphan site" and that "As both gallbladder and bile duct cancers are relatively rare, neither have been studied enough to have an established chemotherapy standard of care." and "The time has come to establish a standard of care from which further studies can build and fine tune biliary cancer treatments."

The two articles involve a debate over whether gallbladder cancer is so different from cancer in the bile duct, "biliary" cancer, that studies should not combine both and trials of treatments should separately measure treatments for gallbladder cancer from treatments for biliary cancer.

Jennifer Knox wrote that : "I would argue that with the current level of knowledge, advancement of both sites would proceed more quickly from large, adequately powered, randomized trials that include both sites."

Dr. Knox calls for such studies to stratify the study according to the "biliary tumor type".

Both articles talk about using gemcitibine, either by iteself, or in combination with other chemos. The primary article argues that while combined chemos with gemcitibine may be indicated, the limited evidence is stronger in support of using gemcitibine alone to fight gallbladder cancer.

Cancer is treated by surgery, radiation, chemotherapy, hormonal therapy and biologic immune therapies, but I do not know of any serious effort to treat gallbladder cancer with hormonal or biologic immune therapies. There is also a discussion of using radiation therapy to supplement the chemo therapy. Why is there no hormonal therapy for gallbladder cancer or biliary cancer? There is no treatment for gallbladder cancer the way Herceptin is a promising therapy for breast cancer. See the web site on Herceptin

c. Below is information about two different leads which may offer insight about what makes gallbladder cancer cells grow. One is about TGFBeta1 and the other is about IGF-IR.

"In 1999 , Researchers at the Massachusetts General Hospital discovered a cellular growth factor called TGFB1 had a previously unsuspected role in regulating the growth of blood vessels associated with metastatic gallbladder cancer. As long as the primary cancer tumor remains in the gallbladder, metastases – pockets of cancer that develop in other parts of the body – are few and very small. But soon after the primary tumor is surgically removed, metastases appear and grow quickly. As a result, only about 5 percent of patients having the surgery, which currently is the only treatment for the disease, survive for five years or more. “ They found that TGFB1 promotes angiogenesis or suppresses it, depending on the “different concentrations at which it is present, its location and other circumstances.” " I forget where I got this quote.

In the MGH information you can find the following:

"Finding out that TGFB1 is important in inhibiting angiogenesis in the spread of gallbladder cancer gives us an opportunity to develop postsurgical treatments," says Gohongi. "If we can learn how to modulate TGFB1 levels after removal of the primary tumor, we may be able to prevent the rapid growth of metastases that proves fatal for so many of these patients."

In the second piece about IGF-IR, the following statement occurs:

"Conclusions: The expression of IGF-IR and its ligands provides evidence for the existence of an auto/paracrine loop of tumour cell stimulation in gallbladder cancer and makes this type of cancer a candidate for therapeutic strategies aimed at interfering with the IGF pathway. The recognition of IGF-IR as a new independent prognostic biomarker may help to identify patients who might benefit from adjuvant treatment. "

QUESTION: Whatever treatment methods resulted from these studies?

The MGH communication contact is: Sue McGreevey

The first article is described in the news or press release, as follows:

MGH researchers identify angiogenesis inhibitor in gallbladder cancer

BOSTON — September 27, 1999 — Researchers at the Massachusetts General Hospital (MGH) have discovered that a cellular growth factor called TGFB1 has a previously unsuspected role in regulating the growth of blood vessels associated with metastatic gallbladder cancer. They also report finding that, in animal studies of the development of blood vessels (angiogenesis) associated with cancer, model systems in which tumor cells are grown in an unnatural location – for example, gallbladder cancer cells grown under the skin – may produce misleading results.

The study’s results, appearing in the October issue of Nature Medicine, may someday lead to strategies to prevent the growth of metastases from gallbladder cancer, a serious problem in treatment of the disease. They also add further complexity to current knowledge about factors that regulate angiogenesis and their role in the growth and spread of cancer.

"We discovered that suppression of the growth of a secondary tumor [metastases] by anti-angiogenic factors released by the primary tumor depended on the primary tumor’s growing in the right environment," says Rakesh Jain, PhD, director of the Steele Laboratory for Tumor Biology at the MGH and the study’s senior author. "That may have implications for the identification of anti-angiogenesis agents that may be useful for cancer treatment."
Rakesh Jain, PhD, director of the Steele Laboratory for Tumor Biology at the MGH and the study’s senior This apparent suppression of the growth of metastases by the presence of a primary tumor is seen in other types of cancer and suggested to researchers that primary tumors emitted some kind of antimetastatic signals. Work in animal models led by Judah Folkman, MD, of Children’s Hospital and other researchers pointed to factors that suppress angiogenesis, the growth of blood vessels required to supply tumors, as being these antimetastatic agents. But exactly what factors were associated with spread of gallbladder cancer were unknown.

Takeshi Gohongi, MD, the study’s first author, is a surgeon who treated patients with gallbladder cancer in his native Japan and may still be a research fellow at the Massachusetts General Hospital Steele Laboratory. "This is a disease with a very poor prognosis, and basic research in the area is not well developed. I came to this country to work with Dr. Jain, who has been studying the physiology and vasculature [blood vessels] of tumors using specialized animal models."

In the first step of their study, the research team implanted human gallbladder carcinoma cells in either the gallbladder wall or a pocket under the skin (subcutaneous) of immunodeficient mice. The cells implanted in the gallbladder grew more rapidly, and no metastases were observed in either group of animals.

To measure suppression of angiogenesis at a secondary tumor site, the researchers implanted either gallbladder tumor cells or gels containing a known angiogenesis promoter (bFGF) into cranial windows – transparent compartments placed into the brain – in both groups of mice, as well as in a control group with no implanted tumors. In mice with tumors in their gallbladder, growth of blood vessels in the cranial windows was significantly less than seen in mice with subcutaneous tumors or with no tumors.

To identify which factors might be involved in the observed suppression of angiogenesis, the researchers analyzed blood levels of five factors known to either stimulate or inhibit angiogenesis. The only one showing a significant difference among the groups was TGFB1, which was three times higher in the mice with tumors in their gallbladders than in the subcutaneous or control groups, suggesting that it was the factor suppressing angiogenesis in the secondary tumors.

"We were very surprised to find that TGFB1 was the only growth factor produced in higher concentrations by the orthotopic [in the right place] tumors," says Jain. "This factor is what we call a pluripotent cytokine – it can have many different effects depending on the concentrations at which it is present, its location and other circumstances. Some studies have shown that it promotes angiogenesis. Finding that it has an opposite effect in this situation is provocative."
Jain adds that TGFB1 suppressed both growth of the tumors in the cranial windows and the development of blood vessels in windows with the bFGF gels, confirming that it acted by suppressing angiogenesis and not just killing the cancer cells. To confirm that the observed activity was the result of TGFB1 and not an unmeasured factor, the researchers added an antibody to TGFB1, which successfully blocked angiogenesis suppression.

Finally the researchers studied samples of human gallbladder tumors from patients treated at the MGH and analyzed them for the presence of TGFB1. In all samples studied, even though they were different grades of cancer, TGFB1 was present. It also was found in metastatic cells found in the patients’ lymph nodes but not in normal gallbladder tissue. "This finding is quite fascinating, because it shows this is not just something that occurs in animals. TGFB1 is also present in human tumors," say Jain.

"Finding out that TGFB1 is important in inhibiting angiogenesis in the spread of gallbladder cancer gives us an opportunity to develop postsurgical treatments," says Gohongi. "If we can learn how to modulate TGFB1 levels after removal of the primary tumor, we may be able to prevent the rapid growth of metastases that proves fatal for so many of these patients."

Additional co-authors of the study are Dai Fukamura, MD, Yves Boucher, PhD, and Chae-Ok Yun, PhD, of the Steele Laboratory; Gerald Soff, MD, of Northwestern University; Carolyn Compton, MD, of the MGH Pathology Department; and Takeshi Todoroki, MD, of the University of Tsukuba in Japan. The research was supported by a grant from the National Cancer Institute.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $200 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women’s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
Contact: Sue McGreevey, MGH Public Affairs
Recent News News Archives Massachusetts General Hospital


The following article from February in 2006 in Austria suggests that Gallbladder treatment be developed to interfere with the IGF pathway.

Journal of Clinical Pathology 2006;59:202-206; doi:10.1136/jcp.2005.028480
© 2006 by BMJ Publishing Group Ltd & Association of Clinical Pathologists

"Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours
P Kornprat1, P Rehak2, J Rüschoff3 and C Langner4
1 Department of Surgery, Medical University Graz, Auenbruggerplatz 29, A-8036 Graz, Austria
2 Division of Biomedical Engineering and Computing, Department of Surgery, Medical University Graz
3 Institute of Pathology, Klinikum Kassel, Mönchebergstr. 41-43, D-34125 Kassel, Germany
4 Institute of Pathology, Medical University Graz
Correspondence to:
Dr C Langner
Institute of Pathology, Medical University Graz, Auenbruggerplatz 25, A-8036 Graz, Austria;
Aims: The insulin-like growth factor (IGF) system has been implicated in tumour development and progression. This study was designed to analyse the expression of the IGF-I receptor (IGF-IR) and its ligands (IGF-I, IGF-II) in gallbladder cancer.
Methods: IGF-I, IGF-II, and IGF-IR immunoreactivity was investigated in 57 gallbladder carcinomas and corresponding lymph node (n = 11) and hepatic (n = 7) metastases using a tissue microarray technique and correlated with tumour stage, grade, and patient outcome.
Results: Cancer tissue allowing a reliable evaluation of IGF-I, IGF-II, and IGF-IR was present in 55 of 57 primary tumours and 17 of 18 metastases. IGF-I and IGF-II immunoreactivity was seen in 25 and 14 of the 55 primary tumours, in addition to six and three of the 17 metastases, respectively. No associations with tumour stage, grade, or prognosis were detected. IGF-IR was expressed in 52 of 55 primary tumours and all 17 metastases. IGF-IR staining intensity decreased with tumour cell dedifferentiation. Moreover, IGF-IR expression in less than 50% of cancer cells was an independent marker of poor prognosis in multivariate analysis (risk ratio, 4.0; 95% confidence interval, 1.4 to 11.2; p = 0.01).

Conclusions: The expression of IGF-IR and its ligands provides evidence for the existence of an auto/paracrine loop of tumour cell stimulation in gallbladder cancer and makes this type of cancer a candidate for therapeutic strategies aimed at interfering with the IGF pathway. The recognition of IGF-IR as a new independent prognostic biomarker may help to identify patients who might benefit from adjuvant treatment.

Abbreviations: CI, confidence interval; IGF-I/II, insulin-like growth factor type I/II; IGF-IR, insulin-like growth factor type I receptor; RR, relative risk; TMA, tissue microarray
Keywords: insulin-like growth factors; insulin-like growth factor receptor; immunohistochemistry; gallbladder cancer; prognosis


Some links you may want to go to are:

For more info see:

Why am I writing this?

I have a friend with gallbladder cancer which has metastasized after surgery 9 months ago and six months of gemcitibine with oxalyplatin and when the cancer reappeared after that, she took Xeloda. She had gallstones over a 14 year history. No one ever suggested she have her gallbladder removed. I began reading and want to share with you some of the articles which I found helpful. Please do what you can to increase knowledge and care for women friends with gallstones.


Myles George Glasgow

We need an International Center to Cure Gallbladder Cancer. Is there one? It needs to collect the research about the genes of those who get gallbladder cancer to see if there is a common pattern which can help persons be detected early enough to be helped before the cancer takes hold and multiplies. This is doable in part because of the concentration of pockets of persons who get gallbladder cancer. Each tumor needs to be sent to a central site in the world and those tumors need to be analyzed for gene similarities for a beginning. I think so, anyway. What do you think?

Saturday, July 08, 2006

Myles George Glasgow: Myles George Glasgow

Myles George Glasgow

Myles George Glasgow

Meeto Malik is someone I encourage you to read about at I also encourage you to do a google search for Kamla Bhasin, Meeto's mother and a dear friend of mine sine 1969 when we met on her way back to India for her arranged marriage following her studies in Germany.

On August 12, 2006 I will walk 20 miles in Chicago with a thousand or so others each of whom has raised at least $1,000 from friends and supporters for the American Suicide Prevention Foundation. I am doing it in memory of Meeto and in solidarity with Kamla. Meeto died in January of 2006. Meeto was doing her doctorate work in Oxford, England, had been home in New Delhi with Kamla, family and friends in 2005 to increase her ability to cope with her stresses and returned to Oxford in late 2005 and had many friends and family available to her.

Myles George Glasgow: Interests

Myles George Glasgow: Interests

We are a family with a variety of interests. Edee is retired from directing Woodley House in Washington, DC where she worked for 40 years until we moved to Skokie, Il. I am employed by another attorney in Chicago where we do civil litigation. Our son is a senior in high school.

Edee is from El Centro in Southern California, a nisei, incarcerated in her early teens in 1942 at Poston in Arizona with her parents, four sisters and surviving brother and thousands of other Japanese Americans. Edee graduated from the University of Illinois as an occupational therapist, trained to work with multi disciplinary staff dealing with troubled and autistic children, with whom she worked in Norway around 1959 and before that having worked in the States in a research program with Fritz Reidl.

Joan Doniger started Woodley House around 1959, a halfway house for mentally ill persons able to avoid hospitalization but needing their own place to live, though they share it with perhaps 25 other men and women as their home while they went to work or volunteered in the Washington, DC area and complied with their medical care. Joan and Edee were professional staff who split staff work by working 24 and 36 or 48 hour shifts at a time, cutting down personnel costs and providing Woodley House with continuity. In 1968 a book was written by Harold L. Raush and his wife Charlotte L. Raush entitled The Halfway House Movement: A Search for Sanity as part of the Century Psychology Series. The dedication is to Joan Doniger and Edith Maeda. Much of the book discusses their experiences.

Joan was killed in New York in 1972 by a cab while she was holding the hand of her oldest daughtet, 4 year old Kiyo. Teresa, her younger daughter, was still in Washington, DC. Joan's death was tragic and a great loss to many, certainly to Edee who took over the directorship of Woodley House with the support of a great many extraordinary Washingtonians who served on the Board of Directors until she retired and moved to Skokie in 2000. Today, Edee and her sister Grace live in Skokie, Illinois and her brother, Robert lives in Massachusetts. Edee has always had strong family ties with her parents, siblings and neices and nephews and has developed that same feeling into our family of herself, me and Jose Luis, our son.

Our son was born in Guatemala and we adopted him when he was 11 months through a series of events that assured me that God wanted the three of us together. Nothing in my life prepared me for the sequencing of accidental events which all fit together at a key time when each seemed most improbable. He is a private person who enjoys his pleasures and friends in a low key fashion with lots of laughter which we share. He is maturing and we are happy to be with him during these important years because he gives us pleasure, laughs and opportunities to share our love with him and his with us.

I lost my dad after first grade as one of the six children of my mom and dad, when they were 37 years of age, due to his cancer of the little intestine, the jujunum, which had spread silently to invade his liver and other organs, so that he was operated on in May 7, 1949 and he died July 11, 1949. I remember that in those two months he went from a strong 37 year older to one who looked like a weak 99 year older in those two months. I abandoned my rebellious emotions, my high school love and a chance to go to Georgetwon University in Washington, DC. when I joined the Augustinian seminary after high school in 1960 till half a year before ordination in 1967 when I quit rather than be delayed due to surperiors' "black ball" votes. I worked for a year in President Johnson's anti-poverty program, finished graduate theology and philosophy studies and obtained a conscientious objector draft status. I wanted to get married and have a family but was obviously not focused, well employed or "timely" , and Nixon got elected on a wave of racism which encouraged me to complete my liberal education by living in Europe where I went to Dijon, France to research and write my thesis for an MA in Philosophy. Instead of living in Dijon for two years as I planned, I moved on once I wrote the thesis and traveled around earth within the next year, mostly by hitch hiking, practicing my French, living on a French speaking Kibbutz for a couple of months, traveling in Africa, by ship to several Asian cities, and hitch hiking in Japan for three weeks before traveling in Mexico for a couple of weeks, which I did with Edee and a dear friend of hers, Janice Matsusuyu from Los Angeles. Ultimately I went to the Antioch School of Law, married Edee, surviving various stresses, undergoing analysis for a couple of years in the late 80's and beginning the 90's as the father at home caring for his son while practicing law from the dining room table in Washington, DC.

In the course of this we have many dear friends, many of whom live far from Skokie, though we are making new ones in the Chicago area. Thank God for email which keeps us close to many of our friends.