INDEX

ALABAMA	University of Alabama, Birmingham	Bruno Cancer Center, St. Vincent's Hospital, Birmingham	Providence Hospital, Mobile
ALASKA	Anchorage Regional Hospital	Anchorage. Providence Medical Center	Fairbanks Memorial Hospital Cancer Treatment Center.
ARIZONA	University Medical Center; Tucson.	City of Hope, Phoenix	Good Samaritan Regional Medical Center
ARKANSAS	Arkansas Cancer Research Center. Little Rock	.....	....
CALIFORNIA	UCLA, University of  California. LA	Scripps Memorial Hospital, La Jolla	City of Hope National Medical Center; Duarte
""          ""	UCSF. University of California.San Francisco	Stanford Health Care	.....
COLORADO	Presbyterian/St. Luke's Medical Center; Denver	University of Colorado; Denver	::::
CONNECTICUT	University of Connecticut Health Center; Farmington	Yale University/Yale New Haven Hospital	....
DELAWARE	Christiana Care Health Services; Newark	.....	....
DISTRICT OF COLUMBIA	Georgetown University Medical Center; Washington D.C	.......	......
FLORIDA	Shands Hospital at the University of Florida; Gainsville	H. Lee Moffitt Cancer and Research Institute; Tampa.	Lakeland Regional Medical Center
GEORGIA	Emory Clinic in Atlanta	Phoebe Putney Memorial Hospital , Albany	Northside Hospital; Atlanta
HAWAAI	Hawaii Bone Marrow Transplant Program; Honolulu	.....	....
IDAHO	......	......	....
ILLINOIS	Thomas Hazen Thorne BMT Center	Rush Presbyterian/St. Luke's Medical Center; Chicago	University of Illinois at Chicago Medical Center
""	Loyola University Medical Center; Maywood	....	....
INDIANA	University of Michigan Comprehensive Cancer Center	.....	....
IOWA	UIH University of Iowa Hospitals and Clinics ; Iowa City	......	....
KANSAS	University of Kansas Medical Center; Kansas City	.....	....
KENTUCKY	University of Kentucky Medical Center; Lexington	University Medical Center, Inc., University of Louisville Hospital	....
LOUISIANA	Louisiana State University Medical Center; New Orleans. .	Memorial Medical Center; New Orleans	LSU Medical Center - Shreveport
	Tulane Cancer Center in New Orleans	......	......
MAINE	.....	.....	....
MARYLAND	Bethesda  NIH	John Hopkins, Baltimore	....
MASSACHUSETTS	Dana Farber Institute,Boston.	Massachusetts General Hospital  ( MGH )	Beth Israel Hospital , Boston
MICHIGAN	Kalamazoo Cancer CenterS	Spectrum Health  Grand Rapids	....
MINNESOTA	Mayo Clinic, Rochester	....	....
MISSISSIPPI	University of Mississippi Medical Center; Jackson. .	....	....
MISSOURI	Barnes-Jewish Hospital at Washington University; St. Louis	St. Louis University Medical Center	....
MONTANA	....	....	....
NEBRASKA	Omaha,UNMC	.....	....
NEVADA	....	....	....
NEW HAMPSHIRE	....	....	....
NEW JERSEY	JFK Hospital Edison	Hackensack UMC	St. Joseph's Hospital and Medical Center; Paterson
NEW MEXICO	....	....	....
NEW YORK	Memorial Sloan-Kettering Cancer Center	New York Presbyterian Hospital-Cornell Medical Center	Roswell Park Cancer Institute; Buffalo
"	Mount Sinai Hospital; New York City. .	.	.........
N. CAROLINA	Duke University Medical Center; Durham	Wake Forest University Baptist Medical Center; Winston-Salem	UNC .University of N. Carolina
N.DAKOTA	....	....	........
OHIO	State University  Arthur James Cancer Center	Cleveland Clinic	UVMC Upper Valley Medical Center
"	Ashtabula Regional Cancer Center	Aultman Hospital, Canton	....
OKLAHOMA	HCA Health Services of Oklahoma, Inc.; Oklahoma City	....	........
OREGON	....	....	........
PENNSYVANIA	Pittsburgh Allegheny General Hospital	HUP - Hospital of the University of Pennsylvania	Thomas Jefferson University Hospital, Inc.; Philadelphia .
RHODE IS	....	........	........
S.CAROLINA	Medical University of  Souh Carolina (MUSC)	........	.......
S:DAKOTA	......	....	........
TENNESSEE	Vanderbilt University Medical Center; Nashville	St. Thomas'Hospital, Nashville	........
TEXAS	Houston, MD.Anderson	Texas Transplant Institute, San Antonio	Arlington Cancer Center....
UTAH	University of Utah; Salt Lake City	........Nal	........
VERMONT	....	........	....
VIRGINIA	Massey Cancer Center	....	....
WASHINGTON	Seattle, Virginia Mason Hospital,	Fred Hutchinson Cancer Research Center, Seattle	UW Hospital, Seattle
W.VIRGINIA	West Virginia University Hospitals, Inc.; Morgantown	.......	....
WISCONSIN	University of Wisconsin Hospital and Clinics; Madison	Froedtert Memorial Lutheran Hospital Cancer Center; Milwaukee .	........
WYOMING	....	....	........

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Canadian Hospitals Province by Province (In process of construction. Email me your choices. Ron)

 

Alberta	Martin Scott Cancer Center	......	.....
British Columbia	Vancouver Cancer Center	Vancouver Island Cancer Center	Cancer Center for the Southern Interior
"	Fraser Valley Cancer Center	....	....
Newfoundland	Newfoundland Cancer Treatment & Research	....	....
Ontario	Ontario Cancer Institute	Northwestern Ontario Regional Cancer Center	Ontario Cancer Treatment & Research Foundation
Quebec	Fondation quebecoise du Cancer		......

Dx

DIAGNOSIS

(See also   FISH  Test , LDH  &   STAGING)

Those who present themselves to a doctor with one or several of the more common symptoms listed in the Symptoms section would expect that the doctor, suspecting some form of leukemia, will arrange a bood test  or a biopsy and, if his suspicions are confirmed, refer them to the Oncology/Hematology of the local hospital. Unfortunately, as some of our case-histories illustrate, this sometimes is not the case an patients may have a long fight before getting to see the correct specialist.

Then, as the report below illustrates, the difficult task of diagnosis begins. It is clear that, even with the most advance techniques, diagnosis of MCL is far from being an exact science. It is also clear that, in some cases, patients are justified in asking for a second opinion when the consultant does not do so as a matter of routine where there is some ambiguity.

DIFFERENTIAL DIAGNOSIS OF MCL

(Quotations from Oncology Conference 2000 summaries)

Immunophenotypic, cytogenetic, and molecular genetic technologies have led identification of a distinct and clinically significant subset of lymphomas that were previously scattered among a variety of morphological descriptions. Mantle cell lymphoma will be a component of the new World Health Organization lymphoma classification.

Despite the improvements in establishing this diagnosis in the past decade, Dr. Medeiros warned that there are still a number of limitations. Mantle cell lymphomas, in which residual benign germinal centers are infiltrated with tumor cells, can resemble follicular lymphomas. Those MCLs with a mantle zone pattern can be confused with marginal zone B-cell lymphoma. In addition, MCL cells with minimal nuclear irregularity resemble B-cell small lymphocytic lymphoma, especially in the leukemic phase. Blastic MCL can be confused with lymphoblastic lymphoma or diffuse large B-cell lymphoma.

Ancillary studies aid in diagnosis. Immunophenotypically, only chronic lymphocytic leukemia/small lymphocytic lymphoma and MCL coexpress B-cell differentiation markers and CD5. CD23 is positive in chronic lymphocytic leukemia/small lymphocytic lymphoma but not MCL. Only MCLs are positive for cyclin D1, and approximately 10% of MCLs are cyclin D1 negative, although cyclin D1 staining is technically difficult.  

At the molecular level, MCL is characterized by the translocation t(11;14)(q13;q32), which deregulates bcl-1 via juxtaposition to the immunoglobulin heavy chain locus. DNA  fluorescent in situ hybridization (FISH) with optimal probes (95%) and cytogenetics (75%) are more sensitive methods for detecting this translocation than the time-consuming Southern blot, which uses multiple probes (65%), or polymerase chain reaction (major breakpoint cluster, 30%-50%). Real-time polymerase chain reaction for cyclin D1 allows quantitation of messenger RNA and may represent a useful diagnostic tool.

The next question to be considered is whether precise quantitation by polymerase chain reaction will allow for use of cyclin D1 as a prognostic indicator in MCL or other lymphomas.

The following excellent summary by Doctor Andy Haynes of Nottingham City General Hospital of the techniques used and the problems encountered in diagnosing MCL summarises and adds to the above.

Standard MCL is characterised by :

1) Phenotype: CD19/20/5/22/FMC7/79a/43 Positive CD23/CD10 Negative Surface Immunoglobulin Strongly positive

2) Genetics: translocation between chromosomes 11 and 14 only detectable by standard PCR in @ 35% of cases detectable by FISH in @ 70% of cases

3) Histochemistry:

As a consequence of 2 the cellular levels of a protein called cyclin D1 are elevated in MCL but this test is fickle..it works quite well on lymph node or bowel but not so well on bone marrow biopsies Follicular lymphoma is a very different entity (CD19,20,79a,22,FMC7,10 positive but 5,23 and 43 negative with characteristic bcl-2  positivity and cyclin D1 negative)

CLL gets confused (CD19,5,79a,23 positive but weak 22 and FMC7 but some cases with this phenotype have the t11,14 and/or overexpress cyclinD1..these are called atypical CLL but we do not understand if they are variants of CLL or MCL)

Mantle Zone lymphoma is a completely different entity (CD19, 20, 22, 79a, FMC7 positive but 5,23 and 43 negative. It gets confused with MCL because clinically it can present with predominantly gut and marrow disease) clinical behaviour or if it is a spectrum of change occuring within a single disease ie if diffuse aggressive disease is the end progression from a more indolent non diffuse follicular MCL itself appears to be heterogeneous and we do not understand if this is because different subtypes exist with different rm.

In lymph nodes there are 3 appearances described; nodular with clumps of lymphoma cells, diffuse with sheets of lymphoma cells and a mantle zone with abnormal cells localised to the normal mantle area of the node. There is evidence that the diffuse form is more aggressive and the blastic or blastoid variant of this behaves like a high grade lymphoma with which it gets confused. The nodular variant can get confused with follicular lymphoma. All should be distinguishable by phenotyping, immunochemistry and FISH. The mantle zone variant is the one which may have a more indolent behaviour with better survival than the other 2 forms and appears to be more common in the more elderly patients.

Leeds have looked at their cases of MCL diagnosed on the basis of phenotyping in blood or node...only @ 25% have the t11,14 detectable by FISH or PCR. At the BSH meeting this week I chaired a session in which Ed Schuuring from Leiden spoke...they make their own FISH reagents and claim to detect 95% of cases. He is sending me their probes to use

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EVIDENCE FOR NEED OF UPPER AND LOWER ENDOSCOPIES WITH BIOPSY IN STAGING OF ASYMPTOMATIC PATIENTS WITH AGGRESSIVE MANTLE CELL LYMPHOMA                                        (See  Diagnostic  RESEARCH)

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LDH

LDH

(Lactate Dehydrogenase)

Article No.1

Testing for high levels of LDH in NHL patients is useful because it is released when body tissues break doen for any reason. While it cannot be used as a sole means of diagnosing  NHL  it is a surrogate for tracking tumour burden in those diagnosed by other means. The normal range is approximately 100-190.

"LDH is one of the most important serologic tests performed in the evaluation of patients with lymphoma. It indirectly indicates tumor burden and proliferative activity and is an important indicator of prognosis. It is so important that it was included as one of five parameters in the International Prognostic Index(IPI) which is now widely used in determining prognosis in patients with non-Hodgkin's lymphoma. The other four indicators are age, performance status, extranodal involvement and stage. The prognostic score used by MD Anderson also used LDH as one of the parameters."

Richard Miller M.D. Hematopathology

Clinical Significance:

Lactate dehydrogenase (LD) is a ubiquitous cellular enzyme composed of four peptides of two subunits: M and H. The number of each subunit varies between the five commonly recognized isoenzymes: LD-1 through LD-5. LD-1 and LD-2 predominate in cardiac muscle, kidneys and RBCs, and LD-4 and LD-5 predominate in liver and skeletal muscle.

The most frequent use of LD isoenzyme analysis is for the diagnosis of myocardial infarction. In the absence of hemolysis, an LD-1/LD-2 ratio greater than 1 ("flipped" ratio) is usually indicative of acute myocardial infarction (AMI). This pattern can be seen in about 80% of patients. In fact, the normal ratio rarely exceeds 0.80 in the absence of AMI. LD activity begins to rise 8-12 hrs after the onset of chest pain, peaking at 24-48 hrs. Elevated levels may persist for 1 week or more.

LD isoenzymes may also provide additional information in cases of muscle trauma, liver damage and a variety of malignancies. In these cases, variations of isoenzyme distribution are frequently helpful when interpreted appropriately

Article No.2

The biological markers of non-Hodgkin's lymphomas (NHL) are distinguished in three categories: serological, immunophenotypic, and molecular markers. The clinical importance of biological markers in NHL is based on their support of morphologic diagnosis, their role in staging and prognostic assessment, and their contribution to monitoring minimal residual disease (MRD).

The most important serological markers reflect the tumor load (beta-2 microglobulin, beta 2-M), proliferative activity (lactic dehydrogenase, LDH), and invasive potential of lymphomas (CA 125). LDH and beta 2-M are included as important prognostic parameters in widely used staging systems.

Immunophenotypic analysis identifies specific markers of lineage (B or T-cells), maturation level, cell proliferation, and clonality. Results of immunophenotyping are particularly useful in low to intermediate-grade NHLs to support the morphologic diagnosis and facilitate the detection of MRD after treatment. The molecular markers are genetic lesions involved in the pathogenesis of some categories of NHL.

Their use as markers for diagnosis is justified by the selective association with specific lymphoma categories: follicular, mantle cell, diffuse large cell, and anaplastic large cell lymphomas.

Molecular lesions are the most specific and sensitive markers for evaluating MRD. Today the biological markers of NHL are widely employed for diagnosis, staging, and prognostic assessment. Their systematic use may complement clinical parameters in the stratification of NHL patients, who may thus become candidates for treatments of different intensity. The detection of MRD after first-line treatment identifies patients at high risk of relapse who require additional therapy to cure their disease.

Morra, E  Division of Hematology,

Niguarda Ca' Granda Hospital, Milano, Italy.

Return to DIAGNOSIS

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Fi

Cyclin D1 FISH Test

Detection of Cyclin D1 Translocation by FISH is Highly Specific and Sensitive in the Diagnosis of Mantle Cell Lymphoma (MCL)

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma characterized by poor prognosis and a median survival of approximately 3 years.

On the basis of morphology and immunophenotype alone, mantle cell lymphoma is difficult to distinguish from indolent lymphomas and leukemias.

Cytogenetically, a t(11:14)(q13;q32) is associated with 75% of mantle cell lymphomas.

PCR for the major translocation cluster (MTC) region of the bcl-1 is positive in only 30-40% of cases.

Southern blot analysis detects translocations in approximately 50% to 70% of the cases.

Translocation breakpoints are scattered within the approximately 120-kb bcl-1 region adjacent to cyclin D1, whereas part of them are clustered in the MTC.

The translocation leads to overexpression of cyclin D1 due to juxtaposition of the Ig heavy chain gene enhancer on 14q32 to the cyclin D1 gene on 11q13.

Cyclin D1/CEP11

Cyclin D1 amplification is common in many types of cancer, second only to the HER2/neu (erb-b2) oncogene.

The LSI Cyclin D1 is approximately 300 kb in size.

This probe may be used to determine the copy number of the Cyclin D1 locus, or as an enumerator probe for chromosome 11 in interphase and metaphase cells. 200 cells will be counted. The result will be expressed as the ratio of Cyclin D1/CEP11.

LYMPHOPROLIFERATIVE DISORDER FISH ANALYSIS

RESULTS:

SAMPLE TYPE: Bone marrow

Signals

Probe 1 2 3 4 5 6 7 8 >8

11CEP(%) 1 98 1 0 0 0 0 0 0

Cyclin D1(%) 0 13.5 87 0 0 0 0 0 0

200 cells counted

For Cyclin D1 test:

Ratio = Total Cyclin D1/Total 11CEP = 287/200 = 1.43

Normal range: Mean ratio +/- SD = 0.99 +/- 0.09. 95% Confident Interval: (0.96, 1.02)

Ratio for Mantle cell positive control: 1.49

Ratio for Mantle cell negative control: 1.00

ISCN DIAGNOSIS: nuc ish 11cep(cep x 2), 11q13(cyclin D1 x 3) [200]

INTERPRETATION:

Elevated ratio Cyclin D1: total 11 CEP at 1.43 with 87% cells showing evidence of Cyclin D1 translocation consistent with extensive involvement by mantle cell lymphoma in bone marrow.

Notes: Based on mixing experiments, in peripheral blood, bone marrow, or lymph-node specimens, the level of detectable translocation t(11;14)(q13;q32) cells is considered positive if 5% or higher numbers of translocated cells are presented.

The in situ hybridization (ish) technique was performed using a Vysis LSI Cyclin D1/CEP11 probe. A total of 200 interphases were analyzed.

In situ hybridization is for investigational use only and should not be used for diagnostic purposes without confirmation by another proven procedure. This test does not rule out abnormalities other than the one for which the probe was designed.

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St

STAGING

Stage I .

Cancer is found in only one lymph node area or in only one area or organ outside the lymph nodes.

Stage II.

Either of the following means that the disease is stage II:

Cancer is found in two or more lymph node areas on the same side of the diaphragm (the thin muscle under the lungs that helps breathing). Cancer is found in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph node areas on the same side of the diaphragm may also have cancer. In contiguous stage II cancer, the positive lymph node areas are next to one another; in non-contiguous stage II, the positive lymph nodes are not next to each other, but are still on the same side of the diaphragm.

Stage III

Cancer is found in lymph node areas on both sides of the diaphragm. The cancer may also have spread to an area or organ near the lymph node areas and/or to the spleen.

Stage IV

Either of the following means that the disease is stage IV:

Cancer has spread to more than one organ or organs outside the lymph system. Cancer cells may or may not be found in the lymph nodes near these organs. Cancer has spread to only one organ outside the lymph system, but lymph nodes far away from that organ are involved.

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SYMPTOM	BLASTIC	DIFFUSE	NODULAR	NOT KNOWN	TOTAL
Allopecia				1	1
Anaemia		1	1	1	3
Breathlessness	1	2	1	9	13
Bruising		1	1	3	5
Burning pains				3	3
Cramps	1	6	2	3	12
Deafness		3	1	1	5
Digestive disorders	1	3	2	5	11
Eustachian tube blocked by tissue				1	1
Excessive reaction to insect bites		1		4	5
Fatigue	3	11	3	37	54
Fevers	2	1		6	9
Headaches		1	1	4	6
Impaired vision			1	1	2
Loss of appetite	1	3	2	4	10
Minor infections		4	1	6	11
Mouth ulcers		2		2	4
Nausea & vomiting	1	1	1		3
Night sweats	3	8	1	20	32
None - routine check or during treatment for other condition		5	2	36	43
Painful joints	1	7	1	5	16
Pain due to undetected  swollen nodes	1	2	1	19	22
Rashes & itching		4	2	14	20
Severe eruptions (Face & head)		1		3	4
Shingles		1	1	1	3
Chronic sinus infections or colds	2	10	1	8	21
Sore tonsils			1	2	3
Stomach disorder& internal bleeding	1	4	1	7	13
Swollen lachrymal  or saluivary glands				3	3
Swollen  lymph nodes	10	19	5	77	111
Swollen spleen	2	7	1	24	32
Weight loss	2	4	1	1	201
Number of participants	239	18/8//2001

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Cs

THE CAUSES OF MCL Helicobacter Pylori, Melanoma, Herbicides & Pesticides http://www.valdezlink.com/mcl.htm

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  He

Me

Reciprocal Risk Increase Seen Between Melanoma and Non-Hodgkin's Lymphoma Survivors of cutaneous melanoma face a higher risk of non-Hodgkin's lymphoma (NHL), and NHL survivors have a higher risk of melanoma, according to a report in the February 15th issue of Cancer. Although previous work has documented an increase in cutaneous melanoma in NHL survivors, no systematic study has examined the incidence of NHL after cutaneous melanoma, the authors explain. An association between the two, they suggest, may indicate similar etiologies. Dr. Hensin Tsao, from Massachusetts General Hospital, in Boston, and colleagues used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registries to study more than 100,000 survivors of NHL and cutaneous melanoma. Melanoma survivors had a risk of NHL 42% more than expected, the authors report. Similarly, NHL survivors were 75% more likely than expected to develop cutaneous melanoma. The investigators suggest that these two malignancies may share etiologic factors, such as exposure to ultraviolet radiation. Moreover, Dr. Tsao told Reuters Health, "There may be genetic links between the etiologies of these two cancers. The extensive ongoing genetic and genomic approaches to cancer will help answer this question." Dr. Tsao advised physicians to "be attentive to the possibility of second cancers in patients with melanoma and lymphoma. A suspicious lymph node detected after melanoma may not necessarily be a melanoma recurrence, but rather, it may represent a lymphoma. Similarly, skin examinations are important for all lymphoma patients." Cancer 2001;91:874-880. Return to Causes of MCL

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Pe

_____________________Dio

Dioxin Added to List of Known Carcinogens WESTPORT, CT (Reuters Health) Jan 22 - The federal government has added the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the list of substances that are known carcinogens. The announcement was made by the National Toxicology Program on Friday and is based on "sufficient evidence of carcinogenicity from studies in humans," according to a statement released by the National Institute of Environmental Health Sciences, a branch of the National Institutes of Health (NIH). It is now clear that there is "a causal relationship between exposure to TCDD and human cancer," the group said. The term "dioxin" is often used to refer to the most well-studied and one of the most toxic dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), according to the Environmental Protection Agency (EPA). "TCDD is not deliberately produced today but has been found as a contaminant in some herbicides and pesticides, and is formed as an inadvertent by-product of incineration of waste," according to the NIH. The chemical was scheduled to appear in the Ninth Report on Carcinogens, released earlier this year, however the addition of TCDD was held up due to litigation. Dioxin can cause "skin rashes, skin discoloration, excessive body hair and possibly mild liver damage," according to the EPA. "Because dioxins exist throughout the environment, almost every living creature including humans has been exposed to dioxins," according to the EPA. "The health effects associated with dioxins depend on a variety of factors including: level of exposure, time of exposure, and frequency of exposure. Because dioxins are so widespread, we all have some dioxins in our bodies." Dioxin came to public attention as the contaminant in Agent Orange, a controversial herbicide used by US forces in Vietnam. In 1983, the EPA forced the evacuation and demolition of the entire town of Times Beach, Missouri, after the discovery of dioxin contamination on city streets. Over the past 5 years, the EPA has imposed regulations on major dioxin emitters, including municipal waste combustors, medical waste incinerators, hazardous waste incinerators, cement kilns that burn hazardous waste, pulp and paper operations, and sources of PCBs. One source likely to be targeted in the future is uncontrolled residential waste burning, such as burning trash in backyards, particularly in rural areas. The agency also is discussing the possible regulation of other sources such as sludge disposal from privately owned waste-treatment facilities and the regulation of other air sources of pollution.

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A book worth dipping into is  'Living Downstream,  An Ecologist Looks at Cancer and the 'Environment'  by Sandra Steingraber,  This was published by in 1997 by Addison-Wesley.

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If any visitor to this website has any information to add to the above articles please email:-

Ron Edwards PapyRonnie@aol.com  (sorry as of July, 2003 - this e-mail address does not work)

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