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Ultima Vez Modificado: 1 de abril del 2002
Table of Contents
1
UI - 11552325
AU - Frutuoso C; Silva MR; Amaral N; Martins I; De Oliveira C; De Oliveira HM
TI -
[Prognosis value of p53, C-erB-2 and Ki67 proteins in ovarian carcinoma]
SO - Acta Med Port 2001 May-Jun;14(3):277-83
AD - Servicos de Ginecologia e Anatomia Patologica, Hospitais da Universidade
de Coimbra, Coimbra.
The prognosis in ovarian carcinoma remains poor. We need to identify
patients who are less likely to respond to treatment. In order to
evaluate the prognostic value of C-erb-B2, p53 and Ki 67 expression and
correlate these markers with classic prognostic factors, we studied
paraffin-embedded tumor tissue from 81 patients with epithelial ovarian
cancer and made a quantitative evaluation of C-erb-B2, p53 and Ki 67
expression by immunohistochemistry. The results were: age 5.4 +/-
15(22-88); 66% with normal physical activity; 48.2% with residual
disease < 2 cm; initial stage--42% and advanced stage--58%. Age,
performance status, residual disease and stage were correlated with 2
and 5 years survival. Positive immunostaining: p53--87%, C-erb B-2--51%
and Ki67--100%. P53 and C-erb B-2 were associated with residual disease
and stage; patients with no C-erbB-2 staining had a significantly better
survival. A direct and significant correlation was found between p53 and
Ki67 and between C-erb B-2 and p53. We conclude that these markers have
a high expression in ovarian carcinoma and p53 and C-er B-2 correlate
with stage and residual disease. Although C-erb B-2 was associated with
better survival, it was not found to be an independent prognostic
factor.
2
UI - 11759816
AU - Chang J; Elledge RM
TI -
Clinical management of women with genomic BRCA1 and BRCA2 mutations.
SO - Breast Cancer Res Treat 2001 Sep;69(2):101-13
AD - Department of Medicine, Baylor-Methodist Breast Care Center, Baylor
College of Medicine, Houston, TX 77030, USA. jcchang@bcm.tmc.edu
PURPOSE: There is increasing evidence that BRCA1 and BRCA2 associated
tumors may differ from sporadic cancers. The purpose of this report is
to review the current state of knowledge of BRCA1 and BRCA2, the biology
of associated tumors, and possible risk reduction strategies in women
with these deleterious mutations. DESIGN AND METHODS: We conducted an
extensive literature search of all published articles (including
Medline) on preclinical data on the function of BRCA1 and BRCA2,
associated tumor pathology, and the clinical management for both
unaffected carriers and affected patients. RESULTS: BRCA1 and BRCA2 are
likely to act as tumor suppressor genes, and together with RAD51 operate
in a common DNA damage response pathway implicated in double-strand
repair. Breast cancers associated with BRCA1 are frequently of a higher
grade, steroid hormone receptor negative, and appear to have a higher
proportion of atypical or typical medullary subtype. Conversely, BRCA2
associated breast cancers do not differ significantly from sporadic
cancers. No special tumor phenotype has been ascribed to BRCA1 or BRCA2
associated ovarian cancers. Guidelines for risk reduction strategies for
the high risk unaffected carrier have been recommended by expert panels
in the USA and Europe. Lifestyle changes, multi-modality screening,
chemoprevention, and prophylactic oophorectomy and mastectomy, with
their possible benefits and attendant risks are described. Finally,
locoregional and systemic treatment in breast and ovarian cancers
associated with these mutations, and differences between these and
sporadic cancers are discussed. CONCLUSIONS: Although the incidence of
breast or ovarian cancers that can be attributed to BRCAI or BRCA2
mutations account for less than 5% of all cancers, these cancers may
differ from sporadic cases in terms of tumor biology and phenotype.
These differences may impact directly on clinical management of breast
and ovarian cancer patients, and their relatives. Further
recommendations of these patients are constantly changing as new
information emerges on the clinical behavior of these cancers.
3
UI - 11801872
AU - Narod SA; Boyd J
TI -
Current understanding of the epidemiology and clinical implications of
BRCA1 and BRCA2 mutations for ovarian cancer.
SO - Curr Opin Obstet Gynecol 2002 Feb;14(1):19-26
AD - The Centre for Research on Women's Health, Women's College Hospital,
University of Toronto, Toronto, Canada. steven.narod@swchsc.on.ca
Genetic testing for susceptibility to ovarian cancer is rapidly becoming
integrated into the clinical practice of oncology. Genetic testing for
BRCA1 and BRCA2 is now recommended to most women with invasive ovarian
cancer. Approximately 10% of these women will have a positive test,
including 4% of women without a family history of cancer. Currently, the
treatment of hereditary ovarian cancer is the same as for non-hereditary
ovarian cancer. It appears that women with ovarian cancer and a BRCA
mutation experience better survival than women without a mutation,
possibly due to enhanced susceptibility to chemotherapy. Strategies for
prevention of ovarian cancer among carriers include oral contraceptives,
tubal ligation and prophylactic oophorectomy.
4
UI - 11846741
AU - Oszurek O; Gorski B; Gronwald J; Prosolow Z; Uglanica K; Murinow A;
TI -
Bobko I; Downar O; Zlobicz M; Norik D; Byrski T; Jakubowska A; Lubinski
J
Founder mutations in the BRCA1 gene in west Belarusian breast-ovarian
cancer families.
SO - Clin Genet 2001 Dec;60(6):470-1
5
UI - 11875732
AU - Bennett KE; Howell A; Evans DG; Birch JM
TI -
A follow-up study of breast and other cancers in families of an
unselected series of breast cancer patients.
SO - Br J Cancer 2002 Mar 4;86(5):718-22
AD - CRC Paediatric and Familial Cancer Research Group, Royal Manchester
Children's Hospital, Hospital Road, Manchester M27 4HA, UK.
The cancer experience among relatives of an unselected cohort of 402
breast cancer patients was previously reported. Cases and their first
degree relatives were flagged at the National Health Service Central
Register for continuous notification of cancer registrations and deaths.
More than 10 years of follow-up data have been analysed to update cancer
risks overall and to estimate breast cancer risk in relatives
prospectively according to family history at the time of breast cancer
diagnosis in the index case. Significant excesses of breast cancer (RR
2.24, P<0.0001), prostate cancer (RR 1.71, P=0.039) and bone sarcoma (RR
6.564, P=0.042) overall and soft tissue sarcoma in mothers only (RR
15.44, P=0.001) were found. There was no excess of any other cancer,
including ovarian. High breast cancer risk in relatives was associated
with young age at diagnosis in the index (index <40 years at diagnosis,
RR in relatives 3.76, P=0.004). Prospective risk of breast cancer was
higher in relatives of index patients who had an affected first degree
relative at the time of their diagnosis (no family history, RR 1.87,
P=0.012; with a family history, RR 3.72, P=0.015). These prospective
risk estimates are valuable in advising relatives of newly diagnosed
breast cancer patients. Copyright 2002 Cancer Research UK
6
UI - 11899542
AU - Krutilkova V; Havlovicova M; Goetz P
TI -
[Specialized genetic counseling in pediatric and adult oncology
patients]
SO - Cas Lek Cesk 2002;141(1):23-7
AD - Ustav biologie a lekarske genetiky 2. LF UK a FNM, Praha.
vera.krutilkova@lfmotol.cuni.cz
Five to ten percent of oncological diseases exhibit monogenic mode of
inheritance. They occur as a consequence of the germline mutations of
tumor suppressor genes and of the genes engaged in reparative processes.
Most common monogenically determined oncological diseases are: AD form
of breast and ovarian cancer, hereditary nonpolyposis colorectal cancer
(HNPCC, Lynch sy.) and familiar adenomatous polyposis (FAP). The aim of
the genetic investigation is to evaluate whether the index family deals
with the hereditary form of tumor predisposition, than, if possible, to
perform DNA analysis in the family and to propose preventive screening
program (methods) for the probands in risk.
7
UI - 11870168
AU - Scheuer L; Kauff N; Robson M; Kelly B; Barakat R; Satagopan J; Ellis N;
TI -
Hensley M; Boyd J; Borgen P; Norton L; Offit K
Outcome of preventive surgery and screening for breast and ovarian
cancer in BRCA mutation carriers.
SO - J Clin Oncol 2002 Mar 1;20(5):1260-8
AD - Clinical Genetics, Breast Cancer Medicine, and Developmental
Chemotherapy Services, Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New york, NY 10021, USA.
PURPOSE: To prospectively determine the impact of genetic counseling and
testing on risk-reduction strategies and cancer incidence in a cohort of
individuals at hereditary risk for breast and ovarian cancer. PATIENTS
AND METHODS: Two hundred fifty-one individuals with BRCA mutations were
identified at a single comprehensive cancer center from May 1, 1995,
through October 31, 2000. Uniform recommendations regarding screening
and preventive surgery were provided in the context of genetic
counseling. Patients were followed for a mean of 24.8 months (range, 1.6
to 66.0 months) using standardized questionnaires, chart reviews, and
contact with primary physicians. RESULTS: Frequency of cancer
surveillance by physical examinations and imaging studies increased
after genetic counseling and testing. Twenty-one breast, ovarian,
primary peritoneal, or fallopian tube cancers were detected after
receipt of genetic test results. Among 29 individuals choosing
risk-reducing mastectomy after testing, two were found to have occult
intraductal breast cancers. Among 90 individuals who underwent
risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm
and one early-stage fallopian tube neoplasm were found. Radiographic or
tumor marker-based screening detected six breast cancers, five of which
were stage 0/I, one early-stage primary peritoneal cancer, and three
stage I or II ovarian cancers. Six additional breast cancers were
detected by physical examination between radiographic screening
intervals; four of these six tumors were stage I. No stage III or stage
IV malignancies were detected after genetic testing. CONCLUSION: This
study provides prospective evidence that genetic counseling and testing
increased surveillance and led to risk-reducing operations, which
resulted in diagnosis of early-stage tumors in patients with BRCA1 and
BRCA2 mutations.
8
UI - 11889215
AU - Fuller PJ; Zumpe ET; Chu S; Mamers P; Burger HG
TI -
Inhibin-activin receptor subunit gene expression in ovarian tumors.
SO - J Clin Endocrinol Metab 2002 Mar;87(3):1395-401
AD - Prince Henry's Institute of Medical Research and Monash University,
Department of Obstetrics and Gynecology, Monash Medical Center, Clayton,
Victoria 3168, Australia. peter.fuller@med.monash.edu.au
Granulosa cell tumors of the ovary (GCT) express the inhibin subunit
genes and secrete dimeric inhibin. Transgenic mice null for the
alpha-inhibin gene develop GCT. It has been suggested that this apparent
contradiction may be reconciled if the human GCT are resistant to the
tumor-suppressive effects of inhibin. Inhibin receptors have recently
been characterized as consisting of either betaglycan or p120 in
association with the type II or type I activin receptor subunits (ActR),
respectively. To test the hypothesis that GCT may exhibit loss of
inhibin receptor expression we have examined the expression of the
receptor subunits in a cohort of GCT and in mucinous and serous
cystadenocarcinomas and normal ovary. Expression was determined by
RT-PCR using gene-specific primers and probes combined with Southern
blot analysis of the PCR products. The ActRI subunits and ActRIIA
exhibited widespread albeit variable expression across tissues, with the
highest levels in the serous tumors. ActRIIB expression was relatively
low in the mucinous tumors and high in the GCT. Betaglycan expression
was abundant, widespread, and variable across all tissues; highest mean
levels occurred in the GCT and normal ovary. p120 expression was low or
absent in all tissues except the GCT. Within the GCT there was parallel
expression of the ActR subunits, betaglycan and p120; the levels,
however, varied considerably between tumors. Expression of betaglycan
and p120 in most GCT argues against the hypothesis, but does not exclude
the possibility that low or absent expression of p120 might be
significant in a subset of these tumors.
9
UI - 11762820
AU - Freyer G; Ligneau B; Schlumberger M; Blandy C; Contedevolx B;
TI -
Trillet-Lenoir V; Lenoir GM; Chau N; Dazord A
Quality of life in patients at risk of medullary thyroid carcinoma and
followed by a comprehensive medical network: trends for future
evaluations.
SO - Ann Oncol 2001 Oct;12(10):1461-5
AD - Medical Oncology Unit, Centre Hospitalier Lyon-Sud, and EA 643,
Universite Lyon I, France. Gilles.Freyer@chu-lyon.fr
BACKGROUND: As shown in a previous study, the knowledge of the genetic
risk in individuals belonging to families at risk of medullary-thyroid
carcinoma (MTC) could be associated with impaired quality of life (QoL).
PATIENTS AND METHODS: In the present study, we compared the QoL scores
obtained in the same period with the subjective quality of life profile
(SQLP): in 82 individuals at risk of MTC who had been tested for
Ret-mutations; in 200 women at risk of familial breast/ovarian cancer
syndrome (BOC); and in a control population of 3,501 healthy volunteers.
RESULTS: Significant differences were observed in favour of healthy
volunteers as well as individuals at risk of MTC, over women at risk of
BOC (mean scores: 0.89, 0.85, and 0.64, respectively, P < or = 0.001),
but QoL scores were not statistically different between individuals at
risk of MTC and the control population (P = 0.2). However, they were
significantly inferior in the subgroup of germline Ret-mutation
carriers, as compared to the control population (mean scores: 0.73 and
0.89, P = 0.04). In the latter, the relationships with the children and
the family were the most important facets of their QoL. CONCLUSION: Our
results confirm the potentially negative impact of the knowledge of the
genetic risk of cancer and its consequences in terms of morbidity and
follow-up, on the QoL in people followed at oncogenetic visits.
10
UI - 11899651
AU - Blanchard DK; Hartmann LC
TI -
Prophylactic surgery for women at high risk for breast cancer.
SO - Clin Breast Cancer 2000 Jul;1(2):127-34; discussion 135
AD - Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
Women at high risk for the development of breast cancer have several
options open to them including increased cancer surveillance,
prophylactic mastectomy and/or oophorectomy, and chemoprevention. We
consider high-risk women to be those with known BRCA mutations or a
strong family history characterized by multiple relatives with breast
cancer, early age at diagnosis, and in some families, ovarian cancer. We
present existing data regarding prophylactic surgery for these women.
Essentially, a woman at high risk for breast cancer may choose to
undergo bilateral prophylactic mastectomy, with or without
reconstruction. For patients who have a known breast cancer,
contralateral mastectomy is also an option. Finally, for women in
families with a strong incidence of ovarian cancer, prophylactic
oophorectomy can be considered.
11
UI - 11907939
AU - Pines A
TI -
Management problems. BRCA mutation, prophylactic oophorectomy and HRT.
SO - Climacteric 1998 Dec;1(4):309-10
AD - Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
12
UI - 11920551
AU - Lee SC; Bernhardt BA; Helzlsouer KJ
TI -
Utilization of BRCA1/2 genetic testing in the clinical setting: report
from a single institution.
SO - Cancer 2002 Mar 15;94(6):1876-85
AD - Department of Oncology, Johns Hopkins Medical Institution, Baltimore, MD
21205, USA.
BACKGROUND: Clinical testing for BRCA1/2 has been available since 1996.
Interest in testing in the research and hypothetical situations has been
consistently high, but there have been limited reports on its clinical
utilization. METHODS: This is a retrospective study of BRCA1/2 test
utilization by high-risk patients who were seen at the Johns Hopkins
carrying a BRCA1/2 mutation were offered genetic testing. Of these, 26
testing. Overall, 68 of 258 (26%) underwent genetic testing. Educational
level, number of children or daughters, breast carcinoma screening
behavior, smoking and drinking behavior, perceived risk of breast
carcinoma, and family history was not associated with test utilization.
Eligibility for free testing, prior history of breast or ovarian
carcinoma, Ashkenazi Jewish versus non-Ashkenazi Jewish heritage,
genetic risk category, and age category were associated with test
utilization, and in multivariate analysis, the first three remained
statistically significant factors associated with genetic testing. Only
26% of the 50 patients who did not have access to free testing sought
insurance reimbursement, of which greater than 50% (7 of 13) had a prior
diagnosis of breast or ovarian carcinoma. CONCLUSIONS: The actual
utilization of BRCA1/2 genetic testing in a clinical setting is lower
than in the research and hypothetical settings. Potential obstacles
include cost, fear of insurance discrimination, and need to involve an
affected family member in the testing process. Copyright 2002 American
Cancer Society.
13
UI - 10925628
AU - Apold J; Heimdal K; Moller P
TI -
[Screening for ovarian cancer]
SO - Tidsskr Nor Laegeforen 2000 Jun 20;120(16):1913-4
14
UI - 11006746
AU - Trope C
TI -
[Ovarian cancer screening of high risk groups]
SO - Tidsskr Nor Laegeforen 2000 Aug 10;120(18):2191
15
UI - 11905804
AU - McCormick F
TI -
Cancer gene therapy: fringe or cutting edge?
SO - Nature Rev Cancer 2001 Nov;1(2):130-41
AD - University of California San Francisco, Cancer Research Institute,
94115, USA. mccormick@cc.ucsf.edu
Direct targeting of cancer cells with gene therapy has the potential to
treat cancer on the basis of its molecular characteristics. But although
laboratory results have been extremely encouraging, many practical
obstacles need to be overcome before gene therapy can fulfil its goals
in the clinic. These issues are not trivial, but seem less formidable
than the challenge of killing cancers selectively and rationally--a
challenge that has been successfully addressed.
16
UI - 11263928
AU - Aziz S; Kuperstein G; Rosen B; Cole D; Nedelcu R; McLaughlin J; Narod SA
TI -
A genetic epidemiological study of carcinoma of the fallopian tube.
SO - Gynecol Oncol 2001 Mar;80(3):341-5
AD - Department of Public Health Sciences, University of Toronto, Toronto,
Ontario, Canada.
OBJECTIVE: The goal of this work was to evaluate the importance of
genetic factors in the etiology of fallopian tube cancer. METHODS: All
pathologically confirmed cases of fallopian tube cancer diagnosed in
Ontario from 1990 to 1998 were identified from the records of the
Ontario Cancer Registry. Living patients were approached to provide
information about their family history and to provide a blood sample for
testing for mutations in BRCA1 and BRCA2. RESULTS: A modest increase in
the risk of ovarian cancer (relative risk (RR) = 2.2; 95% confidence
interval (CI) = 0.4, 6.3) and of early-onset breast cancer (RR = 2.4;
95% CI = 0.6, 6.1) was observed in the first-degree relatives of the
fallopian cancer cases. Five of the forty-four cases were positive for a
mutation in BRCA1 (11%) and two were positive for a BRCA2 mutation (5%).
Five of eighteen women diagnosed at or before age 55 were positive
(28%). Two of the seven mutation carriers had a strong family history of
breast and ovarian cancer, and three carriers had a modest family
history. Three of the forty-four cases were Jewish, and of these, two
carried a founder mutation characteristic of this population.
CONCLUSIONS: Fallopian tube carcinoma should be considered to be a
clinical component of the hereditary breast-ovarian cancer syndrome, and
may be associated with BRCA1 and BRCA2 mutations. Genetic evaluation
should be offered to women who present with fallopian tube carcinoma. It
is important to consider the risk of fallopian tube carcinoma when
prophylactic oophorectomy is performed in high-risk women. Copyright
2001 Academic Press.
17
UI - 11458578
AU - Quinn MA
TI -
Screening for ovarian cancer.
SO - Aust Fam Physician 2001 Jun;30(6):530-4
AD - Melbourne University, Victoria. michael.quinn@hcoa.maynick.com.au
BACKGROUND: Ovarian cancer is the leading cause of death from
gynaecological malignancy, with over 800 Australian women dying
annually, primarily because of late presentation of disease. Although a
screening test for this disease is attractive, currently none are
available for use in the general population. Work is underway in
relation to the benefit for women at 'higher risk'. OBJECTIVE: To
provide clear guidelines for screening for ovarian cancer. DISCUSSION:
No single test currently has the sensitivity or specificity to be used
as a population screening test for this disease. Nonetheless, for
patients at 'high risk' the use of Ca125 and transvaginal ultrasound may
be of benefit. Results from three major international multicentre trials
are awaited.
18
UI - 11520162
AU - Klein M; Graf AH; Rosen A; Hacker GW
TI -
Re: Aziz S, et al. A genetic epidemiological study of carcinoma of the
Fallopian tube. Gynecol Oncol 2001;80:341-5.
SO - Gynecol Oncol 2001 Sep;82(3):590
19
UI - 11896095
AU - Frank TS; Deffenbaugh AM; Reid JE; Hulick M; Ward BE; Lingenfelter B;
TI -
Gumpper KL; Scholl T; Tavtigian SV; Pruss DR; Critchfield GC
Clinical characteristics of individuals with germline mutations in BRCA1
and BRCA2: analysis of 10,000 individuals.
SO - J Clin Oncol 2002 Mar 15;20(6):1480-90
AD - Myriad Genetic Laboratories and Myriad Genetics, Inc, Salt Lake City, UT
84108, USA. tfrank@myriad.com
PURPOSE: To assess the characteristics that correlate best with the
presence of mutations in BRCA1 and BRCA2 in individuals tested in a
clinical setting. PATIENTS AND METHODS: The results of 10,000
consecutive gene sequence analyses performed to identify mutations
anywhere in the BRCA1 and BRCA2 genes (7,461 analyses) or for three
specific Ashkenazi Jewish founder mutations (2,539 analyses) were
correlated with personal and family history of cancer, ancestry,
invasive versus noninvasive breast neoplasia, and sex. RESULTS:
Mutations were identified in 1,720 (17.2%) of the 10,000 individuals
tested, including 968 (20%) of 4,843 women with breast cancer and 281
(34%) of 824 with ovarian cancer, and the prevalence of mutations was
correlated with specific features of the personal and family histories
of the individuals tested. Mutations were as prevalent in high-risk
women of African (25 [19%] of 133) and other non-Ashkenazi ancestries as
those of European ancestry (712 [16%] of 4379) and were significantly
less prevalent in women diagnosed before 50 years of age with ductal
carcinoma in situ than with invasive breast cancer (13% v 24%, P
=.0007). Of the 74 mutations identified in individuals of Ashkenazi
ancestry through full sequence analysis of both BRCA1 and BRCA2, 16
(21.6%) were nonfounder mutations, including seven in BRCA1 and nine in
BRCA2. Twenty-one (28%) of 76 men with breast cancer carried mutations,
of which more than one third occurred in BRCA1. CONCLUSION: Specific
features of personal and family history can be used to assess the
likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals
tested in a clinical setting.
20
UI - 11896105
AU - Vasey PA; Shulman LN; Campos S; Davis J; Gore M; Johnston S; Kirn DH;
TI -
O'Neill V; Siddiqui N; Seiden MV; Kaye SB
Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted
adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in
patients with recurrent/refractory epithelial ovarian cancer.
SO - J Clin Oncol 2002 Mar 15;20(6):1562-9
AD - Beatson Oncology Centre and Stobhill Hospital, Glasgow, United Kingdom.
pav1y@clinmed.gla.ac.uk
PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently
associated with mutations in the p53 gene. The adenovirus dl1520
(ONYX-015) with the E1B 55-kd gene deleted, allowing selective
replication in and lysis of p53-deficient tumor cells, has shown
preclinical efficacy against p53-deficient nude mouse-human ovarian
carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I
trial of intraperitoneal dl1520 in patients with recurrent ovarian
cancer. Sixteen women with recurrent/refractory ovarian cancer received
35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5
in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10)
pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common
significant toxicities related to virus administration were flu-like
symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10)
pfu developed common toxicity criteria grade 3 abdominal pain and
diarrhea, which was dose-limiting. The maximum-tolerated dose was not
reached at 10(11) pfu, and at this dose level patients did not
experience significant toxicity. There was no clear-cut evidence of
clinical or radiologic response in any patient. Blood samples were taken
for adenovirus DNA and neutralizing antibodies. Polymerase chain
reaction data indicating presence of virus up to 10 days after the final
(day 5) infusion of dl1520 are suggestive of continuing viral
replication. CONCLUSION: This article therefore describes the first
clinical experience with the intraperitoneal delivery of any
replication-competent/-selective virus in cancer patients.
21
UI - 11896106
AU - Liede A; Karlan BY; Baldwin RL; Platt LD; Kuperstein G; Narod SA
TI -
Cancer incidence in a population of Jewish women at risk of ovarian
cancer.
SO - J Clin Oncol 2002 Mar 15;20(6):1570-7
AD - Centre for Research in Women's Health, Sunnybrook and Women's College
Health Sciences Centre, Toronto, Ontario, Canada.
PURPOSE: To evaluate the incidence and clinical characteristics of
ovarian and other cancers in a cohort of women at risk of developing
ovarian cancer. PATIENTS AND METHODS: The Gilda Radner Ovarian Cancer
Detection Program in Los Angeles, CA, was established in 1991 to study
the efficacy of screening in the early detection of ovarian cancer. We
present findings from a historical cohort of 290 Jewish women who were
offered BRCA testing for three common founder mutations (BRCA1 185delAG
and 5382insC and BRCA2 6174delT). RESULTS: In 10 years, 17 cancers were
observed (1,111 per 100,000 per year), including six breast and eight
ovarian or related cancers. A high proportion of cancers of peritoneal
origin was observed. The majority (86%) of women with incident breast or
ovarian/peritoneal cancer carried a mutation in the BRCA1 gene. The
overall cancer incidence among carriers of mutations in the BRCA1 gene
was estimated to be 5,450 per 100,000 per year, corresponding to a
cumulative incidence of 47.5% at 10 years. In contrast, the cumulative
incidence of cancer among noncarriers was 2.5% (P < 10(-8)). After
adjustment for sampling, the risks to BRCA1 mutation carriers at 10
years were estimated to be 21% for ovarian/peritoneal/tubal cancer, 16%
for breast cancer, and 36% for all cancers. CONCLUSION: The excess risk
of breast and ovarian cancer in Jewish women with a family history of
ovarian cancer is largely attributable to mutations in BRCA1. Intensive
surveillance by use of CA-125 and ultrasound does not seem to be an
effective means of diagnosing early-stage ovarian cancer in this
high-risk cohort.
22
UI - 11377596
AU - Narod SA; Sun P; Ghadirian P; Lynch H; Isaacs C; Garber J; Weber B;
TI -
Karlan B; Fishman D; Rosen B; Tung N; Neuhausen SL
Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2
mutations: a case-control study.
SO - Lancet 2001 May 12;357(9267):1467-70
AD - Centre for Research on Women's Health, University of Toronto, 790 Bay
Street, Room 750, M5G 1N8, Ontario, Canada. steven.narod@swchsc.on.ca
BACKGROUND: In several case-control and prospective studies, tubal
ligation has been associated with a decreased risk of invasive
epithelial ovarian cancer. We aimed to assess the potential of tubal
ligation in reducing the risk of ovarian cancer in women who carry
predisposing mutations in the BRCA1 or BRCA2 genes. METHODS: We did a
matched case-control study among women from Canada, the USA, and the UK
who had undergone genetic testing and who carried a pathogenic mutation
in BRCA1 or BRCA2. Cases were 232 women with a history of invasive
ovarian cancer, and controls were 232 women without ovarian cancer, and
who had both ovaries intact. Cases and controls were matched for year of
birth, country of residence, and mutation (BRCA1 or BRCA2). The odds
ratio for developing ovarian cancer was estimated for tubal ligation,
adjusting for oral contraceptive use, parity, history of breast cancer,
and ethnic group. FINDINGS: In an unadjusted analysis among BRCA1
carriers, significantly fewer cases than controls had ever had tubal
ligation (30 of 173 [18%] vs 60 of 173 [35%], odds ratio 0.37 [95% CI
0.21-0.63]; p=0.0003). After adjustment for oral contraceptive use,
parity, history of breast cancer and ethnic group, the odds ratio was
0.39 (p=0.002). Combination of tubal ligation and past use of an oral
contraceptive was associated with an odds ratio of 0.28 (0.15-0.52). No
protective effect of tubal ligation was seen among carriers of the BRCA2
mutation. INTERPRETATION: Tubal ligation is a feasible option to reduce
the risk of ovarian cancer in women with BRCA1 mutations who have
completed childbearing.
23
UI - 11822988
AU - Peethambaram PP; Long HJ
TI -
Second-line and subsequent therapy for ovarian carcinoma.
SO - Curr Oncol Rep 2002 Mar;4(2):159-64
AD - Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200
1st Street SW, Rochester, MN 55905, USA.
Ovarian carcinoma continues to be the leading cause of death among
gynecologic malignancies. Paclitaxel and platinum chemotherapy is still
the treatment of choice after primary debulking surgery. Salvage
chemotherapy with several single agents has only modest activity and
does not prolong survival of patients with relapsed ovarian carcinoma.
An intense search has been made for novel approaches to treatment of
ovarian cancer, and several new treatments, such as immunotherapy and
gene therapy, show promise. Newer combination chemotherapy regimens and
molecularly targeted therapy need to be developed. High-dose
chemotherapy with autologous stem-cell transplantation appears to
benefit selected groups of patients and is still investigational. Whole
abdominal radiotherapy for relapsed microscopic disease should be
studied in prospective randomized trials. Women with advanced ovarian
carcinoma should continue to be encouraged to participate in
well-designed clinical trials.
24
UI - 11930655
AU - Xu S; Mou H; Lu G; Zhu C; Yang Z; Gao Y; Lou H; Liu X; Cheng Y; Yang W
TI -
Gene expression profile differences in high and low metastatic human
ovarian cancer cell lines by gene chip.
SO - Chin Med J (Engl) 2002 Jan;115(1):36-41
AD - Zhejiang Cancer Research Institute, Hangzhou 310022, China.
xsh1947@LoL365.com
OBJECTIVES: To study the difference between gene expressions of high
(H0-8910PM) and low (HO-8910) metastatic human ovarian carcinoma cell
lines and screen novel associated genes by cDNA microarray. METHODS:
cDNA retro-transcribed from equal quantities of mRNA derived from high
and low metastatic tumor cells or normal ovarian tissues were labeled
with Cy5 and Cy3 fluorescein as probes. The mixed probe was hybridized
with two pieces of BioDoor 4096 double dot human whole gene chip and
scanned with a ScanArray 3000 laser scanner. The acquired image was
analyzed by ImaGene 3.0 software. RESULTS: A total of 355 genes with
expression levels more than 3 times larger were found by comparing the
HO-8910 cell with normal ovarian epithelial cells. A total of 323 genes
with expression levels more than 3 times larger in HO-8910PM cells
compared to normal ovarian epithelium cells were also detected. A total
of 165 genes whose expression levels were more than two times those of
HO-8910PM cells compared to their mother cell line (HO-8910) were
detected. Twenty-one genes with expression levels > 3 times were found
from comparison of these two tumor cell lines. CONCLUSIONS: cDNA
microarray techniques are effective in screening differential gene
expression between two human ovarian cancer cell lines (H0-8910PM;
HO-8910) and normal ovarian epithelial cells. These genes may be related
to the genesis and development of ovarian carcinoma. Analysis of the
human ovarian cancer gene expression profile with cDNA microarray may
help in gene diagnosis, treatment and prevention.
25
UI - 11880951
AU - Puget N; Gad S; Perrin-Vidoz L; Sinilnikova OM; Stoppa-Lyonnet D; Lenoir
TI -
GM; Mazoyer S
Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the
existence of a recombination hot spot.
SO - Am J Hum Genet 2002 Apr;70(4):858-65
AD - Laboratoire de Genetique, Unite Mixte de Recherche 5641 CNRS, Universite
Claude Bernard, 8 avenue Rockefeller, 69373 Lyon cedex 08, France.
The 5' end of the breast and ovarian cancer-susceptibility gene BRCA1
has previously been shown to lie within a duplicated region of
chromosome band 17q21. The duplicated region contains BRCA1 exons 1A,
1B, and 2 and their surrounding introns; as a result, a BRCA1 pseudogene
(PsiBRCA1) lies upstream of BRCA1. However, the sequence of this segment
remained essentially unknown. We needed this information to investigate
at the nucleotide level the germline deletions comprising BRCA1 exons
1A, 1B, and 2, which we had previously identified in two families with
breast and ovarian cancer. We have analyzed the recently deposited
nucleotide sequence of the 1.0-Mb region upstream of BRCA1. We found
that 14 blocks of homology between the tandemly repeated copies
(cumulative length = 11.5 kb) show similarity of 77%-92%. Gaps between
blocks result from insertion or deletion, usually of repetitive
elements. BRCA1 exon 1A and PsiBRCA1 exon 1A are 44.5 kb apart. In the
two families with breast and ovarian cancer mentioned above, distinct
homologous recombination events occurred between intron 2 of BRCA1 and
intron 2 of PsiBRCA1, leading to 37-kb deletions. Breakpoint junctions
were found to be located at close but distinct sites within segments
that are 98% identical. The mutant alleles lack the BRCA1 promoter and
harbor a chimeric gene consisting of PsiBRCA1 exons 1A, 1B, and 2, which
lacks the initiation codon, fused to BRCA1 exons 3-24. Thus, we report a
new mutational mechanism for the BRCA1 gene. The presence of a large
region homologous to BRCA1 on the same chromosome appears to constitute
a hot spot for recombination.
26
UI - 11920643
AU - Montagna M; Agata S; De Nicolo A; Menin C; Sordi G; Chieco-Bianchi L;
TI -
D'Andrea E
Identification of BRCA1 and BRCA2 carriers by allele-specific gene
expression (AGE) analysis.
SO - Int J Cancer 2002 Apr 10;98(5):732-6
AD - Department of Oncology and Surgical Sciences, Oncology Section,
University of Padova, Padova, Italy.
Mutations in BRCA1 and BRCA2 genes confer a high risk of breast and
ovarian cancer. As such, their identification is essential to reduce the
risk of disease in healthy carriers, as well as in carriers who have
already developed the disease because they are at increased risk for a
second malignancy; moreover, noncarriers of BRCA1 and BRCA2 mutated
families can be spared anxiety and unnecessary medical interventions. A
number of problems, including large gene size, complex mutational
spectra and genetic heterogeneity of the disease, however, make genetic
testing labor intensive and often inconclusive. We devised a new
mutation detection strategy called AGE (allele-specific gene expression)
analysis that relies on the detection of a "functional effect" of the
mutation at the RNA level known as "nonsense-mediated RNA decay," thus
avoiding several of the problems of BRCA1 and BRCA2 genetic testing. In
particular, (i) AGE analysis discriminates among the predisposing genes
and identifies mutation carriers with a single RT-PCR reaction; (ii) it
relies on the effect of truncating mutations, which represent the large
majority of cases and thus identifies mutation carriers regardless of
the specific genomic alteration; and (iii) it is specific for
cis-regulatory mutations that are missed at present by most of the
methods. As AGE analysis has the potential to identify most of the BRCA1
and BRCA2 mutation carriers, it can be used as a preliminary screening
method, thereby accelerating and increasing the sensitivity of the
genetic testing process. Notably, other hereditary diseases whose
genetic analysis is hampered by similar problems could benefit from this
kind of approach. Copyright 2002 Wiley-Liss, Inc.
27
UI - 11920644
AU - Yin BW; Dnistrian A; Lloyd KO
TI -
Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene.
SO - Int J Cancer 2002 Apr 10;98(5):737-40
AD - Immunology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Serum assays based on the CA125 antigen are widely used in the
monitoring of patients with ovarian cancer; however very little is known
about the molecular nature of the CA125 antigen. We recently cloned a
partial cDNA (designated MUC16) that codes for a new mucin that is a
strong candidate for being the CA125 antigen. This assignment has now
been confirmed by transfecting a partial MUC16 cDNA into 2
CA125-negative cell lines and demonstrating the synthesis of CA125 by 3
different assays. Of the 3 antibodies (OC125, M11 and VK-8) tested on
the transfected cells, only the first 2 were strongly positive,
indicating the differential expression of the CA125 epitopes in these
cells. The cloning and expression of CA125 antigen opens the way to an
understanding of its function in normal and malignant cells. Copyright
2002 Wiley-Liss, Inc.
28
UI - 8702663
AU - Drummond JT; Anthoney A; Brown R; Modrich P
TI -
Cisplatin and adriamycin resistance are associated with MutLalpha and
mismatch repair deficiency in an ovarian tumor cell line.
SO - J Biol Chem 1996 Aug 16;271(33):19645-8
AD - Howard Hughes Medical Institute and Department of Biochemistry, Duke
University Medical Center, Durham, North Carolina 27710, USA.
In contrast to parental A2780 ovarian tumor cells, extracts of one
doxorubicin-resistant and two independent
cis-diamminedichloroplatinum(II)-resistant derivatives are defective in
strand-specific mismatch repair. The repair defect of the three
hypermutable, drug-resistant cell lines is only evident when the strand
break that directs the reaction is located 3' to the mismatch, and in
each case repair is restored to extracts by addition of purified
MutLalpha heterodimer. As judged by immunological assay, drug resistance
is associated with the virtual absence of the MutLalpha MLH1 subunit and
greatly reduced levels of the PMS2 subunit. These findings implicate a
functional mismatch repair system in the cytotoxic effects of these
antitumor drugs and may have ramifications for their clinical
application.
29
UI - 9062331
AU - Burke W; Petersen G; Lynch P; Botkin J; Daly M; Garber J; Kahn MJ;
TI -
McTiernan A; Offit K; Thomson E; Varricchio C
Recommendations for follow-up care of individuals with an inherited
predisposition to cancer. I. Hereditary nonpolyposis colon cancer.
Cancer Genetics Studies Consortium.
SO - JAMA 1997 Mar 19;277(11):915-9
AD - Department of Medicine, University of Washington, Seattle 98105-6920,
USA.
OBJECTIVE: To provide recommendations for cancer surveillance and risk
reduction for individuals carrying mutations associated with hereditary
nonpolyposis colon cancer (HNPCC). PARTICIPANTS: A task force with
expertise in medical genetics, oncology, primary care, gastroenterology,
and epidemiology convened by the Cancer Genetics Studies Consortium
(CGSC), organized by the National Human Genome Research Institute
(previously the National Center for Human Genome Research). EVIDENCE:
Studies evaluating cancer risk, surveillance, and risk reduction in
individuals genetically susceptible to colon cancer were identified
using MEDLINE and bibliographies of articles thus identified. Indexing
terms used were "genetics" in combination with "colon cancer," and
"screening" in combination with "cancer family" and "HNPCC." For studies
evaluating specific interventions, quality of evidence was assessed
using criteria of the US Preventive Services Task Force. CONSENSUS
PROCESS: The task force developed recommendations through discussions
over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or
other measures to reduce risk in individuals who carry
cancer-predisposing mutations is unknown. Based on observational
studies, colonoscopy every 1 to 3 years starting at age 25 years is
recommended for individuals known to have HNPCC-associated mutations.
Endometrial cancer screening is also recommended, based on expert
opinion concerning presumptive benefit. No recommendation is made for or
against prophylactic surgery (ie, colectomy, hysterectomy); these
surgeries are an option for mutation carriers, but evidence of benefit
is lacking. It is recommended that individuals considering genetic
testing be counseled regarding the unknown efficacy of measures to
reduce risk and that care for individuals with cancer-predisposing
mutations be provided whenever possible within the context of research
protocols designed to evaluate clinical outcomes.
30
UI - 9797804
AU - Sakamoto M; Umayahara K; Sakamoto H; Kawasaki K; Suehiro Y; Kunugi T;
TI -
Akiya T; Iwabuchi H; Sakunaga H; Muroya T; Kikuchi Y; Sugishita T;
Tenjin Y; Gray JW; Tanaka T
[Cancer-associated gene abnormalities and chemosensitivity]
SO - Gan To Kagaku Ryoho 1998 Oct;25(12):1819-31
AD - Dept. of Gynecology, Sasaki Institute Kyoundo Hospital, Tokyo, Japan.
One of the most important clinical issues in cancer chemotherapy is the
presence of intrinsic resistance or the appearance of acquired
resistance against chemotherapy. As for intrinsic resistance, we had to
perform direct chemo-sensitivity testing, or had to rely on the
knowledge empirically acquired from randomized clinical trials. However,
molecular or genetic markers associated with chemo-sensitivity have been
reported recently. For example, inactivation of p53 or GML gene has been
reported to be associated with chemo-resistance. Overexpression of
topo-isomerase I has been reported to be associated with
chemo-sensitivity to Topo I inhibitor. Overexpression of Thymidine
Phosphorylase has been found to be associated with chemo-sensitivity to
prodrug of 5-FU. By checking the status of such chemo-sensitivity
markers prior to chemotherapy, it would be possible to predict the
chemotherapeutic effect and even the necessity of the chemotherapy in
the near future. In this article, we review the chemo-sensitivity
markers reported so far, and methodology contributing to the discovery
of new chemo-sensitivity markers. As a clinical study, 11 cases of
ovarian cancer with high sensitivity to cisplatin-based chemotherapy and
29 cases of ovarian cancer with chemoresistance were analyzed by
Comparative Genomic Hybridization (CGH). Copy number decrease in Xp, and
copy number increase in 19q were observed in 13, 12 out of 29 resistant
cases (45, 41%) and zero, 1 out of 11 sensitive cases (0, 9%),
suggesting that -Xp and +19q were likely to be a genetic event
associated with intrinsic drug-resistance (p = 0.006, 0.05,
respectively). This effort should contribute to the discovery of new
chemo-sensitivity and resistance markers.
31
UI - 9916789
AU - Tlsty TD
TI -
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