Table of Contents
1
UI - 11551094
AU - Lindor NM; Dechet CB; Greene MH; Jenkins RB; Zincke MT; Weaver AL;
TI -
Wilson M; Zincke H; Liu W
Papillary renal cell carcinoma: analysis of germline mutations in the
MET proto-oncogene in a clinic-based population.
SO - Genet Test 2001 Summer;5(2):101-6
AD - Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA.
nlindor@mayo.edu
Approximately 10% of all renal cell carcinomas (RCCs) present a
distinctive papillary histology. Familial papillary RCC (PRCC) has been
described, but the majority of cases appear to be sporadic. Recently,
germline mutations in the MET proto-oncogene on chromosome 7 have been
identified in families with hereditary PRCC. We evaluated 59 patients
with PRCC for the frequency of MET germline mutations to determine the
value of genetic screening of this patient population. Between 1976 and
1997, 165 patients were identified with PRCC by retrospective chart
review. Fifty-nine of 133 surviving patients agreed to provide a family
history, a blood specimen, and informed consent for genetic research.
DNA was isolated from peripheral blood leukocytes. Denaturing
high-performance liquid chromatography (DHPLC) followed by genomic
sequencing was performed on eight exons of the MET proto-oncogene,
including exons 5-7 of the extracellular domain, exon 14, and exons
16-19 of the tyrosine kinase domain. The 59 patients in this study
included 49 men and 10 women with a mean age at diagnosis of 61 years.
Bilateral and/or multifocal disease was present in 13 cases (22%). No
germline mutations were detected in the studied exons of the MET
proto-oncogene (exons previously reported to contain deleterious
mutations in familial PRCC). No pathological MET proto-oncogene germline
mutations were identified in 59 patients with PRCC. The germline
mutation rate in this clinic-based population of individuals with PRCC
approaches 0% (CI = 0-6.18). MET proto-oncogene germline mutation
screening does not appear to be clinically indicated in patients with
PRCC without additional evidence for a genetic predisposition (positive
family history, unusual age at onset, bilateral disease).
2
UI - 11377295
AU - Parsons JK; Schoenberg MS; Carter HB
TI -
Incidental renal tumors: casting doubt on the efficacy of early
intervention.
SO - Urology 2001 Jun;57(6):1013-5
3
UI - 11840338
AU - Caldwell MC; Hough C; Furer S; Linehan WM; Morin PJ; Gorospe M
TI -
Serial analysis of gene expression in renal carcinoma cells reveals
VHL-dependent sensitivity to TNFalpha cytotoxicity.
SO - Oncogene 2002 Jan 31;21(6):929-36
AD - Laboratory of Cellular and Molecular Biology, National Institute on
Aging-IRP, National Institutes of Health, 5600 Nathan Shock Drive,
Baltimore, MD 21224, USA.
We have used serial analysis of gene expression (SAGE) to investigate
the influence of the von Hippel-Lindau (VHL) gene on global gene
expression profiles. SAGE libraries were prepared from renal cell
carcinoma (RCC) lines that either lack (parental) or express wild-type
VHL (wtVHL). Comparison of these libraries revealed some differentially
expressed genes (Glut-1, for example) that were known to be influenced
by VHL, but the majority of genes had not previously been reported to be
affected by the cell's VHL status. The identification of several genes
involved in TNFalpha-mediated events prompted us to compare the
sensitivity of cells with different VHL status in TNFalpha cytotoxicity
assays. Strikingly, VHL-deficient cells were much more resistant to the
toxic influence of TNFalpha. We propose that VHL-dependent sensitization
of RCC cells to TNFalpha-mediated killing may contribute to VHL's growth
suppressive function.
4
UI - 11830554
AU - Angelo LS; Talpaz M; Kurzrock R
TI -
Autocrine interleukin-6 production in renal cell carcinoma: evidence for
the involvement of p53.
SO - Cancer Res 2002 Feb 1;62(3):932-40
AD - Department of Bioimmunotherapy, The University of Texas M. D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Interleukin (IL)-6 is an autocrine growth factor for renal cell
carcinoma (RCC). We sought to determine whether p53 regulates
constitutive IL-6 production. RCC cell lines containing mutant (mut) p53
produced higher levels of IL-6 than those containing wild-type (wt) p53
(P < 0.05). Transfection of wt p53 into RCC cell lines bearing mut p53
(UOK 121LN) or wt p53 (A498 and ACHN) resulted in repression of IL-6
promoter chloramphenicol acetyltransferase activity (P < 0.05). Mutant
p53 was either less effective at repressing IL-6 promoter activity (ACHN
cells) or enhanced IL-6 promoter activity (A498 cells). A498 cells
stably transfected with mut p53 produced higher levels of IL-6 than A498
cells transfected with an empty expression vector (P < 0.05).
Electrophoretic mobility shift assays showed decreased binding of CAAT
enhancer binding protein, cyclic AMP responsive element binding protein,
+/- nuclear factor-kappaB transcription factors to the IL-6 promoter in
various RCC cell lines transfected with wt p53 (P < 0.05) but not in
those transfected with mut p53. These data suggest that: (a) mutation of
p53 contributes to the overexpression of IL-6 in RCC; and (b) wt p53
represses IL-6 expression, at least in part, by interfering with
specific transcription factor binding to the IL-6 promoter.
5
UI - 11642604
AU - Childs RW
TI -
Nonmyeloablative blood stem cell transplantation as adoptive allogeneic
immunotherapy for metastatic renal cell carcinoma.
SO - Crit Rev Immunol 2001;21(1-3):191-203
AD - National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, MD, USA. childsr@nih.gov
Allogeneic stem cell transplantation has emerged as a potentially
curative form of immunotherapy for patients with hematological
malignancies that are resistant to conventional chemo/radiotherapy.
Donor T cell populations targeting allogeneic minor histocompatibility
antigens expressed on the patient's malignant cells are felt to be the
driving force of the graft-versus-leukemia reaction, although to date
only a handful of these antigens have been fully characterized. Recent
data from experimental animal models and limited clinical data in humans
suggest that graft-versus-tumor effects, analogous to the
graft-versus-leukemia reaction, may be generated against malignancies of
epithelial origin. This article reviews the results of a pilot trial
demonstrating graft-versus-renal cell carcinoma effects following
nonmyeloablative stem cell transplantation, highlighting the potential
of allogeneic immunotherapy for treating cancer.
6
UI - 11750847
AU - Mizutani Y; Nakanishi H; Yoshida O; Fukushima M; Bonavida B; Miki T
TI -
Potentiation of the sensitivity of renal cell carcinoma cells to
TRAIL-mediated apoptosis by subtoxic concentrations of 5-fluorouracil.
SO - Eur J Cancer 2002 Jan;38(1):167-76
AD - Department of Urology, Kyoto Prefectural University of Medicine, Kyoto
602-8566, Japan. ymizutan@koto.kpu-m.ac.jp
Cytotoxic chemotherapy has shown little antitumour activity against
renal cell carcinoma (RCC). Although immunotherapy is relatively
effective against RCC, the response rate is approximately 20%.
Therefore, there is an urgent need to increase this response rate.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L)
is one member of the tumour necrosis factor ligand family that
selectively induces apoptosis of cancer cells. Since several cytotoxic
anticancer drugs including 5-fluorouracil (5-FU) also mediate apoptosis,
we reasoned that combined treatment of cancer cells with TRAIL and drugs
might result in synergy and overcome the resistance of the cancer cell.
This study has examined whether TRAIL can synergise with 5-FU in both
cytotoxic and apoptotic assays against drug-resistant RCC cells.
Cytotoxicity was determined by an 1-day microculture tetrazolium dye
assay. Synergy was assessed by isobolographic analysis. Treatment of
Caki-1 cells with TRAIL in combination with 5-FU resulted in a
synergistic cytotoxic effect. Synergy was also achieved in freshly
derived RCC cells from 3 patients. The enhanced cytotoxicity was
obtained irrespective of the sequence of the treatment, but the highest
cytotoxicity was observed when Caki-1 cells were treated with TRAIL and
5-FU simultaneously. The synergy achieved in cytotoxicity with TRAIL and
5-FU was shown to be due to apoptosis. The mechanisms responsible for
the synergistic cytotoxicity and apoptosis were examined. Treatment of
Caki-1 cells with 5-FU enhanced the expression of p53 and bax, but had
no effect on the expression of bcl-2. Incubation of Caki-1 cells with
TRAIL enhanced the intracellular accumulation of 5-FU and
5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). Treatment of Caki-1
cells with TRAIL downregulated the expression of thymidylate synthase
(TS) and dihydropyrimidine dehydrogenase (DPD) modestly, and upregulated
the expression of orotate phosphoribosyltransferase (OPRT). However, the
expression level of thymidine phosphorylase (TP) was not affected by
TRAIL. This study demonstrates that combined treatment of RCC cells with
TRAIL and 5-FU overcomes their resistance. The sensitisation obtained
with freshly isolated RCC cells required low subtoxic concentrations of
5-FU. These findings support the potential application in vivo of a
combination of TRAIL and 5-FU in the treatment of TRAIL/5-FU-resistant
RCC.
7
UI - 11857297
AU - Delahunt B; Kittelson JM; McCredie MR; Reeve AE; Stewart JH; Bilous AM
TI -
Prognostic importance of tumor size for localized conventional (clear
cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories
and comparison with other prognostic parameters.
SO - Cancer 2002 Feb 1;94(3):658-64
AD - Department of Pathology, Wellington School of Medicine, University of
Otago, Wellington, New Zealand. bd@wnmeds.ac.nz
BACKGROUND: The T1 and T2 classifications of the International Union
Against Cancer TNM classification system for renal cell carcinoma are
based on primary tumor size, and in various editions of the
classification, the cut points between T1 and T2 have been amended to
provide clinical utility. In the current edition, the T1/T2 cut point is
less than or equal to and greater than 7 cm. and more recently a
subdivision of the T1 classification (less than or equal to and < 4 cm)
has been proposed to identify patients suitable for partial nephrectomy.
This study investigates the prognostic significance of tumor size in a
series of organ-confined clear cell renal cell carcinomas. METHODS: One
hundred thirty cases of organ-confined clear cell renal cell carcinomas,
with a minimum of 5 years' follow-up, were identified from the New South
Wales Cancer Registry. Tumor size was compared with survival using the
method of Kaplan and Meier for TNM size categories, and proportional
hazards regression was used for assessing size as a continuous variable.
Proportional hazards regression also was used for multivariable
comparisons of size and other prognostic parameters (Fuhrman grade,
AgNOR score, and Ki-67 index) against survival. RESULTS: Of 116 cases
for which tumor dimension was recorded, 25 patients had died of
cancer-related causes. Primary tumor size ranged from 12 to 140 mm
(mean, 57.3 mm). The association between survival and size was
significant irrespective of the TNM classification and was also
significant when size was modeled continuously (P = 0.000125, hazard of
death increased by 3.51 times for each doubling of tumor size). On
univariate analysis, Fuhrman grade (P = 0.04) and AgNOR score (P =
0.015) were associated with survival; however, on multivariate analysis
only tumor size retained significance. CONCLUSIONS: Although the cut
point of T1 and T2 TNM categories and the proposed T1 subdivision cut
point correlate with survival, our finding that size is a continuous
variable indicates that as a prognostic parameter for clear cell renal
cell carcinoma, primary tumor size is relative rather than indicative.
Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10255
8
UI - 11147860
AU - Jackson RJ; Loh SC; Gokaslan ZL
TI -
Metastatic renal cell carcinoma of the spine: surgical treatment and
results.
SO - J Neurosurg 2001 Jan;94(1 Suppl):18-24
AD - Department of Neurosurgery, Baylor College of Medicine, The University
of Texas MD Anderson Cancer Center, Houston 77030, USA.
OBJECT: Renal cell carcinoma (RCC) is an aggressive malignancy that
frequently metastasizes. When RCC metastasizes to the spine, significant
pain and neurological dysfunction often follow. Because systemic therapy
and radiotherapy have a limited effect in controlling spinal disease,
surgery is frequently required; however, there are very few published
series specifically addressing the role and benefits of the surgical
treatment for this disease. The authors conducted a retrospective study
to review their experience with the surgical treatment of metastatic RCC
of the spine, paying particular attention to methodology and patient
neurological status, pain relief, and survival. METHODS: Between January
age 55 years, range 16-82 years) underwent 107 spinal operations for
metastatic RCC. Indications for surgery included disabling pain (94
[88%] of 107 procedures) and/or neurological dysfunction (55 [51%] of
107 procedures). The anatomical location and extent of tumor determined
the choice of an anterior, posterior, or combined surgical approach.
Internal fixation was performed in all but three patients. Preoperative
embolization was required in approximately one half of the patients.
Radiotherapy was performed in 40 patients prior to surgery, and immuno-
and chemotherapy were administered in 70 patients either pre- or
postoperatively. After an average follow-up duration of 15 months, 57
patients had died. Kaplan-Meier analysis revealed a median postoperative
survival of 12.3 months. Significant pain reduction, as indicated by a
visual analog pain scale, was achieved in 84 (89%) of the 94 cases
presenting with disabling pain. Neurological improvement was seen in 36
(65%) of the 55 patients. The major morbidity and 30-day mortality rates
were 15% (16 of 107 procedures) and 2% (two of 107 procedures),
respectively. CONCLUSIONS: In selected patients with metastatic RCC of
the spine, resection followed by stabilization can provide pain relief
and neurological preservation or improvement.
9
UI - 11808143
AU - Takayama T; Fujita K
TI -
[Renal carcinoma]
SO - Nippon Rinsho 2001 Nov;59 Suppl 7():373-8
AD - Department of Urology, Hamamatsu University School of Medicine.
10
UI - 11850836
AU - Vortmeyer AO; Huang SC; Pack SD; Koch CA; Lubensky IA; Oldfield EH;
TI -
Zhuang Z
Somatic point mutation of the wild-type allele detected in tumors of
patients with VHL germline deletion.
SO - Oncogene 2002 Feb 14;21(8):1167-70
AD - Molecular Pathogenesis Unit, Surgical Neurology Branch, National
Institute of Neurological Disorders and Stroke, Building 10, Room 5D37,
Bethesda, MD 20892, USA.
The majority of patients with Von Hippel-Lindau (VHL) disease are
affected by a VHL germline mutation involving one copy of the VHL gene.
Loss of heterozygosity of the second VHL allele can be consistently
demonstrated in tumor tissue from these patients, suggesting that
allelic deletion is a very early or even initiating event for
tumorigenesis. Approximately 20% of VHL disease patients, however,
exhibit germline deletion of one entire copy or at least a substantial
part of the VHL gene. To investigate the nature of the "second genetic
hit" in this patient population, we analysed two renal cell carcinomas
and one CNS hemangioblastoma from three unrelated patients for genetic
changes of the second copy of the VHL gene. All three tumors showed
retention of one VHL allele by FISH. Single-strand conformation
polymorphism and mutation analysis of microdissected tumor DNA revealed
somatic point mutations of the wild-type VHL copies in each of the three
tumors. The results indicate that the "two hit model" is equally
applicable to patients with VHL germline mutation and VHL germline
deletion. In contrast to tumors from patients with VHL germline
mutation, however, point mutations of the wild-type allele can be
detected in tumors from patients with VHL germline deletion.
11
UI - 11793370
AU - Schraml P; Struckmann K; Hatz F; Sonnet S; Kully C; Gasser T; Sauter G;
TI -
Mihatsch MJ; Moch H
VHL mutations and their correlation with tumour cell proliferation,
microvessel density, and patient prognosis in clear cell renal cell
carcinoma.
SO - J Pathol 2002 Feb;196(2):186-93
AD - Institute of Pathology, University of Basel, Schonbeinstrasse 40,
CH-4031 Basel, Switzerland. Peter.Schraml@unibas.ch
Mutations of the von Hippel-Lindau (VHL) gene are considered critical
for the initiation of clear cell renal cell carcinoma. The VHL protein
is involved in regulation of the cell cycle and neo-vascularization. In
this study, the association of VHL mutations with tumour cell
proliferation, angiogenesis, and clinical outcome was analysed in 113
clear cell renal cell carcinomas. The degree of angiogenesis and tumour
cell proliferation was immunohistochemically determined by counting
microvessels (microvessel density, anti-CD34 antibody) and cells with
proliferating activity (Ki-67 labelling index, MIB-1 antibody).
Forty-eight different VHL sequence alterations were found in 38 of 113
patients (34%) by direct sequencing. Nineteen VHL mutations were
frameshifts and nonsense mutations, predicted to change the open reading
frame of VHL. These 'loss-of-function' mutations correlated with worse
prognosis in univariate analysis (p=0.02). Tumour grade, stage,
microvessel density, and tumour cell proliferation were not associated
with VHL alterations. These findings may indicate that
'loss-of-function' VHL mutations are involved in the progression of a
clear cell renal cell carcinoma subset, whereas regulation of
angiogenesis and proliferation of renal carcinoma in vivo is apparently
not directly influenced by VHL alterations. Copyright 2001 John Wiley &
Sons, Ltd.
12
UI - 11561691
AU - Berg WJ; Schwartz L; Yu R; Mazumdar M; Motzer RJ
TI -
Phase II trial of irofulven (6-hydroxymethylacylfulvene) for patients
with advanced renal cell carcinoma.
SO - Invest New Drugs 2001;19(4):317-20
AD - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New
York, NY 10021, USA.
The aim of this study was to determine the antitumor activity of
irofulven (6-hydroxymethylacylfulvene) in patients with advanced renal
cell carcinoma (RCC). Eligible patients had advanced renal cell
carcinoma with bidimensionally measurable disease, a Karnofsky
performance status of at least 70, life expectancy of greater than three
months, no prior treatment with chemotherapy, and no evidence of brain
metastases. Irofulven was administered at a dose of 11 mg/m2 by 5-min
intravenous infusion, on 5 consecutive days. Cycles were repeated every
28 days. Thirteen patients were enrolled in this study and 12 were
evaluable for response. Of the twelve evaluable patients, no major
responses were achieved. Eight patients had stable disease as best
response. Toxicity included myelosuppression and gastrointestinal side
effects. At the dose and schedule used in this trial, irofulven did not
produce clinical response in RCC.
13
UI - 11561693
AU - Kuebler JP; King GW; Triozzi P; Moore T; Kraut EH
TI -
Phase II study of pyrazoloacridine in metastatic renal cell carcinoma.
SO - Invest New Drugs 2001;19(4):327-8
AD - Grant/Riverside Hospital, Columbus, OH, USA.
14
UI - 11769879
AU - Moyad MA
TI -
Obesity, interrelated mechanisms, and exposures and kidney cancer.
SO - Semin Urol Oncol 2001 Nov;19(4):270-9
AD - Department of Surgery, University of Michigan Medical Center, Ann Arbor
48109-0330, USA.
Obesity has been shown to increase the risk or be associated with
numerous conditions from cardiovascular disease and type II diabetes to
erectile dysfunction and osteoarthritis. Obesity may also be associated
with numerous cancers, and kidney cancer or renal-cell cancer (RCC) may
have one of the strongest correlations to obesity compared with cancer
at any other site. Almost every epidemiologic investigation has
demonstrated an association that tends to affect women more than men,
but both genders are impacted. In general, past studies suggest that
with increasing weight, a threshold point exists whereby a certain range
of body mass index dramatically changes risk. Men and women at the most
extreme ends of obesity tend to have the highest risk or only risk in
past studies. Individuals at the more extreme ends of obesity may be
affected by an almost indefinite number of mechanisms and exposures that
could determine incidence and possibly prognosis. For example, higher
estrogen levels, elevated insulin levels, a greater concentration of
growth factors in adipose tissue, hypertension, cholesterol metabolism
abnormalities, and immune malfunction are just some of the potential
mechanisms that may increase kidney cancer risk. Obese individuals may
also have lower serum levels of vitamin D and engage in less physical
activity. Smoking or genetic predisposition to RCC may synergistically
contribute to the effect of obesity on risk. The potential mechanisms
and associations are numerous and complex. Regardless of the actual
cancer risk now and in the future, the overall effect of obesity on
general health is clear, and this should be kept in mind in the
discussion between health professional and patient.
15
UI - 11769880
AU - Moyad MA
TI -
Review of potential risk factors for kidney (renal cell) cancer.
SO - Semin Urol Oncol 2001 Nov;19(4):280-93
AD - Department of Surgery, University of Michigan Medical Center, Ann Arbor
48109-0330, USA.
Renal cell cancer (RCC) is responsible for a small percentage of total
cancer cases and deaths throughout the world, but the incidence rates of
RCC have been steadily increasing over the past decade, whereas numerous
other cancers have stabilized or even decreased in number. Even in
countries that were observed to have a lower incidence of this disease
many are now experiencing large increases in the rates of this cancer.
Most kidney cancers are RCC, and blacks are currently experiencing RCC
rates that are higher than any other race. Older individuals are also at
a higher risk compared with young individuals, but this observation may
also be changing. The reasons for these potential increases are not
understood beyond the partial impact and greater use of newer diagnostic
procedures. Other reasons for higher rates of RCC and a better
understanding of which individuals may be at the highest risk need to be
examined to provide the clinician with possible clues as to who should
be tested and what prevention measures should be offered. Most of the
past investigations into risk factors have been case-control or
retrospective studies, but some generalizations can still be made.
Family history and genetics seem to increase risk, but overall are
responsible for a small number of the total cases. Smoking, obesity, and
even hypertension seem to be risk factors for RCC. Reducing these
behaviors and conditions may also reduce the risk of RCC. Healthier
eating habits (fruits and vegetables, and a lower caloric intake) and
more physical activity may also reduce the risk of RCC. Therefore, it is
possible that the increases in RCC may also be due, in part, to
unhealthy lifestyle factors that have been on the increase over the past
several decades. Recommendations for cardiovascular disease prevention
should also be applied to patients or clinicians concerned about RCC
risk. Finally, numerous occupations, occupational exposures,
reproductive and hormonal changes or manipulations, and a variety of
other factors may impact risk, but overall their contribution seems
small compared with other more consistent risk factors.
16
UI - 11826016
AU - Takahashi M; Kahnoski R; Gross D; Nicol D; Teh BT
TI -
Familial adult renal neoplasia.
SO - J Med Genet 2002 Jan;39(1):1-5
AD - Laboratory of Cancer Genetics, Van Andel Research Institute, Grand
Rapids, MI 49503, USA.
Our understanding of the molecular mechanisms underlying the
tumorigenesis of renal cell carcinoma (RCC) has partially come from
studies of RCC related familial cancer syndromes such as von
Hippel-Lindau (VHL) disease and hereditary papillary RCC (HPRC). These
studies have led to the identification of RCC related genes, which,
besides allowing accurate diagnosis of these diseases, have been found
mutated or abnormally expressed in the sporadic counterparts of these
familial renal tumours. To date, a number of renal tumour related
syndromes have been described. We review recent advances in this field
and discuss a genetic approach to managing familial cases of renal
tumours occasionally encountered by cancer geneticists and urologists.
17
UI - 11848468
AU - Scheltema JM; Romijn JC; van Steenbrugge GJ; Schroder FH; Mickisch GH
TI -
Inhibition of apoptotic proteins causes multidrug resistance in renal
carcinoma cells.
SO - Anticancer Res 2001 Sep-Oct;21(5):3161-6
AD - Department of Urology, Erasmus University and Academic Hospital,
Rotterdam, The Netherlands.
Renal Cell Carcinomas (RCCs) exhibit strong resistance to the most
chemotherapeutic treatments probably due to the expression of various
multidrug resistance (MDR) genes. Overexpression of P-glycoprotein (Pgp)
is established as one such factor, but other mechanisms such as at-MDR,
characterized by attenuated DNA-topoisomerase II (topoII) activity, may
be functional as well. In addition, regulating proteins involved in
apoptosis can exhibit multidrug resistant features. However, prevention
of apoptosis as a mechanism of MDR has not yet been assessed in RCC, nor
has the cytotoxicity of a variety of chemotherapeutic agents known to
trigger apoptotic or necrotic cell death been tested in RCC in a
systematic fashion. Using immunohistochemistry and Western blotting,
Bcl-2 and Bax expression was determined in a panel of multidrug
resistant RCC lines featuring Pgp and/or at-MDR. The results were
related to apoptotic activity and kind of cell death in these cell
lines, demonstrated by incubation with Hoechst 33342 and propidium
iodide after treatment with various cytotoxic agents and quantitated by
MTT. In the drug resistant sublines, some decreased Bax and strongly
increased Bcl-2 expression was seen by immunohistochemistry indicating
prevention of apoptosis as a distinct feature of MDR in RCC. This was
confirmed by Western blotting. Sublines revealed significant resistance
for all drugs, except for CC-313 and DiMIQ. However, these drugs induced
necrotic cell death, in contrast to all other drugs tested, which
induced apoptotic cell death. We conclude that, in chemoselected RCC
sublines, multidrug resistance appears to be functional due to
inhibition of apoptosis, apart from the MDR1 and at-MDR resistance
mechanisms. CC-313 and DiMIQ are very potent cytotoxic agents in RCC,
probably because they do not kill by induction of apoptosis.
18
UI - 11848472
AU - Koga F; Arai K; Kamai T; Abe H; Yoshida K
TI -
Fas labeling status does not correlate with apoptosis of renal cell
carcinoma in vivo.
SO - Anticancer Res 2001 Sep-Oct;21(5):3193-7
AD - Department of Urology, Dokkyo University School of Medicine,
Shimotsuga-gun, Tochigi, Japan. f-koga@wine.plala.or.jp
BACKGROUND: Contribution of the Fas system to apoptosis of renal cell
carcinoma (RCC) was investigated in vivo. MATERIALS AND METHODS: Tissues
from 30 RCC cases were immunostained for Fas and Fas ligand (FasL) to
assess associations between Fas labeling status of RCC, indices of
FasL-positive tumor-infiltrating mononuclear cells (FasL-TIM) and
apoptotic indices (AI) of RCC. RESULTS: In all cases, tumor cells
co-expressed Fas and FasL; strongly and diffusely in 13 cases (43%) and
weakly in 17 (57%). Despite the constitutive co-expression of Fas and
FasL, AI was low in most cases (median, 7 per 1,000 tumor cells; range,
1 to 257). The Fas labeling status did not significantly associate with
AI while FasL-TIM index positively correlated with AI. CONCLUSION: These
results suggest that the Fas system is not the principal mechanism of
apoptosis of RCC while activated tumor-infiltrating mononuclear cells
induce apoptosis via mechanisms other than the Fas system.
19
UI - 11848517
AU - Ramp U; Mahotka C; Kalinski T; Ebel E; Gabbert HE; Gerharz CD
TI -
Topotecan (Hycamtin) responsiveness in human renal carcinoma cell lines
of the clear cell and papillary types.
SO - Anticancer Res 2001 Sep-Oct;21(5):3509-17
AD - Institute of Pathology, Heinrich Heine University, Duesseldorf, Germany.
BACKGROUND: Since no effective therapeutic approach is yet known for
metastatic renal cell carcinoma (RCC), we analyzed the effects of
topotecan (Hycamtin), a novel topoisomerase I-inhibitor, in RCC cell
lines of the clear cell and papillary/chromophilic types. MATERIALS AND
METHODS: The anti-proliferative and apoptosis-inducing effects of
topotecan were analyzed in 20 RCC cell lines by MTT-assay and light
microscopic apoptosis counting. Moreover, Bcl-2 and Bax expression was
investigated by Northern blot and immunocytochemistry while the p53
mutation status was analyzed by DNA sequencing. RESULTS: Exposure to
clinically relevant concentrations of topotecan (i.e. < or = 1
microg/ml) resulted in a significant (p<0.05) dose-dependent reduction
of cell number in 17 out of 20 RCC cell lines. The reduction of cell
number was paralleled by an increase in apoptotic cell death.
Papillary/chromophilic RCCs exhibited a significantly (p<0.05) more
pronounced responsiveness to topotecan than clear cell RCCs. Moreover,
the effects of topotecan proved to be superior to those of
5-fluorouracil (5-FU), an anticancer drug currently used in the therapy
of RCCs. No correlation became evident between responsiveness to
topotecan and the expression levels of Bcl-2 and Bax. Moreover, the
response to topotecan could not be correlated with the p53 mutation
status of our RCC cell lines. CONCLUSION: Clinically relevant
concentrations of topotecan induced apoptosis in RCC cell lines more
effectively than 5-FU. Further testing will show whether
topotecan-induced apoptosis can be exploited for the treatment of RCCs
in vivo as well.
20
UI - 11867357
AU - Parker AS; Cerhan JR; Lynch CF; Ershow AG; Cantor KP
TI -
Gender, alcohol consumption, and renal cell carcinoma.
SO - Am J Epidemiol 2002 Mar 1;155(5):455-62
AD - Department of Health Sciences Research, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, USA. parker.alexander@mayo.edu
The nature of the association between alcohol consumption and renal cell
carcinoma (RCC) is not well understood, but there are indications of
effect modification by gender. The authors report data from a
population-based case-control study conducted in Iowa from 1986 to 1989.
RCC cases (261 men and 145 women) were identified through the Iowa
Cancer Registry, while controls (1,598 men and 831 women) were randomly
selected from the general population, frequency matched on age and
gender. Subjects provided detailed information on a mailed questionnaire
regarding demographic, anthropometric, lifestyle, dietary, and medical
history risk factors. In age-adjusted analysis, there was a decrease in
risk for women who reported consuming more than three servings (median
among drinkers) of alcohol per week (odds ratio = 0.5, 95% confidence
interval: 0.2, 0.9) compared with never drinkers. No evidence of an
association among men was noted (odds ratio = 1.1, 95% confidence
interval: 0.8, 1.5). Multivariate adjustment for anthropometric,
lifestyle, smoking, and dietary factors did not alter the findings.
Analysis by type of alcohol suggested that the inverse association was
strongest for beer consumption, but estimates were imprecise. These
findings suggest an inverse association of alcohol consumption and RCC
development among women but not among men.
21
UI - 11870503
AU - Hotakainen K; Ljungberg B; Paju A; Rasmuson T; Alfthan H; Stenman UH
TI -
The free beta-subunit of human chorionic gonadotropin as a prognostic
factor in renal cell carcinoma.
SO - Br J Cancer 2002 Jan 21;86(2):185-9
AD - Department of Clinical Chemistry, Helsinki University Central Hospital,
Biomedicum Helsinki, Rm A418a Haartmaninkatu 8, FIN-00029, Helsinki,
Finland. kristina.hotakainen@hus.fi
The free beta-subunit of human chorionic gonadotropin beta is expressed
in several nontrophoblastic tumours and this is usually associated with
aggressive disease. Little is known about human chorionic gonadotropin
beta expression in renal cancer. We determined the pretreatment levels
of human chorionic gonadotropin beta in serum of patients with renal
cell carcinoma, and studied whether elevated levels predicted the
clinical outcome. Serum samples were collected before surgery from 177
patients with renal cell carcinoma and from 84 apparently healthy
controls. Human chorionic gonadotropin beta in serum was measured by a
highly sensitive time-resolved immunofluorometric assay. The prognostic
value of human chorionic gonadotropin beta, and of usual clinical and
pathological variables was analyzed by the Kaplan-Meier method, the log
rank test and Cox multiple hazard regression. The serum concentrations
of human chorionic gonadotropin beta were increased in 23% of the renal
cell carcinoma patients and they were significantly higher in patients
with renal cell carcinoma than in controls (P<0.0001). The
concentrations did not correlate with clinical stage and
histopathological grade, but patients with increased human chorionic
gonadotropin beta levels had significantly shorter survival time than
those with levels below the median (cut-off 1.2 pmol l(-1), P=0.0029).
In multivariate analysis human chorionic gonadotropin beta, tumour stage
and grade were independent prognostic variables. The serum concentration
of human chorionic gonadotropin beta is an independent prognostic
variable in renal cell carcinoma. The preoperative value of human
chorionic gonadotropin beta in serum may be used to identify patents
with increased risk of progressive disease. Copyright 2002 The Cancer
Research Campaign
22
UI - 11849150
AU - Bromwich E; Aitchison M
TI -
How should patients be followed up after radical nephrectomy for renal
cell cancer?
SO - BJU Int 2002 Jan;89(1):1-4
AD - Department of Urology, Gartnavel General Hospital, Glasgow, UK.
emma.bromwich@virgin.net
23
UI - 11849151
AU - Latif Z; Watters AD; Bartlett JM; Underwood MA; Aitchison M
TI -
Gene amplification and overexpression of HER2 in renal cell carcinoma.
SO - BJU Int 2002 Jan;89(1):5-9
AD - Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK.
zaklatif@hotmail.com
OBJECTIVE: To determine the frequency of HER2 genetic abnormalities in
renal cell carcinoma (RCC) and hence assess the potential suitability of
Herceptin immunotherapy. PATIENTS AND METHODS: Tumours from 27 patients
with RCC were assessed; all patients had undergone nephrectomy. Benign
renal tissue from the nephrectomy specimens was studied in seven
patients. Gene amplification was assessed using fluorescent in-situ
hybridization, and protein over-expression using immunohistochemistry.
RESULTS: Twenty-four patients had clear cell renal carcinoma, two had
papillary renal carcinoma and one a sarcomatoid variant carcinoma. There
was no HER2 amplification in the tumours or the benign renal tissue.
Polysomy 17 was detected in 11 of 27 tumours (41%) and increased HER2
copy number in seven (26%). Both polysomy 17 and increased HER2 copy
number were absent in the benign renal tissue. Three tumours (11%) and
six of the seven benign renal tissue samples over-expressed the HER2
protein. CONCLUSIONS: HER2 amplification is absent and protein
over-expression uncommon in RCC. This casts doubt on the suitability of
Herceptin in the treatment of RCC.
24
UI - 11111187
AU - Nonomura N; Ono Y; Nozawa M; Fukui T; Harada Y; Nishimura K; Takaha N;
TI -
Takahara S; Okuyama A
Bacillus Calmette-Guerin perfusion therapy for the treatment of
transitional cell carcinoma in situ of the upper urinary tract.
SO - Eur Urol 2000 Dec;38(6):701-4;discussion 705
AD - Department of Urology, Osaka University Medical School, Suita City,
Osaka, Japan. nono@uro.med.osaka-u.ac.jp
OBJECTIVES: The aim of this study is to evaluate the efficacy and safety
of intrarenal bacillus Calmette-Guerin (BCG) instillation as a treatment
for transitional cell carcinoma in situ (CIS) of the upper urinary
tract. METHODS: Diagnostic criteria of upper urinary tract CIS were (1)
positive urinary cytology, (2) negative multiple random biopsy of the
bladder and prostatic urethra, (3) negative radiographic findings in the
upper urinary tract and (4) two serial positive cytologies in selective
ipsilateral urine sampling from the pyeloureteral system. Eleven
patients diagnosed as having upper urinary tract CIS were enrolled in
this study. Thus, 11 renal units were treated with BCG instillation.
After placing a 6-french Double-J stent, BCG (80 mg) in 40 ml saline was
instilled into the bladder weekly, 6 times in total as one course.
RESULTS: At the end of one course, 9 cases showed negative urinary
cytology. Among these 9 cases, 2 showed recurrence in the upper urinary
tract after 4 months and 8 months of disease-free interval,
respectively. These 2 cases have received an additional course of BCG
instillation, but the urinary cytology did not normalize. Mean
recurrence-free time was 19.6 months. Of the other 7 cases who responded
to the first course of instillation, 6 cases were alive with no evidence
of the disease. The remaining patient died of rectal cancer with no
evidence of transitional cell carcinoma (TCC). Of the 2 cases who showed
positive urinary cytology even after the first course, 1 underwent
nephroureterectomy. The other case was diagnosed as having malignant
lymphoma 3 months after the end of this instillation therapy, and he
died of malignant lymphoma. As side effects, 8 cases (72.7%) showed
bladder irritability, and 4 presented fever higher than 38 degrees C.
However, no patient needed antitubercular treatment. CONCLUSION: As for
the short-term response, BCG instillation for the treatment of upper
urinary tract CIS is considered to be effective and safe. Longer
follow-up and further experience with this treatment are required.
25
UI - 11700888
AU - Mai KT; Landry DC; Robertson SJ; Commons AS; Burns BF; Thijssen A;
TI -
Collins J
A comparative study of metastatic renal cell carcinoma with correlation
to subtype and primary tumor.
SO - Pathol Res Pract 2001;197(10):671-5
AD - Department of Laboratory Medicine, The Ottawa Hospital, Ontario, Canada.
ktmai@ottawahospital.on.ca
Clear cell (CRCC), papillary (PRCC) and chromophobe (CHRC) renal cell
carcinoma (RCC) are the three most frequent subtypes of RCC. The rate
and distribution of their metastatic lesions have not been well
documented. We compared metastatic RCC according to subtype and primary
tumor characteristics to better understand their behavior and to aid in
the diagnosis of metastatic RCC. Pathology reports and clinical charts
related to 283 CRCC, 48 PRCC and 13 CHRCC, including their respective
sarcomatoid variants, were reviewed. A hundred and thirty-seven CRCC, 5
PRCC and 1 CHRCC with metastases were identified. CRCC and non-CRCC
(PRCC and CHRCC) had different patterns of metastasis and primary tumor
growth. CRCC metastases were predominantly distributed in lungs, bone,
brain, lymph nodes, and adrenal glands. The associated primary CRCC
measured 1.5 to 15 cm, were of all grades and stages, and were often
associated with invasion of small or large veins. Three PRCC had
regional lymph node metastases, 1 PRCC had both regional and mediastinal
lymph node metastases. Bone metastasis was present in 1 case each of
PRCC and CHRCC. One PRCC with metastasis solely to regional nodes
measured 4 cm. The other 4 cases of PRCC with regional lymph node and/or
distant metastases as well as the CHRCC with distant metastases were
greater than 8 cm in diameter. In metastasizing and non-metastasizing
non-CRCC, invasion of small veins was rare and invasion of renal veins
was not seen. We cannot comment with any certainty on the metastatic
behavior of CHRCC. In our experience, PRCC tend to loco-regional
invasion with lymph node spread. They have a low potential for vascular
invasion and distant metastases that likely occur only at late stages of
the disease. CRCC has a propensity for vascular invasion and may be
associated with distant metastasis at an early stage. Therefore,
metastatic RCC at a distant location are most likely to be of CRCC
origin than PRCC origin.
26
UI - 11773466
AU - Mothes H; Heidet L; Arrondel C; Richter KK; Thiele M; Patzer L; Sado Y;
TI -
Gubler MC; Antignac C; Scheele J
Alport syndrome associated with diffuse leiomyomatosis: COL4A5-COL4A6
deletion associated with a mild form of Alport nephropathy.
SO - Nephrol Dial Transplant 2002 Jan;17(1):70-4
AD - Department of General and Visceral Surgery,
Friedrich-Schiller-University Jena, Bachstrasse 18, D-07740 Jena,
Germany. Henning.mothes@med.uni-jena.de
BACKGROUND: The X-linked Alport syndrome (AS) is an inherited
nephropathy due to mutations in the COL4A5 gene, encoding the alpha5
chain of type IV collagen, a major component of the glomerular basement
membrane (GBM). Here, we report a new kindred with the rare association
of X-linked AS and diffuse leiomyomatosis (DL), which is a tumourous
process involving smooth muscle cells of the oesophagus, the
tracheobronchial tree and, in females, the genital tract. For this
syndrome, an almost constant association of large COL4A5 rearrangements
with a severe juvenile form of nephropathy has been described for male
patients. METHODS: DNA rearrangement at the COL4A5-COL4A6 locus was
studied in several members of this family using polymerase chain
reaction and pulsed field gel electrophoresis. Furthermore,
immunohistochemical staining of tumour and skin samples was performed.
RESULTS: The affected patients in this family carry a 120 kb deletion by
which the COL4A5 exon 1 and COL4A6 exons 1, 1', and 2 are removed.
Immunohistochemical investigation of a skin biopsy of an affected male
patient confirmed the absence of both the alpha5 and the alpha6 chains
of type IV collagen in the basement membrane of the skin. Surprisingly,
both affected male patients had a rather mild renal phenotype.
CONCLUSIONS: This report shows that, contrary to what has been reported
to date, patients suffering from AS associated with DL can be associated
with a late onset renal failure (adult) form of nephropathy.
27
UI - 11847024
AU - Ravaud A; Bay JO
TI -
[Update on renal cell carcinoma]
SO - Bull Cancer 2002 Jan;89(1):31-6
AD - Institut Bergonie, Centre regional de lutte contre le cancer, 229, cours
de l'Argonne, 33076 Bordeaux Cedex. ravaud@bergonie.org
Authors have selected and presented radiofrequency tissue ablation for
primary renal tumors and cellular therapy with dendritic cells or
nonmyeloablative allogeneic transplantation as the main results in
2000-2001 on renal cell carcinoma. Furthermore other points are
developed as hypertension increasing the risk of renal cell carcinoma,
chromosomal events until renal cell carcinoma and prognosis of
incidentally detected tumors.
28
UI - 11693562
AU - Weinstein MH; Dal Cin P
TI -
Genetics of epithelial tumors of the renal parenchyma in adults and
renal cell carcinoma in children.
SO - Anal Quant Cytol Histol 2001 Oct;23(5):362-72
AD - Department of Pathology, Brigham and Women's Hospital and Harvard
Medical School, Boston, Massachusetts 02115, USA.
mhweinstein@partners.org
The classification of renal cell carcinomas has been affected by both
the delineation of new histologic subtypes and the understanding that
recognized histomorphologic patterns are reflective of specific sets of
cytogenetic abnormalities. In fact, standard methods of
clinicopathologic study and cytogenetic analysis have been cooperatively
contributory in the evolution of current concepts regarding the biologic
nature and classification of renal parenchymal epithelial tumors. In
this review, the current classification scheme for these tumors is
discussed from the perspective of both the defining histologic and
cytogenetic features. Limited molecular data are described as well.
29
UI - 11880070
AU - Mejean A; Chretien Y; Vogt B; Cazin S; Balian C; Thiounn N; Dufour B
TI -
Coloepiploic mobilization during left radical nephrectomy for renal cell
carcinoma is indicated to reduce the risk of iatrogenic splenectomy.
SO - Urology 2002 Mar;59(3):358-61
AD - Department of Urology, Hopital Necker, Paris, France.
OBJECTIVES: To determine whether coloepiploic mobilization (CEM) is
indicated to reduce the incidence of iatrogenic splenectomy during left
radical nephrectomy for renal cell carcinoma. The incidence of
iatrogenic splenectomy during a left nephrectomy is estimated to be
between 1.4% and 24%. In a recent study, we reported that the incidence
of iatrogenic splenectomy was 8% during a left nephrectomy performed for
renal cell carcinoma through a transperitoneal anterior subcostal
incision. METHODS: A left radical nephrectomy was performed in 233
consecutive patients for renal cell carcinoma through a transperitoneal
anterior subcostal incision with a CEM procedure in which the left
colonic flexure was completely detached from the epiploa. Perioperative
and postoperative complications, including splenic injury, were noted in
a database. The mean patient age was 51.3 years (range 21.3 to 90.2).
The mean tumor size was 58 mm (range 15 to 230). RESULTS: An iatrogenic
splenectomy was required in 3 patients, and in 1 patient, a splenic
injury was treated conservatively. The incidence of iatrogenic
splenectomy accompanying left radical nephrectomy was 1.3%. The mean
operative time was 120 minutes (range 80 to 240). The mean time to
normal gut motility was 3.4 days (range 2 to 11) and to discharge from
the hospital it was 9.3 days (range 6 to 19). Regarding CEM, we did not
observe any significant abdominal complications. CONCLUSIONS: The
incidence of iatrogenic splenectomy during a left radical nephrectomy
through a transperitoneal anterior subcostal incision may be reduced by
performing the technique of CEM.
30
UI - 11888084
AU - Witte D; Truong LD; Ramzy I
TI -
Transitional cell carcinoma of the renal pelvis the diagnostic role of
pelvic washings.
SO - Am J Clin Pathol 2002 Mar;117(3):444-50
AD - Department of Pathology, Baylor College of Medicine and the Methodist
Hospital, Houston, TX 77030, USA.
One hundred renal pelvic washings were reviewed blindly for 12 cytologic
features. Of 52 washings with tissue confirmation, the cytologic
diagnosis
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