Thursday, November 22, 2012
Journal of Ovarian Research - Attributes of Oct4 in stem cell biology: perspectives on cancer stem cells of the ovary
Journal of Ovarian Research Attributes of Oct4 in stem cell biology: perspectives on cancer stem cells of the ovary
Review
Published: 21 November 2012
Abstract (provisional)
Epithelial ovarian cancer (EOC) remains the most lethal of all the gynaecological
malignancies with drug resistance and recurrence remaining the major therapeutic barrier
in the management of the disease. Although several studies have been undertaken to
understand the mechanisms responsible for chemoresistance and subsequent recurrence
in EOC, the exact mechanisms associated with chemoresistance/recurrence continue to
remain elusive. Recent studies have shown that the parallel characteristics commonly
seen between embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC)
are also shared by a relatively rare population of cells within tumors that display
stem cell-like features. These cells, termed 'cancer initiating cells' or 'cancer
stem cells (CSCs)' have been shown not only to display increased self renewal and
pluripotent abilities as seen in ESCs and iPSCs, but are also highly tumorigenic in
in vivo mouse models. Additionally, these CSCs have been implicated in tumor recurrence
and chemoresistance, and when isolated have consistently shown to express the master
pluripotency and embryonic stem cell regulating gene Oct4. This article reviews the
involvement of Oct4 in cancer progression and chemoresistance, with emphasis on ovarian
cancer. Overall, we highlight why ovarian cancer patients, who initially respond to
conventional chemotherapy subsequently relapse with recurrent chemoresistant disease
that is essentially incurable.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
paywalled: Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay
Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay
Abstract
Objective
To
validate the effectiveness of a multivariate index assay in identifying
ovarian malignancy compared to clinical assessment and CA125-II, among
women undergoing surgery for an adnexal mass after enrollment by
non-gynecologic oncology providers.
Methods
A
prospective, multi-institutional trial enrolled female patients
scheduled to undergo surgery for an adnexal mass from 27 non-gynecologic
oncology practices. Pre-operative serum samples and physician
assessment of ovarian cancer risk were correlated with final surgical
pathology.
Results
A
total of 494 subjects were evaluable for multivariate index assay,
CA125-II, and clinical impression. Overall, 92 patients (18.6%) had a
pelvic malignancy. Primary ovarian cancer was diagnosed in 65 patients
(13.2%), with 43.1% having FIGO stage I disease. For all ovarian
malignancies, the sensitivity of the multivariate index assay was 95.7%
(95%CI = 89.3-98.3) when combined with clinical impression. The
multivariate index assay correctly predicted ovarian malignancy in 91.4%
(95%CI = 77.6-97.0) of cases of early-stage disease, compared to 65.7%
(95%CI = 49.2-79.2) for CA125-II. The multivariate index assay correctly
identified 83.3% malignancies missed by clinical impression and 70.8%
cases missed by CA125-II. Multivariate index assay was superior in
predicting the absence of an ovarian malignancy, with a negative
predictive value of 98.1% (95%CI = 95.2-99.2). Both clinical impression
and CA125-II were more accurate at identifying benign disease. The
multivariate index assay correctly predicted benign pathology in 204
patients (50.7%, 95%CI = 45.9-55.6) when combined with clinical
impression.
Conclusion
The
multivariate index assay demonstrated higher sensitivity and negative
predictive value for ovarian malignancy compared to clinical impression
and CA125-II in an intended-use population of non-gynecologic oncology
practices.
Prognostic Factors and Oncological Outcomes after Radical Nephroureterctomy for Upper Tract Urothelial Carcinoma: Review of Contemporary Multi-Center Series
Blogger's Note: there is no specific reference to Lynch Syndrome mutation carriers
~~~~~~~~~~~~~~~~~~~~
Prognostic Factors and Oncological Outcomes after Radical Nephroureterctomy for Upper Tract Urothelial Carcinoma
OJU>Vol.2 No.4, November 2012
Prognostic
Factors and Oncological Outcomes after Radical Nephroureterctomy for
Upper Tract Urothelial Carcinoma: Review of Contemporary Multi-Center
Series
Full Text(PDF,
125KB) PP.246-252 DOI:
10.4236/oju.2012.24045
Author(s)
Open Journal of Urology, 2012, 2, 246-252
doi:10.4236/oju.2012.24045 Published Online November 2012 (http://www.SciRP.org/journal/oju)
www.scirp.org/journal/PaperDownload.aspx?paperID=24540...
File Format: PDF/Adobe Acrobat - www.scirp.org/journal/PaperDownload.aspx?paperID=24540...
1 day ago - Upper tract urothelial carcinoma (UTUC) is rare disease that accounts .... Architecture. Papillary. Sessile. 81. 45. 79. 40. 86. 55. 82. 46. Concomitant CIS. No. Yes ...
Wednesday, November 21, 2012
Tuesday, November 20, 2012
TWO-TIER RADIOLOGY: QUEBEC’S CREEPING PUBLIC-PRIVATE SYSTEM
TWO-TIER RADIOLOGY: QUEBEC’S CREEPINGPUBLIC-PRIVATE SYSTEM
"The report shows (below - recap via email):
“While
it has more material and human resources, Quebec is less effective than
Canada as a whole in providing accessible medical imaging services. The
exclusion from public coverage of CAT scan, MRI and ultrasound tests
performed outside a hospital leads to joint public-private practice that
has the effect of draining resources from the public to the private
sector. This damaging distortion leads to problems of access to medical
imaging for most patients…”
The
report documents the inequitable, inefficient, costly and potentially
unsafe utilization of medical imaging technology in Quebec’s unique and
highly privatized system. One aspect, the relatively effective use of
technology in hospitals compared to private clinics (which would be
better yet if the system were entirely public), is clearly not limited
to Quebec."
ContentsPrivatization is underway: The case of joint public-private practice in radiology...............4
1. A historic achievement, and then a retreat........................................................................5
Medical imaging...............................................................................................................6
2. On the ground: The impact of exclusion from public coverage .......................................8
The exodus of personnel ..................................................................................................8
Wait times: Interminable and inequitable ........................................................................8
Waiting list confusion ......................................................................................................9
Hours wasted by doctors, support personnel and patients................................................9
Tests that aren’t optimal..................................................................................................10
Conflict of interest, marketing….....................................................................................10
… and risks .....................................................................................................................10
Private tests with no quality control ...............................................................................10
3. An overview: Misuse of resources ..................................................................................12
The Quebec exception ....................................................................................................12
Radiology in Quebec : Doing more with less .................................................................15
The public-private gap ....................................................................................................16
Interregional distortions ..................................................................................................17
A distortion that damages the system .............................................................................18
Workers’ compensation: A special case .........................................................................19
4. The lead actors: Medical Imaging Laboratories ..............................................................21
5. What is to be done?: MQRP’s positions and demands..............................................23
6. What others say.................................................................................................................26
Once bitten, twice shy: The false option of joint public-private practice..............................30
(media) Opinion: Scientist fires latest shot in mandatory flu vaccine debate
Blogger's Note: and the debates continue; further information/background/research can be found on the Cochrane Collaboration's website
Opinion: Scientist fires latest shot in mandatory flu vaccine debate
Epigallocatechin Gallate Acts Synergistically in Combination with Cisplatin and Designed trans-palladiums in Ovarian Cancer Cells
Epigallocatechin Gallate Acts Synergistically in Combination with Cisplatin and Designed trans-palladiums in Ovarian Cancer Cells
Abstract
In this study, synergism in activity from
the sequenced combinations of three trans-palladiums (denoted as TH5,
TH6 and TH7)
with green tea polyphenol
(–)-epigallocatechin-3-gallate (EGCG), as well as that with cisplatin,
was investigated in a number
of human ovarian tumour models as a function of
sequence of administration. Cellular accumulation of platinum and
palladium,
and the levels of platinum–DNA and palladium–DNA
binding were also determined for the 0/4 h and 0/0 h sequences of
administration.
The results of the study show that
co-administration of cisplatin with EGCG (0/0 h) produces weak synergism
in both cisplatin-sensitive
(A2780) and cisplatin-resistant (A2780cisR) cell lines whereas (0/4 h) administration produces pronounced synergism in both. In contrast, bolus administration of EGCG
with TH5, TH6 and TH7 produces marked antagonism except that with TH5, in the A2780cisR cell line, where a mild synergism is observed. In the case of TH5, TH6 and TH7, administration of drugs with a time gap (0/4
h or 4/0 h combinations) produces sequence-dependent synergism in both A2780 and A2780cisR
cell lines, whereas in the case of cisplatin, marked antagonism is
observed with the 4/0 h sequence of administration in
the A2780 cell line. Whereas the highly synergistic
0/4 h sequence of combination of cisplatin with EGCG is found to be
associated
with pronounced cellular accumulation of platinum
and a high level of platinum–DNA binding, no such clear trend can be
seen
for any of the combinations of TH5, TH6 and TH7
with EGCG. The results of the present study provide support to the idea
that
sequenced combinations of platinum drugs and
tumour-active palladium compounds with selected phytochemicals such as
EGCG may
provide a means of overcoming drug resistance.
Initial Activation Status of the Antioxidant Response Determines Sensitivity to Carboplatin/Paclitaxel Treatment of Ovarian Cancer
Initial Activation Status of the Antioxidant Response Determines Sensitivity to Carboplatin/Paclitaxel Treatment of Ovarian Cancer
Abstract
Background/Aim: Ovarian carcinoma is the
main cause of gynecological cancer related deaths. The aim of this study
was to determine
the activation status of the antioxidant response
in samples of ovarian serous carcinoma from paraffin-embedded biopsies
and
compare them with the response of patients to
carboplatin-paclitaxel treatment.
Materials and Methods: Estrogen
receptor alpha
(ERα), antioxidant enzymes, and uncoupling protein
(UCP) levels were analyzed by western blotting and the presence of
estrogen
receptor beta (ERβ) was investigated by
immunohistochemistry (IHC).
Results: Lower levels of ERα, antioxidant
enzymes and
UCPs were found in patients resistant to treatment
in comparison to the carboplatin/paclitaxel-sensitive ones; IHC revealed
a greater presence of ERβ in sensitive patients.
Conclusion: These results indicate that patients resistant to treatment
have
a lower level of antioxidant response activation
compared to sensitive patients, fact which may be related to the
efficacy
of this treatment.
Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review, Immunotherapy, Future Medicine
Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review, Immunotherapy, Future Medicine
After
decades of extensive research, epithelial ovarian cancer still remains a
lethal disease. Multiple new studies have reported that the immune
system plays a critical role in the growth and spread of ovarian
carcinoma. This review summarizes the development of dendritic cell (DC)
vaccinations specific for ovarian cancer. So far, DC-based vaccines
have induced effective antitumor responses in animal models, but only
limited results from human clinical trials are available. Although
DC-based immunotherapy has proven to be clinically safe and efficient at
inducing tumor-specific immune responses, its clear role in the therapy
of ovarian cancer still needs to be clarified. The relatively
disappointing low-response rates in early clinical trials point to the
need for the development of more effective and personalized DC-based
anticancer vaccines. This article reviews the basic mechanisms,
limitations and future directions of DC-based anti-ovarian cancer
vaccine development.
Monday, November 19, 2012
The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers
The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers
Abstract
BACKGROUND:
The
objective of this study was to assess the incidence of primary breast
cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2-associated epithelial ovarian cancer (OC).
METHODS:
From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA-associated
OC without a history of unilateral breast cancer (BC) (at risk of PBC; n
= 79) or with a history of unilateral BC (at risk of CBC; n = 37) were
selected. The control groups consisted of unaffected BRCA
mutation carriers (n = 351) or mutation carriers who had a previous
unilateral BC (n = 294), respectively. The risks of PBC and CBC were
calculated using the Kaplan-Meier survival method with death considered
as a competing risk event.
RESULTS:
Women with BRCA-associated
OC had lower 2-year, 5-year, and 10-year risks of PBC (3%, 6%, and 11%,
respectively) compared with unaffected mutation carriers (6%, 16%, and
28%, respectively; P = .03), although they had a considerably
higher mortality rate at similar time points (13%, 33%, and 61%,
respectively, vs 1%, 2%, and 2%, respectively; P < .001). In BRCA
mutation carriers with a previous unilateral BC, the 2-year, 5-year,
and 10-year risks of CBC were nonsignificantly lower in patients with OC
than in those without OC (0%, 7%, and 7%, respectively, vs 6%, 16%, and
34%, respectively; P = .06), whereas the mortality rate was
higher in patients with OC (19%, 34%, and 55%, respectively, vs 4%, 11%,
and 21%, respectively; P < .001).
CONCLUSIONS:
Patients with BRCA-associated
OC had a lower risk of developing a subsequent PBC or CBC than mutation
carriers without OC, whereas the risk of dying from OC was greater than
the risk of developing BC. These data may facilitate more tailored
counseling for this patient subgroup, although confirmative studies are
warranted. Cancer 2012. © 2012 American Cancer Society.
Risk of metachronous breast cancer after BRCA mutation–associated ovarian cancer
Risk of metachronous breast cancer after BRCA mutation–associated ovarian cancer:
Abstract
BACKGROUND:
This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC).
METHODS:
The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up.
RESULTS:
A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively.
CONCLUSIONS:
OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC.
Cancer 2012. © 2012 American Cancer Society.
Cancer 2012. © 2012 American Cancer Society.
Doublet Chemotherapy in the Elderly Patient With Ovarian Cancer
Doublet Chemotherapy in the Elderly Patient With Ovarian Cancer:
The aging of the population has focused on the need to evaluate older patients with cancer. Approximately 50% of patients with ovarian cancer will be older than age 65 years. Increasing age has been associated with decreased survival. It is uncertain whether this relates to biologic factors, treatment factors, or both. There is concern that undertreatment may be associated with decreased survival. Older patients with ovarian cancer have been underrepresented in clinical trials. Therefore, the evidence base on which make decisions is lacking. Clinicians need to be aware of the currently available data to aid in treatment decisions. Doublet therapy is the most common standard treatment in epithelial ovarian cancer. It usually consists of a taxane and a platinum compound. A series of cooperative group studies in both the United States and Europe established intravenous paclitaxel and carboplatin as the most common standard in optimally debulked patients. The recent introduction of intraperitoneal therapy has complicated decision making in terms of which older patients would benefit from this more toxic therapy. In relapsed patients, the issue of platinum sensitivity is critical in deciding whether to reutilize platinum compounds. It is unclear whether single agents or combinations are superior, particularly in older patients. Geriatric assessment is an important component of decision making. Prospective studies are needed to develop strategies to determine the optimal treatment for older patients with ovarian cancer.
Validated Gene Targets Associated with Curatively Treated Advanced Serous Ovarian Carcinoma
Validated Gene Targets Associated with Curatively Treated Advanced Serous Ovarian Carcinoma: Publication year: 2012
Source:Gynecologic Oncology
Objectives
High-grade serous ovarian cancer (HGSOC) mostly presents at an advanced stage and has a low overall survival rate. However, a subgroup of patients are seemingly cured after standard initial therapy. We hypothesize that molecular profiles of these patients vary from long-term survivors who recur.
Methods
Patients with advanced HGSOC who underwent primary cytoreductive surgery and platinum-based chemotherapy were identified from The Cancer Genome Atlas (TCGA) and institutional (MSKCC) samples. A curative-intent group was defined by recurrence-free survival of >5years. A long-term recurrent group was composed of patients who recurred but survived >5years.
RNA was hybridized to Affymetrix U133A transcription microarrays. The NanoString nCounter gene expression system was used for validation in an independent patient population.
Results
In 30 curative and 84 recurrent patients, class comparison identified twice as many differentially expressed probes between the groups than expected by chance alone. TCGA and MSKCC data sets had 19 overlapping genes. Pathway analyses identified over-represented networks that included nuclear factor kappa B (NFkB) transcription and extracellular signal-regulated kinase (ERK) signaling. External validation was performed in an independent population of 28 curative and 38 recurrent patients. Three genes (CYP4B1, CEPT1, CHMP4A) in common between our original datasets remained differentially expressed in the external validation data.
Conclusions
There are distinct transcriptional elements in HGSOC from patients likely to be cured by standard primary therapy. Three genes have withstood rigorous validation and are plausible targets for further study, which may provide insight into molecular features associated with long-term survival and chemotherapy resistance mechanisms.
Highlights
► Tumors from long-term, disease-free ovarian cancer survivors have a unique gene expression profile.► Long-term, disease-free ovarian cancer survivors provide insight into the mechanisms of acquired drug resistance.
Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells
Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells
Highlights
►
Navitoclax and other BH3 mimetics have previously shown synergy with
chemotherapeutic agents
► Where antagonism between carboplatin and/or paclitaxel was observed, this was reduced by the inclusion of navitoclax.
► Navitoclax improves the activity of carboplatin and/or paclitaxel in Igrov-1 spheroids.
► Where antagonism between carboplatin and/or paclitaxel was observed, this was reduced by the inclusion of navitoclax.
► Navitoclax improves the activity of carboplatin and/or paclitaxel in Igrov-1 spheroids.
Evolving concepts in the management of drug resistant ovarian cancer: Dose dense chemotherapy and the reversal of clinical platinum resistance
Evolving concepts in the management of drug resistant ovarian cancer: Dose dense chemotherapy and the reversal of clinical platinum resistance: Publication year: 2013
Source: Cancer Treatment Reviews, Volume 39, Issue 2
Despite the initially high response rate to standard front-line debulking surgery followed by platinum-based chemotherapy, the relapse rate in ovarian cancer is high and many patients will recur within 6months of completing platinum based treatment. These patients may still require further chemotherapy despite being considered “platinum resistant”. In this setting, response rates to conventionally scheduled second line platinum and non-platinum agents is low, ranging between 5% and 15%. There is an emerging body of evidence that in this scenario, chemotherapeutic activity can be enhanced using unconventionally scheduled “dose-dense” platinum and non-platinum based regimens with improved response rates of up to 65%. Randomised studies to evaluate the impact of this approach on survival in recurrent, platinum resistant disease are urgently required to confirm the promising phase II findings if there is to be a change in the standard of care of patients with platinum resistant disease. In this review we discuss the evolving strategies to overcome resistance in patients with platinum resistant ovarian cancer with a particular focus on alterations in dose schedule as a means of reversing platinum resistance.
Sunday, November 18, 2012
Does tumour biology determine surgical success in the treatment of epithelial ovarian cancer? A systematic literature review
Does tumour biology determine surgical success in the treatment of epithelial ovarian cancer? A systematic literature review
Full text not available from this repository.
Abstract
BACKGROUND:
Ovarian cancer is the most lethal gynaecological cancer. Progression-
free and overall survival is significantly related to surgical success
and residual disease volume. It is unclear whether this survival
advantage is due to an intrinsic biological element of the tumour cells
which enables successful surgery and improved prognosis, or
alternatively the number of tumour sustaining cells remaining
irrespective of differences in biology.
METHODS: A systematic review of
the literature was performed identifying studies that have investigated
the association between biomarkers and surgical outcomes. We attempted
validation of these results using The Cancer Genome Atlas ovarian cancer
data sets.
RESULTS: Thirty studies were identified of which sixteen
determined protein expression, eight gene expression and one DNA
methylation in association with surgical debulking. Individualised
linear models adjusting for batch, stage and age identified only
expression of the genes MTDH and insulin-like growth factor-1 receptor
(IGFIR) to be significantly associated with debulking surgery (P <
0.05, false discovery rate (FDR) < 5%), although in the case of IGFIR
this was in the opposite direction to previous findings.
CONCLUSION:
The majority of studies are limited by design, include heterogeneous
samples and lack adjustment for major confounding factors. High quality
detailed clinical annotations should be routinely collected in future to
more accurately evaluate biomarkers of surgical outcome.
British
Journal of Cancer (2012) 107, 1069-1074. doi:10.1038/bjc.2012.376
www.bjcancer.com Published online 30 August 2012 (c) 2012 Cancer
Research UK
Toxicities, complications, and clinical encounters during intraperitoneal chemotherapy in 17 women with ovarian cancer
Toxicities, complications, and clinical encounters during intraperitoneal chemotherapy in 17 women with ovarian cancer
Conclusions
Treatment-related
toxicities and complications were common in women with ovarian cancer
who received IP chemotherapy. Use of IP chemotherapy results in multiple
clinical encounters, such as outpatient clinic visits and inpatient
admissions. Nursing is a critical part of the interdisciplinary approach
in caring for women treated with IP chemotherapy. Interdisciplinary
teams with high levels of knowledge and skills related to IP
chemotherapy administration are needed to manage treatment-related
toxicities and complications, and support multiple clinical encounters
during treatment.
Uncertainty in the Utility of Immunohistochemistry in Mismatch Repair Protein Expression in Epithelial Ovarian Cancer
Uncertainty in the Utility of Immunohistochemistry in Mismatch Repair Protein Expression in Epithelial Ovarian Cancer
Abstract
Background: Utility of
immunohistochemistry (IHC) for mismatch repair (MMR) protein expression
has been demonstrated in colorectal
cancer but remains incompletely defined in ovarian
cancer. We evaluated MMR protein expression in three population-based
samples
of epithelial ovarian cancers. Materials and
Methods: IHC staining was performed on full-section (FS) or tissue
microarray
(TMA) slides for MLH1, MSH2, and MSH6 expression.
Results: Out of 487 cases, 147 and 340 were performed through FS and
TMA,
respectively. Overall, Loss of Expression (LoE) of
at least one MMR protein was observed in 12.7% based on an expression
score
of ≤3 (on a scale of 9). Notably, LoE was
significantly higher in TMAs (17.9%) compared to FS cases (0.7%)
(p<0.001). Conclusion:
A substantial proportion of epithelial ovarian
cancers have a loss of MMR protein expression. Protein expression
results vary
significantly by the tissue sampling methodology
utilized, raising concerns about the clinical utility of this test for
ovarian
tumors.
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