Tuesday, October 09, 2012
PLOS ONE: An RNA Interference Lethality Screen of the Human Druggable Genome to Identify Molecular Vulnerabilities in Epithelial Ovarian Cancer
PLOS ONE: An RNA Interference Lethality Screen of the Human Druggable Genome to Identify Molecular Vulnerabilities in Epithelial Ovarian Cancer
"... It is now well established that both oncogenic and non-oncogenic addictions contribute to the extensively rewired pathways that underlie the malignant phenotype in cancer cells. [55] We have concentrated on genes which have activities across multiple ovarian cancer cell lines representing primarily the serous subtype. Future studies which expand our screening panel to include additional cell lines which represent other EOC subtypes (clear cell, endometrioid, and mucinous) should provide us with subtype related/specific sensitization patterns that can further be explored. In addition, we will need to establish if any or all of the validated targets have oncogenic properties, the efficacy of targeting these candidates in vivo, and whether targeting these candidates exhibits “genotype dependent lethality” [55] that exploits the enhanced sensitivity of cancer cells to DNA damage. As we continue to move towards better treatments for ovarian cancer patients, it will be essential to clearly define critical and functional nodes whose perturbation will lead to cancer cell lethality......
Ovarian Cancer: Future of PARP Inhibitor Olaparib Still Uncertain in Platinum-Sensitive Serous Disease
Ovarian Cancer: Future of PARP Inhibitor Olaparib Still Uncertain in platinum-sensitive disease
"....Median overall survival reported here at the Society of
Gynecologic Oncology's Annual Meeting on Women's Cancer was 29.7 months
for olaparib and 29.9 for placebo.
Because of this, the drug's manufacturer is not moving forward with a Phase III trial in this disease...."
British Journal of Cancer - Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer
British Journal of Cancer - Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer
Conclusion:
We show for the first time that FGF1 is differentially expressed in high-grade serous ovarian tumours, and that individuality in FGF1 expression significantly influences progression-free survival and response to platinum-based chemotherapy.
Evolution of Cancer-Related Symptoms Ov - PubMed Mobile
Evolution of Cancer-Related Symptoms Over an 18-Month Period.
Abstract
CONTEXT: Previous studies have revealed inconsistent findings about the longitudinal evolution of cancer-related symptoms. In addition, the contribution of medical factors (e.g., cancer site, and treatments) in explaining the changes in these symptoms is yet to be established.
OBJECTIVES: This prospective study investigated longitudinal changes of five symptoms (i.e., depression, anxiety, insomnia, fatigue, and pain) in patients scheduled to undergo surgery for cancer (N=828).
METHODS: The patients completed the Hospital Anxiety and Depression Scale, the Insomnia Severity Index, the Multidimensional Fatigue Inventory, and a pain questionnaire at baseline and after 2, 6, 10, 14 and 18 months.
RESULTS: Several time changes were statistically significant but effect sizes only revealed one change of a medium magnitude, that is, a reduction of anxiety from T1 to T2 (d=-0.58). Women with breast or gynecological cancer were the only subgroups to exhibit significant changes (i.e., reduction of a small magnitude of anxiety symptoms from T1 to T2; ds=-0.27 and -0.30, respectively). However, numerous differences were found across adjuvant treatments, including greater variations in depression and insomnia scores in the chemotherapy group (ds=-0.71 to 0.20) and a transient increase in fatigue symptoms in patients receiving "all" adjuvant treatments (ds=-0.24 to 0.37).
CONCLUSION: The severity of cancer-related symptoms varies during the cancer care trajectory, especially anxiety scores, which importantly reduce during the first few months after the surgery. This study also suggests that treatment regimens better account for individual differences than cancer site in the evolution of symptoms.
Monday, October 08, 2012
Value of Tertiary Cytoreductive Surgery in Epithelial Ovarian Cancer: An International Multicenter Evaluation
Value of Tertiary Cytoreductive Surgery in Epithelial Ovarian Cancer: An International Multicenter Evaluation
Abstract
Results
We evaluated 406 patients (median age, 55 years; range, 16–80 years). Median time from first to second recurrence was 18 months
(2–204 months). Median follow-up from TCS was 14 months (0–182 months), and median OS was 26 months (95 % CI, 19.62–32.38 months).
Median OS for patients without versus any tumor residuals was 49 months (95 % CI, 42.5–56.4 months) versus 12 months (95 %
CI 9.3–14.7 months) (p < 0.001). The majority of the patients had an advanced initial FIGO stage III/IV (69 %), peritoneal carcinomatosis (51.7 %),
and absence of ascites (72.2 %). A total of 224 patients (54.1 %) underwent complete tumor resection. The most frequent tumor
dissemination site was the pelvis (73 %). Rates of major operative morbidity and 30-day mortality were 25.9 % and 3.2 %, respectively.
Multivariate analysis identified platinum resistance, tumor residuals at secondary surgery, and peritoneal carcinomatosis
to be of predictive significance for complete tumor resection, while tumor residuals at secondary and tertiary surgery, decreasing
interval to second relapse, ascites, upper abdominal tumor involvement, and nonplatinum third-line chemotherapy significantly
affected OS.
(2–204 months). Median follow-up from TCS was 14 months (0–182 months), and median OS was 26 months (95 % CI, 19.62–32.38 months).
Median OS for patients without versus any tumor residuals was 49 months (95 % CI, 42.5–56.4 months) versus 12 months (95 %
CI 9.3–14.7 months) (p < 0.001). The majority of the patients had an advanced initial FIGO stage III/IV (69 %), peritoneal carcinomatosis (51.7 %),
and absence of ascites (72.2 %). A total of 224 patients (54.1 %) underwent complete tumor resection. The most frequent tumor
dissemination site was the pelvis (73 %). Rates of major operative morbidity and 30-day mortality were 25.9 % and 3.2 %, respectively.
Multivariate analysis identified platinum resistance, tumor residuals at secondary surgery, and peritoneal carcinomatosis
to be of predictive significance for complete tumor resection, while tumor residuals at secondary and tertiary surgery, decreasing
interval to second relapse, ascites, upper abdominal tumor involvement, and nonplatinum third-line chemotherapy significantly
affected OS.
Is MRI a useful tool to distinguish between serous and mucinous borderline ovarian tumours?
Is MRI a useful tool to distinguish between serous and mucinous borderline ovarian tumours?
Publication year: 2012Source:Clinical Radiology
Aim To analyse the morphological magnetic resonance imaging (MRI) features of borderline ovarian tumours (BOT) and to evaluate whether MRI can be used to distinguish serous from mucinous subtypes. Materials and methods A retrospective study of 72 patients who underwent BOT resection was undertaken. MRI images were reviewed blindly by two radiologists to assess MRI features: size, tumour type, grouped and irregular thickened septa, number of septa, loculi of different signal intensity, vegetations, solid portion, signal intensity of vegetations, normal ovarian parenchyma, and pelvic ascites. Statistical analysis was performed using Mann–Whitney and Fisher's exact tests. Logistic regression analysis was used to assess the predictive value of the MRI findings for histological subtypes.
Results At histology, there were 33 serous BOT (SBOT) and 39 mucinous BOT (MBOT). Predictive MRI criteria for SBOT were bilaterality, predominantly solid tumour, and the presence of vegetations, especially exophytic or with a high T2 signal (p < 0.01), whereas predictive MRI criteria for MBOT were multilocularity, number of septa, loculi of different signal intensity, and grouped and irregular thickened septa (p < 0.01). Using multivariate analysis, vegetations were independently associated with SBOT [odds ratio (OR) = 29.5] and multilocularity with MBOT (OR = 3.9).
Conclusion Vegetations and multilocularity are two independent MRI features that can help to distinguish between SBOT and MBOT.
A case of small cell carcinoma of the ovary hypercalcemic variant in a teenager
A case of small cell carcinoma of the ovary hypercalcemic variant in a teenager
Publication year: 2012Source:Gynecologic Oncology Case Reports, Volume 2, Issue 4
Arvind Bakhru, J. Rebecca Liu, Amir Lagstein
Highlights
► Young women with hypercalcemic type small cell ovarian cancer face a poor prognosis. ► Tumors respond to multi-agent chemotherapy, although rapid recurrence is typical. ► Using updated immunohistochemical staining patterns, this tumor can be identified.Sent from my iPhone
Friday, October 05, 2012
'Talking the talk or walking the walk?'
'Talking the talk or walking the walk?' A bibliometric review of the literature on public involvement in health research published between 1995 and 2009.
http://www.ncbi.nlm.nih.gov/m/pubmed/23033933/Sent from my iPhone
Waiting for all the facts
Waiting for all the facts
"I'm just going to wait until all the facts are in..."
All the facts are never in. We don't have all the facts on the sinking of the Titanic, on the efficacy of social media or on whether dogs make good house pets. We don't have all the facts on hybrid tomatoes, global warming or the demise of the industrial age, either.
The real question isn't whether you have all the facts. The real question is, "do I know enough to make a useful decision?" (and no decision is still a decision).
If you don't, then the follow up question is, "What would I need to know, what fact would I need to see, before I take action?"
If you can't answer that, then you're not actually waiting for all the facts to come in.
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Thursday, October 04, 2012
Phase I trial of overlapping long peptides from a tumor self-antigen and Poly-ICLC shows rapid induction of integrated immune response in ovarian
Phase I trial of overlapping long peptides from a tumor self-antigen and Poly-ICLC shows rapid induction of integrated immune response in ovarian
Abstract
PURPOSE: Long peptides are efficiently presented to both CD4+ and CD8+ T-cells after intracellular processing by antigen presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. Experimental design: Twenty-eight advanced ovarian cancer patients in second or third remission were enrolled sequentially in 3 cohorts and received at least one vaccination. Patients in Cohort 1 (n=4) received 1.0 mg OLP, Cohort 2 (n=13) received OLP in Montanide-ISA-51, and Cohort 3 (n=11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, tetramer staining).
RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8+ T-cells were undetectable after vaccination with OLP alone, but found in 6/13 (46%) and 8/13 (62%) patients respectively after vaccination with OLP+Montanide, and in 10/11 (91%) and 10/11 (91%) patients respectively after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4+ T-cells were detected in all patients, with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as adjuvant further accelerated induction of NY-ESO-1-specific immune responses.
CONCLUSIONS: The current study demonstrates that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants.
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Reoperation combining re-cytoreductive surgery and re-HIPEC for recurrent peritoneal carcinomatosis.
Reoperation combining re-cytoreductive surgery and re-HIPEC for recurrent peritoneal carcinomatosis.
Abstract
Purpose: Cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the proper treatment for resectable peritoneal carcinomatosis (PC). The aim of this study was to evaluate the postoperative course and long-term outcome of repeat CS (reCS) plus repeat HIPEC (reHIPEC) in patients with recurrent disease, after primary CS plus primary HIPEC. Methods: From 2004 to 2012 85 patients were subjected to primary CS + HIPEC. Fourteen of those patients developed recurrent PC and were subjected to reCS+reHIPEC during the same time period. Eligibility criteria included limited extent of the peritoneal disease, and interval of more than 12 months from the primary CS+HIPEC. The origins of the tumors were ovarian cancer (n=7) colorectal cancer (n=3), pseudomyxoma peritonei (n=3), and uterine sarcoma (n=1). Results: At second laparotomy, mean peritoneal cancer index (PCI) was 5.3 + 2.8. Among the 14 procedures, HIPEC was used in all patients. The postoperative mortality was 0% and grade 3-4 postoperative complications occurred in 4 patients. The overall 1-, 2- and 3- year overall survival rate was 90, 40 and 30%, respectively. Conclusion: ReCS+reHIPEC is feasible and yields an accepted survival in highly selected patients.
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Reoperation combining re-cytoreductive - PubMed Mobile
Reoperation combining re-cytoreductive surgery and re-HIPEC for recurrent peritoneal carcinomatosis.
Abstract
Purpose: Cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the proper treatment for resectable peritoneal carcinomatosis (PC). The aim of this study was to evaluate the postoperative course and long-term outcome of repeat CS (reCS) plus repeat HIPEC (reHIPEC) in patients with recurrent disease, after primary CS plus primary HIPEC. Methods: From 2004 to 2012 85 patients were subjected to primary CS + HIPEC. Fourteen of those patients developed recurrent PC and were subjected to reCS+reHIPEC during the same time period. Eligibility criteria included limited extent of the peritoneal disease, and interval of more than 12 months from the primary CS+HIPEC. The origins of the tumors were ovarian cancer (n=7) colorectal cancer (n=3), pseudomyxoma peritonei (n=3), and uterine sarcoma (n=1). Results: At second laparotomy, mean peritoneal cancer index (PCI) was 5.3 + 2.8. Among the 14 procedures, HIPEC was used in all patients. The postoperative mortality was 0% and grade 3-4 postoperative complications occurred in 4 patients. The overall 1-, 2- and 3- year overall survival rate was 90, 40 and 30%, respectively. Conclusion: ReCS+reHIPEC is feasible and yields an accepted survival in highly selected patients.
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Irrelevance of microsatellite instability in pancreatic cancer
CONCLUSIONS:
MSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers.
http://www.ncbi.nlm.nih.gov/m/pubmed/23029359/?i=1&from=lynch%20syndrome
DNA repair gene variants in relation to - PubMed Mobile
DNA repair gene variants in relation to overall cancer risk: A population-based study.
Abstract
The hypothesis that germ-line polymorphisms in DNA repair genes influence cancer risk has previously been tested primarily on a cancer site-specific basis. The purpose of this study was to test the hypothesis that DNA repair gene allelic variants contribute to globally elevated cancer risk by measuring associations with risk of all cancers that occurred within a population-based cohort. In the CLUE II cohort study established in 1989 in Washington County, MD, the present study was comprised of all 3,619 cancer cases ascertained through 2007 compared to a sample of 2,296 with no cancer. Associations were measured between 759 DNA repair gene single nucleotide polymorphisms (SNPs) and risk of all cancers. A SNP in O6-methylguanine-DNA methyltransferase, MGMT, (rs2296675) was significantly associated with overall cancer risk (per minor allele odds ratio (OR) 1.30, 95% Confidence Interval (CI) 1.19-1.43, p-value 4.1x10-8). The association between rs2296675 and cancer risk was stronger among those <=54 years old than those who were >=55 years at baseline (pinteraction 0.021). Odds ratios were in the direction of increased risk for all 15 categories of malignancies studied (p<0.0001), ranging from 1.22 (p=0.42) for ovarian cancer to 2.01 (p=0.008) for urinary tract cancers; the smallest p-value was for breast cancer (OR 1.45, p=0.0002). The results indicate that the minor allele of MGMT SNP rs2296675, a common genetic marker with 37% carriers, was significantly associated with increased risk of cancer across multiple tissues. Replication is needed to more definitively determine the scientific and public health significance of this observed association.
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Wednesday, October 03, 2012
(2004) Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma
Blogger's Note: more recent research can be found on this blog (eg. Lynch Syndrome/UUTC) including 2 recent (posted Sept 2012) research papers; European Guidelines/Mount Sinai, Toronto
~~~~~~~~~~~~
Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cellcarcinoma
"Upper urinary tract transitional cell carcinoma was never the first cancer in their personal history."
Key points
Hereditary non-polyposis colorectal cancer (HNPCC) is
an autosomal dominant syndrome predisposing to
colorectal cancer which is revealed by colorectal
cancer (63%) or extracolonic cancers, most often of
the endometrium (9%) or ovary, but sometimes of the
upper urinary tract (5%).
Our aim was: (a) to establish the benefits of routine
screening for microsatellite instability in patients with
upper urinary tract transitional cell carcinoma
(UUTTCC) who did not meet the Amsterdam criteria
for hereditary non-polyposis colorectal cancer, (b) to
establish selection criteria for patients in whom testing
for germline mutation of the MSH2 repair gene should
be performed.
164 patients treated for sporadic upper urinary tract
transitional cell carcinoma were screened for microsatellite
instability. Twenty seven patients had high
microsatellite instability levels. For those patients, we
collated clinical data, and performed immunohistochemistry
to investigate loss of hMSH2 protein and PCR
single strand conformation polymorphism gene
sequence analysis to detect hMSH2 mutations.
The presence of a mutation was significantly related
to (a) a history of a HNPCC associated cancer
(p = 0.038), (b) the occurrence of upper urinary tract
transitional cell carcinoma before 60 years of age
(p = 0.04), and (c) the indication by loss of protein
expression on immunohistochemistry.
In cases of upper urinary tract transitional cell
carcinoma with high microsatellite instability levels,
hereditary predisposition should be investigated if the
patient has a history of a HNPCC associated cancer or
is under 60. Patients with hMSH2 protein loss on
immunohistochemistry should undergo testing for a
germline mutation.
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