- •Women were satisfied with their decision to undergo robotic surgery.
- •General health, symptom burden, and sexual function returned to baseline quickly after robotic surgery.
Tuesday, August 04, 2015
Psychosocial Factors Associated With Withdrawal From the United Kingdom Collaborative Trial of Ovarian Cancer Screening After 1 Episode of Repeat Screening
open access (pdf)
Abstract: Objective: The United Kingdom Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS) aims to establish the efficacy of 2 different ovarian cancer screening schedules. The psychosocial substudy examines the psychological factors associated with the screening program.
Methods: Women aged 50 to 75 years from 16 UK gynecologic centers randomized to annual multimodal screening or ultrasound screening (US) groups were followed up for 7 years. Psychosocial data from women who withdrew from the study after a repeat screen were examined.
Results: Sixteen percent (3499/21,733) of women requiring a repeat screening test in addition to annual screen withdrew from the study: 12.9% (1560/12,073) from the multimodal group and 20.1% (1939/9660) from the US group. An estimated relative risk of withdrawal is 1.46 (95% confidence interval, 1.36Y1.56; P e 0.001) for the US arm. High anxiety trait and increased psychological morbidity significantly influenced withdrawal, even when age, screening center, and group were taken into account (P G 0.001). The risk of withdrawal decreased significantly the longer a woman stayed in UKCTOCS, irrespective of the number of screens and intensity in the preceding year.
Conclusions: Withdrawal rate was greater in women undergoing US screening and in those who had repeats earlier inUKCTOCS. Having a high predisposition to anxiety, high current state anxiety, and above threshold general psychological morbidity all increased the withdrawal rate.
Interpretation
There are no other OCS studies of comparable design
and size with which to compare these UKCTOCS withdrawal
results. What we have shown is that women with a high
predisposition toward anxiety are more likely to drop out of
screening, as do those who experience high anxiety after their
most recent scan. Furthermore, the more invasive the initial
screening procedure is, that is TVS, rather than a multimodal
approach, the more likely withdrawal will be after a repeat
scan or false-positive result.
CONCLUSIONS
The United Kingdom Collaborative Trial of Ovarian
Cancer Screening included a comprehensive psychosocial
arm that has permitted an in-depth appraisal of not only the
psychosocial harms and benefits of OCS but also some of the
factors that might enhance or inhibit attendance and re attendance.
Next year, the National Screening Committee is
scheduled to review its policy on OCS in women after the
UKCTOCS study against criteria that include psychosocial
factors. These results should assist policy makers when
considering the optimal screening methods and any accompanying
educational resources, especially aimed at ameliorating
anxiety.
Monday, August 03, 2015
An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian (HGSC) cancer (CA125; carboplatin...)
open access - Nature Communications (technical)
Abstract: High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells.....
Discussion .... This study provides evidence that CA125-negative HGSC cells have stem properties and are inherently platinum resistant. The de novo platinum resistance of this tumour subpopulation can explain why these cancers consistently reappear after first-line platinum-based chemotherapy. On the basis of the promising preclinical results here, improving outcomes for this deadly malignancy could be achieved simply by supplementing existing therapies that work well against the majority of tumour cells with agents that sensitize the CA125-negative cells to carboplatin.
How to cite this article: Janzen, D. M. et al. An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nat. Commun. 6:7956 doi: 10.1038/ncomms8956 (2015).
media (easier to comprehend)
A common type of ovarian cancer, high-grade serous ovarian cancer, often responds well to the chemotherapy drug carboplatin; however, it frequently recurs following the treatment. Now, UCLA researchers has discovered that malignant cells that do not produce the protein CA125, which is a biomarker used to test for ovarian cancer, have an increased ability to repair their DNA and resist cell death from the chemotherapy. This allows the cells to elude the drug and live long enough to regrow the original tumor. The results of the five-year study were published on August 3 in the peer-reviewed journal Nature Communications.......
Urinary melatonin and risk of ovarian cancer (eg. night shift work)
abstract
PURPOSE:
Melatonin has anti-carcinogenic properties, including modulation of estradiol production, cell cycle regulation, and promotion of apoptosis. Urinary melatonin has been inversely associated with breast cancer in some studies, but the association with ovarian cancer has not been investigated.
CONCLUSIONS:
These results are consistent with our previous study in which we reported no association between night shift work and ovarian cancer; however, given the small sample size in our study, additional evaluation in larger studies is warranted.Cellular and molecular processes in ovarian cancer metastasis
abstract
Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-year survival rate of less than 30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis3. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and importance of the "seed and soil" hypothesis for ovarian cancer metastasis. In this review, we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.
New and emerging factors in tumorigenesis: an overview
Blogger's Note: frequent references to ovarian cancer (serous, clear cell...)
open access
.... Alternatively, TP53 or PIK3CA mutations may drive cancers originating from different cell types. For example, the ovarian cancer found with high-frequency mutations in TP53 (Table 1) is the serous epithelial ovarian carcinoma subtype that makes up 90% of ovarian cancer. Another histologic subtype of ovarian cancer is called clear cell ovarian carcinoma that constitutes 1%–10% of ovarian cancers. The clear cell ovarian-subtype tumors have been shown to contain largely wild-type TP53 but high-frequency mutations in PIK3CA, up to 40%.28 Together, these may suggest that TP53 or PIK3CA mutations occur in different cell types, each driving a different subtype of cancer (serous ovarian cancer vs clear cell ovarian cancer).....
An International Survey of Health Care Providers Involved in the Management of Cancer Patients Exposed to Cardiotoxic Therapy
Abstract
.... Cardiac oncology is a rapidly emerging but relatively new area of clinical medicine. It is encouraging to find a high level of concern for cardiac safety among health care providers treating cancer patients. Strikingly, there continues to be a lack of consensus on the definition of cardiotoxicity and a discrepancy in clinical practice between cardiologists and oncologists, the two specialties mostly involved in caring for cardiac oncology patients. These differences in opinion will need to be resolved through more effective research collaboration, formulation of evidence-based guidelines, and educational strategies to standardize the diagnosis, management, and monitoring of cardiac toxicity.....
Multimodality Imaging in Cardiooncology
open access
3. Cancer Treatment and Cardiotoxicity: Who Are the Actors?
The majority of studies on cardiotoxicity focus on patients treated with anthracyclines and trastuzumab. Anthracyclines (doxorubicin, daunorubicin, and epirubicin) use has been related to onset of HF within 1 year in about 2% of treated patients [1]. The HF incidence increases to 28% when the patients are exposed to the association of anthracyclines and trastuzumab [1]. Cardiotoxic effect has been described for classes of drugs other than the anthracyclines and trastuzumab such as inhibitors of tyrosine kinases (imatinib, dasatinib, nilotinib, sunitinib, sorafenib, and bevacizumab), antimetabolites (5-fluorouracil), alkylating agents (cisplatin, cyclophosphamide), and taxanes (docetaxel and paclitaxel) [10]. Radiotherapy has become an important instrument in the treatment of several malignances and is more often associated to standard chemotherapy treatment. Irradiation of the mediastinum with a cumulative dose >30 Gy and a daily fractioning >2 Gy appeared to be related to a high risk of developing cardiac dysfunction [11]......
Clinical Experience of Patients Referred to a Multidisciplinary Cardiac Oncology Clinic: An Observational Study
open access
Table 1: Patient demographics ( = 428). (Other tumour sites: gynaecologic, skin, sarcoma, neurologic, amyloidosis, thyroid, musculoskeletal.)
Cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors. The purpose of this retrospective observational study is to report on the clinical and cardiac outcomes in patients with early stage and advanced cancer who were referred to our multidisciplinary cardiac oncology clinic (COC). A total of 428 patients were referred to the COC between October 2008 and January 2013. The median age of patients at time of cancer diagnosis was 60. Almost half of patients who received cancer therapy received first-line chemotherapy alone (169, 41.7%), of which 84 (49.7%) were exposed to anthracyclines. The most common reasons for referral to the cardiac oncology clinic were decreased LVEF (34.6%), prechemotherapy assessment (11.9%), and arrhythmia (8.4%). A total of 175 (40.9%) patients referred to the COC were treated with cardiac medications. The majority (331, 77.3%) of patients were alive as of January 2013, and 93 (21.7%) patients were deceased. Through regular review of cardiac oncology clinic referral patterns, management plans, and patient outcomes, we aim to continuously improve delivery of cardiac care to our patient population and optimize cardiac health.
1. Introduction
With the evolution of systemic and targeted therapies in cancer treatment, it has become increasingly evident that damage to the heart may occur as a result of cancer therapy. While cancer survivorship has significantly increased over the last decade [1], cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors [2]. In addition, there are an increasing number of cancer patients with preexisting heart disease, for whom treatment with potentially cardiotoxic cancer therapy may pose a challenge [1]. Prevention and management strategies of cardiotoxicity will be important to optimize cancer care while maintaining cardiovascular health. Hence, the need for collaboration between oncologists and cardiologists from diagnosis to survivorship is imperative to ensure patients are receiving the best possible cancer care.......
Sunday, August 02, 2015
Loss of heterozygosity: what is it good for?
open access
Ovarian tumour cohort
A tumour cohort (n = 86) comprising a variety of histological subtypes including serous (n = 45), endometrioid (n = 28), mucinous (n = 7) and clear cell (n = 6) were obtained through the Australia Ovarian Cancer Study, the Peter MacCallum Cancer Centre Tissue Bank, or from patients presenting to hospitals in the south of England [8].
Background
Loss of heterozygosity (LOH) is a common genetic event in cancer development, and
is known to be involved in the somatic loss of wild-type alleles in many inherited
cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking
a somatically mutated tumour suppressor gene through loss of the wild type allele.
Methods
We analysed 86 ovarian carcinomas for mutations in 980 genes selected on the basis
of their location in common regions of LOH.
Results
We identified 36 significantly mutated genes, but these could only partly account
for the quanta of LOH in the samples. Using our own and TCGA data we then evaluated
five possible models to explain the selection for non-random accumulation of LOH in
ovarian cancer genomes: 1. Classic two-hit hypothesis: high frequency biallelic genetic
inactivation of tumour suppressor genes. 2. Epigenetic two-hit hypothesis: biallelic
inactivation through methylation and LOH. 3. Multiple alternate-gene biallelic inactivation:
low frequency gene disruption. 4. Haplo-insufficiency: Single copy gene disruption.
5. Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline
predisposition alleles. We determined that while high-frequency biallelic gene inactivation
under model 1 is rare, regions of LOH (particularly copy-number neutral LOH) are enriched
for deleterious mutations and increased promoter methylation, while copy-number loss
LOH regions are likely to contain under-expressed genes suggestive of haploinsufficiency.
Reduction to homozygosity of cancer predisposition SNPs may also play a minor role.
Conclusion
It is likely that selection for regions of LOH depends on its effect on multiple genes.
Selection for copy number neutral LOH may better fit the classic two-hit model whereas
selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency.
LOH mapping alone is unlikely to be successful in identifying novel tumour suppressor
genes; a combined approach may be more effective.
Shared genetics underlying epidemiological association between endometriosis and ovarian cancer
abstract
Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3,194 cases and 7,060 controls) and a large ovarian cancer dataset genotyped on the customised iCOGS arrays (10,065 cases and 21,663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI=0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI=0.07-0.89 and 0.40, 95% CI=0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI=0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
Postoperative HRT for epithelial ovarian cancer patients: a systematic review/meta-analysis
abstract
BACKGROUND:
. Hormone replacement therapy (HRT) has been proven highly effective for menopausal symptoms caused by radical surgery. However, the impact of postoperative HRT on the clinical outcomes of patients previously treated for epithelial ovarian cancer (EOC) remains unclear.OBJECTIVE:
. To determine whether postoperative HRT use has any positive or negative impacts on prognosis and recurrence among EOC survivors.Saturday, August 01, 2015
A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, FT or PP carcinoma
Gynecol Oncol. 2014 Sep;134(3):478-85. doi: 10.1016/j.ygyno.2014.06.029. Epub 2014 Jul 10.
A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
OBJECTIVE:
Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR).METHODS:
Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks.RESULTS:
Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2.CONCLUSIONS:
Although antitumor activity was observed, the predetermined efficacy endpoints were not met.Note: Risk of gastrointestinal perforation in cancer patients receiving ramucirumab: a meta-analysis of randomized controlled trials
Risk of gastrointestinal perforation in cancer patients receiving ramucirumab: a meta-analysis of RCTs
abstract
Purpose:
Methods:
Results:
Ramucirumab in Ovarian Cancer - clinical trial
ClinicalTrials.gov
This study is ongoing, but not recruiting participants.
Sponsor:
Eli Lilly and Company
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT00721162
First received: July 21, 2008
Last updated: January 12, 2015
Last verified: January 2015
BRCA Mutations, DNA Repair Deficiency and Ovarian Aging
open access
..... We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo evidence and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and due to masking of most severe cases by prophylactic oophorectomy
or cancer, it is less likely to see an effect of BRCA mutations on fertility until later in
reproductive age......
Cellular and molecular processes in ovarian cancer metastasis
abstract
Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-year survival rate of less than 30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis3. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and importance of the "seed and soil" hypothesis for ovarian cancer metastasis. In this review, we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.
Trends & Analysis of Cancer Incidence for Common Male & Female Cancers (Pakistan)
abstract
Trends and Analysis of Cancer Incidence for Common Male and Female Cancers in the Population of Punjab Province of Pakistan during 1984 to 2014.
BACKGROUND:
The Pakistan Atomic Energy Commission Cancer Registry (PAECCR) program has made availability of a common cancer incidence database possible in Pakistan. The cancer incidence data from nuclear medicine and oncology institutes were gathered and presented.MATERIALS AND METHODS:
The cancer incidence data for the last 30 years (1984-2014) are included to describe a data set of male and female patients. The data analysis concerning occurrence, trends of common cancers in male and female patients, stage-wise distribution, and mortality/follow-up cases is also incorporated for the last 10 years (2004-2014).RESULTS:
The total population of provincial capital Lahore is 9,800,000. The total number of cancer cases was 80,390 (males 32,156, females 48,134). The crude incidence rates in PAECCR areas were 580.8/105 during 2010 to 885.4/105 in 2014 (males 354.1/105, females 530.1/105). The cancer incidence rates for head and neck (15.70%), brain tumors (10.5%), and non-Hodgkin lymphoma (NHL, 9.53%) were found to be the highest in male patients, whereas breast cancer (46.7%), ovary tumors (6.80%),Effect of Previous Chemotherapy on the Quality of Cryopreserved Human Ovarian Tissue In Vitro.
abstract
BACKGROUND:
Cryopreservation of ovarian tissue has been widely accepted as an option for fertility preservation among cancer patients. Some patients are exposed to chemotherapy prior to ovarian tissue cryopreservation. Consequently, assessment of the developmental capacity of human ovarian tissue after chemotherapy is of primary importance.MATERIALS:
In order to study the impact of previous chemotherapy on in vitro development and viability of ovarian follicles, quality control samples from 34 female cancer patients at median age of 15 years (range 1‒35),Targeting c-MYC in platinum-resistant ovarian cancer
Friday, July 31, 2015
Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes
2015 open access
Abstract
More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.
1. Introduction
2. Clinical, Histopathological, and Molecular Features of Ovarian Cancer
3. Mismatch Repair Genes and Lynch Syndrome
4. TP53 and Li-Fraumeni Syndrome
5. Genes Involved in Double-Strand Breaks Repair
6. Next-Generation Sequencing with Multigene Panels
7. Conclusions
.....The centralization of genetic testing enables the improvement of access and quality of testing and allows for the creation of a more comprehensive database for research, guiding evidence-based management recommendations [89–91].
Call for Abstracts & Surgical Films: SGO 2015
2016
The 2016 SGO International Program will emphasize global gynecologic cancer epidemiology. Our goals are to identify geographic variations in the worldwide gynecologic cancer incidence with a particular emphasis on the burden of gynecologic cancers in low- and middle-income countries, the challenges of public health reporting, and examples of successful models for the development and implementation of reliable and accurate cancer registries.
The key concepts for presentation consideration include:
- Epidemiology
- Regional demographics and trends
- Treatment in developing countries
- Challenges in public health and data ascertainment
- Screening challenges
- Breast cancer
Thursday, July 30, 2015
Impact of Age and Primary Disease Site on Outcome in Women With Low-Grade Serous Carcinoma of the Ovary or Peritoneum
abstract
Impact of Age and Primary Disease Site on Outcome in Women With Low-Grade Serous Carcinoma of the Ovary or Peritoneum: Results of a Large Single-Institution Registry of a Rare Tumor
Purpose Low-grade
serous carcinoma of the ovary (LGSOC) or peritoneum (LGSPC) is a rare
subtype of ovarian or peritoneal cancer characterized
by young age at diagnosis and relative
resistance to chemotherapy. The purpose of this study is to report our
updated experience
with women diagnosed with LGSOC or LGSPC to
assess the validity of our original observations.
Patients and Methods
Eligibility criteria for patients from our database were: stage I to IV
LGSOC or LGSPC, original diagnosis before January
2012, and adequate clinical information. All
patients were included in progression-free survival, overall survival,
and multivariable
Cox regression analyses. A subset analysis was
performed among patients with stage II to IV low-grade serous carcinoma
treated
with primary surgery followed by platinum-based
chemotherapy.
Epidemiology in ovarian carcinoma: Lessons from autopsy
abstract
Highlights
- •
- Autopsy data challenges epidemiologic knowledge regarding incidence and prevalence of ovarian carcinoma.
- •
- Previous epidemiological data overestimate incidence because up to 10% of carcinomas in the ovary were metastases from other primary sites.
- •
- In 16% of autopsies, ovarian carcinoma in its final stage was first diagnosed by autopsy.
Objective
We challenge epidemiologic knowledge regarding ovarian carcinoma (OC) by bridging the gap between clinical and autopsy data.
Methods
Autopsy
reports, histological slides and clinical files from 660 patients in
whom OC was diagnosed from 1975-2005 were studied (autopsy cohort,
n = 233; Clinical Cancer Registry from the local gyneco-oncologic
center, n = 427).
Results
Out of
the autopsy cohort, we identified four distinct subgroups of patients:
1) OC was diagnosed before autopsy, n = 156 (67.0%). 2) OC was an
incidental finding, n = 16 (6.8%). 3) The ovarian tumors were not
primary OC but rather metastases from other primary tumors; this revised
diagnosis was first made by using current histopathological
knowledge/techniques, n = 24 (10.3%). 4) Death was directly due to OC in
its final stage and OC was first diagnosed by autopsy, n = 37 (15.9%);
when these cases were added to the Clinical Cancer Registry to an
adjusted OC incidence model, the autopsy cases comprised 8.8% of the
adjusted cohort and almost doubled the percentage of oldest patients
(≥ 80 years at diagnosis) from 4.9% to 9.3% (p = 0.013).
Conclusions
Epidemiological
data from the 1970s-1990s may overestimate true incidence because up to
10% of carcinomas in the ovary were not properly classified. Patients
who were first diagnosed with OC by autopsy comprise a distinct
subgroup. These are patients who have not been seen by specialized
oncologists and thus play no role in their perception of the disease.
Nevertheless, these cases have impact on prevalence and incidence data
of OC and in an era of reduced autopsy rates will probably be
overlooked.
Improvement in quality of life after robotic surgery results in patient satisfaction
abstract
Highlights
Background
There are well-described benefits to minimally invasive surgery including decreased blood loss, shorter hospital-stay, and faster recovery. The role of robotic surgery in gynecologic oncology has become increasingly prominent; however limited data are available on quality of life (QOL) after robotic surgery.Methods
In this prospective, IRB-approved study, women scheduled for robotic surgery for a gynecologic indication between May 2008 and February 2012 completed validated QOL measures at baseline, 6 weeks (6 wk), and 4 months postoperative (4 mo).Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced stage Müllerian cancer
abstract
Highlights
- •Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status.
- •The outcomes of NAC in BRCA mutation positive patients were more favorable than the outcomes reported in the literature.
- •This is the first study evaluating the outcome of NAC in BRCA mutation positive patients with advanced-stage mullerian cancer.
Objectives
To investigate whether patients with germline BRCA1/2 mutations who received neoadjuvant chemotherapy (NAC) for advanced stage Mullerian cancer (MC) have an improved outcome compared to patients who did not undergo genetic testing.Methods
Three hundred and two patients who received NAC for stage III-IV MC were identified from a multi-institutional study involving Cleveland Clinic and Brigham and Women’s Hospital for 2000–2014 and 2010–2014 respectively. Patients were divided into 3 cohorts: patients with germline BRCA 1/2 mutations (BRCA_mut+; N = 30), patients with no genetic testing (BRCA_unk; N = 166) and patients with negative genetic testing (BRCA mut-, N = 106).Results
There were no differences in the clinical characteristics and rates of complete cytoreduction and bowel resection between the three groups. BRCA_mut + had longer PFS compared to BRCA_unk and BRCA_mut- (19.1 vs. 15.1 vs. 15.7 months respectively. However, this difference was not statistically significant (p = 0.48). Patients with BRCA 2 mutation had non-significant trend toward longer PFS compared to patients with unknown BRCA or BRCA 1 mutation (20.2 vs. 15.1 vs. 14.8 months respectively, p = 0.58). BRCA-mut + and BRCA_mut-had longer overall survivals (OS) compared to BRCA_unk patients (50.5 vs. 54.1 vs. 36.5 months respectively, p = 0.009). In multivariable analyses, controlling for age, stage and complete cytoreduction, BRCA_mut_unk was associated with worse PFS (HR 1.44, 95% CI 1.01-2.05, p = 0.045) and OS (HR 2.67, 95% CI 1.33-5.36, p = 0.006).Conclusions
Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status. These outcomes were more favorable compared to the outcome of NAC in prior studies.Ascites predicts treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube and peritoneal cancers: An NRG Oncology/GOG study
Abstract
Highlights
- •We analyzed data from GOG 0218 to determine if ascites predicts response to bevacizumab.
- •Ascites was shown to be a negative prognostic factor in epithelial ovarian cancers.
- •Ascites is a significant clinical factor that may predict response to bevacizumab.
Objectives
Predictive factors for efficacy of bevacizumab in advanced ovarian cancer have remained elusive. We investigated ascites both as a prognostic factor and as a predictor of efficacy for bevacizumab.Methods
Using data from GOG 0218, patients receiving cytotoxic therapy plus concurrent and maintenance bevacizumab were compared to those receiving cytotoxic therapy plus placebo. The presence of ascites was determined prospectively. Chi-square and Wilcoxon–Mann–Whitney tests compared baseline variables between subgroups. Survival was estimated by Kaplan–Meier method, and Cox proportional hazard models were used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on survival.Results
Treatment arms were balanced with respect to ascites and other prognostic factors. Overall, 886 (80%) women had ascites, 221 (20%) did not.Wednesday, July 29, 2015
Postoperative hormone replacement therapy for epithelial ovarian cancer patients: a systematic review and meta-analysis - Gynecologic Oncology
abstract
Highlights
- •This is the first meta-analysis on the effect of HRT on prognosis and recurrence of EOC survivors.
- •Postoperative HRT use is not associated with poorer clinical outcomes of EOC patients.
Background
. Hormone replacement therapy (HRT) has been proven highly effective for menopausal symptoms caused by radical surgery. However, the impact of postoperative HRT on the clinical outcomes of patients previously treated for epithelial ovarian cancer (EOC) remains unclear.Objective
. To determine whether postoperative HRT use has any positive or negative impacts on prognosis and recurrence among EOC survivors.Methods
. Studies that provided an assessment of postoperative HRT use and prognosis or recurrence in EOC patients were included for analysis. Two reviewers independently evaluated the eligibility of identified studies and abstracted the data. A fixed effects model was used to pool study-specific estimates of hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs).Results
. Two randomized controlled trials (RCTs) and four cohort studies included 419 EOC survivors who used HRT and 1,029 non-users. The aggregated HR of overall survival (OS) suggested that HRT use after surgery for EOC had a favorable impact on OS (HR = 0.69, 95% CI: 0.61–0.79), but when these studies were categorized into cohort study and RCT subgroups, not all of them demonstrated positive results (HR = 0.63, 95% CI: 0.49–0.81 and HR = 1.03, 95% CI: 0.58–1.83, respectively). The meta-analysis of EOC recurrence of three available studies demonstrated that postoperative HRT use was not associated with an increased risk of recurrence in EOC survivors (RR = 0.83, 95% CI: 0.64–1.07). This pattern also emerged in the subgroup analysis for the stage and type of HRT.Conclusions
. In EOC patients, postoperative HRT does not have a negative effect on overall survival and tumor recurrence. However, well-designed and large-scale RCTs are needed to verify this relationship in the future.Setting the bar: compliance with ovarian cancer quality indicators at a NCI-designated Comprehensive Cancer Center
abstract
Highlights
- •Appropriate quality indicator thresholds must take into account our complex patients
- •Complete surgical staging and timely administration of chemotherapy warrant attention
- •Existing perioperative quality measures demonstrate excellent compliance
Objectives
Ovarian cancer quality measures are being developed to improve health care delivery and outcomes. Our objective is to evaluate compliance with 8 quality indicators proposed by the Society of Gynecologic Oncology.Methods
Review of 123 ovarian cancer patients who underwent primary surgical staging/cytoreduction and chemotherapy from 2010–2012 was undertaken. Medical records were reviewed, and descriptive statistics were performed to determine compliance.Results
A timely operative report documenting residual disease was dictated for 121/123 (98.4%) patients. Complete surgical staging was performed in 33/55 (60.0%) stage I-IIIB patients, with lymphadenectomy most frequently omitted. For optimally debulked stage III patients, 52/56 (92.9%) were offered intraperitoneal chemotherapy. Ultimately, 29/56 (51.8%) received this route and 19/56 (33.9%) within 42 days (range 18–48, median 40 days). Clinical trial randomization and co-morbidities accounted for most cases of non-compliance. All 105 patients for whom chemotherapy was indicated received platin/taxane therapy, and 79/105 (75.2%) within 42 days (range 4–82, median 37 days). Venous thromboembolism prophylaxis was provided mechanically in 122/123 (99.2%) and pharmacologically in 99/123 (80.5%) patients within 24 hours of surgery. Prophylactic parenteral antibiotics were administered within 60 minutes of cytoreduction in 119/123 (96.7%) and discontinued within 24 hours after surgery in 120/123 (97.6%) cases.Conclusions
Compliance with strict definitions of ovarian cancer quality indicators varies depending on the care delivered and documentation of that care. Increased attention to comprehensive surgical staging and timely initiation of chemotherapy appears warranted. With the move toward value-based payment models, quality indicators will play a significant role in health care delivery.Biobank consent models – are we moving toward increased participant engagement in biobanking?
open access
Abstract: Engagement, involvement, and active participation are buzzwords used in today's ethical debate on research biobanking. There are a variety of context-sensitive governance frameworks for research biobanks. However, many biobanks, especially large-scale population-based ones, seem to endorse a framework of broad consent, participation with minimal or no ongoing engagement, and no return of results. An alternative vision of involvement and active participation in this type of research has become increasingly visible in the literature. The problem, seen from the biobankers' perspective, is that the alternative vision might be costly, cumbersome, and risky, while the prevailing system for governance will maximize the scientific value of the biobank with minimal ethical, legal, and social efforts. Therefore, solid and convincing arguments are needed to determine if biobank institutions should take a radical step toward more ongoing engagement and donor involvement. In this paper, we review the arguments found in articles addressing dynamic consent, participatory research, reciprocity, and participant engagement in biobank research. We identify four core ideas on which the arguments for increased involvement are based. The strength of the arguments are then analyzed. We conclude that despite challenges with increased engagement, there seem to be substantial reasons to increase participant engagement in biobanking.
Keywords: biobank ethics, participatory research, dynamic consent, reciprocity
Download Article [PDF]
Doctors busy prolonging life have lost sight of end of life care - audio (25 min)
CBC Radio
Oncologist Atul Gawande believes doctors spend so much
time helping people live longer, they've neglected how to improve the
quality of life at the end. (Tim-Llewellyn)
Listen 24:59
The Dr. Henry T. Lynch Symposium: Advances in Hereditary Cancer Sept 2015
announcement
The Dr. Henry T. Lynch Symposium: Advances in Hereditary Cancer
Creighton University Health Sciences Continuing Education
Thursday, September 17, 2015 at 7:00 AM - Friday, September 18, 2015 at 5:00 PM (CDT) Omaha, NE
Non-genetic cancer mechanism found - Akt pathway (Oncogene)
Cancer can be caused solely by protein imbalances within cells, a study of ovarian cancer has found. The discovery is a major breakthrough because, until now, genetic aberrations have been seen as the main cause of almost all cancer.
.....The research, led by scientists at the University of Leeds and The University of Texas MD Anderson Cancer Center, focused on the "Akt pathway," ( Protein kinase B (PKB), also known as Akt ) a signalling pathway within cells that drives cancer formation and the spread of cancers through the body......
ScienceDaily
Journal Reference:
- Z Timsah, Z Ahmed, C Ivan, J Berrout, M Gagea, Y Zhou, G N A Pena, Xin Hu, C Vallien, C V Kingsley, Y Lu, J F Hancock, J Liu, A B Gladden, G B Mills, G Lopez-Berestein, M-C Hung, A K Sood, M Bogdanov, J E Ladbury. Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer. Oncogene, 2015; DOI: 10.1038/onc.2015.279
Too much, too late: Aggressive measures and the timing of end of life care discussions in women with gynecologic malignancies
abstract
Highlights
- •
- Reviews timing and location of end of life discussions with gyn-oncology patients
- •
- Evaluates compliance with National Quality Forum (NQF) metrics of care
- •
- A high rate of inpatient and late end of life discussions is noted in this cohort.
Objective
This
study describes the patterns of end of life (EOL) discussions and their
impact on the use of aggressive measures in women with terminal
gynecologic malignancies at a single institution.
Methods
An
IRB-approved retrospective chart review identified 136 patients who
died of gynecologic cancer between 2010 and 2012 with at least one
interaction with their oncologists in the last 6 months of life.
Aggressive measures were defined as chemotherapy within the last 14 days
of life, emergency department (ED) visits, hospital and intensive care
unit (ICU) admissions within the last 30 days of life, and inpatient
deaths. The frequency and timing of EOL conversations were recorded.
Utilization of hospice care was also described.
Results
In
the last 30 days of life, 54 (40%) patients were evaluated in the ED,
67 (49%) were admitted into hospital, and 16 (12%) were admitted to the
ICU. Thirteen patients (10%) had chemotherapy in the last 14 days of
life. Ninety-seven (71%) patients had a documented EOL conversation,
eighteen (19%) as outpatients, and 79 (81%) as inpatients. Thirty (22%)
patients died in the hospital. At the time of death, 55 (40%) patients
were enrolled in outpatient hospice care. The mean amount of time in
hospice was 28 days.
Conclusions
End
of life care discussions rarely occurred in the outpatient setting or
> 30 days before death. Inpatient encounters led to discussions about
hospice and code status. Evaluation in the ED frequently resulted in
escalation of care. Earlier EOL care discussions resulted in less
aggressive measures.
Do All BRCA Mutations Come with the Same Cancer Risk?
Insight
Women born with mutations in the genes BRCA1 or BRCA2 have an increased risk of developing breast and ovarian cancer, but the degree of increase depends on a variety of factors.
....Investigators at Dana-Farber are tracking the links between environment, heredity, and cancer in a study known as Project SEARCH.....
Cancer symptom awareness and barriers to symptomatic presentation in England[mdash]are we clear on cancer[quest]
open access
.... Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor......Women were more likely than men to recognise each cancer symptom, except ‘persistent unexplained pain’.....
..... Finally, understanding the reasons why people in our sample identified certain barriers, for example, why people worry about wasting the doctor’s time, could further improve the effectiveness of future campaigns. Our findings could contribute to improving cancer survival in England to match the best in Europe by helping to develop targeted campaigns promoting early presentation of cancer symptoms.
BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts
open access
.... Clinical data in ovarian cancer show that patients with
BRCA1 and BRCA2 mutations show higher response rates to treatment with
cisplatin and other DNA-damaging agents resulting in improved outcome (Dann et al, 2012; Muggia and Safra, 2014).
Similar observations have been made in case reports of patients with
pancreatic cancer, suggesting that BRCA1 and BRCA2 mutations may
sensitise to treatment with platinum drugs (Lowery et al, 2011; Sonnenblick et al, 2011). This is supported by preclinical studies using established pancreatic cancer cell lines (van der Heijden et al, 2005),
and also by a large retrospective analysis of 71 pancreatic cancer
patients with germline BRCA1 and BRCA2 mutations, where it was reported
that patients with stage 3/4 disease who were
treated with a platinum-containing regimen had a median survival of 22
months, compared with 9 months for those who did not receive platinum (Golan et al, 2014).
There
are important unanswered questions concerning the optimum design of
platinum-containing treatment protocols for this group of patients, as
well as the role of newer agents such as inhibitors of poly-ADP-ribose
polymerase (PARP) that have shown early promise in other cancer patients
carrying germline BRCA mutations......Discussion
- Background:
- Methods:
- Results:
- Discussion:
- Materials and methods
- Results
- Discussion
- Conflict of interest
- References
- Acknowledgements
- Figures and Tables
Tumour response, correlates of survival and clinical benefit
Nature Reviews Clinical Oncology
We are all familiar with the metrics of tumour shrinkage and time to the development of disease progression as important end points in clinical trials. This tenet is based on findings of numerous studies over several decades that have demonstrated a link between agents that cause tumour shrinkage in a cancer population and its correlation with an overall survival improvement. The problem is that the inevitable variation in how these definitions and criteria have been applied over many decades in clinical trials has led to different conclusions about the efficacy of a treatment. Added to this complexity are the following issues: non-measurable lesions, differences obtained with the method of assessment of progression (imaging versus clinical examination), changes in non-target lesions versus target lesions, impact of lesions that coalesce or split on treatment, to name but a few. When considering the additional complexities posed by these factors, it is perhaps not surprising that tumour response is often a poor indicator of survival outcome. Yet, how can this be reconciled to allow the field of oncology to move forward............
AllTrials US campaign officially launched
announcement
29th July 2015
We are delighted to announce that today AllTrials USA has officially launched. Today 50 patient support groups, medical societies, universities and consumer groups are coming together to launch the AllTrials campaign in the US and to say:
“We are calling on everyone in
our sector to join us in supporting the AllTrials campaign. Hundreds of
thousands of patients have taken part in clinical trials which have
never reported results. For every day that passes, more information is
at risk of being lost forever. We have to make every clinical trial
count. Join us today.”
AllTrials – AllTrials US campaign officially launched
announcement
29th July 2015
We are delighted to announce that today AllTrials USA has officially launched. Today 50 patient support groups, medical societies, universities and consumer groups are coming together to launch the AllTrials campaign in the US and to say:
“We are calling on everyone in
our sector to join us in supporting the AllTrials campaign. Hundreds of
thousands of patients have taken part in clinical trials which have
never reported results. For every day that passes, more information is
at risk of being lost forever. We have to make every clinical trial
count. Join us today.”
ecancer - Cancer and metabolism (special issue)
ecancer
Cancer and metabolism
Guest Editor: Luca MazzarellaThis special issue centres around the field of metabolism, which has become one of the hot topics of the moment, especially as applied to cancer.....
Special Issue articles
Why does obesity promote cancer?
open access
Special Issue
Why does obesity promote cancer? Epidemiology, biology, and open questions
Keywords: obesity, body mass index, insulin, inflammation, DNA damage
Abstract
The association between obesity and/or metabolic syndrome and an
elevated mortality from cancer has been confirmed by an astonishing
number of studies across nations and ethnicities, such that obesity is
now recognised to be among the most prominent cancer risk factors
worldwide.
Despite this overwhelming evidence and the societal impact of obesity,
we know surprisingly little about the underlying molecular mechanisms.
This knowledge gap is a major obstacle to the implementation of
effective lifestyle change policies. As the scientific community is
insecure on what messages it should deliver, administrators are
uncertain as to what exactly to recommend, and consumers are confused
about whom to believe. This leaves the field flooded with
pseudo-scientific recommendations that are hard to eradicate.....
Gynaecological cancers (note: nothing on ovarian cancer)
Conclusion
The discourse on obesity and cancer has become dominant in public
debate. Some aspects of this issue are clearly established beyond any
reasonable doubt, namely the impact of obesity prior to diagnosis on
specific cancer risks and on survivor outcome. Other aspects, such as
the exact molecular mechanisms and the extent to which lifestyle changes
can modify risk, still await definitive proof. Ultimately, the debate
revolves on how much we can modify our cancer risk by intervening on the
most basic of animal activities: nutrition. Some might find it tempting
to dismiss this debate on the grounds that cancer risk (especially for
those cancers where a single environmental factor cannot be identified)
is mostly determined by ‘bad luck’, an un-escapable randomness in our
stem cells’ DNA mutation accumulation rate [52].
It is clearly not so, but it is also true that our understanding of how
nutrition impacts on cancer is far from complete. This creates fertile
ground for the proliferation of pseudo-scientific recommendations and
bogus ‘super healthy’ nutritional supplements. Likely, some mechanisms
and specific lifestyle interventions may have stronger impact on
specific cancers. It is also likely that an individual’s genetic makeup
may influence response to diet, as we find variable genetic
predisposition to specific cancers and genetically determined
differences in metabolism. In the wave of medicine personalisation, it
is not hard to imagine a future in which lifestyle plans will be
tailored to individual risk profile and metabolism.
Pharmacological treatments for fatigue associated with palliative care
Cochrane: Featured Review (update)
Objectives
Authors' conclusions
Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials.
Tuesday, July 28, 2015
Screening for pancreatic cancer in familial high-risk individuals: A systematic review
HRI = High Risk Individuals
open access
..... We chose familial HRIs as research subjects. In this population, there are also individuals with high risks for other diseases. Peutz-Jeghers syndrome with STK11/LKB1 gene mutation[36], hereditary pancreatitis with PRSS1 gene[37,38] or SPINK1 gene mutation[39], familial atypical multiple mole melanoma syndrome with CDKN2A or p16 gene mutations[40], hereditary breast ovarian cancer syndrome with BRCA2 and BRCA1 gene mutations[41,42], and Lynch syndrome with mismatch repair genes[43] are found in high risk populations, who should also receive attention. Nevertheless, these are not completely independent. Familial HRIs may also have gene mutations. The PRSS1 gene mutation is the main influencing factor in hereditary pancreatitis, an autosomal dominant disease. BRCA2 is one of the most common mutations, and was as high as 17% in one study[44]. Future studies on HRIs with gene mutations should be carried out to determine if they have a higher risk than HRIs without gene mutations. In addition, because of the complex nature of the pedigrees in pancreatic cancer, Wang et al[45] designed a tool known as PancPRO to identify familial HRIs, which was used for selecting and screening......
Peer-review
This
is a good systematic review in which the authors analyzed the benefits
and harms of pancreatic cancer screening in familial high-risk
individuals. The results are interesting, and suggest that pancreatic
cancer screening in familial HRIs can improve detection rate and prolong
lifetime. In addition, it can influence psychological functions and
increase the economic burden.
selected references (all references see article above)
36. (open access - pdf file link)
Giardiello
FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV,
Cruz-Correa M, Offerhaus JA. Very high risk of cancer in familial
Peutz-Jeghers syndrome. Gastroenterology. 2000;119:1447-1453.[PubMed]
41. (open access)
Thompson D, Easton DF. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358-1365.[PubMed]
42. (open access)
van
Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S,
Vasen HF, Ausems MG, Menko FH, Gomez Garcia EB, Klijn JG. Cancer risks
in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005;42:711-719.[PubMed] [DOI]
43. (open access)
Kastrinos
F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P,
Stoffel EM, Gruber SB, Syngal S. Risk of pancreatic cancer in families
with Lynch syndrome. JAMA. 2009;302:1790-1795.[PubMed] [DOI]
Subscribe to:
Posts
(
Atom
)
