Wednesday, April 17, 2013
Fool's gold, lost treasures, and the randomized clinical trial
open access
Debate
Background
Randomized controlled trials with a survival endpoint are the gold standard for clinical
research, but have failed to achieve cures for most advanced malignancies. The high
costs of randomized clinical trials slow progress (thereby causing avoidable loss
of life) and increase health care costs.
Discussion
A malignancy may be caused by several different mutations. Therapies effective vs
one mutation may be discarded due to lack of statistical significance across the entire
population. Conversely, expensive large randomized trials may have sufficient statistical
power to demonstrate benefit despite the therapy only working in subgroups. Non-cost-effective
therapy is then applied to all patients (including subgroups it cannot help). Randomized
trials comparing therapies with different mechanisms of action are misleading since
they may conclude the therapies are "equivalent" despite benefitting different subpopulations,
or may erroneously conclude that one therapy is superior simply because it targets
a larger subpopulation. Furthermore, minor variances in patient selection may determine
study outcome, a therapy may be discarded as ineffective despite substantial benefit
in one subpopulation if harmful in another, randomized trials may more effectively
detect therapies with minor benefit in most patients vs marked benefit in subpopulations,
and randomized trials in unselected patients may erroneously conclude that "shot-gun"
combinations are superior to single agents when sequential administration of personalized
single agents might work better and spare patients treatment with drugs that cannot
help them. We must identify predictive biomarkers early by comparing responding to
progressing patients in phase I-II trials. Enriching randomized trials for biomarker-positive
patients can markedly reduce required patient numbers and costs despite expensive
screening for biomarker-positive patients. Available data support approval of new
drugs without randomized trials if they yield single-agent sustained responses in
patients refractory to standard therapies. Conversely, new approaches are needed to
guide development of drug combinations since both standard phase II approaches and
phase II-III randomized trials have a high risk of misleading.
Summary
Traditional randomized clinical trials approaches are often inefficient, wasteful,
and unreliable. New clinical research paradigms are needed. The primary outcome of
clinical research should be "Who (if anyone) benefits?" rather than "Does the overall
group benefit?"
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
Background Evaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and HE4 for the diagnosis of epithelial ovarian cancer (EOC) (serous, endometrioid, mucinous)
Blogger's Note: industry sponsored research article
open access
Background
Evaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and HE4 for the diagnosis of epithelial ovarian cancer (EOC).
Conclusions
CA125 remains the best single biomarker for diagnosis and monitoring of ovarian cancer. However, additional markers are sought for use independently or in combination with CA125 to improve the sensitivity for ovarian cancer detection whilst retaining specificity. The current study presents data on the utility of a novel marker, folate receptor alpha, FRA; with respect to discrimination between ovarian cancer, for example, the serous histotype, and normal controls. Further, data was presented for additional markers including MSLN and MPF and the use of these markers in a multi-marker panel that outperforms CA125 alone.
Development of additional markers for use either individually or in a panel for the diagnosis or detection of ovarian cancer, especially early stage disease, is critical. The novel ECL assays described herein provide a powerful tool for such development.
Tuesday, April 16, 2013
(technical) ATP11B mediates platinum resistance in ovarian cancer
open access
Introduction
Platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin have a broad range of activity in malignant diseases and are used to treat many types of cancer (1). Since the introduction of cisplatin into clinical trials almost 40 years ago, this drug has had a major impact on the therapeutic management of several tumors, such as those of the ovary, testes, and head and neck (2). Its cytotoxic mode of action is mediated by its interaction with DNA to form adducts, mostly intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, culminating in the activation of apoptosis (3). Unfortunately, emergence of primary or acquired resistance to platinum agents eventually limits their efficacy (1).The molecular mechanisms of resistance to cisplatin can be broadly divided into 2 main groups: (a) mechanisms that reduce cisplatin accumulation and, thereby, attenuate DNA damage and (b) mechanisms that inhibit propagation of cisplatin-mediated DNA damage signaling to the apoptotic machinery (3). Earlier studies have documented the development of resistance as a result of increased cisplatin efflux (4, 5). Recently, interest in this resistance mechanism has reemerged as new exporter proteins have been identified. For example, the multidrug resistance-associated gene family includes at least 7 (MRP1–MRP7) ABC-membrane proteins that are involved in the cellular efflux of a variety of drugs (6). However, only MRP2 (also known as cMOAT) seems to be important in cisplatin efflux (7). A second important group of proteins associated with cisplatin resistance comprises ATP7A and ATP7B, 2 copper-membrane transporting P-type ATPases that are overexpressed in cisplatin-resistant tumor cells (8, 9). These copper transporters have been shown to be involved in intracellular cisplatin trafficking and export (10, 11).
Here, we undertook a search for candidate genes that could confer cisplatin resistance in cancer cells. Using genomic analyses, we found that ATP11B gene expression was substantially increased in cisplatin-resistant cells. Moreover, ATP11B enhanced cisplatin efflux and ATP11B silencing restored sensitivity of ovarian cancer cells to cisplatin. These findings identify ATP11B as a potential target for overcoming cisplatin resistance.......
Clinical Notes: FDA Turns Up Heat on Compounders
FDA Turns Up Heat on Compounders
Among the deficiencies:
- "Unidentified black particles floating in vials of supposedly sterile medicine"
- Mold in clean rooms
- Workers handling sterile products with their bare hands and wearing nonsterile lab coats
Changes in Symptom Intensity Among Cancer Patients Receiving Outpatient Palliative Care
Abstract
Context
Symptom
changes are usually reported using summary statistics such as mean
and/or median, which may obscure the treatment effect.
Objectives
The
main objective of this retrospective study was to determine the
magnitude of symptom changes as assessed by the Edmonton Symptom
Assessment System (ESAS) after outpatient palliative care at the first
follow-up visit.
Methods
We
reviewed 1612 consecutive patients with cancer who were referred to the
outpatient Supportive Care Center and who completed the ESAS at the
initial and first follow-up visits between January 2003 and December
2010. All patients received interdisciplinary care led by the palliative
care specialists following an institutional protocol.
Results
The
distribution of the magnitude of symptom changes was stratified by
baseline intensities. Patterns were similar for different ESAS items. At
the follow-up visit (median: 15 days later), 52–74% of patients showed a
decrease of one or more points in the ESAS score. However, 48–80% of
the patients with moderate/severe intensity at baseline complained of
symptoms with an ESAS score of four or more after outpatient palliative
care. Symptoms with absent/mild intensity worsened, ranging from a mean
of −3.04 to 0.12 at the first follow-up visit, whereas symptoms with
moderate/severe intensity improved from −0.2 to 3.86 (P < 0.001).
Conclusion
A
considerable proportion of patients with moderate or severe intensity
at baseline still had symptoms with an ESAS score of four or more.
Patients with absent/mild intensities at baseline complained of symptom
exacerbation at the first follow-up visit. Various strategies are needed
to optimize symptom control in advanced cancer.
The EORTC Gynaecological Cancer Group (and co-operative groups)
The EORTC Gynaecological Cancer Group
The EORTC Gynaecological Cancer Group has increased its collaboration with different other groups substantially.
We collaborate with the following groups:
- AGO Austria
- ANZGOG
- Arbeitsgemeinschaft fûr Gynäkologische Onkologie (AGO)
- GINECO
- GEICO
- GOG
- Medical Research Council (MRC)/ NCRN National Cancer Research network (gynaecological cancers)
- NCIC-Canada
- Nordic Society of Gynaecological Oncology (NSGO)
- Scottish Gynaecological Cancer Group
Representatives from each group usually attend the meetings and this is reciprocal whenever possible.
 |
The EORTC Gynaecological Cancer Group is one
of the founding groups of the “European Network of Gynaecological Trial
groups – ENGOT”. More information on ENGOT you can find on the website http://www.esgo.org/Research/Pages/AboutENGOT.aspx.
|
 |
In addition, the EORTC-GCG is one of the founding members
of the Gynaecological Cancer Intergroup (GCIG). In this
group the major multicentric groups studying gynaecological cancer are
represented. Meetings are held twice a year.
|
Does Extensive Upper Abdomen Surgery During Primary Cytoreduction Impact on Long-term Quality of Life?
Abstract
Objectives: The objective of this study was to
evaluate the feasibility in terms of safety and quality of life in a
sample of Italian patients affected by advanced ovarian cancer and
submitted to either extensive upper abdomen or standard surgery, through
validated questionnaires.
Methods: From January 2006 to November 2011, a
prospective, observational study was conducted to compare quality of
life in patients affected by advanced ovarian cancer and submitted to
primary cytoreduction in the Division of Gynecology of the University
Campus Bio-Medico of Rome. After surgery patients were stratified into 2
groups (group A: standard surgery or group B: extensive upper abdomen
surgery). All patients were submitted to standard chemotherapy. At
completion of treatment, during the first follow-up visit, all eligible
patients were asked to fill in Quality of Life Questionnaire-C30
(QLQ-C30) (version 3.0) and European Organisation for Research and
Treatment of Cancer Quality of Life Questionnaire-OV28 (QLQ-OV28)
questionnaires.
Results: Eighty-nine patients were enrolled into our
study. Nine were excluded, so finally 80 patients were considered in
this study. Group A included 40 patients and underwent standard surgery
(pelvic surgery); group B, included 40 patients and underwent extensive
upper abdomen surgery. There were no statistical differences in terms of
major surgical complication rates (15% vs 10%). We registered same
times of beginning of chemotherapy (median, 19 vs 21 days) and no severe
related toxicities. Quality-of-life scores of both questionnaires were
comparable between groups, with the exception of Global Health Status in QLC-30.
Conclusions: Upper abdomen surgery is a feasible and
safe therapeutic option. Patients present same times of beginning of
chemotherapy without an increase in chemorelated toxicities and
experience the same general quality of life.
"A questionnaire can consist of several scales and items. The QLQ-C30 for
example includes five functional scales (physical, role, emotional,
cognitive and social), three symptom scales (fatigue, nausea &
vomiting and pain) and a global health status/QOL scale. Furthermore, it
contains six single items (dyspnoea, insomnia, appetite loss,
constipation, diarrhea and financial difficulties)."
Justices at odds over patents for human genes (BRCA) - CNN.com
CNN.com
updated 5:26 PM EDT, Mon April 15, 2013
Washington (CNN) -- It is a case at the intersection of science and finance, an evolving 21st century dispute that comes down to a simple question: Should the government allow patents for human genes?
The Supreme Court offered
little other than confusion during oral arguments on Monday on nine
patents held by a Utah biotech firm.
Myriad Genetics isolated
two related types of biological material, BCRA-1 and BCRA-2, linked to
increased hereditary risk for breast and ovarian cancer.
At issue is whether
"products of nature" can be treated the same as "human-made" inventions,
and held as the exclusive intellectual property of individuals and
companies.
Mapping genes of breast cancer
Who owns your genes?
A ruling is expected by late June.........
PLOS Biology – open for cancer research | PLOS Biologue
open for cancer research
Cancer can take hold in numerous locations in the body, can metastasize and travel to other sites, and generally results from cumulative mutations in many genes and pathways. Although the (open access) Annual Report to the Nation on the Status of Cancer [1] reports an encouraging overall decline in cancer death rates, many of us will have lost someone, or know someone currently battling with cancer, and it continues to devastate lives.
Despite research and advanced treatment options leading to an increased survival rate for many kinds of cancer, there is still a lot that we don’t understand.
April 15, 2013 - JCO - Precision Oncology - articles included in the special series
Blogger's Note: with the exception of the Overview, full access requires a paid subscription, abstracts are free to view
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
- [PDF]
JCO: Special Series Overview - Precision Oncology
open access
"In this Special Series issue, Journal of Clinical Oncology presents a
systematic assessment of cancer genomic information and its accelerating clinical impact. In the scientific literature and lay press, the
relevant discipline is often called personalized, or precision, cancer
medicine. The word personalized conveys the sense that cancer
genomic data may facilitate rational treatment choices that are tailored
to individual patients. The term precision refers to prospects for enhanced molecular resolution, mechanistic clarity, and therapeutic cogency that may accompany clinical implementation of genomics
technologies. Wehave chosen the term genomics-driven cancer medicine
in recognition of the fact that knowledge that emanates specifically
from the cancer genome will likely continue to direct the opening
act of precision oncology as it plays out in clinical and translational
studies over the next several years......
The issue concludes with a perspective by Mendelsohn,13 who
chronicles the transformation in cancer care over the last 40 years
through the lens of genetics and molecularly targeted therapies. Its
overarching theme, borrowed from a Tahitian painting by Gauguin,
surveys the past, present,andfuture of the genomics-driven paradigm.
Together with the other articles in this Special Series issue, this perspective blends the promise of precision cancer medicine with a sobering reminder of the many obstacles that must be circumvented even to render a thorough test of its inherent hypotheses. Despite the hype, one presently cannot assert with confidence that genomics-driven
medicine will win the day across all cancers. Nonetheless, the confluence
of science, technology, and drug discovery has produced a tractable
investigative path with a reasonable chance to improve the
outcomes of many patients with cancer. From the perspective of
patients and their oncologists who struggle daily with advanced cancer,
the genomics-driven framework seems to echo the Ce´sar Vallejo
poem,14 the content of which speaks of suffering, but the title of which
reads: “I am going to speak of hope.”"
Monday, April 15, 2013
Intraoperative Detection of Lesions Using PET (Positron Emission Tomography) Probe During Secondary Cytoreductive Surgery for Recurrent Ovarian Cancer - Full Text View - ClinicalTrials.gov
ClinicalTrials.gov
ClinicalTrials.gov Identifier:
NCT01826227
First received: April 1, 2013
Last updated: April 5, 2013
Last verified: April 2013
'Art' of Interpersonal Medicine Improves Patient Outcomes
'Art'
".....Patient-centered care can become more contextualized by addressing not only the 'who,' 'what,' and 'why' of health care but also the 'who else,' 'what matters most,' 'where,' 'when,' and 'how' of improving patient outcomes and, in so doing, can fulfill its promise." .....
Farewell Message From the President : International Journal of Gynecologic Pathology
International Journal of Gynecologic Pathology
"The Boston United States and Canadian Academy of Pathology (USCAP) Companion Meeting will mark the end of my 2-year tenure as President of The International Society of Gynecological Pathologists (ISGyP), a society that I inaugurated in 1976 together with my mentor and first President, Dr Robert E. Scully....
" There remains, however, some unfinished business in the way of FIGO staging. Although our intention was to ensure that ISGyP input was included in the process, FIGO brought us in as the staging for carcinomas of the vulva, cervix, and endometrium was nearing completion without pathologists' participation. At that point, all we were able to do was complete uterine sarcoma staging and offer last minute suggestions for the ongoing staging of the aforementioned cancers. Nevertheless, in response to our request that a member of ISGyP should participate in FIGO decisions regarding staging, Dr Sergio Pecorelli, director of the Gynecological Oncology chapter at FIGO, has recently obtained the approval for the formal participation of ISGyP at the FIGO staging committee. There is still work to be carried out in preparing proposals for staging cancers of the ovary, fallopian tube, and trophoblast....
Bill to Imprison Doctors for Aid in Dying Defeated in Montana Legislature -- HELENA, Mont., April 15, 2013 /PRNewswire-USNewswire/ --
Blogger's Note: there have been a number of recent research publications on 'end-of-life' assisted suicide, for those interested, this press release being one of the political/advocacy side; most of the very recent research describes 'assisted-dying' as less prevalent than perceived; a very 'hot' topic amongst many including dying patients and their families and the prevelance of dying within ones' own wishes and with dignity
press release
Senate Reverses Course from Last Week
HELENA, Mont., April 15, 2013 /PRNewswire-USNewswire/ -- The nation's leading end-of-life choice advocacy group, Compassion & Choices, praised the Montana Senate today for reversing course and rejecting a House-passed bill that would imprison doctors for up to 10 years if they provide aid in dying to terminally ill patients. The 27-23 bipartisan vote against the so-called Doctor Imprisonment Act, HB505, came after both Democrats and Republicans spoke out against the legislation. Just last week, the Senate voted 31-17 to approve a motion to "blast" the legislation out of committee to the Senate floor.
"This
bipartisan vote is a win for Montanans and the doctors who honor the
wishes of their terminally ill patients by supporting their choice to
die with dignity on their own terms,".....
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