abstract: Can online learning adequately prepare medical students to undertake a first female pelvic examination?

 

J Obstet Gynaecol Can. 2012 Mar;34(3):264-8.

Source

Department of Obstetrics and Gynaecology, Queen's University, Kingston ON.

Abstract

Objective:
To determine whether a novel web-based learning module could adequately prepare first-year undergraduate medical students to skilfully perform their first female pelvic examination.

Methods:
First-year Queen's University medical students without prior training or experience in female pelvic examination were recruited for this study. After viewing key segments of the learning module, students were evaluated while performing a pelvic examination on a female volunteer using a standardized assessment checklist (total score = 30 points). Descriptive and comparative statistics were generated.

Results:
Forty-five students participated with a mean age of 24 years (range 20 to 40). The mean score (±SD) on the assessment checklist was 23.9 ± 3.6 points, (range 17 to 30). All study participants received a passing grade of ≥ 50% (15/30 points), and 53.3% (24/45) received an honours grade of ≥ 80% (24/30 points). Of the participants, 88.9% (40/45) agreed that they were well prepared for their first female pelvic examination after viewing the training video. Mean scores were similar for male students (23.9, n = 22) and female students (23.8, n = 23) (P = 0.90, t test). Mean scores were not higher in those who watched key segments of the learning module more than once.

Conclusion:
This learning module viewed immediately prior to a simulated clinic session afforded first-year medical students the necessary knowledge and skills to perform a first female pelvic examination. This was accomplished with as little as one viewing, and could lead to savings in organizational costs and instruction time for medical school curricula.

abstract: Genetic Considerations for a Woman's Annual Gynaecological Examination - Obstet Gynaecol Can.

Obstet Gynaecol Can. 2012 Mar;34(3):276-84.

Genetic Considerations for a Woman's Annual Gynaecological Examination.

Source

Calgary AB.

Abstract

Objective: 
To provide the physician with an overview of common genetic conditions that should be considered during a women's annual gynaecological assessment to determine the patient's risk or to initiate specific testing or referral to another subspecialty service, depending on personal or family history.

Options: 
This genetic information can be used for patient education and possible disease and/or mutation screening or diagnosis.

Outcomes: 
The use of this genetic information may allow improved risk-benefit assessment and management at the annual gynaecological examination.

Evidence:
Studies published in English up to and including May 2010 were retrieved through searches of PubMed and the Cochrane Library, using appropriate controlled vocabulary (gynaecological diagnosis, genetic inheritance) and key words (genetic risk, genetic mutation, inheritance, family history, uterus, ovary, endometrial, vagina, colon, gastric, renal, breast, cardiac, thrombophilia, diabetes, epilepsy, leiomyomata uteri). Other literature sources were identified through searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values:
The levels of evidence are not adequate for evidence-based recommendations to be made.

Benefits, harms, and costs: 
This committee opinion will enhance the use of new genetic knowledge and its application to the annual gynaecological care of women. Risk management and diagnostic opportunities for genetic gynaecological conditions will be improved. A more complete understanding of genetic conditions may increase anxiety and psychological stress for women and their families.

Sponsors: Society of Obstetricians and Gynaecologists of Canada.

Recommendations 
The levels of evidence are not adequate for evidence-based recommendations to be made.

JNCI Commentary (open access): CYP2D6 Genotype as a Marker for Benefit of Adjuvant Tamoxifen in Postmenopausal Women: Lessons Learned

Blogger's Note: see extensive references including current papers regarding this issue

 "Since 2003, there has been considerable interest and a good degree of credence given to the role of cytochrome P450 2D6 (CYP2D6) genotyping to predict tamoxifen benefit in adjuvant therapy (1–5). This construct was based on the fact that a variety of CYP2D6 polymorphisms lead to reduced CYP2D6 enzyme activity and hence result in lower plasma concentrations of endoxifen, a clinically active metabolite of tamoxifen.....


"In the end, it is crucial to obtain data from randomized trials for clinical demonstration of associations between biomarkers and disease outcomes. To advance breast cancer therapy, laboratory observations that raise hypotheses must be at the very core of what we do; however, it is only after independent validation that they can begin guide clinical practice."

1. 15.↵
   1. Regan MM,
   2. Leyland-Jones B,
   3. Bouzyk M,
   4. et al

   . CYP2D6 genotype and tamoxifen response in postmenopausal women with estrogen-responsive early breast cancer: the Breast International Group 1-98 Trial. J Natl Cancer Inst. 2012;104(6):441-451.
2. 16.↵
   1. Rae JM,
   2. Drury S,
   3. Hayes DF,
   4. et al

   . CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012;104(6):452-460.

JNCI - The Challenges of Cancer Vaccines

The Challenges of Cancer Vaccines

open access: British Journal of Cancer - Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer (safety, adverse events, disease progression, conflicting research.....)

Blogger's Note: note ties to industry
          
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"Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions.

Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings.

This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth.

Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported."

"This review summarised results from clinical and preclinical studies that evaluated whether ESAs affect disease progression. Although there are important limitations on the quality and assessment of disease progression in these studies, the current meta-analyses suggest no overall effect of ESAs on disease progression. Several individual studies have shown a potential trend associating ESA use with increased disease progression. This suggests that ESAs may affect disease progression in particular cancer patient populations (e.g., head and neck cancer patients receiving radiotherapy only) and that additional research is needed to define these populations and how ESAs mediate this effect. Although indirect effects on tumours induced by increased RBC production are theoretically possible, preclinical data to date suggest that tumour cells either do not express EpoR or express low levels of EpoR molecules that are non-functional and/or are not present at the cell surface. Overall, the balance of current evidence does not support an effect of ESAs on either activating EpoR on tumour cells or indirectly stimulating disease progression via angiogenesis. Future clinical trials, meta-analyses, and preclinical research should provide additional data to guide evidence-based use of ESAs in cancer patients."

NIH launches consumer-friendly tips series on complementary health practices, March 6, 2012 News Release - National Institutes of Health (NIH)

Tuesday, March 6, 2012

NCCAM Press Office

NIH launches consumer-friendly tips series on complementary health practices

A new series of monthly health tips, Time to Talk Tips, will provide consumers with easy-to-read information on complementary health practices. The effort is managed by the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health.A resource in NCCAM's Time to Talk campaign, the series highlights specific health topics, such as the safe use of dietary supplements, natural products used for the flu and colds, and mind and body approaches used to manage symptoms of a variety of conditions.
The series will include simple tips, such as: Taking vitamin C regularly does not reduce the likelihood of getting a cold but may improve some cold symptoms, and some dietary supplements may interact with medications (prescription or over-the-counter) or other dietary supplements.

“An increasing number of consumers and patients use the Internet to answer health questions, yet the information they find can be overwhelming and is not always relevant or credible,” said Josephine P. Briggs, M.D., director of NCCAM. “This series will give people evidence-based facts to help them make more informed health care decisions. Health care providers can also provide these tips to their patients who are interested in learning more about complementary health practices.”

The tips accompany topics found in the NCCAM Clinical Digest, a monthly e-newsletter for health care providers that addresses the state of science on complementary health practices for a variety of health conditions. These same topics will also be discussed in monthly Twitter chats (@NCCAM), allowing the public to interact with the center, ask questions, and receive answers in real time.

Nearly 40 percent of Americans use some form of complementary health practice, according to the 2007 National Health Interview Survey. Through its Time to Talk campaign, NCCAM encourages patients and providers to talk about the use of complementary health practices by offering tools and resources—such as wallet cards and tip sheets—that are available for free at nccam.nih.gov/timetotalk.
To learn more about NCCAM's Time to Talk Tips, visit http://nccam.nih.gov/timetotalk.

The mission of the National Center for Complementary and Alternative Medicine (NCCAM) is to define, through rigorous scientific investigation, the usefulness and safety of complementary and alternative medicine interventions and their roles in improving health and health care. For additional information, call NCCAM’s Clearinghouse toll free (in the U.S.) at 1-888-644-6226, or visit the NCCAM Web site at nccam.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

abstract: Palliative Chemotherapy for Malignant Ascites Secondary to Ovarian Cancer

Am J Hosp Palliat Care. 2012

Palliative Chemotherapy for Malignant Ascites Secondary to Ovarian Cancer.

Source

College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA.

Abstract

Although research has shown that palliative chemotherapy is beneficial compared to lack of treatment (Schorge JO, Schaffer JI, Halvorson LM, et al. ed. Williams Gynecology. New York, NY: McGraw Hill Medical; 2008.), other studies show aggressive end-of-life treatment adversely affects quality of life and shortens life span (Arriba L, Fader A, Frasure H, von Gruenigen V. A review of issues surrounding quality of life among women with ovarian cancer. Gynecol Oncol. 2010;119(2):390-396.).

Without a consensus on palliative chemotherapy, underutilization during end of life prevails, and likely will continue without additional research (Barbera L, Elit L, Krzyzanowska M, et al. End of life care for women with gynecologic cancers. Gynecol Oncol. 2010;118(2):196-201.).

This article aims to evaluate and examine existing chemotherapy for palliation of malignant ascites secondary to ovarian cancer and compare commonly used regimens. Agents will be evaluated by their modes of administration. Oral agents include cyclophosphamide and thalidomide, and intraperitoneal vehicles include taxane-based agents, platinum-based agents, antibiotics, and biologic agents. In addition, cost, ethics, and quality of life discussions factor into this review.

Palliative care's goal is to find a balance between life expectancy and symptom relief with minimal adverse effects.

open access: PLoS Medicine: Injectable and Oral Contraceptive Use and Cancers of the Breast, Cervix, Ovary, and Endometrium in Black South African Women: Case–Control Study

Background

Oral contraceptives are known to influence the risk of cancers of the female reproductive system. Evidence regarding the relationship between injectable contraceptives and these cancers is limited, especially in black South Africans, among whom injectable contraceptives are used more commonly than oral contraceptives.

Study Sample

The Johannesburg Cancer Case Control Study is a large ongoing case–control study recruiting self-defined black (not mixed race/ancestry) male and female cancer patients with all cancer types, conducted at the greater Johannesburg public referral hospitals that offer cancer treatment. Female patients recruited from 8 March 1995 to 31 December 2006 were included in the present analysis.

Table 1. Demographic and risk factor characteristics of case and control participants, according to use of hormonal contraceptives.
doi:10.1371/journal.pmed.1001182.t001
Table 2. Frequencies and adjusted odds ratios for breast, cervical, ovarian, and endometrial cancer according to ever/never oral and injectable contraceptive use combinations.
doi:10.1371/journal.pmed.1001182.t002
Figure 2. Odds ratio for ovarian and endometrial cancer in relation to use of hormonal contraceptives, according to duration of use.
Adjusted OR (95% CI) for (A) ovarian cancer and (B) endometrial cancer in relation to use of oral and injectable contraceptives, adjusted for age at diagnosis, year of diagnosis, education, tobacco smoking, alcohol consumption, parity/age at first birth, number of sexual partners, urban/rural residence, and province of birth. Squares represent ORs, and horizontal lines indicate 95% CI. Diamonds represent the ORs and confidence intervals for the group comprising women from all three exposure categories immediately above.
doi:10.1371/journal.pmed.1001182.g002

  
Conclusions

In this study, use of oral and of injectable hormonal contraceptives was associated with a transiently increased risk of breast and cervical cancer and, for long durations of use, with a reduced risk of ovarian and endometrial cancer. The observed effects of injectable and of oral contraceptives on cancer risk in this study did not appear to differ substantially.

Medpage: LaCroix A, et al "Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial" JAMA 2011; 305: 1305-1314.

Blogger's Note: also see website for video

   ~~~~~~~~~~~~~~~

New WHI Estrogen Analysis Shows Lower Breast Ca Risk

By John Gever, Senior Editor, MedPage Today

Published: April 05, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

• Explain that post-intervention follow-up of the WHI Estrogen-Alone Trial showed that both risks and benefits of unopposed estrogen largely disappeared after therapy stopped.
• Note that while the risk of breast cancer remained decreased for the intervention and post-intervention period combined, the decreased risk during the post-intervention period itself was not statistically significant.

In contrast to other studies of unopposed postmenopausal estrogen therapy, long-term follow-up of Women's Health Initiative (WHI) Estrogen-Alone Trial participants showed a persistent reduction in breast cancer risk, researchers said.

But other benefits and risks associated with use of conjugated equine estrogens (CEE) quickly dissipated after the therapy was stopped, according to Andrea Z. LaCroix, PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

"Considering the entire follow-up period, rates of total mortality and the global index of chronic diseases were essentially the same in the conjugated equine estrogen and placebo groups," LaCroix and co-authors wrote in the April 6 issue of the Journal of the American Medical Association.
"Statistically significant age interactions for conjugated equine estrogen use, suggesting greater safety and possible benefit among women in their 50s and potential harm among older women, were observed for coronary heart disease, total MI, colorectal cancer, total mortality, and the global index of chronic diseases," they added.

An editorial in the same issue suggested more caution in interpreting the breast cancer results.

Medical News:Estrogen Benefit in Breast Cancer Affirmed - in Oncology/Hematology, Breast Cancer from MedPage Today

Medical News:Estrogen Benefit in Breast Cancer Affirmed - in Oncology/Hematology, Breast Cancer from MedPage Today

Action Points

• Explain that reduced breast cancer risk with use of estrogen-only hormone therapy after hysterectomy persists long term.
• Point out that the benefit was concentrated largely among low-risk groups, such as those without benign breast disease or a family history of breast cancer.

Commentary: Oestrogen and breast cancer: results from the WHI trial : The Lancet Oncology

 Blogger's Note: this Lancet Oncology article is subscriber based  ($$$)


Commentary

The Lancet Oncology, Early Online Publication, 7 March 2012

Oestrogen and breast cancer: results from the WHI trial

"In The Lancet Oncology , the Women's Health Initiative (WHI) investigators report 1 that receipt of conjugated equine oestrogen for a median of 5·9 years reduced the risk of invasive breast cancer by 23% compared with placebo (151 cases in 5310 women who received oestrogen vs 199 cases in 5429 controls; p=0·02). Women who did develop breast cancer after receipt of oestrogen had significantly reduced breast cancer-specific mortality (six deaths in the oestrogen group vs 16 deaths in controls; p=0·03) and ..."

The Lancet Oncology: Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial

The Lancet Oncology, Early Online Publication,  

7 March 2012

doi:10.1016/S1470-2045(12)70075-XCite or Link Using DOI

 Feature

The Women's Health Initiative

Women who use the oestrogen-only form of hormone replacement therapy (HRT) appear less likely to develop breast cancer in the longer term, according to new research published in The Lancet Oncology. A follow-up study of over 7500 women from the Women's Health Initiative trial who took oestrogen for about 6 years and then stopped has found that they are over 20% less likely to develop breast cancer and remain significantly less likely to die from the disease than those who never used HRT, a period of nearly 5 years after stopping treatment. The findings are discussed further in a Comment.

 Summary

Background

By contrast with many observational studies, women in the Women's Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort.

Methods

Between 1993 and 1998, the WHI enrolled 10 739  postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50—79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611.

Findings

After a median follow-up of 11·8 years (IQR 9·1—12·9), the use of oestrogen for a median of 5·9 years (2·5—7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62—0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61—1·02) and post-intervention phase effects (0·75, 0·51—1·09).

In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13—0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39—0·97; p=0·04).

Interpretation

Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.

Complete response with pegylated liposomal doxorubicin as a second-line therapy in metastatic ovarian carcinosarcoma: Significance of assessment of the response by FDG-PET 10.1016/j.gynor.2012.02.004 : Gynecologic Oncology Case Reports

".....Furthermore, our case illustrates that the Response Evaluation Criteria in Solid Tumors (RECIST) metric is unreliable in predicting the histopathological treatment response in carcinosarcomas. In our patient, pathological analyses of the tissue removed during the debulking surgery showed more than 75% pathological necrosis, whereas the CT scan revealed stable disease. Furthermore, changes in tumor size evaluated on the CT scan after the treatment with PLD were poorly correlated with the metabolic changes and the tumoral viability (and outcome). A recent study showed that FDG-PET was significantly more accurate than size-based criteria at assessing the histopathological response to neoadjuvant therapy in high-grade, soft-tissue sarcomas (Evilevitch et al., 2008). In our opinion, FDG-PET should be considered as a modality to monitor the treatment response in patients with carcinosarcoma of the ovary.

In conclusion, our case illustrates that PLD might have a role in the treatment of ovarian carcinosarcoma that should be evaluated in future studies. This case also emphasizes the need to monitor the treatment response in these patients with FDG-PET."

Interferon after surgery for women with advanced (Stage II-IV) epithelial ovarian cancer - The Cochrane Library - Lawal - Wiley Online Library

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of interferon after surgery in the treatment of advanced (stage II-IV) epithelial ovarian cancer.

Long-term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance (risk reducing surgery - breasts/bilateral salpino-oophorectomies)

Abstract

BACKGROUND:

For BRCA1/BRCA2 gene testing to benefit public health, mutation carriers must initiate appropriate risk management strategies. There has been little research examining the long-term use and prospective predictors of the full range of risk management behaviors among women who have undergone BRCA1/2 testing. We evaluated long-term uptake and predictors of risk-reducing mastectomy (RRM), risk-reducing bilateral salpingo-oophorectomy (RRBSO), chemoprevention, and cancer screening among women at a mean of 5.3 years after testing.

METHODS:

The study participants comprised 465 women who underwent BRCA1/2 testing. Prior to genetic counseling, we measured family/personal cancer history, sociodemographics, perceived risk, cancer-specific distress, and general distress. We contacted patients at a mean of 5.3 years after testing to measure use of RRM, RRBSO, chemoprevention, and breast and ovarian cancer screening.

RESULTS:

Among participants with intact breasts and/or ovaries at the time of testing, BRCA1/2 carriers were significantly more likely to obtain RRM (37%) and RRBSO (65%) compared with women who received uninformative (RRM, 6.8%; RRBSO, 13.3%) or negative (RRM, 0%; RRBSO, 1.9%) results. Among carriers, precounseling anxiety was associated with subsequent uptake of RRM. RRO was predicted by age. Carriers were also more likely have used breast cancer chemoprevention and have undergone magnetic resonance imaging screening.

CONCLUSION:

This prospective evaluation of the uptake and predictors of long-term management outcomes provides a clearer picture of decision making in this population. At a mean of 5.3 years after testing, more than 80% of carriers had obtained RRM, RRBSO, or both, suggesting that BRCA1/2 testing is likely to have a favorable effect on breast and ovarian cancer outcomes.

Earlier age of onset of BRCA mutation-related cancers (breast and ovarian cancers)... [Cancer. 2012] - PubMed - NCBI

Earlier age of onset of BRCA mutation-related cancers in subsequent generations.

Abstract

BACKGROUND:

Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations.

METHODS:

Of the 132 BRCA-positive women with breast cancer who participated in a high-risk protocol at The University of Texas MD Anderson Cancer Center (Gen 2), 106 women could be paired with a family member in the previous generation (Gen 1) who was diagnosed with a BRCA-related cancer (either breast cancer or ovarian cancer). Age at diagnosis, location of the mutation, and year of birth were recorded. A previously published parametric anticipation model was applied in these genetically predisposed families.

RESULTS:

The median age of cancer diagnosis was 42 years (range, 28-55 years) in Gen 2 and 48 years (range, 30-72 years) in Gen 1.
In the parametric model, the estimated change in the expected age at onset for the entire cohort was 7.9 years. Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer-identified and ovarian cancer-identified families.

CONCLUSIONS:

Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations. The authors concluded that patients who are younger at the onset of BRCA-related cancers should continue to be tracked to offer appropriate screening modalities at appropriate ages.

CureToday.com: Winter 2011 Article - "Connecting the Dots: Why It's So Hard to Pin Down Environmental Causes of Cancer"

 "Connecting the Dots: Why It's So Hard to Pin Down Environmental Causes of Cancer"

"Today, the list of possible environmental carcinogens reads like a catalog of modern conveniences, including cellphones, plastic bottles, styrene in Styrofoam, imported drywall, high-voltage power lines, light at night. Other environmental causes of cancer may be rooted in lifestyle factors, such as obesity, drinking alcohol, a fondness for suntans and smoking. Or infections with viruses and bacteria. In fact, knowing all the ways the environment can conspire to fuel cancer growth, perhaps the real wonder is how so many people can remain cancer-free for so long......

Survey - Cure Magazine/Extra - Do you think environmental factors contributed to your cancer?

Tell CURE what you think!

Do you think environmental factors contributed to your cancer?

Do you think environmental factors contributed to your cancer? Yes No

Submit your answers to see current poll results.

This poll is not conducted scientifically and represents the opinions of site visitors. (to answer yes or no click on the survey below)

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ACP Calls for Colon Cancer Screening at 50 - in Primary Care, Preventive Care from MedPage Today

Action Points

• Explain that colorectal cancer screening should begin at age 50 for all average-risk individuals, according to a new clinical guideline from the American College of Physicians (ACP), and options include fecal occult blood testing (FOBT), flexible sigmoidoscopy, and colonoscopy.
• Point out that high-risk patients should begin screening at 40 (or 10 years younger than the age when the youngest affected relative was diagnosed), and colonoscopy is the recommended screening modality.

A Heart Helper May Come at a Price for the Brain - NYTimes.com

"Statins are the most prescribed drugs in the world, and there is no doubt that for people at high risk of cardiovascular problems, the drugs lower not only cholesterol but also the risk of heart attack and stroke. But for years doctors have been fielding reports from patients that the drugs leave them feeling “fuzzy,” and unable to remember small and big things, like where they left the car, a favorite poem or a recently memorized presentation. Last week, the Food and Drug Administration finally acknowledged what many patients and doctors have believed for a long time: Statin drugs carry a risk of cognitive side effects. The agency also warned users about diabetes risk and muscle pain...........

March 6, 2012 - Screening for Colorectal Cancer: A Guidance Statement From the American College of Physicians (pdf) including high risk

Blogger's Note: if searching for Lynch Syndrome, the older term 'HNPCC' will need to be used


       ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~


"Genetic or clinical diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC): colonoscopy every one to two years beginning at age 20 to 25 years or 10 years before the age of the youngest case in the immediate family."

UK - March is Ovarian Cancer Awareness Month

March is Ovarian Cancer Awareness Month

For Doctors, Luck Can Explain What They Themselves Cannot - NYTimes.com

"The hospital I work at has no 13th floor.

The absence can be a bit awkward to explain to people. I mean, here sits a building at the center of the modern evidence-based scientific empire. Yet as soon as we set foot in the elevator, it is clear that we have decided to hedge our bets a little, and play the dark side too.....

abstract: Knowledge engineering for health: A new discipline required to bridge the ‘ICT Gap’ between research and healthcare

Knowledge engineering for health: A new discipline required to bridge the ‘ICT Gap’ between research and healthcare:

Abstract

Despite vast amounts of money and research being channelled towards biomedical research, relatively little impact has been made on routine clinical practice.
At the heart of this failure is the information and communication technology (ICT) 'chasm' that exists between research and healthcare. A new domain of 'knowledge engineering for health' is needed to facilitate knowledge transmission across the research-healthcare gap. This discipline is required to engineer the bi-directional flow of data: research data and knowledge processed to identify clinically relevant advances and delivered into healthcare use; conversely, outcomes from the practice of medicine made suitably available for use by the research community. This system will be able to self-optimise, in that outcomes for patients treated by decisions that were based on the latest research knowledge will be fed back to the research world. A series of meetings, culminating in the 'I-Health 2011' workshop, have brought together interdisciplinary experts to map the challenges and requirements for such as system. Here we describe the main conclusions from these meetings.
An 'I4Health' interdisciplinary network of experts now exists to promote the key aims and objectives, namely “integrating and interpreting information for individualised healthcare”, by developing the 'knowledge engineering for health' domain.

news: FDA clears UELS contactless breast cancer imaging tool

"UE LifeSciences Inc. plans to offer NoTouch BreastScan™ services to Gynecology, Medical Oncology and Radiology clinics in the U.S. starting from New York, New Jersey and Pennsylvania regions."

Fallopian Tube Removal as a Method of Ovarian Cancer Prevention: A Descriptive Study - Full Text View - ClinicalTrials.gov

Fallopian Tube Removal as a Method of Ovarian Cancer Prevention: A Descriptive Study

This study is currently recruiting participants.

Verified February 2012 by University of Washington

First Received on February 28, 2012. Last Updated on March 2, 2012 History of Changes

Purpose

The purpose of this study is to better understand why women choose to have their fallopian tubes removed as a method for ovarian cancer prevention. This will be done through a paper questionnaire and phone interviews. The investigators hope to gain information that will allow us to better counsel women about ovarian cancer prevention.

Sponsor:	University of Washington
Information provided by (Responsible Party):	Elizabeth Swisher, University of Washington
ClinicalTrials.gov Identifier:	NCT01544049

phase 11 - Trial of Adjuvant FANG™ Vaccine for High Risk Stage IIIc Ovarian Cancer - Full Text View - ClinicalTrials.gov

Primary Outcome Measures:

• To determine and compare time to recurrence (TTR) [ Time Frame: Participants will be followed for life. ] [ Designated as safety issue: No ]
  • To determine and compare time to recurrence (TTR) following the administration of bi-shRNAfurin and GMCSF autologous tumor cell (FANG™) vaccine in high risk patients with stage IIIc ovarian cancer NED following tumor debulking surgery and chemotherapy to standard of care post treatment observation.
  
  

Secondary Outcome Measures:

• Immune Function [ Time Frame: Blood will be collected at baseline, Months 2, 4, 6, 9, 12, 18 and EOT ] [ Designated as safety issue: Yes ]
  • To identify and determine the effect of FANG™ autologous tumor cell vaccine on immune surrogate markers in this group of patients.
  • To enlarge the safety database of FANG™ autologous tumor cell vaccine in patients with minimal disease.
  
  

Estimated Enrollment:	60
Study Start Date:	February 2011
Estimated Study Completion Date:	January 2016
Estimated Primary Completion Date:	February 2014 (Final data collection date for primary outcome measure)

abstract: Alternative and complementary therapies for the menopause

Alternative and complementary therapies for the menopause:

"Despite a re-evaluation of risks in recent years, hormone replacement therapy is still surrounded by controversy. Almost 30% of women in a recent survey sought a natural approach to combat climacteric symptoms. Nevertheless, a large proportion of patients felt that they wanted a good safety profile and strong evidence base for treatment. This article seeks to review the evidence supporting non-hormonal approaches to treatment. There is only conflicting evidence at best to support alpha-2 agonists, e.g. clonidine and limited evidence for dihydroepiandrosterone and natural progesterones. There is limited randomized controlled trial data for gabapentin, selective norepinephrine re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs), many of these studies being related to breast cancer patients. Of the herbal medicinal products, the largest evidence base rests with phytoestrogens. A Cochrane Database review looking at all types of phytoestrogens, e.g. red clover extracts, dietary soya and soya extracts concluded that there was no evidence to support improvement in climacteric symptoms and the meta-analysis of a 178 studies on soy products was inconsistent. Nevertheless, other studies disagree. Mammographic density is not affected by soy or phytoestrogen products and recent in vitro work shows only a weakly proliferative effect of soy isoflavone on breast cancer cells and evidence that soy isoflavone blocks the proliferative effect of estradiol on these cells. There are no studies looking at clinical outcome measures for cardiovascular disease but a number of studies looking at biochemical markers including arterial wall stiffness and apolipo protein B. Recent studies have also looked at the effects of red clover isoflavone on mood and depression, using specific depression rating scales. Finally, it is important to note that herbal medicinal products should not be used without caution. Some may produce quite marked side-effects in high doses and others can interact with pre-existing medication. A strategy for which patients are suitable for herbal medicinal products is reviewed."

Understanding Evidence-based Healthcare: A Foundation for Action | US Cochrane Center - 6 modules

Course Description:
In these six modules, we will illustrate key concepts with compelling real-world examples, covering the following topics and issues. Run times do not take into account interruptions or a second review of selected slides.

• Module 1. INTRO: What is evidence-based healthcare and why is it important? (45 minutes)
• Module 2. ASK: The importance of research questions in evidence based healthcare. (40 minutes)
• Module 3. ALIGN: Research design, bias and levels of evidence. (1 hour)
• Module 4. ACQUIRE: Searching for healthcare information. Assessing harms and benefits. (1 hour 10 minutes)
• Module 5. APPRAISE: Behind the numbers: Understanding healthcare statistics. Science, speed and the search for best evidence. (1 hour 20 minutes)
• Module 6: APPLY: Critical appraisal and making better decisions for evidence-based healthcare, Determining causality. (1 hour)

The Power of Observational Studies (critical commentaries)

The Power of Observational Studies (GoozNews)

(article and responses)

Greg Pawelski

We tend to forget that medicine and most of its discoveries have been observational. .......
I think both Gooznews and Healthnewsreview have been invaluable resources in pointing out the various calamities of health journalism.

abstract - EvidenceUpdates: Cochrane Review: Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy (including professional commentaries)

Abstract

BACKGROUND:  Venous thromboembolism (VTE) often complicates the clinical course of cancer disease. The risk is further increased by chemotherapy but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. OBJECTIVES:  To assess the efficacy and safety of primary thromboprophylaxis in ambulatory cancer patients receiving chemotherapy.  AUTHORS' CONCLUSIONS:   Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. However, the lack of power hampers definite conclusions on the effects on major safety outcomes, which mandates additional studies to determine the risk to benefit ratio of LMWH in this setting.

Comments from Clinical Raters
Oncology - Breast

UK media: Charity calls for ovarian cancer awareness campaign (one percent aware of ovarian cancer symptoms)

"ONLY one per cent of women in the East of England are very confident in noticing symptoms of ovarian cancer, and a leading charity says symptom awareness could prevent needless deaths.....".

"The Target Ovarian Cancer Pathfinder Study 2012 did find the number of women who recognised bloating as a major sympton has nearly doubled from nine per cent to 17 per cent, but in the East of England this was 13 per cent.

The charity said this still compares poorly to other cancers with 76 per cent of women knowing a breast lump is a sign of breast cancer.
Ms Jones said: “The evidence is piling up. Women are being let down by the failure to act in the UK. We need a national awareness campaign now to end needless deaths from this disease......"

Polymorphisms in MSH2 gene and risk of gastric cancer, and interactions with lifestyle factors in a Chinese population ( IVS10+12G>A and IVS12−6T>C )

Polymorphisms inMSH2gene and risk of gastric cancer, and interactions with lifestyle factors in a Chinese population

Background:
Although polymorphisms in DNA mismatch repair (MMR) gene MSH2 have been associated with risks of many cancers, little is known about their etiology role in gastric cancer (GC) and the potential interacting role with lifestyle factors known to damage DNA.

Conclusion:
The IVS10+12G>A and IVS12−6T>C polymorphisms in MSH2 gene appear to be associated with risk of GC in this Chinese population. Risk for GC, stratified by related genotypes, was further modified by drinking, high pickled food or fried food intake. Larger prospective studies are needed to confirm these findings.

FDA U.S. Drug Shortages - Paclitaxel (Taxol)

Paclitaxel Injection (updated 3/2/2012)

Company/Products	Reason	Related Information
Sandoz: 1-800-525-8747 6 mg/mL injection 30 mg/5 mL vial (NDC 66578-0043-01) 100 mg/16.7 mL vial (NDC 66578-0043-02) 300 mg/50 mL vial (NDC 66578-0043-03)	Manufacturing delays	Sandoz is currently on backorder.
APP 1-888-386-1300 6 mg/mL injection 30 mg/5 mL vial (NDC 63323-0763-05) 100 mg/16.7 mL vial (NDC 63323-0763-16) 300 mg/50 mL vial (NDC 63323-0763-50)	Increase in demand	APP is on intermittent back order and is releasing product as it becomes available.
Hospira Inc. Customer Service: 1-877-946-7747 300 mg/50 mL vial (NDC 0409-0342-50) 30 mg/5 mL vial (NDC 0409-0342-09) 100 mg/16.7 mL vial (NDC 0409-0342-22)	Higher than anticipated market demand.	Product 30 mg/5 mL vial (NDC 0409-0342-09): ample levels of inventory to support market demand. Product 300 mg/50 mL vial (NDC 0409-0342-50): next delivery March. Product 100 mg/16.7 mL vial (NDC 0409-0342-22): next delivery April. Please check with your wholesaler for available inventory.
Bedford Laboratories 1-800-562-4797 6 mg/mL injection 30 mg/5 mL vial (NDC 55390-0114-05) 100 mg/16.7 mL vial (NDC 55390-0114-20) 300 mg/50 mL vial (NDC 55390-0114-50)	Manufacturing delays	Bedford has all paclitaxel presentations on backorder and the company cannot estimate a release date.
Teva 1-800-545-8800 6 mg/mL injection 30 mg/5 mL vial (NDC 00703-4764-01) 100 mg/16.7 mL vial (NDC 00703-4766-01) 150 mg/25 mL vial (NDC 00703-4767-01) 300 mg/50 mL vial (NDC 00703-4768-01)	Manufacturing delays	Teva continues to release Paclitaxel 30mg/5mL vial (NDC 00703-4764-01), Paclitaxel 100mg/16.7mL vial (NDC 00703-4766-01), Paclitaxel 150mg/25mL (NDC 00703-4767-01) and Paclitaxel 300mg/50mL (NDC 00703-4768-01) as it becomes available
Sagent Pharmaceticals 1-866-625-1618 30mg/5mL NDC 25021-213-05 100mg/16.7mL NDC 25021-213-17 300mg/50mL NDC 25021-213-50		Sagent has the 5mL and 16.7mL on allocation and the 50mL product is available.

The silent minority - unpublished data on cancer care - Impact Factor - Isseus 46 - Articles - Cancer World

The silent minority - unpublished data on cancer care

From 1989 to 2003, 709 phase III trials evaluating systemic cancer treatment were presented at ASCO meetings. Tam and collaborators have now reported that 9% of these trials were never published, and 13% were published after a five-year delay. More than half of these studies would have had clinical impact if published promptly.

» Daniel F. Hayes

Two key elements of the scientific method are methodology transparency and reproducibility of results by others. Traditionally, these elements have been facilitated by the well-entrenched system of peer-review publication. This concept has had almost universal acceptance among the scientific community, although in the past few years there have been calls for open publication of all scientific results without the peer-review process. Some experts have advocated the creation of a type of ‘free-for-all’ post-publication peer review, with the view that classic, pre-publication peer review is usually selective (based on whom the editor knows and on who actually agrees to referee the article) and arbitrary (based on the respective biases of the reviewers).[1]........

2012 Hormone Therapy Position Statement of the North American Menopause Society (PDF/repost)

POSITION STATEMENT The 2012 Hormone Therapy Position Statement of The North American Menopause Society

FDA: The Quality Problems Causing The Drug Shortage Were Not News To Those Making The Medicines - blog

Dr Len's Cancer Blog:

"Sometimes you have the opportunity to be educated, or to learn a bit more about a topic of importance. Yesterday was one of those opportunities.

Attending a meeting (as an observer) of the National Cancer Institute Director's Consumer Liaison Group on the issue of cancer drug shortages, there were some messages delivered that provided a bit more clarity surrounding a very complex problem. And there were messages delivered that had even me sit up and take notice, and frame the seriousness and depth of the problems that confront patients, their families and those who treat them. The observations were--to say the least--very unsettling.

Try this one, for example:......

[Comment] Offline: Is CDC a science-based organisation? The Lancet

[Comment] Offline: Is CDC a science-based organisation?:

"When we published our first report describing discontent about the work of the Center for Global Health (CGH) at the US Centers for Disease Control and Prevention, CDC immediately contacted us to ask for an opportunity to reply. We agreed and await their response. Meanwhile, two further letters have arrived. They again signal severe concerns about the way in which CDC organises its global health work. Both correspondents are well informed about the details of the CDC's work in global health. Their allegations are serious." (subscription required $$$)

media: Benefits of Bevacizumab in Ovarian Cancer Clarified - Michael J. Birrer, MD, PhD

"Bevacizumab (Avastin) has failed to demonstrate statistically significant improvements in overall survival (OS) for women with recurrent ovarian cancer in 2 recent clinical trials, but those results may be affected by factors not related to the drug’s efficacy, according to Michael J. Birrer, MD, PhD......

[Lancet Oncology News] US firm corners exclusive license for RAD51C cancer gene

[News] US firm corners exclusive license for RAD51C cancer gene:

"Already facing a legal challenge to its BRCA1 and BRCA2 patents, Myriad Genetics (Salt Lake City, UT, USA) has secured an exclusive licence for another breast and ovarian cancer-associated gene, RAD51C, under agreement with the German Consortium for Hereditary Breast and Ovarian Cancers, which will share exclusivity in Germany. RAD51C will be used to test patients' hereditary breast and ovarian cancer risks."

High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway - Japan

Abstract

Purpose: 

High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. 

Experimental Design: 

In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. 

Results: 

An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10⁻²⁰).. ........ Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response–related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. 

Conclusions: 

This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. 

Phase I Study of the Vascular-Disrupting Agent OXi4503

Phase I Study of the Vascular-Disrupting Agent OXi4503:

Purpose:
Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.

Experimental Design:
Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.

Results:
Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m², then expanded cohorts to 15.4 mg/m² in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m² or higher.

Conclusions:
The maximum tolerated dose was 8.5 mg/m² but escalation to 14 mg/m² was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m² and maximum tumor perfusion reductions were seen at doses of 11 mg/m² or higher, the recommended phase II dose is from 11 to 14 mg/m². Clin Cancer Res; 18(5); 1415–25. ©2012 AACR.

Amlodipine (Brand name: Norvasc)

www.nlm.nih.gov

Amlodipine is used alone or in combination with other medications to treat high blood pressure and chest pain (angina). Amlodipine is in a class of medications called calcium channel blockers. It lowers blood pressure by relaxing the blood vessels so the heart does not have to pump as hard. It controls chest pain ...

Side effects - How to take - Precautions - Dietary Instructions - Missed a dose

abstract: Histology-specific long-term trends in the incidence of ovarian cancer and borderline tumor in Japanese females: A population-based study from 1983 to 2007

 Blogger's Views:
there are a number of interesting subjects here - Japan appears historically to have a higher rate of clear cell than other nations; Japan has also studied clear cell ovarian cancer more extensively than elsewhere (for obvious reasons); increasing incidence rates observed in the Japanese population seems to be contrary to other nation's research (eg. stable/declining incidence rates) however the key is in the data compliation (eg. exclusion of LMP; peritoneal cancers), it can be noted however that there has been reported in the North America's that ovarian cancer rates have been increasing but for some unknown (or unpopular?) reason less is known about the reasons for these discrepancies; past blogs have been posted about increasing incident rates; it is unfortunate that this paper is not open access

~~~~~~~~~~~~~~~~~~~~


Histology-specific long-term trends in the incidence of ovarian cancer and borderline tumor in Japanese females: A population-based study from 1983 to 2007 in Niigata:

Abstract

Aim: 
The histology-specific long-term trends in the incidence of ovarian cancer and borderline tumors in Japanese women were examined, based on data from the population-based cancer registry in Niigata, Japan.

Material and Methods: 
Data were obtained from the Niigata Gynecological Cancer Registry, which covered the entire female population in Niigata prefecture, Japan, during the period from 1983 to 2007.

Results: 
A total of 3134 females with epithelial ovarian cancer, including borderline tumor cases, were diagnosed between 1983 and 2007. The age-standardized rates (ASRs) of both ovarian cancer and borderline tumors have steadily increased, with significant changes in ovarian cancer in all age groups, and borderline ovarian tumors in subjects aged <50. The ASRs of endometrioid adenocarcinoma showed a steady increasing trend, and those of clear cell and mucinous adenocarcinomas showed significant increasing trends in the total population. The ASRs of clear cell, mucinous, and endometrioid adenocarcinomas in the 50+ age group were significantly increased, especially the incidence of clear cell adenocarcinoma, which strikingly increased by approximately threefold from 1.2 (1983–1989) to 3.5 (2000–2007) per 100 000 females.

Conclusion: 
This prefecture-wide study showed the practical trends in ovarian cancer and borderline tumors in Japanese females. The incidence of ovarian cancer has steadily increased, with significant increases in the incidence of clear cell and mucinous adenocarcinomas in the total population during the past two decades. Because of the poor response rate of these histological subtypes to platinum-based regimens, novel treatment approaches should be adopted to improve the prognostic outcome in patients with ovarian cancer in Japan.

Bioinformatics and epigenetics - computer-aided cancer diagnosis - medical press

The relatively young research field of epigenetics is the talk of the town. Many scientists expect the research on biochemical modifications beyond the actual DNA strand to lead to huge progress in the understanding of the regulation of gene activity in the years to come. Just how promising the results of epigenetic research are in terms of concrete medical applications is demonstrated by the work of Thomas Lengauer and Christoph Bock from the Max Planck Institute for Informatics in Saarbrücken. With the help of computers, they trawl through the genomes of cancer patients in search for suspect structures, and develop fast and simple new tools for improving cancer diagnosis in hospitals.


"Although Thomas Lengauer regards epigenome analysis as playing a crucial role in the attainment of rapid progress in cancer diagnosis in the near future, he plays down expectations with regard to the development of new drugs. “Many scientists point to the potential of future drugs that can repair defects in the epigenome of diseased cells. I tend to be more cautious in this regard. Such targeted interventions involve significant risks, not least because little or nothing is currently known about the highly-complex gene regulation mechanisms being manipulated here.”"