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1.  Pituitary metastases from papillary carcinoma of thyroid: a case report and literature review 
Metastases to the pituitary gland are an uncommon complication of thyroid cancer. They resemble pituitary neoplasms posing a diagnostic challenge. We present a case of an aggressive non-radioiodine avid papillary thyroid cancer with recurrent pituitary metastases and a review of the literature. A 70-year-old woman with a history of papillary thyroid cancer and bony metastases presented with symptoms of hypoadrenalism and peripheral vision loss. Magnetic resonance imaging showed a large pituitary mass impinging on the optic chiasm. She underwent transsphenoidal resection followed by 131I ablation. Post-therapy scintigraphy showed no iodine uptake in the sellar region or bony metastases. Histology of the pituitary mass confirmed metastatic papillary thyroid cancer. Fifteen months later, she had a recurrence of pituitary metastases affecting her vision. This was resected and followed with external beam radiotherapy. Over 2 years, the pituitary metastases increased in size and required two further operations. Radioactive iodine was not considered due to poor response in the past. Progressively, she developed a left-sided III and IV cranial nerve palsy and permanent bitemporal hemianopia. There was a rapid decline in the patient's health with further imaging revealing new lung and bony metastases, and she eventually died 8 months later. To our knowledge, this is the first case of pituitary metastases from a radioiodine-resistant papillary thyroid cancer. Radioiodine-resistant metastatic thyroid cancer may exhibit rapid aggressive growth and remain poorly responsive to the currently available treatment.
Learning points
Differentiated thyroid cancer (DTC) has an excellent prognosis with <5% of the cases presenting with distant metastases, usually to lung and bone.Metastasis to the pituitary is a rare complication of DTC.The diagnosis of pituitary insufficiency secondary to pituitary metastases from DTC may be delayed due to the non-specific systemic symptoms of underlying malignancy and TSH suppression therapy for thyroid cancer.The imaging characteristics of metastases to the pituitary may be similar to non-functioning pituitary adenoma.Radioiodine refractory metastatic thyroid cancer has significantly lower survival rates compared with radioactive iodine-avid metastases due to limited therapeutic options.
PMCID: PMC3922192  PMID: 24616765
2.  Adrenal metastasis from differentiated thyroid carcinoma documented on post-therapy 131I scan: A case based discussion 
World Journal of Radiology  2014;6(3):56-61.
Adrenal metastasis is an unusual site of disease involvement in the natural course of differentiated thyroid carcinoma (DTC). This paper discusses the clinical and imaging features of DTC with adrenal metastasis. An unusual case of unilateral solitary asymptomatic adrenal metastasis in the setting of DTC is described in this report with the imaging features including 131I scintigraphy and Fluorodeoxyglucose- Positron emission tomography/computed tomography. The adrenal metastasis was associated with other sites of metastatic disease involvement and was unidentified on initial pre-treatment evaluation studies. All such suspicious lesions should be further evaluated with clinicoradiological correlation by other imaging modalities. A post-radioiodine therapy scan revealed radioiodine uptake in the thyroid bed, sternum and a focus of intense radioiodine concentration in the left suprarenal region. Spot oblique images and single photon emission computed tomography of the upper abdomen was undertaken to ascertain the position and better characterization of the lesion. A subsequent whole body PET-CT (non-contrast) was done which revealed a well defined 6.5 cm × 5.0 cm left adrenal lesion with a SUVmax (standardized uptake value-maximum) of 9.5 in addition to a fluorodeoxyglucose avid osteolytic sternal lesion. The serum thyroglobulin level was significantly raised (more than 250 ng/mL) with thyroid stimulating hormone being 4.9 μΙU/mL (even following an adequate period of levothyroxine withdrawal), indicating the functioning nature of the metastases. In addition to demonstrating an atypical site of metastatic disease in DTC patients, this case emphasizes the importance of carefully interpreting and correlating a post radio-iodine therapy scan, particularly those with focal abdominal radio-iodine uptake which could aid in detecting metastatic lesions that are not characterized or identified on initial evaluation. The other important feature that can be deciphered from this report is that an adrenal metastasis could be unilateral and solitary, unlike that of renal metastases which are almost always bilateral and multiple at presentation, although both are usually asymptomatic.
PMCID: PMC3986421  PMID: 24765241
Thyroid carcinoma; Adrenal metastasis; 131I scan; Fluorodeoxyglucose F18; Fused positron emission tomography and computerized tomography
3.  Robotic-Assisted Minimally Invasive Surgery for Gynecologic and Urologic Oncology 
Executive Summary
An application was received to review the evidence on the ‘The Da Vinci Surgical System’ for the treatment of gynecologic malignancies (e.g. endometrial and cervical cancers). Limitations to the current standard of care include the lack of trained physicians on minimally invasive surgery and limited access to minimally invasive surgery for patients. The potential benefits of ‘The Da Vinci Surgical System’ include improved technical manipulation and physician uptake leading to increased surgeries, and treatment and management of these cancers.
The demand for robotic surgery for the treatment and management of prostate cancer has been increasing due to its alleged benefits of recovery of erectile function and urinary continence, two important factors of men’s health. The potential technical benefits of robotic surgery leading to improved patient functional outcomes are surgical precision and vision.
Clinical Need
Uterine and cervical cancers represent 5.4% (4,400 of 81,700) and 1.6% (1,300 of 81,700), respectively, of incident cases of cancer among female cancers in Canada. Uterine cancer, otherwise referred to as endometrial cancer is cancer of the lining of the uterus. The most common treatment option for endometrial cancer is removing the cancer through surgery. A surgical option is the removal of the uterus and cervix through a small incision in the abdomen using a laparoscope which is referred to as total laparoscopic hysterectomy. Risk factors that increase the risk of endometrial cancer include taking estrogen replacement therapy after menopause, being obese, early age at menarche, late age at menopause, being nulliparous, having had high-dose radiation to the pelvis, and use of tamoxifen.
Cervical cancer occurs at the lower narrow end of the uterus. There are more treatment options for cervical cancer compared to endometrial cancer, however total laparoscopic hysterectomy is also a treatment option. Risk factors that increase the risk for cervical cancer are multiple sexual partners, early sexual activity, infection with the human papillomavirus, and cigarette smoking, whereas barrier-type of contraception as a risk factor decreases the risk of cervical cancer.
Prostate cancer is ranked first in men in Canada in terms of the number of new cases among all male cancers (25,500 of 89,300 or 28.6%). The impact on men who develop prostate cancer is substantial given the potential for erectile dysfunction and urinary incontinence. Prostate cancer arises within the prostate gland, which resides in the male reproductive system and near the bladder. Radical retropubic prostatectomy is the gold standard treatment for localized prostate cancer. Prostate cancer affects men above 60 years of age. Other risk factors include a family history of prostate cancer, being of African descent, being obese, consuming a diet high in fat, physical inactivity, and working with cadium.
The Da Vinci Surgical System
The Da Vinci Surgical System is a robotic device. There are four main components to the system: 1) the surgeon’s console, where the surgeon sits and views a magnified three-dimensional image of the surgical field; 2) patient side-cart, which sits beside the patient and consists of three instrument arms and one endoscope arm; 3) detachable instruments (endowrist instruments and intuitive masters), which simulate fine motor human movements. The hand movements of the surgeon’s hands at the surgeon’s console are translated into smaller ones by the robotic device and are acted out by the attached instruments; 4) three-dimensional vision system: the camera unit or endoscope arm. The main advantages of use of the robotic device are: 1) the precision of the instrument and improved dexterity due to the use of “wristed” instruments; 2) three-dimensional imaging, with improved ability to locate blood vessels, nerves and tissues; 3) the surgeon’s console, which reduces fatigue accompanied with conventional laparoscopy surgery and allows for tremor-free manipulation. The main disadvantages of use of the robotic device are the costs including instrument costs ($2.6 million in US dollars), cost per use ($200 per use), the costs associated with training surgeons and operating room personnel, and the lack of tactile feedback, with the trade-off being increased visual feedback.
Research Questions
For endometrial and cervical cancers,
1. What is the effectiveness of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
2. What are the incremental costs of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
For prostate cancer,
3. What is the effectiveness of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
4. What are the incremental costs of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
Research Methods
Literature Search
Search Strategy
A literature search was performed on May 12, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2000 until May 12, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles (January 1, 2000-May 12, 2010)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a primary data source (e.g. obtained in a clinical setting)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a secondary data source (e.g. hospital- or population-based registries)
Study design and methods must be clearly described
Health technology assessments, systematic reviews, randomized controlled trials, non-randomized controlled trials and/or cohort studies, case-case studies, regardless of sample size, cost-effectiveness studies
Exclusion Criteria
Duplicate publications (with the more recent publication on the same study population included)
Non-English papers
Animal or in-vitro studies
Case reports or case series without a referent or comparison group
Studies on long-term survival which may be affected by treatment
Studies that do not examine the cancers (e.g. advanced disease) or outcomes of interest
Outcomes of Interest
For endometrial and cervical cancers,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Number of complications*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of conversions to laparotomy*
Number of lymph nodes recovered
For prostate cancer,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Amount of morphine use/pain*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of transfusions*
- Duration of catheterization
- Number of complications*
- Number of anastomotic strictures*
Number of lymph nodes recovered
Oncologic factors
- Proportion of positive surgical margins
Long-term outcomes
- Urinary continence
- Erectile function
Summary of Findings
Robotic use for gynecologic oncology compared to:
Laparotomy: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations.
The beneficial effect of robotic surgery was shown in pooled analysis for complications, owing to increased sample size.
More work is needed to clarify the role of complications in terms of safety, including improved study designs, analysis and measurement.
Laparoscopy: benefits of robotic surgery in terms of shorter length of hospitalization, less blood loss and fewer conversions to laparotomy likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for length of hospitalizations and blood loss is low.
Fewer conversions to laparotomy indicate clinical effectiveness in terms of reduced morbidity.
Robotic use for urologic oncology, specifically prostate cancer, compared to:
Retropubic surgery: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss/fewer individuals requiring transfusions. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations. There was a beneficial effect in terms of decreased positive surgical margins and erectile dysfunction. These results indicate clinical effectiveness in terms of improved cancer control and functional outcomes, respectively, in the context of study design limitations.
Surgeon skill had an impact on cancer control and functional outcomes.
The results for complications were inconsistent when measured as either total number of complications, pain management or anastomosis. There is some suggestion that robotic surgery is safe with respect to less post-operative pain management required compared to retropubic surgery, however improved study design and measurement of complications need to be further addressed.
Clinical significance of significant findings for length of hospitalizations is low.
Laparoscopy: benefits of robotic surgery in terms of less blood loss and fewer individuals requiring transfusions likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for blood loss is low.
The potential link between less blood loss, improved visualization and improved functional outcomes is an important consideration for use of robotics.
All studies included were observational in nature and therefore the results must be interpreted cautiously.
Economic Analysis
The objective of this project was to assess the economic impact of robotic-assisted laparoscopy (RAL) for endometrial, cervical, and prostate cancers in the province of Ontario.
A budget impact analysis was undertaken to report direct costs associated with open surgery (OS), endoscopic laparoscopy (EL) and robotic-assisted laparoscopy (RAL) based on clinical literature review outcomes, to report a budget impact in the province based on volumes and costs from administrative data sets, and to project a future impact of RAL in Ontario. A cost-effectiveness analysis was not conducted because of the low quality evidence from the clinical literature review.
Hospital costs were obtained from the Ontario Case Costing Initiative (OCCI) for the appropriate Canadian Classification of Health Intervention (CCI) codes restricted to selective ICD-10 diagnostic codes after consultation with experts in the field. Physician fees were obtained from the Ontario Schedule of Benefits (OSB) after consultation with experts in the field. Fees were costed based on operation times reported in the clinical literature for the procedures being investigated. Volumes of procedures were obtained from the Ministry of Health and Long-Term Care (MOHLTC) administrative databases.
Direct costs associated with RAL, EL and OS included professional fees, hospital costs (including disposable instruments), radiotherapy costs associated with positive surgical margins in prostate cancer and conversion to OS in gynecological cancer. The total cost per case was higher for RAL than EL and OS for both gynecological and prostate cancers. There is also an acquisition cost associated with RAL. After conversation with the only supplier in Canada, hospitals are looking to spend an initial 3.6M to acquire the robotic surgical system
Previous volumes of OS and EL procedures were used to project volumes into Years 1-3 using a linear mathematical expression. Burden of OS and EL hysterectomies and prostatectomies was calculated by multiplying the number of cases for that year by the cost/case of the procedure.
The number of procedures is expected to increase in the next three years based on historical data. RAL is expected to capture this market by 65% after consultation with experts. If it’s assumed that RAL will capture the current market in Ontario by 65%, the net impact is expected to be by Year 3, 3.1M for hysterectomy and 6.7M for prostatectomy procedures respectively in the province.
RAL has diffused in the province with four surgical systems in place in Ontario, two in Toronto and two in London. RAL is a more expensive technology on a per case basis due to more expensive robot specific instrumentation and physician labour reflected by increased OR time reported in the clinical literature. There is also an upfront cost to acquire the machine and maintenance contract. RAL is expected to capture the market at 65% with project net impacts by Year 3 of 3.1M and 6.7M for hysterectomy and prostatectomy respectively.
PMCID: PMC3382308  PMID: 23074405
4.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
5.  Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling 
A postpartum diagnosis of breast cancer is an independent predictor of metastases, however the reason is unknown. In rodents, the window of postpartum mammary gland involution promotes tumor progression, suggesting a role for breast involution in the poor prognosis of human postpartum breast cancers. Rodent mammary gland involution is characterized by the programmed elimination of the secretory lobules laid down in preparation for lactation. This tissue involution process involves massive epithelial cell death, stromal remodeling, and immune cell infiltration with similarities to microenvironments present during wound healing and tumor progression. Here, we characterize breast tissue from premenopausal women with known reproductive histories to determine the extent, duration and cellular mechanisms of postpartum lobular involution in women.
Adjacent normal breast tissues from premenopausal women (n = 183) aged 20 to 45 years, grouped by reproductive categories of nulliparous, pregnant and lactating, and by time since last delivery were evaluated histologically and by special stain for lobular area, lobular type composition, apoptosis and immune cell infiltration using computer assisted quantitative methods.
Human nulliparous glands were composed dominantly of small (approximately 10 acini per lobule) and medium (approximately 35 acini per lobule) sized lobules. With pregnancy and lactation, a >10 fold increase in breast epithelial area was observed compared to nulliparous cases, and lactating glands were dominated by mature lobules (>100 acini per lobule) with secretory morphology. Significant losses in mammary epithelial area and mature lobule phenotypes were observed within 12 months postpartum. By 18 months postpartum, lobular area content and lobule composition were indistinguishable from nulliparous cases, data consistent with postpartum involution facilitating regression of the secretory lobules developed in preparation for lactation. Analyses of apoptosis and immune cell infiltrate confirmed that human postpartum breast involution is characterized by wound healing-like tissue remodeling programs that occur within a narrowed time frame.
Human postpartum breast involution is a dominant tissue-remodeling process that returns the total lobular area of the gland to a level essentially indistinguishable from the nulliparous gland. Further research is warranted to determine whether the normal physiologic process of postpartum involution contributes to the poor prognosis of postpartum breast cancer.
PMCID: PMC4053254  PMID: 24678808
6.  Two cases of acrometastasis to the hands and review of the literature 
Current Oncology  2008;15(5):51-58.
This paper reports two cases of acrometastasis to the hands. The first case involved a 78-year-old woman with a permeative osteolytic lesion in her proximal second metacarpal. A biopsy of this lesion suggested a diagnosis of non-small-cell lung carcinoma with secondary osseous metastasis. This was the first presentation of the woman’s primary diagnosis. A single 8-Gy fraction of palliative radiotherapy was delivered to the patient’s left hand. The treatment proved successful: the woman soon experienced pain relief and regained the use of her hand. The second case involved a 69-year-old woman with extensive lytic destruction involving the proximal two thirds of her third metacarpal. This patient had been diagnosed with carcinoma of the breast in 1990. She also received a single 8-Gy fraction of radiation, which improved both her pain and her hand mobility.
An extensive review of the literature uncovered 257 previously reported cases of acrometastasis. Articles were analyzed based on age and sex of the patient, site of the primary carcinoma, metastatic locations within the hand and affected appendage or appendages, the treatment given, and the patient’s length of survival. Men were almost twice as likely to experience acrometastasis as women, and the median age of the patients overall was 58 years (range: 18 months–91 years). Lung, kidney, and breast carcinoma were the three most prevalent primary diagnoses reported in the literature. Cancers of the colon, stomach, liver, prostate, and rectum affected the remainder of the population.
Overall, the right hand was more often host to the metastatic lesions. In addition, almost 10% of the patients experienced lesions in both hands. The third finger was the digit most affected by osseous metastases reported in the literature. Lesions of the thumb, fourth finger, second finger, and fifth finger were less commonly reported. The region of the digit most often affected within the patient population was the distal phalanx. The metacarpal bones, proximal phalanges, and middle phalanges comprised the remainder of the four most frequent acrometastatic sites. In the literature, single lesions were more prevalent than multiple bony lesions.
Based on the reported cases, amputation appeared to be the preferred method of treatment. Radiation, excision, and systemic therapy were the next most frequently used treatments. Patient survival was not well documented within the literature. However, the median survival of patients in the reported cases was 6 months. Thus, our review suggested that a diagnosis of hand metastasis is an indication of poor prognosis.
This report serves to emphasize the importance of properly diagnosing acrometastases. Identifying and effectively treating these metastases in a timely manner can lead to a dramatic improvement in a patient’s quality of life.
PMCID: PMC2582515  PMID: 19008991
Acrometastasis; hand metastasis; bone metastases
7.  The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland 
PLoS Medicine  2006;3(7):e217.
Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.
Methods and Findings
The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11–3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22–4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16–8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.
Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
Editors' Summary
About 13% of women (one in eight women) will develop breast cancer during their lifetime, but many factors affect the likelihood of any individual woman developing this disease, for example, whether she has had children and at what age, when she started and stopped her periods, and her exposure to certain chemicals or radiation. She may also have inherited a defective gene that affects her risk of developing breast cancer. Some 5%–10% of all breast cancers are familial, or inherited. In 20% of these cases, the gene that is defective is BRCA1 or BRCA2. Inheriting a defective copy of one of these genes greatly increases a woman's risk of developing breast cancer, while researchers think that the other inherited genes that predispose to breast cancer—most of which have not been identified yet—have a much weaker effect. These are described as low-penetrance genes. Inheriting one such gene only slightly increases breast cancer risk; a woman has to inherit several to increase her lifetime risk of cancer significantly.
Why Was This Study Done?
It is important to identify these additional predisposing gene variants because they might provide insights into why breast cancer develops, how to prevent it, and how to treat it. To find low-penetrance genes, researchers do case–control association studies. They find a large group of women with breast cancer (cases) and a similar group of women without cancer (controls), and examine how often a specific gene variant occurs in the two groups. If the variant is found more often in the cases than in the controls, it might be a variant that increases a woman's risk of developing breast cancer.
What Did the Researchers Do and Find?
The researchers involved in this study recruited Icelandic women who had had breast cancer and unaffected women, and looked for a specific variant—the Cys557Ser allele—of a gene called BARD1. They chose BARD1 because the protein it encodes interacts with the protein encoded by BRCA1. Because defects in BRCA1 increase the risk of breast cancer, defects in an interacting protein might have a similar effect. In addition, the Cys557Ser allele has been implicated in breast cancer in other studies. The researchers found that the Cys557Ser allele was nearly twice as common in women with breast cancer as in control women. It was also more common (but not by much) in women who had a family history of breast cancer or who had developed breast cancer more than once. And having the Cys557Ser allele seemed to increase the already high risk of breast cancer in women who had a BRCA2 variant (known as BRCA2 999del5) that accounts for 40% of inherited breast cancer risk in Iceland.
What Do These Findings Mean?
These results indicate that inheriting the BARD1 Cys557Ser allele increases a woman's breast cancer risk but that she is unlikely to have a family history of the disease. Because carrying the Cys557Ser allele only slightly increases a woman's risk of breast cancer, for most women there is no clinical reason to test for this variant. Eventually, when all the low-penetrance genes that contribute to breast cancer risk have been identified, it might be helpful to screen women for the full set to determine whether they are at high risk of developing breast cancer. This will not happen for many years, however, since there might be tens or hundreds of these genes. For women who carry BRCA2 999del5, the situation might be different. It might be worth testing these women for the BARD1 Cys557Ser allele, the researchers explain, because the lifetime probability of developing breast cancer in women carrying both variants might approach 100%. This finding has clinical implications in terms of counseling and monitoring, as does the observation that Cys557Ser carriers have an increased risk of a second, independent breast cancer compared to non-carriers. However, all these findings need to be confirmed in other groups of patients before anyone is routinely tested for the BARD1 Cys557Ser allele.
Additional Information.
Please access these Web sites via the online version of this summary at
• MedlinePlus pages about breast cancer
• Information on breast cancer from the United States National Cancer Institute
• Information on inherited breast cancer from the United States National Human Genome Research Institute
• United States National Cancer Institute information on genetic testing for BRCA1 and BRCA2 variants
• GeneTests pages on the involvement of BRCA1 and BRCA2 in hereditary breast and ovarian cancer
• Cancer Research UK's page on breast cancer statistics
In a population-based cohort of 1090 Icelandic patients, a Cys557Ser missense variant of the BARD1 gene, which interacts with BRCA1, increased the risk of single and multiple primary breast cancers.
PMCID: PMC1479388  PMID: 16768547
8.  Functional Radionuclide Imaging, In-Vitro Radioiodine Uptake Estimation and RT-PCR in the Evaluation of Sodium Iodide Symporter (NIS) Expression and Functionality in Breast Cancer: A Pilot Study 
Breast cancer is a common malignancy in females, which is considered as a systemic disease, whose treatment involves combined modality including systemic as well as local treatment. Recent studies have shown that breast cancer also expresses Sodium Iodide Symporter (NIS) gene, like in the thyroid, which is the factor responsible for the uptake of iodide by the thyroid, enabling radioiodine therapy of thyroid disorders. This study aimed to evaluate various radionuclide imaging characteristics, in vitro radioiodine uptake (RAIU) and evaluation of NIS expression by using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) to explore sodium iodide symporter (NIS) expression and iodine uptake in breast cancer and to explor e whether radioiodine can be used for the diagnosis and treatment of breast cancer. Ways of differential regulation of NIS expression in breast cancer has also been explored. Female patients with palpable breast lump and histologically proven infiltrating duct carcinoma were taken up for the study, which included 50 females of mean age 49 years. (range: 23–73 years). The patients were categorized into different groups, depending on the type of the study performed. The uptake patterns in various imaging modalities were analyzed and compared with invitro and RT-PCR studies. 68 % of breast cancer cases showed 99mTc-pertechnetate uptake at the initial images. This finding could partly be due to tumor vascularity, which is usually higher compared to the normal tissues. The uptake in the delayed imaging could be related to that due to NIS in the breast. Use of perchlorate or stable iodine did not alter the pertechnetate uptake pattern in breast tumor. Good correlation between 99mTc-pertechnetate and 99mTc-tetrofosmin uptake in breast cancer was demonstrated. In vitro radioactive iodine uptake in the breast tumor was significantly higher than that in the normal breast tissue. Only 42 % of breast tumor samples studied using RT-PCR showed NIS expression. Correlation between 99mTc-pertechnetate uptake and NIS expression could not be well established. Further studies with higher dose of radioiodine and/or mechanisms of differentially blocking the thyroid are required to assess the feasibility of radioiodine therapy for breast cancer.
PMCID: PMC3578538  PMID: 24426705
Breast carcinoma; Sodium iodide symporter; Radioiodine uptake; Reverse transcriptase-polymerase chain reaction (RT-PCR); 99mTc-pertechnetate
9.  Delayed involution of lactation presenting as a non-resolving breast mass: a case report 
Involution of lactation is a physiological process. Rarely, it may be delayed and troublesome for the lactating woman. Though lactation-induced changes in breast are well known, morphological features of delayed involution are not clear.
Case presentation
We report a case of a 22-year-old lactating mother who presented with a painful, non-resolving breast mass 5 months after delivery. Clinically, it simulated an inflammatory carcinoma. Histopathology, however, revealed involuting lactational changes.
To the best of our knowledge, lactational involution with such a presentation has not been described in the English literature. The case needs to be reported so that this entity can be considered among the differential diagnoses of breast masses in a lactating patient.
PMCID: PMC2572069  PMID: 18851738
10.  Laparoscopic partial nephrectomy of thyroid cancer metastasis: case report and review of the literature 
OncoTargets and therapy  2013;6:355-360.
Follicular cell thyroid carcinoma is a quite aggressive form of thyroid cancer. About 10% of follicular thyroid carcinoma shows multiple metastases: lung and bone are the most common sites of metastasis. Renal involvement from thyroid primary cancer is very rare with incidence of 4.5%–5.9%.
We report the first laparoscopic conservative treatment of renal metastasis from thyroid cancer. This is a new and useful approach in order to delay malignant disease progression and to reduce the surgical discomfort of the patient.
Patients and methods
We present the case of a 67-year-old woman, undergoing total thyroidectomy for follicular thyroid cancer with bone and lung metastasis. During adjuvant radiometabolic treatment, renal metastasis was diagnosed. Renal metastasis showed high metabolic activity, reducing the effectiveness of radioiodine therapy for secondary lesions. For this reason, we performed a laparoscopic simple enucleation of the single renal metastasis using extraperitoneal access and a clampless procedure.
The excision of the renal lesion improved the effectiveness of adjuvant radioiodine therapy: two months after surgery, the patient underwent adjuvant radiometabolic treatment with iodine-131 (150 mCi) and the following whole body scan showed only a small uptaking area at the level of the vertebral metastasis. The lung micrometastases were not detectable. At 36 months follow-up, malignant disease was clinically stable and well controlled.
Minimally invasive renal surgery with preservation of renal function and rapid recovery contributed to the success of radioiodine therapy and delayed the progression of the disease.
PMCID: PMC3627344  PMID: 23596352
follicular thyroid carcinoma; renal metastasis; simple enucleation; laparoscopy; clampless; radiometabolic treatment
11.  Live birth after in vitro fertilization and single embryo transfer in a kidney transplant patient: a case report and review of the literature 
To present a successful case of in vitro fertilization (IVF) and single embryo transfer (SET) in a kidney transplant (NTX) patient and review of the literature.
Case report and review of the literature.
IVF-Unit in a university medical center.
A 31 year-old nulliparous woman with primary infertility and a history of two kidney transplants.
Main outcome measure(s)
Live birth, renal transplant function.
IVF-SET resulted in a pregnancy with labor induction and cesarean delivery in the 37th week of gestation due to rising serum creatinine. There was no significant maternal or fetal morbidity.
Successful IVF-SET is possible in NTX patients. To date, including this case, five cases of IVF in NTX patients have been reported in the literature without an apparently increased renal morbidity.
PMCID: PMC3114966  PMID: 21161364
Kidney transplant; In vitro fertilization; Single embryo transfer
12.  Molecular imaging of potential bone metastasis from differentiated thyroid cancer: a case report 
Molecular imaging of the spine is a rarely used diagnostic method for which only a few case reports exist in the literature. Here, to the best of our knowledge we present the first case of a combination of molecular imaging by single photon emission computer tomography and positron emission tomography used in post-operative spinal diagnostic assessment.
Case presentation
We present the case of a 50-year-old Caucasian woman experiencing progressive spinal cord compression caused by a vertebral metastasis of a less well differentiated thyroid cancer. Following tumor resection and vertebral stabilization, total thyroidectomy was performed revealing follicular thyroid carcinoma pT2 pNxM1 (lung, bone). During follow-up our patient underwent five radioiodine therapy procedures (5.3 to 5.7 GBq each) over a two-year period. Post-therapeutic I-131 scans showed decreasing uptake in multiple Pulmonary metastases. However, following an initial decrease, stimulated thyroglobulin remained at pathologically increased levels, indicating further neoplastic activity. F18 Fludeoxyglucose positron emission tomography, which was performed in parallel, showed remaining hypermetabolism in the lungs but no hypermetabolism of the spinal lesions correlating with the stable neurological examinations. While on single photon emission computer tomography images Pulmonary hyperfixation of I-131 disappeared (most likely indicating dedifferentiation), there was persistent spinal hyperfixation at the operated level and even higher fixation at the spinal process of L3. Based on the negative results of the spinal F18 fludeoxyglucose positron emission tomography, a decision was made not to operate again on the spine since our patient was completely asymptomatic and the neurological risk seemed to be too high. During further follow-up our patient remained neurologically stable.
Molecular imaging by F18 fludeoxyglucose positron emission tomography helps to exclude metabolically active spinal metastases and to spare further risky surgery.
PMCID: PMC3214152  PMID: 22018056
13.  False-positive uptake on radioiodine whole-body scintigraphy: physiologic and pathologic variants unrelated to thyroid cancer 
Radioiodine whole-body scintigraphy (WBS), which takes advantage of the high avidity of radioiodine in the functioning thyroid tissues, has been used for detection of differentiated thyroid cancer. Radioiodine is a sensitive marker for detection of thyroid cancer; however, radioiodine uptake is not specific for thyroid tissue. It can also be seen in healthy tissue, including thymus, breast, liver, and gastrointestinal tract, or in benign diseases, such as cysts and inflammation, or in a variety of benign and malignant non-thyroidal tumors, which could be mistaken for thyroid cancer. In order to accurately interpret radioiodine scintigraphy results, one must be familiar with the normal physiologic distribution of the tracer and frequently encountered physiologic and pathologic variants of radioiodine uptake. This article will provide a systematic overview of potential false-positive uptake of radioiodine in the whole body and illustrate how such unexpected findings can be appropriately evaluated.
PMCID: PMC3477738  PMID: 23133823
Differentiated thyroid cancer; radioiodine; I-131; I-123; whole-body scintigraphy; false-positive; physiologic uptake; pathologic uptake
14.  Primary lymphoma of the breast involving both axillae with bilateral breast carcinoma 
Primary Non-Hodgkin's Lymphoma (PHNL) of the breast is a rare entity, while secondary involvement of the breast with diffuse disease of Non-Hodgkin's lymphoma (NHL) is more common. However, PNHL is the most frequent haematopoietic tumour of the breast. Diagnostic criteria for PNHL of the breast are presence of technically adequate pathologic specimens, close association of mammary tissue and lymphomatous infiltrate, no prior diagnosis of an extarammamary lymphoma, and no evidence of concurrent widespread disease, except for ipsilateral axillary lymph nodes if concomitant with the primary lesion.
Case presentation
A 57-year-old woman was recalled because her screening mammograms revealed three separate lesions in her right breast and one in the left. Histology of the lesions confirmed lymphoma in one breast with ductal carcinoma in the other.
Most of reported cases in literature have been involving the right breast, and almost all the patients were females. NHLs of the breast typically present as unilateral mass; the frequency of bilateral disease at first presentation ranges from 5–25%. Our objective is to report a case of primary lymphoma of the breast involving both axillae with concomitant bilateral primary breast cancer which has not been reported yet to our best of knowledge in literature.
PMCID: PMC2405783  PMID: 18492251
15.  The protective role of pregnancy in breast cancer 
Breast Cancer Research  2005;7(3):131-142.
Epidemiological, clinical, and experimental data indicate that the risk of developing breast cancer is strongly dependent on the ovary and on endocrine conditions modulated by ovarian function, such as early menarche, late menopause, and parity. Women who gave birth to a child when they were younger than 24 years of age exhibit a decrease in their lifetime risk of developing breast cancer, and additional pregnancies increase the protection. The breast tissue of normally cycling women contains three identifiable types of lobules, the undifferentiated Lobules type 1 (Lob 1) and the more developed Lobules type 2 and Lobules type 3. The breast attains its maximum development during pregnancy and lactation (Lobules type 4). After menopause the breast regresses in both nulliparous and parous women containing only Lob 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women indicates that Lob 1 in these two groups of women might be biologically different, or might exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that Lob 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and are therefore susceptible to undergo neoplastic transformation. These epithelial cells are called Stem cells 1, whereas Lob 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the contrary, are composed of an epithelial cell population that is refractory to transformation, called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the 'genomic signature' that differentiates Lob 1 of the early parous women from that of the nulliparous women by shifting the Stem cells 1 to Stem cells 2 that are refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full-term pregnancy. The identification of a putative breast stem cell (Stem cells 1) has, in the past decade, reached a significant impulse, and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although further work needs to be carried out in order to better understand the role of the Stem cells 2 and their interaction with the genes that confer them a specific signature, collectively the data presently available provide evidence that pregnancy, through the process of cell differentiation, shifts Stem cells 1 to Stem cells 2 – cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis.
PMCID: PMC1143568  PMID: 15987443
16.  Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland 
Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor, and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women) showed minimal OCT4 nuclear expression (0.9%). However, this increased in the normal lactating breast (11.4%), with further increase in lactating adenomas, lactating carcinomas, and pregnancy-associated breast cancer (30.7–48.3%). OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs) demonstrated upregulation of OCT4, SOX2, and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the normal remodeling of the breast toward a milk-secretory organ during pregnancy and lactation. Deregulation of this gene network either within or outside pregnancy and lactation may lead to aberrant breast cell proliferation and malignant transformation, suggesting a role of these genes in both normal lactation and breast oncogenesis.
PMCID: PMC3622876  PMID: 23596564
mammary gland; breastmilk; breast cancer; transcription factors; OCT4; adult stem cell; cancer stem cell; self-renewal
17.  Hyperreactio luteinalis with preeclampsia 
Hyperreactio luteinalis (HL) is a condition associated with bilateral and, in rare cases, unilateral ovarian enlargement due to theca lutein cysts. HL is a benign condition, usually found incidentally at cesarean section, which can appear anaplastic and lead to unnecessary ovarian resection. A 24-year-old woman with 35 weeks of gestation attended with bilaterally enlarged ovaries. She had preeclampsia and preterm contractions. Due to breech presentation of baby and nulliparity and possible severe preeclampsia, she delivered by cesarean section. The ovaries had an anaplastic appearance and a biopsy was taken during cesarean section. Pathology revealed multiple benign theca lutein cysts. There are 51 reported cases of HL associated with a normal pregnancy in the literature. It is estimated that approximately 60% of the cases of HL is not associated with trophoblastic disease and occurs with normal singleton pregnancy. Only three of them were found to be associated with preeclampsia and this is the fourth case. HL may help explain the underlying cause of preeclampsia in these cases. There are multiple benign ovarian lesions in HL, which can mimic ovarian neoplasms. Accordingly, it is important to exclude these from the differential diagnosis via a wedge biopsy and frozen section to avoid unnecessary surgical excision.
PMCID: PMC2938501  PMID: 20930978
Hyperreactio luteinalis; preeclampsia; pregnancy
18.  Perfluorinated compounds and subfecundity in pregnant women 
Epidemiology (Cambridge, Mass.)  2012;23(2):257-263.
Perfluorinated compounds are ubiquitous pollutants; epidemiologic data suggest they may be associated with adverse health outcomes, including subfecundity. We examined subfecundity in relation to two perfluorinated compounds, perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA).
This case-control analysis included 910 women enrolled in the Norwegian Mother and Child Cohort Study in 2003 and 2004. Around gestational week 17, women reported their time to pregnancy and provided blood samples. Cases consisted of 416 women with a time to pregnancy greater than 12 months, considered subfecund. Plasma concentrations of perfluorinated compounds were analyzed using liquid chromatography-mass spectrometry. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each pollutant quartile using logistic regression. Estimates were further stratified by parity.
The median plasma concentration of PFOS was 13.0 ng/ml (interquartile range [IQR]=10.3-16.6 ng/ml) and of PFOA was 2.2 ng/ml (IQR=1.7-3.0 ng/ml). The relative odds of subfecundity among parous women was 2.1 (95% CI=1.2-3.8) for the highest PFOS quartile and 2.1 (1.0-4.0) for the highest PFOA quartile. Among nulliparous women, the respective relative odds were 0.7 (0.4-1.3) and 0.5 (0.2-1.2).
Previous studies suggest that the body burden of perfluorinated compounds decreases during pregnancy and lactation through transfer to the fetus and to breast milk. Afterwards, the body burden may rise again. Among parous women, increased body burden may be due to a long interpregnancy interval rather than the cause of a long time to pregnancy. Therefore, data from nulliparous women may be more informative regarding toxic effects of perfluorinated compounds. Our results among nulliparous women did not support an association with subfecundity.
PMCID: PMC3276687  PMID: 22081060
19.  Evaluation of an anti-p185HER2 (scFv-CH2-CH3)2 fragment following radioiodination using two different residualizing labels: SGMIB and IB-Mal-D-GEEEK 
Nuclear medicine and biology  2009;36(6):671-680.
A 105 kDa double mutant single-chain Fv-Fc fragment (scFv-Fc DM) derived from the anti-p185HER2 hu4D5v8 antibody (trastuzumab; Herceptin™) has been described recently. The goal of this study was to investigate whether improved tumor targeting could be achieved with this fragment through the use of residualizing radioiodination methods.
The scFv-Fc DM fragment was radioiodinated using N-succinimidyl 4-guanidinomethyl 3-[131I]iodobenzoate ([131I]SGMIB) and N-(3-[131I]iodobenzoyl)-Lys5-N- maleimido-Gly 1-GEEEK ([131I]IB-Mal-D-GEEEK), two residualizing radioiodination agents that have been used successfully with intact antibodies. Paired-label internalization assays of the labeled fragments were performed in vitro using MCF7 human breast cancer cells transfected to express HER2 (MCF7-HER2); comparisons were made to scFv-Fc DM directly radioiodinated using Iodogen. The tissue distribution of the scFv-Fc DM labeled with [125I]IB-Mal-D-GEEEK and [131I]SGMIB was compared in athymic mice bearing MCF7-HER2 xenografts.
The scFv-Fc DM fragment was labeled with [131I]SGMIB and [131I]IB-Mal-D-GEEEK in conjugation yields of 53% and 25%, respectively, with preservation of immunoreactivity for HER2. Internalization assays indicated that labeling via SGMIB resulted in a 1.6- to 3.5-fold higher (p < 0.05) retention of radioactivity, compared to that from the directly labeled fragment, in HER2-expressing cells during a 24 h observation period. Likewise, the amount of radioactivity retained in cells from the IB-Mal-D-GEEEK-labeled fragment was 1.4- to 3.3-fold higher (p < 0.05). Tumor uptake of radioiodine activity in athymic mice bearing MCF7-HER2 xenografts in vivo was significantly higher for the [125I]IB-Mal-D-GEEEK-labeled scFv-Fc DM fragment compared with that of the [131I]SGMIB-labeled fragment, particularly at later time points. The uptake of 125I was 3-fold (3.6 ± 1.1%ID/g versus 1.2 ± 0.4%ID/g) and 4-fold (3.1 ± 1.7%ID/g versus 0.8 ± 0.4%ID/g) higher than that for 131I at 24 and 48 h, respectively. However, the [125I]IB-Mal-D-GEEEK-labeled scFv-Fc DM fragment also exhibited considerably higher levels of radioiodine activity in liver, spleen and kidney.
The overall results further demonstrate the potential utility of these two prosthetic groups for the radiohalogenation of internalizing monoclonal antibodies and their fragments. Specifically, the trastuzumab-derived double mutant fragment in combination with these residualizing agents warrants further evaluation for imaging and possibly treatment of HER2 expressing malignancies.
PMCID: PMC2720881  PMID: 19647173
HER2; radioiodination; monoclonal antibody; internalization
20.  Extremely high doses of radioiodine required for treatment of Graves’ hyperthyroidism: a case report 
Cases Journal  2009;2:8479.
Radioactive iodine (131I) is widely prescribed for treatment of Graves’ disease. A dose of 370 to 555 MBq (10 to 15 mCi) is usually enough, but reports of improved remission rates with single doses up to 20-30 mCi, and 38.5 mCi at most, exist.
Case presentation
A 53-year-old male patient was evaluated in September 2005, with symptoms of thyrotoxicosis for 2 years. He presented with tachycardia (130 bpm) and a large goiter. Thyrotropin was <0.01 uIU/ml (0,41-4,5), free thyroxin >7.77 ng/dl (0.9-1.8), anti-thyreoperoxidase antibody: 374 IU/ml (<35) and anti-thyroglobulin antibody: 749 IU/ml (<115). Ultrasound: diffuse goiter, no nodules; right lobe: 7.9 × 3.8 × 3.8 cm; left: 7.7 × 3.5 × 3.8 cm; isthmus: 1.6 cm. Propylthiouracil 300 mg t.i.d. and propranolol were prescribed. Thyroid 99mTc-pertechnetate uptake: 52% (0.35-1.7%) and estimated thyroid volume: 149 mL. After 30 days, he received 555 MBq (15 mCi) of 131I-iodide. Six months after radioiodine therapy, under methimazole 40 mg, thyroid stimulating hormone was 1.5 uIU/ml; free thyroxine 0.54 ng/dl. Methimazole was suspended. In 21 days, thyroid stimulating hormone was 0.03 uIU/ml; free thyroxine 0.96 ng/dl. Methimazole was reintroduced. One year later, thyroid stimulating hormone was <0.01 uIU/ml and free thyroxine >7.77 ng/dl. Thyroid 99mTc-pertechnetate uptake was 45% and estimated thyroid volume 144 mL. A 1110 MBq (30 mCi) radioiodine therpy was administered. He used Methimazole for 8 months, when overt hypothyroidism appeared (TSH: 25.30 uIU/ml; free thyroxine: 0.64 ng/dl). Methimazole was interrupted. Hyperthyroidism returned 6 weeks later (thyroid stimulating hormone <0.01 uIU/ml; free thyroxine >7.77 ng/dl). Thyroid 99mTc-pertechnetate uptake was 25% and estimated thyroid volume 111 mL. Methimazole was prescribed again. In March 2008 he received a 2590 MBq (70 mCi) radioiodine therapy. By may/2008, under methimazole 20 mg, his TSH was 0.07 uIU/ml; free thyroxine 1.31 ng/dl. In October 2008 he presented overt hypothyroidism (TSH 91.6 uIU/ml; free thyroxine 0.34) and was given levothyroxine 75 mcg/day. He remains euthyroid under hormone replacement.
Our presented case of Graves’ disease received a cumulative dose of 4255 MBq (115 mCi). The high uptake could indicate accelerated iodine turnover with 131I short time of action. Impaired hormone synthesis could also be present. We believe the extremely high dose required was due to the initial very high iodine uptake and large thyroid volume.
PMCID: PMC2769445  PMID: 19918435
21.  Smoking and high-risk mammographic parenchymal patterns: a case-control study 
Breast Cancer Research  1999;2(1):59-63.
Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
Overall, epidemiological studies [1,2,3,4] have reported no substantial association between cigarette smoking and the risk of breast cancer. Some studies [5,6,7] reported a significant increase of breast cancer risk among smokers. In recent studies that addressed the association between breast cancer and cigarette smoking, however, there was some suggestion of a decreased risk [8,9,10], especially among current smokers, ranging from approximately 10 to 30% [9,10]. Brunet et al [11] reported that smoking might reduce the risk of breast cancer by 44% in carriers of BRCA1 or BRCA2 gene mutations. Wolfe [12] described four different mammographic patterns created by variations in the relative amounts of fat, epithelial and connective tissue in the breast, designated N1, P1, P2 and DY. Women with either P2 or DY pattern are considered at greater risk for breast cancer than those with N1 or P1 pattern [12,13,14,15]. There are no published studies that assessed the relationship between smoking and mammographic parenchymal patterns.
To evaluate whether mammographic parenchymal patterns as classified by Wolfe, which have been positively associated with breast cancer risk, are affected by smoking. In this case-control study, nested within the European Prospective Investigation on Cancer in Norfolk (EPIC-Norfolk) cohort [16], the association between smoking habits and mammographic parenchymal patterns are examined. The full results will be published elsewhere.
Study subjects were members of the EPIC cohort in Norwich who also attended the prevalence screening round at the Norwich Breast Screening Centre between November 1989 and December 1997, and were free of breast cancer at that screening. Cases were defined as women with a P2/DY Wolfe's mammographic parenchymal pattern on the prevalence screen mammograms. A total of 203 women with P2/DY patterns were identified as cases and were individually matched by date of birth (within 1 year) and date of prevalence screening (within 3 months) with 203 women with N1/P1 patterns who served as control individuals.
Two views, the mediolateral and craniocaudal mammograms, of both breasts were independently reviewed by two of the authors (ES and RW) to determine the Wolfe mammographic parenchymal pattern.
Considerable information on health and lifestyle factors was available from the EPIC Health and Lifestyle Questionnaire [16]. In the present study we examined the subjects' personal history of benign breast diseases, menstrual and reproductive factors, oral contraception and hormone replacement therapy, smoking, and anthropometric information such as body mass index and waist:hip ratio.
Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression [17], and were adjusted for possible confounding factors.
The characteristics of the cases and controls are presented in Table 1. Cases were leaner than controls. A larger percentage of cases were nulliparous, premenopausal, current hormone replacement therapy users, had a personal history of benign breast diseases, and had had a hysterectomy. A larger proportion of controls had more than three births and were current smokers.
Table 2 shows the unadjusted and adjusted OR estimates for Wolfe's high-risk mammographic parenchymal patterns and smoking in the total study population and in postmenopausal women separately. Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern (OR 0.37, 95% CI 0.14-0.94). Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results were still strongly suggestive. There was no interaction between cigarette smoking and body mass index.
In the present study we found a strong inverse relationship between current smoking and high-risk mammographic parenchymal patterns of breast tissue as classified by Wolfe [12]. These findings are not completely unprecedented; Greendale et al [18] found a reduced risk of breast density in association with smoking, although the magnitude of the reduction was unclear. The present findings suggest that this reduction is large.
Recent studies [9,10] have suggested that breast cancer risk may be reduced among current smokers. In a multicentre Italian case-control study, Braga et al [10] found that, relative to nonsmokers, current smokers had a reduced risk of breast cancer (OR 0.84, 95% CI 0.7-1.0). These findings were recently supported by Gammon et al [9], who reported that breast cancer risk in younger women (younger than 45 years) may be reduced among current smokers who began smoking at an early age (OR 0.59, 95% CI 0.41-0.85 for age 15 years or younger) and among long-term smokers (OR 0.70, 95% CI 0.52-0.94 for those who had smoked for 21 years or more).
The possible protective effect of smoking might be due to its anti-oestrogenic effect [1,2,19]. Recently there has been renewed interest in the potential effect of smoking on breast cancer risk, and whether individuals may respond differently on the basis of differences in metabolism of bioproducts of smoking [20,21]. Different relationships between smoking and breast cancer risk have been suggested that are dependent on the rapid or slow status of acetylators of aromatic amines [20,21]. More recent studies [22,23], however, do not support these findings.
The present study design minimized the opportunity for bias to influence the findings. Because subjects were unaware of their own case-control status, the possibility of recall bias in reporting smoking status was minimized. Systematic error in the assessment of mammograms was avoided because reading was done without knowledge of the risk factor data. Furthermore, the associations observed are unlikely to be explained by the confounding effect of other known breast cancer risk factors, because we adjusted for these in the analysis. We did not have information on passive smoking status, however, which has recently been reported to be a possible confounder [5,6,21,24].
The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate smoking as a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It seems that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
PMCID: PMC13911  PMID: 11056684
mammography; screening; smoking; Wolfe's parenchymal patterns
22.  Induction of Sodium/Iodide Symporter (NIS) Expression and Radioiodine Uptake in Non-Thyroid Cancer Cells 
PLoS ONE  2012;7(2):e31729.
This study was designed to explore the therapeutic potential of suppressing MAP kinase and PI3K/Akt pathways and histone deacetylase (HDAC) to induce the expression of sodium/iodide symporter (NIS) and radioiodine uptake in non-thyroid cancer cells.
We tested the effects of the MEK inhibitor RDEA119, the Akt inhibitor perifosine, and the HDAC inhibitor SAHA on NIS expression in thirteen human cancer cell lines derived from melanoma, hepatic carcinoma, gastric carcinoma, colon carcinoma, breast carcinoma, and brain cancers. We also examined radioiodine uptake and histone acetylation at the NIS promoter in selected cells.
Overall, the three inhibitors could induce NIS expression, to various extents, in melanoma and all the epithelial carcinoma-derived cells but not in brain cancer-derived cells. SAHA was most effective and its effect could be significantly enhanced by RDEA119 and perifosine. The expression of NIS, at both mRNA and protein levels, was most robust in the melanoma cell M14, hepatic carcinoma cell HepG2, and the gastric carcinoma cell MKN-7 cell. Radioiodine uptake was correspondingly induced, accompanied by robust increase in histone acetylation at the NIS promoter, in these cells when treated with the three inhibitors.
This is the first demonstration that simultaneously suppressing the MAP kinase and PI3K/Akt pathways and HDAC could induce robust NIS expression and radioiodine uptake in certain non-thyroid human cancer cells, providing novel therapeutic implications for adjunct radioiodine treatment of these cancers.
PMCID: PMC3281006  PMID: 22359623
23.  The Sodium Iodide Symporter (NIS): Regulation and Approaches to Targeting for Cancer Therapeutics 
Pharmacology & therapeutics  2012;135(3):355-370.
Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.
PMCID: PMC3408573  PMID: 22750642
Sodium iodide symporter; thyroid cancer; breast cancer; Transcriptional regulation; Posttranslational regulation
24.  Vulvar lactating adenoma associated to a fibroadenoma: common neoplasms in an uncommon site 
Ectopic breast tissue is defined as glands located outside of the breast. Ectopic breast tissue should be excised because it may develop benign (fibroadenoma) or malignant pathologic processes. Less than forty cases of fibroadenomas have been reported in the literature. Although lactation changes can occur, lactating adenoma in the vulva are extremely rare. Only four cases have been reported. We report a case of a young woman who presented with vulvar mass during her lactation. The mass was excised, and histology confirmed vulvar lactating adenoma associated with fibroadenoma. This is the first case of vulvar heterotopic breast lesion associating lactating adenoma and fibroadenoma.
PMCID: PMC3542777  PMID: 23330038
Ectopic breast tissue; vulva; lactating adenoma; fibroadenoma; pathology
25.  F-18 fluorodeoxyglucose positron emission tomography and/or computed tomography findings of an unusual breast lymphoma case and concurrent cervical cancer: a case report 
Breast lymphoma accounts for less than 1% of all non-Hodgkin's lymphomas and approximately 0.1% of all breast neoplasms. Most breast lymphomas are classified as diffuse large B-cell lymphomas or as mucosa associated lymphoid tissue lymphomas. Concurrent cases of breast lymphoma and cervical cancer are extremely rare.
Case presentation
We report a case of a 46-year-old woman of unknown ethnic origin diagnosed with concurrent diffuse large B-cell lymphoma of the breast and squamous cell cancer of the cervix that was detected and followed with F-18 fluorodeoxyglucose (FDG) positron emission tomography and/or computed tomography (PET/CT). The metastatic pattern of this case of breast lymphoma is similar to that of a typical metastatic breast carcinoma. These findings have never been described in the literature. PET/CT also demonstrated an incidentally intense FDG focus in the uterine cervix ultimately leading to the pathologic diagnosis of squamous cell carcinoma of the uterine cervix. An appropriate staging of breast lymphoma and cervical cancer with FDG PET/CT is important because of therapeutic consequence. This case report and review of the literature highlights the role of FDG PET/CT in staging and restaging of both breast lymphoma and cervical cancer.
We report a case of a breast lymphoma with a metastatic pattern similar to that of typical metastatic breast carcinoma. The FDG PET/CT scan also diagnosed a rare case of concurrent breast lymphoma and cervical cancer. This concurrence has not been reported previously in the medical literature.
PMCID: PMC2933636  PMID: 20727168

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