Power Doppler of the Urethra in Continent or Incontinent, Pre- and Postmenopausal Women

Urethral pressure should exceed bladder pressure, both at rest and on stress, for urinary continence to occur. A decrease in urethral pressure is a major factor explaining the pathogenesis of urinary incontinence. A number of elements, such as smooth and striated periurethral muscles, and connective, vascular and elastic tissues, contribute to urethral pressure. The periurethral vessels are influenced by hormonal changes during the menstrual cycle, during pregnancy and postmenopause. We studied the periurethral vessels in 97 women, 57 of whom were incontinent and 40 continent, using power color Doppler velocimetry. The number of periurethral vessels, systolic peak, minimum diastolic values, pulsatility and resistance indexes, as well as systolic–diastolic ratio, were assessed. Statistically significant differences were found between incontinent women in the premenopausal period and those in the postmenopausal period, regarding the number of periurethral vessels, systolic peak, minimum diastolic values, pulsatility and resistance indexes.     

Changing role of the oestrogen receptor in the life and death of breast cancer cells

The oestrogen receptor (ER) has proven to be an extraordinarily successful target for breast cancer treatment and prevention. The clinical use of tamoxifen, a nonsteroidal antioestrogen, demonstrated (1) that the strategic use of adjuvant tamoxifen in ER-positive patients could save lives and (2) that a selective ER modulator (SERM) could reduce the incidence of breast cancer in high-risk women. The ER is now the target for new and safer therapies such as the aromatase inhibitors and the pure antioestrogens that either block oestrogen synthesis or destroy the ER. However, the use of raloxifene, a SERM to prevent osteoporosis with the potential to prevent breast cancer has introduced a new dimension into preventive oncology. The widespread use of endocrine modulators (SERMs, aromatase inhibitors, and pure antioestrogens) raised the question of drug resistance. It is now clear that endocrine resistance can evolve through stages. Once a breast tumour becomes resistant to SERMs, the growth is stimulated by either the SERM or oestrogen. This is why an aromatase inhibitor is effective following SERM resistance and withdrawal. However, the extended use of repeated endocrine therapies now supersensitized the cells to oestrogen that causes apoptosis through the ER. We suggest that future clinical treatment strategies incorporate an 'oestrogen purge' to both enhance the actions of chemotherapy or completely reverse endocrine resistance and restore endocrine sensitivity. These new data build on the idea that breast cancer can be controlled as a chronic disease and will permit patients to live long and productive lives during targeted maintenance treatment.     

From adjuvant therapy to breast cancer prevention: BCPT and STAR

The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first-generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P-1) in which 13,388 women > or = 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow-up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor-positive tumors, by 49% (two-sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P-1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second-generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P-2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women > or = 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.     

Doppler Velocimetry Parameters of Periurethral Vessels in Postmenopausal Incontinent Women Receiving Estrogen Replacement

Estrogen deficit causes significant alterations in the lower urinary tract of women, largely affecting urinary continence mechanisms. The urethral vascular bed accounts for about one-third of urethral pressure, and as it undergoes marked hormonal influence we became interested in investigating its behaviour both prior to and during estrogen replacement. We selected 25 postmenopausal patients with urinary stress incontinence and studied the periurethral vessels by means of Doppler velocimetry, analyzing the number of vessels, systolic peak, minimum diastole, resistance and pulsatility indexes and the A/B ratio, prior to estrogen replacement and after 1 and 3 months of hormone use. We concluded that estrogen replacement alone in postmenopausal women with urinary stress incontinence increased the number of periurethral vessels, systolic peak and minimum diastole; however, a trend of no statistical significance towards the reduction of resistance and pulsatility rates of periurethral vessels was found; nor was a significant difference in the A/B ratio shown.     

Cell cycle regulation of human pancreatic cancer by tamoxifen

Background: Clinical trials have suggested a survival advantage for selected patients with metastatic pancreatic cancer treated with tamoxifen. We sought to identify the molecular mechanism by which tamoxifen inhibits human pancreatic cancer cell (HPCC) growth. Methods: HPCCs were grown in tamoxifen and growth inhibition was determined by³H-thymidine uptake and by the MTT assay; changes in cell viability were determined by cell counts. Cell cycle alterations were evaluated by FACS, and the induction of apoptosis was evaluated using the TUNEL assay. Total cellular RNA was isolated after tamoxifen treatment, and Northern blot analysis was performed for p21 ^waf1 . Results: Tamoxifen inhibited HPCC growth as measured by inhibition of³H-thymidine incorporation and by the MTT assay. However, there was no decrease in the total number of viable cells after 6 days of treatment with 10 μM of tamoxifen and no evident apoptosis, confirming the absence of a cytotoxic effect. Cell cycle analysis revealed cellular arrest in the G₀/G₁ phase, which correlated with p21 ^waf1 mRNA upregulation in response to tamoxifen treatment. Conclusions: Tamoxifen inhibits HPCC growth by inducing G₀/G₁ arrest with an associated increase in p21 ^waf1 mRNA expression. Tamoxifen is an effective inhibitor of HPCC growth in vitro and warrants further in vivo study.     

Tamoxifen alters levels of serum insulin-like growth factors and binding proteins in postmenopausal breast cancer patients: A prospective paired cohort study

Background: Recent data suggest that tamoxifen may act by altering serum levels of insulin-like growth factors (IGFs) and their binding proteins (BPs). This prospective paired cohort study evaluated the influence of tamoxifen on serum levels of IGFs and BPs in postmenopausal patients with breast cancer. Methods: Blood was collected from 32 postmenopausal patients with breast cancer before and during tamoxifen therapy for at least 6 months. All patients had undergone primary surgery. Serum concentrations of IGF-I, IGF-II, BP-1, and BP-3 were determined by immunoradiometric assays, and Western ligand blots provided a semiquantitative measurement of BP-2, BP-3, and BP-4. Statistical analysis was performed by paired Student'st-test. Results: Mean serum IGF-1 level was significantly lower after tamoxifen treatment (pretreatment: 116.2 ng/mL±13.6 [SEM] vs. posttreatment: 77.5 ng/mL±7.8;P=.003). In contrast, mean IGF-II levels increased from 651.5±62.2 ng/mL to 812.5±35.1 ng/mL during treatment (P=.006). Posttreatment levels of BP-1 (92.9 ng/mL±7.5) were significantly higher compared to the pretreatment values (28.1 ng/mL±4.7;P<.001). Serum concentration of BP-3 also was elevated (pretreatment: 2228.1 ng/mL±145.2 vs. posttreatment: 3539.1 ng/mL±172.3;P<.001). Densitometric measurements showed a similar significant increase in BP-3 (P<.001) as well as BP-4 (P=.017) after hormonal therapy. Levels of BP-2 were not influenced by tamoxifen treatment. Conclusions: These significant alterations in serum concentrations of IGFs and BPs with tamoxifen therapy suggest that the IGF system is a potential mechanism by which tamoxifen exerts its growth inhibitory effect on breast carcinomas.     

Bulking agents for stress urinary incontinence: short-term results and complications in a randomized comparison of periurethral and transurethral injections

The purpose of our study was to compare the two standard routes of urethral bulking injection in a prospective randomized trial. Forty women with genuine stress incontinence (n=36), or mixed incontinence with a minor and controlled urge component (n=4), participated in a urethral bulking agent trial. All patients had a standardized preoperative evaluation which included history, physical examination, assignment of incontinence status on a Stamey grading scale, postvoid residual (PVR) determination, Valsalva leak-point pressure, maximal urethral closure pressure, functional urethral length, Q-tip excursion angle, quantitative pad test, and completion of a quality of life questionnaire. On the day of injection they were randomly assigned to a periurethral or transurethral route of injection based on a computer-generated block randomization scheme. An ultrasound-determined PVR was obtained on all patients after injection. If self-catheterization was necessary, and the PVR was >200 ml, urinary retention was diagnosed. Postoperative assessment included a patient interview, subjective assessment of improvement, PVR, voiding diary, and assignment of incontinence grade. At the screening visit there were no significant differences between the groups for any variables except type of stress incontinence. With short-term follow-up both transurethral and periurethral routes of injection seem to be equally efficacious. In the periurethral injection group there was a higher rate of postoperative retention; this group had a significantly higher volume of injectable agent used. There was no significant difference in risk of urinary tract infections between the two groups. We conclude that both periurethral and transurethral methods of bulking agent injection for stress urinary incontinence are equally efficacious, with minimal morbidity.Abbreviations FUL Functional urethral length - ISD Intrinsic sphincter deficiency - MUCP Maximum urethral closure pressure - PVR Postvoid residual - SUI Stress urinary incontinence - VLPP Valsalva leak-point pressureEditorial Comment: This pilot study is the first randomized controlled trial comparing the short-term efficacy of periurethral and transurethral injections. The poor 1-year success rates found in this study are disappointing if compared to other studies (showing up to a 70% success rate). In addition, owing to the small sample size and lack of power to find a statistical difference in efficacy rates, larger studies with longer follow-up periods are required.     

Transurethral collagen injection for female stress incontinence

Periurethral collagen injections have been used to treat female urinary incontinence secondary to intrinsic sphincteric deficiency (ISD). As an alternative, a transurethral submucosal collagen injection was used in 33 consecutive women suffering from stress incontinence secondary to ISD at Tulane University Medical Center. Prior to the procedure, careful clinical examination with a videofluorourodynamic study was performed for each case. The procedure was carried out under local anesthesia assisted with monitored anesthesia care (MAC). The collagen was injected transurethrally by the long collagen needle (C. R. Bard). In the first 11 cases the average cumulative collagen injected per patient was 6.1 ml, whereas in the last 22 cases the average was 3.5 ml. As a result of the injection 16 patients were dry (48.5%) and 11 were improved (33.3%), with an overall success rate of 81.8%. The injection failed in 6 patients (18.1%). The mean follow-up was 18.8 months, with a range of 2–33 months. In the successful group there was a significant decrease in pretreatment frequency, from an average of 8 to 4.9 (P=0.005) and in nocturia from an average of 2.14 to 0.76 (P=0.001). Also, there was a significant decrease in the number of pads, from an average of 3.7 to 1.1 (P=0.001). The stress leak-point pressure showed a significant increase, from an average of 68.1 to 93.5 cmH₂O (P=0.03). There was no relation between grade of incontinence and the success of the injection. Two cases suffered from temporary urinary retention. This study revealed that the transurethral submucosal collagen injection is an effective method for treating cases of intrinsic sphincteric deficiency. The volume of collagen required to produce the seal effect is small and it may decrease the reinjection rate. As experience is gained, the procedure time is typically 15 minutes. This makes it a reliable, cost-effective and well-controlled method. However, it has a learning curve and the cystoscope instruments require minor adaptation for its use.Presented at the 17th Annual Scientific Meeting of the American Urogynecologic Society, New Oreleans, LA, 4–7 October 1996.Editorial Comment: The authors present the results of 33 patients who underwent transurethral submucosal collagen injection for the treatment of intrinsic sphincter deficiency. All injections were performed using a 5-Fr long needle-tipped catheter introduced through the cystoscope channel. The collagen was placed just under the urethral mucosa, between the lamina propria and muscularis layers. This approach alleviated the risk of injury to blood vessels and periurethral abscess, present with the periurethral route. The authors noted a significantly reduced amount of collagen required, with an 81.8% cure/improvement rate. The amount of anesthetic time was reduced, along with hospital stay and complication rate, which lowers the overall cost of this treatment. They point out that minor modifications are needed for routine cystoscopic equipment to be utilized for this technique, and that a commercially available unit can be purchased. Transurethral injection offers a relatively safe and easy alternative to the use of urethral bulking agents in the treatment of intrinsic sphincter deficiency.     

Urethral sphincter needle electromyography in women: Comparison of periurethral and transvaginal approaches

Needle electromyography (EMG) of the striated urethral sphincter is the only technique that permits detection of individual motor unit action potentials (MUAPs) and is a valuable diagnostic tool in the evaluation of women with urinary incontinence and voiding disorders. The purpose of this study was to compare two methods of urethral needle EMG with respect to the number of MUAPs identified, the amount of patient discomfort, and the duration of the examination. Twenty consecutive women referred for electrodiagnostic testing to evaluate symptoms of urinary incontinence and/or voiding dysfunction underwent both methods of the needle examination in a prospective randomized cross-over study design with each patient acting as her own control. A full cross-over analysis was conducted to detect period and sequence effects using analysis of variance with a power of 0.85 and a significance level of P < 0.05. Twice as many MUAPs were identified using the periurethral approach (8.8 versus 3.9) with a mean difference of 5.0 (P = 0.0008). There was a non-significant trend to greater patient discomfort with the periurethral approach; however, the discomfort was generally rated as mild to moderate. The length of time required to count all identifiable MUAPs did not vary significantly between the two methods. We conclude that the periurethral approach is superior to the transvaginal approach with respect to the quantity of electrodiagnostic information obtained and propose that this method be standardized to characterize more accurately the neurogenic component of urinary incontinence and voiding dysfunction for future electrodiagnostic studies. Neurourol. Urodynam. 17:531–535, 1998. © 1998 Wiley-Liss, Inc.     

The effect of local anaesthetic infiltration on urethral function during the tension-free vaginal tape (TVT) procedure

Different anaesthetic techniques are used for the tension-free vaginal tape (TVT) procedure. Using local anaesthetic and spinal techniques allows surgeons to adjust sling tension with the cough test. The aim of this study was to asses whether the periurethral infiltration of the local anaesthetic technique for TVT results in a significant alteration in urethral function. Twenty-five women who underwent a TVT procedure for stress incontinence were studied prospectively. Urethral function was assessed with the urethral retro-resistance pressure (URP) before and after the infiltration of local anaesthetic. Paired t tests were used to compare values. The mean URP value was 48.0 cm/H₂O (SD, 18.4) before and 52.0 cm/H₂O (SD, 34.5) after the periurethral infiltration of local anaesthetic. There was no statistical significance between the two groups (p = 0.37). Local anaesthetic does not alter urethral function, as measured by URP, allowing coughing to mimic non-anaesthetic conditions.     

Regional distribution of epidermal growth factor,testosterone and dihydrotestosterone in benign prostatic hyperplasia tissue

In benign prostatic hyperplasia (BPH), basic fibroblast growth factor (bFGF) is found to have a regional distribution, with concentrations in the periurethral zone (where the primitive fibrostromal nodule originates) higher than those of the peripheral subcapsular zone. The aim of the present investigation was to verify whether androgens and epidermal growth factor (EGF) are uniformly distributed from the periurethral to the peripheral zone or whether they show regional differences. Tissue samples, removed by transvesical resection from nine untreated BPH patients, sectioned in periurethral, subcapsular, and intermediate zones, were examined. In the periurethral zone, dihydrotestosterone (DHT), testosterone, and EGF, determined by radioimmunoassay (RIA) techniques after purification on Celite microcolumns and Sep-pak C18 cartridge, showed values significantly higher (mean ± SD: 1121±482 pg, 250±129 pg, and 6.89±3.28 ng/mg DNA, respectively;P<0.01) than those of the subcapsular zone (489±190 pg, 114±70 pg, and 3.40±1.90 ng/mg DNA, respectively). A positive linear correlation between EGF, testosterone, and DHT was also observed. The regional distribution of EGF, testosterone, and DHT was similar to that found for bFGF: the highest levels of these factors in the periurethral region allow us to hypothesize on their possible involvement in the rewakening of mesenchymal tissue, leading to the formation of the primitive fibrostromal nodule and then to BPH development.     

Evaluation of endometrial thickness in hormone receptor positive early stage breast cancer postmenopausal women switching from adjuvant tamoxifen treatment to anastrozole

Evaluation of endometrial thickness by transvaginal ultrasonography (TVUS) in postmenopausal estrogen receptor positive breast cancer patients treated with anastrozole after tamoxifen therapy. This study included 70 postmenopausal estrogen receptor positive breast cancer patients who switched to anastrozole after tamoxifen; patients had endometrial thickness >4 mm and no endometrial malignancy. Endometrial thickness was measured after anastrozole treatment. Endometrial thickness during anastrozole therapy was lower than after tamoxifen therapy (p < 0.001); the mean reduction in endometrial thickness was 4.5 mm (±3.0). Cystic endometrial appearance was more frequent in patients under tamoxifen than in those under anastrozole (p < 0.001). Duration of tamoxifen therapy was not correlated to the endometrial thickness at the time of its suspension. Duration of tamoxifen therapy and endometrial thickness at the time of tamoxifen suspension was correlated to the relative reduction of endometrial thickness during anastrozole therapy. Anastrozole reverses tamoxifen-induced increased endometrial thickness and sonographic endometrial cystic appearance.     

Estrogen and Cancellous Bone Loss in the Fowl

Female birds model a type of woven bone prior to egg laying which is known as medullary bone. Medullary bone modeling is estrogen dependent and in the female fowl coincides with a decrease in cancellous bone volume. Medullary bone modeling was induced in male laying-strain fowl by the administration of estrogen and prevented in females by the administration of tamoxifen. In estrogen-treated males, medullary bone modeling was accompanied by cancellous bone loss; cancellous bone volume was significantly lower than in control males (P < 0.001). In females, the prevention of medullary bone modeling by tamoxifen treatment resulted in significantly higher cancellous bone volumes than in control females (P < 0.001). Estrogen therefore appears to play a role in cancellous bone loss in the fowl. Received: 29 April 1997 / Accepted: 3 September 1997     

Hormonal Therapy and Chemoprevention

Hormone replacement therapy (HRT) can increase the quality as well as the length of life, but a prolonged use can also increase the risk of breast cancer. The combination of HRT and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. A post hoc analysis of the Italian Tamoxifen Prevention Study showed a borderline significant reduction of breast cancer among women who were on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Recent studies suggest that the standard dose of tamoxifen may be reduced to one-quarter (i.e., 10 mg every other day) without loss of its beneficial biological effects. Since the endometrial effect of tamoxifen seems to be both dose and time dependent, a dose reduction could substantially reduce the risk of endometrial cancer while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could also minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and urogenital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. Notably, in the National Surgical Adjuvant Breast Project (NSABP) P-1 trial, women ages 50 or younger had no increased incidence of adverse events, including endometrial cancer and venous thromboembolic events. One possible explanation for the lack of toxicity in premenopause is the presence of adequate circulating estrogen levels which prevent tamoxifen to act as an estrogen agonist at these target tissues. Moreover, data from the current Italian tamoxifen prevention trial indicate that the compliance was substantially higher for de novo and current HRT users as compared to women who never received HRT during the study. The combination of HRT and tamoxifen at low doses could thus reduce the risks and side effects while retaining the benefits of either agent.     

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

Background

Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option.

Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: Effects of raloxifene HCl, tamoxifen, estrogen, and alendronate

Bone loss associated with postmenopausal osteoporosis can be reduced by treatment with antiresorptive agents such as estrogen or bisphosphonates. Whereas bisphosphonates primarily affect bone loss, estrogens have an advantage of also lowering serum cholesterol levels, although they have a detrimental effect in the uterus. Recently, raloxifene HCl, a selective estrogen receptor modulator (SERM), has been shown to decrease both bone loss and cholesterol levels without the negative uterine effects. These antiresorptive agents reduce bone turnover, which can be evaluated by measuring bone turnover markers. To compare the effects of estrogen, two SERMs (raloxifene HCl and tamoxifen), and alendronate, a bisphosphonate that inhibits bone loss by an estrogen-independent pathway, on metabolic bone markers and cholesterol levels, rats were ovariectomized 2 weeks prior to 3 weeks of daily oral treatment with raloxifene HCl (3 mg/kg), ethynyl estradiol (0.1 mg/kg), tamoxifen (3 mg/kg), or alendronate (3 mg/kg). Raloxifene HCl, tamoxifen, and ethynyl estradiol reduced serum cholesterol to levels below control values within 4 days after initiation of treatment, whereas alendronate had no effect. After 3 weeks of treatment, serum cholesterol values in ethynyl estradiol treated animals, although still below the control value, had risen 6.4-fold; raloxifene HCl and tamoxifen values rose by only 1.4–1.5-fold. Therefore, compared with estrogen, SERMs may have a longer-term suppressive effect on serum cholesterol. At 4 days of treatment, ovariectomized rats had a 1.4-fold increase in serum osteocalcin level compared with controls. Ethynyl estradiol lowered this level within 1 week of treatment by 18%, with a more pronounced reduction of 34% at 3 weeks. In contrast, raloxifene HCl, tamoxifen, or alendronate had very little effect after the first week (6% to 13% reduction), although there was an 18% to 25% reduction by 3 weeks. Urinary pyridinoline levels, elevated 1.4-fold in the ovariectomized rat compared with controls 2 weeks after surgery, were reduced to control values after 2 weeks of treatment with raloxifene HCl, ethynyl estradiol, tamoxifen, or alendronate. These data support the concept that estrogen, raloxifene HCI, tamoxifen, and alendronate inhibit bone loss in the ovariectomized animal by reducing bone resorption. The results also indicate that for treatment of postmenopausal osteoporosis, raloxifene HCl may have an advantage over the other antiresorptives studied in having both non-uterotrophic and hypocholesterolemic effects in addition to its ability to inhibit bone resorption.     

POWERPIINC (PreOperative Window of Endocrine TheRapy Provides Information to Increase Compliance) trial: Changes in tumor proliferation index and quality of life with 7 days of preoperative tamoxifen

ObjectivesA decrease in Ki67 during neoadjuvant therapy predicts response to tamoxifen. Previous trials have shown a decreased Ki67 in breast tumors with as little as two or more weeks of preoperative tamoxifen. Shortening the preoperative treatment time in window of opportunity clinical trials makes these trials more attractive to women. POWERPIINC examined the effect of 7 days of preoperative tamoxifen on breast tumor proliferation and patient symptoms.MethodsWomen with untreated stage I/II, ER-positive, invasive breast cancer with no contraindications to tamoxifen were enrolled. Women received 20 mg of tamoxifen for 7 days up to the day of surgery. Proliferation was assessed by Ki67 immunohistochemistry before and after 7 days of tamoxifen. Symptoms and QOL were assessed by the FACT-ES and MENQOL. Adherence was measured by pill counts.Results52 women were enrolled, and 44 were evaluable for Ki67. The median age was 58.5 years, and the median tumor diameter was 1.2 cm. Most women (73%) were post-menopausal. Most tumors were PR positive (88%) and HER2-negative (92%). The Ki67 decreased by a geometric mean of 40% (95% CI 29%–63%), and 73% (95% CI 57%–85%) of women had tumors with decreased proliferation (p = 0.0001 by paired t-test). Adherence to taking tamoxifen during the preoperative period was 100%. Women reported minimal bother from psychosocial or physical symptoms at baseline or on the day of surgery.ConclusionSeven days of tamoxifen showed a similar relative decrease in Ki67 as that reported for longer courses, was acceptable to women, and could be considered for window of opportunity studies.     

MODIFICATION OF GROWTH OF DESMOID TUMOURS IN TISSUE CULTURE BY ANTI-OESTROGENIC SUBSTANCES: A PRELIMINARY REPORT

Background : Tamoxifen and toremifene have been used in patients with advanced desmoid tumours with response rates of 51%. Method : We developed an experimental model of desmoid tumour cells in tissue culture to study their effect. Four cell lines were established in tissue culture. All native and corresponding cultured tumours were oestrogen receptor negative. Tumour I was from a 22 year old with familial adenomatous polyposis (FAP) and recurrent abdominal wall desmoid turnours. She remains disease free on tamoxifen 4 years following surgery. Both her mother and sister also have shown regression of their FAP-associated desmoid tumours at the menopause and on tamoxifen, respectively. We assessed the effect of tamoxifen on desmoid tumours in tissue culture at 780 ng/mL. The results were assessed by cell density counting. Results : Tumours 1 and 2 have responded with an approximately 50% reduction in growth to tamoxifen at 780 ng/mL. Conclusions : This apparent growth inhibitory effect of tamoxifen on two desmoid tumour cell lines appears to be independent of oestrogen and correlates with the in vivo effect of tamoxifen on three desmoid tumours in an FAP family.     

Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients

Background and AimThe aim of this study was to identify the effect of selective estrogen receptor modulator (SERM) on non-alcoholic fatty liver disease (NAFLD) in Asian women.MethodsWe retrospectively evaluated fatty liver development and/or serum alanine aminotransferase (ALT) elevation during SERM treatment in 1061 women who were diagnosed and treated with breast cancer in 2005 at Asan Medical Center.Results45 of 618 SERM-treated patients with normal ALT at baseline experienced ALT elevation during SERM treatment. Among the 112 SERM-treated patients who underwent liver imaging test, fatty liver was observed in 47 and both fatty liver and ALT elevation developed in 16 of 102 SERM-treated patients with normal baseline ALT. The cumulative rates of ALT elevation (10.7 vs. 4.3%; P = 0.002), fatty liver (48.5 vs. 20.9%; P < 0.001), and both fatty liver and ALT elevation (17.7 vs. 7.1%; P = 0.02) at 60 months were significantly higher in the SERM group than non-SERM group. By multivariate analysis, SERM treatment increased the risk of ALT elevation (hazard ratio [HR], 2.20; P = 0.01), fatty liver development (HR, 3.59; P < 0.001), and both fatty liver and ALT elevation (HR, 4.98; P = 0.01). After discontinuation of SERM, elevated serum ALT normalized in 39 (92.9%) and there were no instances of liver-related death or progression to liver cirrhosis in patients who experienced fatty liver or ALT elevation.ConclusionsAlthough SERM treatment is significantly associated with NAFLD in Asian women, considering the tolerability and reversibility of NAFLD induced by SERM, it can be continued with liver function monitoring in relevant patients.     

Effects of arzoxifene on bone, lipid markers, and safety parameters in postmenopausal women with low bone mass

Summary  

In this Phase 2 study of postmenopausal women with low bone, arzoxifene (a selective estrogen receptor modulator (SERM)) significantly reduced bone turnover marker levels and increased bone mineral density (BMD) versus placebo. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene, a SERM in current clinical use. Arzoxifene’s safety profile appeared similar to raloxifene.