Carbon tattooing for targeted lymph node biopsy after primary systemic therapy in breast cancer: prospective multicentre TATTOO trial.

BACKGROUND: Several techniques for targeted lymph node biopsy in patients with node-positive breast cancer receiving primary systemic therapy are in use, each with their inherent advantages and disadvantages. The aim of the TATTOO trial was to evaluate the feasibility and accuracy of carbon tattooing of positive lymph nodes as a method for targeted lymph node biopsy avoiding radiation exposure, high costs, and preoperative localization procedures. METHODS: Patients with initially cT1-4c cN1-3 cM0 invasive breast cancer were included in this prospective multicentre trial. Before initiation of primary systemic therapy, a carbon suspension was injected into the most suspicious axillary lymph node. Targeted lymph node biopsy was performed in all patients after completion of primary systemic therapy. Additional sentinel lymph node biopsy was done in those with axillary downstaging, and completion axillary lymph node dissection in patients still presenting with suspicious lymph nodes. RESULTS: A total of 118 patients were included and 110 were eligible for data analysis. The detection rate for the targeted lymph node was 93.6 per cent (103 of 110), and the sentinel lymph node was identical to the targeted lymph node in 60 per cent. The false-negative rate for the combination of targeted and sentinel node lymph node biopsy (targeted axillary dissection) was 9 per cent. CONCLUSION: Targeted axillary dissection after carbon tattooing is associated with a high detection rate, an acceptable false-negative rate, and appears feasible for clinical use even in healthcare settings with limited resources.

De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel.

BACKGROUND: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy. PATIENTS AND METHODS: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients. RESULTS: From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population. CONCLUSION: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.

BACKGROUND: In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight for obese patients due to safety reasons. MATERIALS AND METHODS: Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. RESULTS: Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m2. A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. CONCLUSION: Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications.

[CAMIC Recommendations for Surgical Laparoscopy in Non-Obstetric Indications during Pregnancy]. / CAMIC-Empfehlungen zur chirurgischen Laparoskopie aus nicht geburtshilflicher Indikation während der Schwangerschaft.

In the operative surgical primary care, the laparoscopic surgical technique has firmly established itself in recent years. Meanwhile, in the normal population over 90 % of all cholecystectomies and over 80 % of all appendectomies are performed in a minimally invasive manner. The proven benefits of the laparoscopic surgical technique, compared with conventional open surgery, are a comparatively rapid early postoperative recovery with early resumption of the general physical and occupational activity. As these benefits are equally applicable for necessary interventions during pregnancy, in recent years laparoscopy has become the preferred treatment for non-obstetric indications in the gravid patient. Overall, it can be assumed that such interventions have to be performed in approximately 2 % of all pregnant patients. Numerous studies have proven here that the use of laparoscopic techniques, in particular for the expectant mother, is safe and not associated with an increased risk. On the other hand, the current pregnancy makes necessary an adapted approach to the solution of surgical problems to ensure the protection of the unborn child. On the basis of currently available data situation, recommendations are formulated which can be used as a decision-making support for a variety of clinical situations.

Patient-Report Satisfaction and Health-Related Quality of Life in TiLOOP® Bra-Assisted or Implant-Based Breast Reconstruction Alone.

INTRODUCTION: Implant-based breast reconstructions (IBBR) using alternatives to acellular dermal matrixes are increasing. Data on complications are limited, and information concerning health-related quality of life (HR-QoL) following the use of these synthetic meshes do not exist. METHODS: Between January 2006 and January 2013, patients undergoing immediate or delayed-immediate IBBR with or without titanium covered polypropylene mesh (TiLOOP® Bra) were investigated. HR-QoL was assessed using the validated self-reporting BREAST-Q questionnaire. Patient demographics and complications were evaluated retrospectively. Stepwise regression backward elimination analysis was performed to identify influential factors on each BREAST-Q domain. RESULTS: Of the 90 women, 42 had IBBR alone and 48 in combination with TiLOOP® Bra. The mean follow-up was 18 months in the TiLOOP® Bra and 17.5 months in the implant alone group (p = 0.827). The overall complication rate was 21.1 %, with 14.6 % in the TiLOOP® Bra and in 28.6 % in the implant alone group (p = 0.105). Capsular contraction rate was 4.4 % in the TiLOOP® Bra and 16.7 % in the implant alone group (p = 0.052). The analysis of the HR-QoL showed no significant differences between the groups. Surgeries prior to IBBR had a positive influence on HR-QoL. TiLOOP® Bra was associated with a negative effect on "satisfaction with breast" (ß = -5.72; p < 0.001), as it was no longer observed for "satisfaction with outcome" and other domains.

Intra- and postoperative catumaxomab in patients with epithelial ovarian cancer: safety and two-year efficacy results from a multicentre, single-arm, phase II study.

BACKGROUND: This is the first study investigating the safety and efficacy of the trifunctional antibody catumaxomab administered i.p. at the end of cytoreductive surgery and postoperatively prior to standard chemotherapy in patients with primary epithelial ovarian cancer (EOC). METHODS: Patients received i.p. catumaxomab 10 µg intraoperatively and 10, 20, 50 and 150 µg on days 7, 10, 13 and 16, respectively, postoperatively. After the study, patients received standard chemotherapy and were followed for 23 months. The primary endpoint was the rate of postoperative complications. RESULTS: Forty-one patients entered the study and were evaluable for safety and 34 were alive at 24 months. Complete tumour resection rate was 68%. Postoperative complications were observed in 51%, the most common anastomotic leakage (7%) and wound infections (5%). The most common catumaxomab-related adverse events were abdominal pain, nausea, vomiting and pyrexia. Thirty-nine percent discontinued catumaxomab therapy, and 98% received chemotherapy post study. Kaplan-Meier estimates of disease-free and overall survival after 24 months were 56% and 85%, respectively. CONCLUSIONS: Intra- and close postoperative catumaxomab seems feasible, but efficacy and safety were limited by postsurgical complications. In the future prospective trials are needed to investigate the best schedule of integration of catumaxomab into current treatment strategies for EOC.

Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer.

BACKGROUND: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). PATIENTS AND METHODS: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS). RESULTS: Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA- (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77). CONCLUSIONS: DA treatment did not impact EFS or OS in routine adjuvant BC treatment.

Palbociclib combined with endocrine treatment in hormone receptor-positive, HER2-negative breast cancer patients with high relapse risk after neoadjuvant chemotherapy: subgroup analyses of premenopausal patients in PENELOPE-B.

BACKGROUND: The PENELOPE-B study demonstrated that the addition of 1-year post-neoadjuvant palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) did not improve invasive disease-free survival (iDFS) compared to placebo. Here, we report results for premenopausal women. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative BC at high risk of relapse [defined as no pathological complete response after neoadjuvant chemotherapy and a clinical, pathological stage, estrogen receptor, grading (CPS-EG) score ≥3 or 2/ypN+] were randomized to receive 13 cycles of palbociclib or placebo + standard ET. Ovarian function (OF) was evaluated by centrally assessed estradiol, follicle-stimulating hormone and anti-Müllerian hormone serum levels. RESULTS: Overall, 616 of 1250 randomized patients were premenopausal; of these, 30.0% were <40 years of age, 47.4% had four or more metastatic lymph nodes, and 58.2% had a CPS-EG score ≥3. 66.1% of patients were treated with tamoxifen alone, and 32.9% received ovarian function suppression (OFS) in addition to either tamoxifen or aromatase inhibitor (AI). After a median follow-up of 42.8 months (97.2% completeness) no difference in iDFS between palbociclib and placebo was observed [hazard ratio = 0.95, 95% confidence interval (CI) 0.69-1.30, P = 0.737]. The estimated 3-year iDFS rate was marginally higher in the palbociclib arm (80.6% versus 78.3%). Three year iDFS was higher in patients receiving AI than tamoxifen plus OFS or tamoxifen alone (86.0% versus 78.6% versus 78.0%). Patients receiving tamoxifen plus OFS showed a favorable iDFS with palbociclib (83.0% versus 74.1%, hazard ratio = 0.52, 95% CI 0.27-1.02, P = 0.057). Hematologic adverse events were more frequent with palbociclib (76.1% versus 1.9% grade 3-4, P < 0.001). Palbociclib seems not to negatively impact the OF throughout the treatment period. CONCLUSIONS: In premenopausal women, who received tamoxifen plus OFS as ET, the addition of palbociclib to ET results in a favorable iDFS. The safety profile seems favorable and in contrast to chemotherapy palbociclib does not impact OF throughout the treatment period.

Differentiating between malignant and benign breast masses: factors limiting sonoelastographic strain ratio.

PURPOSE: We compared strain ratio vs. qualitative elastography for the further differentiation of focal breast lesions, with special focus on limiting factors. MATERIALS AND METHODS: 215 patients with 224 histologically proven breast masses (116 malignant, 108 benign) were prospectively examined using a high-end ultrasound system (Philips iU22) with serial elastography function. B-mode scans and available mammograms were reviewed according to the BIRADS classification, raw elastogram data was analyzed qualitatively using the Tsukuba score and semiquantitatively by calculating the strain ratio (fat to lesion ratio). For diagnostic performance, Receiver Operating Characteristic (ROC) curve analysis was obtained. A sub-group analysis regarding breast density, lesion size, lesion depth and histological subtypes was performed. RESULTS: Mean strain ratio values were 3.04 ± 0.9 for malignant and 1.91 ± 0.75 for benign lesions (p < 0,001). The areas under the ROC curve values were 0.832 (95 % CI 0.777; 0.888) for strain ratio, 0.869 (95 % CI 0.822; 0.917) for Tsukuba score, 0.822 (95 % CI 0.768; 0.876) for B-mode ultrasound and 0.853 (95 % CI 0.799; 0.907) for mammography. Sensitivity, specificity, positive predictive value and negative predictive value of the strain ratio were 90.7 %, 58.2 %, 70.3 % and 85.1 %, when a cutoff point of 2.0 was used. Only lesion depth ≤ 4 mm was associated with diagnostic failure in the multivariate analysis of factors influencing accuracy, whereas no significant correlation between breast density and lesion size and the accuracy of the strain ratio could be found. CONCLUSION: The addition of strain ratio to B-mode ultrasound increases specificity without loss of sensitivity in differentiating between malignant and benign breast tumors. Strain ratio measurements should not be carried out on tumors with a lesion depth ≤ 4 mm.

Ruptured poly-implant protheses breast implant after aesthetic breast augmentation: diagnosis, case management, and histologic evaluation.

Since the scandal of the poly-implant protheses (PIP) breast implants, all patients with PIP are advised to have their implants removed. With approximately 400,000 PIP implants sold worldwide breast, surgeons will be confronted with these patients. Histologic examination in the reported case showed silicone infiltration into fatty tissue and breast tissue without signs of malignancy. A general histologic analysis for the rare event of an anaplastic large T cell lymphoma is not advised. The malignant potential of PIP implants currently is uncertain, and further investigation is required. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Two different entities of spontaneous ovarian hyperstimulation in a woman with FSH receptor mutation.

Spontaneous ovarian hyperstimulation syndrome (OHSS) is an extremely rare event. Normally OHSS is seen in the context of IVF. In 2003 a mutation of the FSH receptor (FSHR D567N) was identified for the first time as a cause of spontaneous OHSS. In most FSHR mutations, a hypersensitivity to human chorionic gonadotrophin (HCG) or thyroid-stimulating hormone (TSH) is described. This clinical case presents for the first time two occurrences of spontaneous OHSS in a single woman with a FSHR mutation and two different entities. Pathophysiology of both pregnancies was completely different. During the first pregnancy, elevated HCG and androgen concentrations led to spontaneous OHSS and finally to miscarriage. The second pregnancy with spontaneous OHSS was dominated by a latent hypothyroidism and normal HCG concentrations and ended in a delivery of a healthy female newborn. Due to the unusual courses of the pregnancies, the study looked for a mutation in the FSHR and surprisingly identified the same mutation previously described. This report confirms for the first time the in-vitro findings in a single clinical case that TSH as well as HCG leads to spontaneous OHSS in patients with FSHR D567N mutation. Hypothyroidism has to be treated or ruled out.

Sulfur Isotopes in Swaziland System Barites and the Evolution of the Earth's Atmosphere.

Sedimentary barites from the Swaziland System of South Africa (more than 3000 million years old) have sulfur-34 ratios that are enriched by only 2.5 per mil with respect to contemporary sulfides. To explain this small fractionation, it is proposed that oxygen pressure in the earth's atmosphere was very low and that local oxidation occurred in a photosynthetic layer of the ocean.

Restricted Axillary Staging in Clinically and Sonographically Node-Negative Early Invasive Breast Cancer (c/iT1-2) in the Context of Breast Conserving Therapy: First Results Following Commencement of the Intergroup-Sentinel-Mamma (INSEMA) Trial.

Axillary lymph node status remains an important prognostic factor in early breast cancer. It is regarded as an indicator for (neo)adjuvant systemic treatment and postoperative radiotherapy of the regional lymphatics. Commenced in September 2015, the INSEMA trial is investigating whether operative determination of nodal status as part of breast conserving therapy (BCT) for early stage breast cancer (c/iT1-2 c/iN0) can be avoided without reducing oncological safety. After inclusion of 1001 patients there was general acceptance of the complex study design by patients and study doctors so that recruitment for the first randomisation (axillary sentinel lymph node biopsy [SLNB]: yes or no) achieved predicted case numbers. The second randomisation however (SLNB alone versus complete axillary dissection when one or two macrometastases are present at SLNB) recruited fewer cases than expected for the following three reasons: a) the 13 % rate of one or two macrometastases after SLNB in the INSEMA trial collective was lower than expected; b) around 20 % of patients refused the second randomisation; c) there was delayed inclusion of the Austrian study centres, which only recruited for the second randomisation. Lack of knowledge of nodal status when SLNB is avoided represents a new challenge for the postoperative tumour board. In particular decisions on chemotherapy for luminal-like tumours and irradiation of the lymphatics (excluding axilla) must be guided by tumour biological parameters. The INSEMA trial does not provide answers to some important questions, e.g. it remains unclear whether patients without SLNB can be offered partial breast irradiation alone in low-risk situations and whether SLNB can also be avoided in patients with stage T1-2 tumours who have a mastectomy indication.

Differentiation of HELLP patients from healthy pregnant women by proteome analysis--on the way towards a clinical marker set.

As the pathogenesis of the HELLP-syndrome is unknown, a complex consideration regarding the changes in the plasma as the main transport medium in the body is of great benefit because it is well available and can rapidly be investigated in the clinics. Besides that, the liver which is early affected in HELLP-syndrome produces the main part of plasma proteins. For the purpose of our study plasma protein abundances from patients with HELLP-syndrome and from control individuals were determined before and after delivery. In the differential analysis using two-dimensional gel electrophoresis, six areas with variable protein spot intensities were detected. The reference gel that we developed for HELLP plasma samples integrates the changes of plasma proteins when comparing HELLP patients to healthy women prior to and after delivery. A specific plasma protein profile for the HELLP-syndrome was generated involving protein areas that contain inter-alpha-trypsin inhibitor heavy chain H4, kininogen 1, fibrinogen gamma chain, transthyretin, haptoglobins, and serum amyloid A with statistically significant expression differences when compared to controls. The most striking difference between the majority of the gels from HELLP patients and the gels from non-HELLP samples were clearly overexpressed protein spots at about 11 kDa which were identified as serum amyloid A (SAA). This differential expression was validated and quantitatively assayed by ELISA measurements against human SAA in plasma. Our results show that significant differences in SAA expressions between healthy controls and HELLP patients were obtained, that could function as markers for the HELLP-syndrome. According to our data it is possible to draw a line of separation with no overlap between the HELLP group for which SAA plasma levels were found to be above 3.51 mg/L and the non-HELLP groups in which SAA plasma levels were below 3.51 mg/L. It now is possible to clinically elucidate if the differentially expressed proteins are suited for longitudinal studies concerning both, to function as markers or perhaps even as disease predictors that might become relevant for diagnostic tests.

FasL:Fas ratio--a prognostic factor in breast carcinomas.

Programmed cell death (apoptosis) is primarily mediated by Fas ligand (FasL; CD95L) and the Fas receptor (Fas; CD95). In this study, FasL was detected by immunohistochemical analysis in 85% of breast carcinomas and 14% of fibroadenomas randomly chosen, indicating that high expression of FasL might play a role in tumor pathology. FasL and Fas levels as well as FasL:Fas ratios were further ascertained in 215 human breast tumors, including 199 invasive ductal carcinomas, by real-time quantitative reverse transcription-PCR and compared with expression levels and ratios found in 25 normal human tissues, in 37 fibroadenomas, and in 5 normal breast tissues. Among breast carcinomas, high FasL mRNA expression seems to be positively correlated with histological grading (n = 212; P<0.0001). A ratio of FasL:Fas mRNA transcripts >1 is found to be significantly associated with decreased patient's disease-free survival (n = 211; P<0.03) and increased mortality (n = 211; P = 0.19). A FasL:Fas ratio >1 is related to tumor progression scored by histological grading (n = 212; P<0.02). The selection process leading to highly aggressive breast tumor variants might be enhanced by FasL-mediated tumor fratricide, eventually a possible target for novel therapeutic strategies.

The role of specimen radiography in breast-conserving therapy of ductal carcinoma in situ.

BACKGROUND: To assess the role of intraoperative specimen radiography (SR) and to define risk factors for positive margins in breast-conserving therapy (BCT) of ductal carcinoma in situ (DCIS). METHODS: In a retrospective study in calcification-associated DCIS treated with BCT between January 2009 and December 2011, digital mammographs and SR were reviewed and radiological margin width was determined. Clinical, radiological, and histological data were correlated with surgical histological data, and a histologically free margin of at least 2 mm was taken as evidence of successful BCT. RESULTS: 47/91 patients (51.6%) fulfilling the inclusion criteria had histologically involved surgical margins. Univariate analyses revealed DCIS size, mammographic extension of calcification, presence of comedo necrosis, negative progesterone receptor status, and a small radiological margin on SR to be risk factors for unsuccessful BCT. Receiver Operating Characteristic (ROC) analysis showed a radiological margin width of 4 mm to be optimal, with a sensitivity of 72.3% and specificity of 52.3%. The likelihood of surgical free margins was increased 2.9-fold with a radiological margin width ≥4 mm. On multivariate logistic regression analysis, only histological DCIS size >20 mm clearly emerged as an independent predictive factor for surgically involved margins (p < 0.001), while an SR margin <4 mm trended toward significance (p = 0.066). CONCLUSIONS: SR is a reliable method for predicting free surgical margins in non-invasive breast cancer where a minimum radiological free margin of 4 Fmm is achieved. However, histological DCIS size remains the most important factor determining successful BCT.

High prevalence of vaterite in sagittal otoliths causes hearing impairment in farmed fish.

The rapid growth of aquaculture raises questions about the welfare status of mass-produced species. Sagittal otoliths are primary hearing structures in the inner ear of all teleost (bony) fishes and are normally composed of aragonite, though abnormal vaterite replacement is sometimes seen in the wild. We provide the first widespread evaluation of the prevalence of vaterite in otoliths, showing that farmed fish have levels of vaterite replacement over 10 times higher than wild fish, regardless of species. We confirm this observation with extensive sampling of wild and farmed Atlantic salmon in Norway, the world's largest producer, and verify that vateritic otoliths are common in farmed salmon worldwide. Using a mechanistic model of otolith oscillation in response to sound, we demonstrate that average levels of vaterite replacement result in a 28-50% loss of otolith functionality across most of a salmonid's known hearing range and throughout its life cycle. The underlying cause(s) of vaterite formation remain unknown, but the prevalence of hearing impairment in farmed fish has important implications for animal welfare, the survival of escapees and their effects on wild populations, and the efficacy of restocking programs based on captive-bred fish.

Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound.

PURPOSE: To study the value of transvaginal ultrasound (TVS) in endometrial screening of postmenopausal breast cancer patients treated with tamoxifen. PATIENTS AND METHODS: In 247 tamoxifen-treated (20 to 30 mg/d for >/= 2 years) women and 98 controls, the endometrium was prospectively followed-up by means of TVS every 6 months for up to 5 years. Patients with homogeneous endometrium of more than 10-mm thickness were then scanned repeatedly every 3 months. RESULTS: The mean endometrial thickness was 3.5 +/- 1.1 mm before treatment and increased to a maximum of 9. 2 +/- 5.1 mm after 3 years of tamoxifen application (P: <.0001), which was significantly (P: <.0001) thicker compared with controls. Fifty-two asymptomatic patients with thickened or morphologically suspect endometrium underwent hysteroscopy and dilatation and curettage (D&C), resulting in four uterine perforations. Histopathologically, atrophy was found in 38 patients (73.1%), polyps in nine, hyperplasia in four, and endometrial cancer in one case. In 20 screened patients who reported vaginal bleeding, five atrophies (25%), five polyps, four hyperplasias, and two endometrial cancers were found. Before hysteroscopy and D&C were performed, 36 (69.2%) of 52 asymptomatic and four (20%) of 20 symptomatic patients were scanned by repeated TVS over 2 to 30 months. Invasive diagnostic procedures were significantly (P: <.05) more frequent in younger and obese patients. In the controls, one asymptomatic polyp and one symptomatic hyperplasia were found. CONCLUSION: In tamoxifen-treated patients, TVS offered a high false-positive rate, even with a cutoff value of 10 mm for endometrial thickness and repeated TVS scans. Increased iatrogenic morbidity and only one asymptomatic endometrial carcinoma do not warrant endometrial screening by TVS in tamoxifen-treated patients.